Immunology Usmle Hsu Notes PDF

Hsu
notes usmle immunology

Lymph node:

Cortex Outer most layer
Consist of:
-follicles
-subcapsular macrophages
dendritic cells
(in cortex) -site of b cell localization + prolif
Germinal Follicle -size increase in viral infection (reactive lymphadenopathy)
-shrink when healthy or no use (e.g bruton agamaglobenimia)

subtype:
Hsu notes usmle immunology

primary or secondary
-primary: dense, dormant
-secondary: pale, active (contain oporlif b cell and follicular dendritic cell)

clinical: agammaglobenima: germinal center and primary lymphoid follicles do nto form due to absence
of b cell
Paracortex -house t cell
-region of cortex between follicle and medulla

-coontain high endothelial venules through which T and B cell enter from blood

-note
clinical:
rd th
-not well developed in Di George (3 and 4 pharyngeal pouch fail to develop and dont have T cell**)
-enlarge in cellular immune response (E.g viral infection)
Medulla Consist of: cords + sinuses

Cords:

-consist of lymphocyte (e.g hisocyte) + plasma cells

Sinsues: -> communicate with -> efferent lymphatics
-contain reticular cells + macrophages

Note:
Histiocytosis X
-prolif of medullary sinuses

SCID
-low B and T cell
-see just medullary sinus(as prolif histiocyte but nothing other cells)

SPLEEN:

Located in LUQ of abdomen, anto to l eft kidney, 9-11 ribs

White pulp
-immunologic part of spleen

-contains:

Germinal center:
-activated B cell
Periarteriolar lymphatic sheaths:
-T cells
Marginal zone:
-macrophage, APC etc

Red pulp Hematological active:

-artieroles
-deliver of rbc

resident macrophage
-ingest dying rbc and encap bacteria

sinusoids with fenestrated basememt membrane to
-allow for red rbc exist

innate immunity vs adaptive immunity

Innate immunity Adaptive immunity
Component -neutrophil, macrophage, monocyte, dendritic cell, NK cell, T cell, B cell, circulating antibody
complement (soluble proteins e.g)
-others: physical barriers,
Mechanism Germline encoded Variation through V(D)J recombinaing
during lympho cyte production
Resistance Persist through generation Not heritable
Response to Non specific Specific
pathogens Occur rapidly (min to hrs) Refined ver time
Non memory response Develop over long periods,
memory response fast, robus t
Physical barriers Epithelial tight junction, mucus
Secreted protein Lysozyme, complement, CRP, defensins Immunoglobins
Pattern recognition Toll like receptor (TLR): -> recognizes pathogen associated Memory cells -> activate -> B and T ells ->
molecular patterns (PAMPS) strong quicker immune response
-> trigger acute inflammatory response*
e.g LipoPolySaccharides (gram neg nbact), lipoteichoic acid in gram
positive bacteria, flagellin (bacteria), nucleic acid ds rna (viruses)
(PAMP NOT PRESNT on mamilian cell == innate immunity does not
damage the host)

MHC histocompatibility complex


Notes uworld:
HLA region of Chromosome 6.The human leukocyte antigen system (HLA) is the name of the major histocompatibility
complex (MHC) in humans. The super locus contains a large number of genes related to immune system function in humans.
This group of genes reside on chromosome 6, and encode cell-surface antigen-presenting proteins and many other genes.
The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most
studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic
discovery as factors in organ transplantations. The major HLA antigens are essential elements for immune function. Different
classes have different functions:

HLA antigens corresponding to MHC class I (A, B & C) present peptides from inside the cell (including viral peptides if present).
These peptides are produced from digested proteins that are broken down in the proteasomes. The peptides are generally small
polymers, about 9 amino acids in length. Foreign antigens attract killer T-cells (also called CD8 positive- or cytotoxic T-cells) that
destroy cells.
HLA antigens corresponding to MHC class II (DP,DM, DOA,DOB,DQ, & DR) present antigens from outside of the cell to T-
lymphocytes. These particular antigens stimulate T-helper cells to multiply, and these T-helper cells then stimulate antibody-
producing B-cells to produce Antibodies to that specific antigen. Self-antigens are suppressed by suppressor T-cells.

General notes:
-ALSO refer to as section of the genome wich codes for HLA proteins***
-surface antigen presenting protein
-protein can either process some foreign antigen and present outside OR present self made molecule and present outside
-both have anchorage in lipid membrane (but MHC2 has 2 anchorage) (MHC1 has 1 anchorage)
-both have peptide binding site
-
-recognize only specific foreign particles
-found on eukaryote cell
-all nucleated cell has MHC1 but vary between person and cells
-MHC2 only found in antigen presenting cels (in immune systes like macrophage, dendritic cell, b cell)**
-(antigen presenting cell function: engulf pathogen by phagocytosis and turn it into fragments called antigen then load them on receptor MHC1
and MHC2 to all immune cells)
-(function of MHC1: to designate one cell to be sick and to be killed)

MHC1:
-virus -> chewed up by proteasome -> form antigen peptide -> brought into RER via TAP1 -> loaded onto MHC1 -> MHC1 then fuse with cell
membrane -> brought onto outside surface

MHC2:
If detect bacteria -> then fuse into cell into endosome -> break down -> fragments fuse with MHC2 molecule and CLIP released from MHC2 ->
load onto MHC -< go onto outsie cell surface

how to prepare MHC structure (present load etc):
-all in RER
-in cytosol have proteasome (break down protein in to small fragemtns)
-when there is an engulfment o fsmall pathogen -> endocytosis -> now inside cytosl -> fuse with lysosome -> fragements in cytosol -> further
broken down by proteasome into very tiny fragments -> go into RER (between RER membrane and cytsol via transporters)-> loaded ONTO
MHC***

MHC2
-inside RER, have MHC complexes ready (e.g in MHC2, alpha and beta chain prepared and there is a protein that blocks binding region normally;
and when fragments taken into RER then blocking protein released (but still has CLIP present on attachement binding site)-> CLIP released and
antigen replaces it -> NOW MHC2 loaded with antigen is now fused with cell membrane thus cell has MHC2 with antigen on SURFACE OF CELL

MHC 1 MHC2
Loci (ususally 3 genes: code for HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-DR
on arm of
chromosome 6)
binding TCR, CD8 TCR, CD4

-CD8: cytotoxic t cell (fct: kill the target cell***) -CD4: T helper cells (fct: active other t cell, active B cell,
proliferate macrophage or other APC)
structure 1 long chain, 1 short chain 2 equal length
expression All nucleated cell, APC, platelet, not on RBC APC: macrophage, dendritic cell, B cell

fct Present by ALL NUCLEATED CELL an endogenously Apresent endogenously synthesized antigen (e.g bacterial
synthesized antigens (e.g viral or cytosolic proteins) -> protein) to CD4 T helper cell
to CD8+ cytotoxic t cell
Antigen Antigen peptides -> delivery via TAP (Transporter Antigen loaded following release of invariant chain in an
loading associated with antigen processing)-> loaded onto acidified endosome
MHC 1 in RER
Antigen RER Acidified endosome**

loading site
Source of Cytosolic proteins (mostly sysnthesized in ecell) Endosomol/lysosomal proteins (internilzied from etracellular
protein antigen -endogenously synthezied antigen (e.g viral) -extracellular antigen that has been phagocytized (e.g
bacterial proteins)
obligate or facultative intracellular bacteria.
in case of virus MHC class 1 associated peptides virus particle, or freely circulating antigenic material.
derived from nucleocapsid protein can kill in case of virus>>>expression of nucleocapsid protein on
infected cell and limit disease severity but are MHC class 2 stimulates CD 4 TH 1 type T-cell response
not thought to prevent infection (which stimulates CD 8 + cell production through
cytokines) and CD4 + Th 2 response that generate
antinucleocapid antibodies that do not appear to play
a role in protective immunity
Enzyme re Cytosolic protesome Endosomal and lyssomal preotease
sponsible for
peptide
generation
Molecule TAP Invariant chain, DM
involved in
transport of
peptides and
loading of MHC
Binding partner T cell receptor T cell receptor
CD8 co receptor CD4 co receptor
Loading Endogenous protein are degraded by Exogenous proteins are enocytosed from the cell
mechanism proteasome surface
Antigenic peptide are transported into the Antigens are produced by degreadation within
RER by TAP transporter endosomal compartment
Antiens bind to MHC molecules direclty Antigens bind to MHC molecules after release of
the invariant chain
-invariant chain is originally attached to MHC 2
when this MHC is outside the endosome
-invariant chain degraded by proettease within
endosome thus allow peptide fragment antigen to
attach to MHC class 2 protein ONLY WHITHIN tHAT
COMPARTMENT


Structure 2 chains: polymorphic alpha chain (1+2+3) + partial Polymorphic Alpha chain (1+2) + Beta chain
beta 2 microglobulin (2)

Note: Viral vaccine DO NOT ACTIVATE CD8 t cell
cytotic tx cell DUE TO virus NOT REPLIACTE
within cell thus viral antigen not presented
with class 1 MHC

HLA

Human leukocyte antigens (HLA) are encoded by HLA genes on MHC regions of the genome which is located on the short arm of chr
6
HLA are alloantigen (i.e. they differ among members of the same sepcicies)
3 of these genes (HLA-A, HlA-B, HLA-c) code for the class 1 MHC proteins
HLA DP, DQ DR code cfor class 2
Each person has 2 haplotypes (2 sets of these genes) (one on paternal and t he other on maternal chr 6)
These genes are diverse (polymorphic = many alleles of the class 1 and 2 genes)(e.g 47 different HLAA genes)

But any individual inherits only a single allele at each locus from each parents thus can make no more than 2 class 1 and 2 proteins
at each gene locus

Expression is codominait: proteins encoded by both paternal and ma ternal genes are produced

Codominant means that each indivudal inherit a complete set or haplotype from each parent THUS 2 genetically unrelated indivudal
will have distinctive differences in the antigens expressed n their cells

(note there is a class 3 which is a third gene loci: encodes 2 ctyokines (TNF, llymphotoxins) and 2 compmenet (c2 and c4)) (but does
nto encode MHC)

HLA subtype associated with diseases:

A3 Hemochromatosis A3 freaking 3

B8 Addison disease, myasthenia gravis, graves disease
B27 Psoriatic arthritis, ank spon, IBD associated arthritis, reactive arthritis PAIR
DQ2, DQ8 Celiac disease I 8 2 much gluten at DQ

DR2 MS, hay fever, sle, good pastures Multiple hay pasture
DR3 DM type 1, SLE, graves disease, hashimoto thyroiditis, Addison
DR4 RA, dm type 1, addidson
DR5 Pernicious anemia -> vit B12 def, hashimoto thyroiditis

Extra notes about HLA and MHC:
Transplantation
Definition: process of taking cells, tissues or organs ( a graft) from one individual (the donor) and implanting them into another
indivudal or another site in the same individual (host or receipient)
- Autograft:
- Definition: transfer of an individual own tissue to another site in the body is always permantely accepted
-
- Syngenic graft:
- Defintio: transfer of titsue between genetically identical twin ie identical twis and almost always takes permantently

- Xeno graft:
- Definition: transfer of tissue between different species is always rejected by an immunocompetent receipeint

- Allograft
- Definition: graft between genetically diferent memebers of same sepciies, usualy rejected unless receipit is given
immunosuppressive drugs, severity and rapidity o rejection vary depden on degree of differeneces between donor and receipeint at
the MHC loci
- If allograft rejected, a process is initated: allograft reaction
- ACUTE REACTION
Onset Pathogenesis Feature

Weeks to months Cellular: Vasculitis of graft vessel with
-CD 8+ T cells activated -> ense interstitial lymphocytic
against donor MHC (type 4 HS infiltrate
rxn)

Humoral:
Antibodies developed after
sensitization react to donor
antigen (type 2 hs rxn) - >
activate complement

- (1) vascularization of graft normal initially
- as vascularization occurs, CD8+ cells that migrate into graft from host become sensitized and proliferate in response to both major
and minor histocompability difference
- Th cytokines stimulate -> macrophage, cytotxic t cell, etc -> increase expression of class 1 + 2 MHC in graft thus incrase suspecitibility
in graft to mhc restricted killing
- (2) 11-14 days: marked reduction in circulation + mononuclear infiltration occurs then necrosis [FIRST SET OR PRIMARY REACTION]

- ACUTE REJECTION
- Occur day to weeks
- Induced by allotantigens (predominatly MHC) in the graft
- Both CD4 and CD8 play role thus immunosuppressive works well
- t cell or antibody mediated reactions are causes
- (3) if second allograft from same donor applied to sensitized receipeint (ACCELERATED ACUTE REJECTION)

- (4) rejection in 5-6 days (accelerated or second set reaction***) CAUSED BY PRESENTITIZED CYTOTOXIC T CELLS (or memory cells)

- acceptance or rejection of transplant is determined by class 1 MHC + class 2 MHC (class 2 more than class 1) proteins on the donor
cells
- foreign MHC activate more T cell (much stronger reaction) than do foreign proteins that are not MHC
- DUE TO:
- (1) antigen presenting cell (e.g macrophages + dendritic cells) in graft can present self (donors) proteins in association with their
class 1 + class 2 MHC proteins and activate recipient immune response
- (2) APC in grat can present the recipient proteins and activate recipeient immune response (because recipient protein are
recognized as foreign when presented by aforeign mhc)
- (3) donor self proteins + class 1 and 2 mhc protein can be shed and subsequent processed by recipeient APC thus activate recipeient
immune response

Ischemia-reperfusion injury (or reperfusion edema) is a form of noncardiogenic pulmonary edema that can occur in the allograft
due to surgical trauma, organ ischemia, denervation, or interruption of lymphatic outflow. Reperfusion edema is seen during the
first few days following transplantation.

(acute jection in kindey; diffuse cellular infiltrate)
- chronic rejection:

- after graft survive an acute allograft

- occur months to years after negraftment

- t cell mediated

chronic rejection
is a major cause of morbidity and mortality and occurs in almost half of all patients within 5 yearss of transplantation.
these patients commonly present with dyspnea and a dry cough.spirometry shows an airflow limitation with a drop in
both the forced expiratry volume in 1 seconds (FEV1)and the FEV1 to forces vital capacity (FVC) ratio.
chronic rejection affects the small bronchioli producing the obstructive lung disease knowns as bronchiolitis
obliterans.
initially histopathilogy shows lymphocytic inflammation and destruciton of the epithelium of the small
airways.subsequently fibrinopurulent exudate and granulation tissue are found in the lumen of the bronchioli. which
ultimtely results in fibrosis, scarring and the progressive obliteration of small airways.
- CMV is the most significant opportunistic infection in lung transplant recipients

rejection of lung transplant differs form rejection of an intraabdominal organ (eg renal tranpant).
in chronic rejection (major cause of mortality in lung transplantation). causes inflammation of the small
bronchioles(ie bronchiolitis obliterans), inflammation and fibrosis of the bronchiolar walls lead to narrowing and
obstruciton of the affected bronchioli.
clinically bronchiolitis obliterans present with dyspnea, non-productive cough and wheezing.
this mechanism contrast to the chronic rejection often seen in renal transplantation (primarily vascular
obliteration)
-

- dx:


- main apthological finding: atherosclerosis of vascular endo***

- onset - pathogeneis - fature
- mon to years - cd4+ T cell respond to - receipent t cell react and
reciepeont APC presenting donor secrete cytokines -> prolfi of vasc
peptides incl allogenic MHC cscmooth muscle, parenchymal atrophy,
- both cellular and humoral interstitial fibrosis
compoennts (type 2 and 4 hyperesnity) dominated by arteriosclerosis
-

-hyperacute rejection:
-occur minute to hour
-hyper acute rejection occur minutes of engraftment due to reaction of preformed anti-ABO ab in the recipient with ABO ag on the surface of
the end of graft
-preformed anti ABO ab bind to grafted tissue and -> activate complement -> cascae resulting in thrombosis + ischemic necrosis
-also known as WHITE GRAFT reaction because graft turn whit as result of loss of blood suplly cause by spasm and occlusion of vessel serving
the graft

Onset Pathogenesisi Features
Within min Pre exist receipeient ab react to donor Wide spread thrombosis of graft vessel*
antigen (type 2 hs rxn) -> activate
compelemnt Tx: graft must be removed

Hyperacute Min to hours -complement activation, endothelia
ldamage, infl and thrombosis
Acute Days to weeks Parenchymal cell damage, interstitial infl

tx: immunosuppressant
such as calcineurin inhibitor (eg
cyclosporine and tacrolimus) and
mycophenolate
treatment of active acute rejection is
with systemic corticosteroids and
continuation of calcineurin inhibitor.
calcineurin inhibitors itself reduce renal
blood flow and are directly toxic to renal
endothelial and tubular
cells>>>histologic finding is early
arteriole hyalinization and tubular
vacuolization. despite their
nephrotoxicity, these agents are
beneficial for prevention of acute
rejection
Accelerated acute Days
Chronic Months to years Vessel occ, intimal smooth muscle cell
prolif, vessel wall chornic DTH reaction

HLA typing in lab

- performed to determine the closest MHC match between donor and recipient
- 2 methods (to determine the haplotype (the class 1 and class 2 alleles on both chromosome) of both the potential donors and
recipient:
- (1) DNA sequencing:
- using PCR amplication + specific probes to detect different alleles
- highly specific and senstivitive and method of choice
- (2) serologic assays
- cells from donor + recipeient are reacted wit ha battery of antbodies, each one of which is specific for a different class 1 and 2
protein the ncomplement is added and any cell bearing an MHC protein homologous to the known antibody will yse
- (3) follow up if both cant work: mixed lymphocyte culture technique:

- stimulator llymphocyte from a potential ldonor are first killed by iiridation and then mixed with live responder lymphocyte from
recipient and mixture is incubated in cell culture to permit dna synthesis
- the greater the moaunt of dna syntehss in responder cell, the more foreign are the class 2 mhc proteins of the donor cell
- a large amount of dna synthesis indicate an unsatisfactory match thus donor and recipient class 2 (HLA-D) MHC porteins ARE NOT
Similar and graft likely to be rejected

(4) cross matching
-preformed cytotixic antbibody in receipt serum reactive after the graft detected by observe the lysis of donor lymphocyte by the recipeient
serum plus complemetnt***
Graft vs host reaction:
reaction occur because frafted immunocompetent T cell proliferate in the irradiated immunocompromised host + reject cells
with foreign proteins thus resulting in severe organ dysfunction
usualy in bone marrow and liver transplant (rich in lymphocyte
type 4 hypersentivit
donors cytotoxic T cell play major role in destroying recipient cell
px: maculopapular rash, jaundice, hepatospenmegaly, diarrhea
NEEDS 3 REQUIRMENTS TO OCCUR
(1) graft must contain immunocompotent T cell
(2) host must be immunocompromised
receipeint must express antigen (e.g mhc proteins) foregin to donor (donor tc ells recognize the recipient cell as foeign)
-note: even though when donor and recipient have identical class 1 and class 2 MHC thus identical hpolotypes, a GVH reaction
can occur because it can be elicited by difference in antigens

tx: reduce GVH by: treat donor tissue with antithymocyte globulin or monoclonal antibodies before grafting thus
eleimate mature t cell from graft OR cyclosporine

Monoclonoal antibody to reduce graft rejection

Others:

Cyclosporine, Fct: Tacrolimus (more side effect)
tacrolimus -Prevent activation of T lymphocyte by inhibit the
synthesis of IL2 + IL2 receptor
-VIA inhibitiong calcineurin (serin phosphatase involved
in ac tivation of transcription of the genes for IL2 and
IL2 receptor)

Corticosteroids Mechanisms:
-inhibit cytokine (e.g IL1 + TNF)production by
macrophage and lyse certain type of T cell VIA blocking
transcription factors (e.g NFkB and Ap-!)which prevent
the mrna for these cytokines from being synthesized
Azathioprine Inhibitor of dna synthesis and block growth of t cell

Mycophenolate Inhibit dna synthesis
mofetil
Alemtuzumab (anti Depletes pool of T cell by bind and cause complement
cd52) mediated lysis

Clinical function Monoclonal antibody
Transplant related Basiliximab, daclizumab IL2 recepetor Prevent or treat allograft
immunosuppression rejection and graft vs host
reaction
Muromonab (OKT3) CD3 on T cell

-lblock t cell activation by
causing cell apoptosis
Treatment of autoimmune Infliximab Tumour necrosis factor alpha Treat RA, chron
disease
Adalimunab
Natalizumab Alpha integrin Ms, crohn
Prevent of infectious disease PAlivizumab Fusion protein of RSV Prevent pneumonia in
suecptible neonate
Cancer Ritizumab CD 20 protein on B cell Treat non Hodgkin lymphoma
Trasuzumab Epidermal growth factor Treat breast cancer
receptor

Type of cell:

Cell surface protein

T cells in general TCR
CD3 a/w with TCR for singal transduction
CD28 Binds B7 on APC
CXCR4/CCR5 Co receptor for HIV
Helper T cell CD4, TCr, CD28
Cytotoxic t cell CD8, TCR, CXCR4/CCR5
REG t cell CD4, CD25
B cell Ig Binds antigen
CD19,CD20, CD21 Receptor for EBV
CD 40
MHC 2
B7

Macrophage Class 2 mhc, B7 (CD80/86)
CD 14 Receptor for PAMP (e.g LPS)
CD 40, CCR5
Fc + C3b receptors Enhanced phogcytosis

Nk cell MHC1, CD56
All cells other than mature cell MHC1
Hematopoetic stem cell CD34

Innate vs adaptive immunity:

Innate Adaptive
Specificity For pathogen associated molecular Specific antigens of microbial and non
patterns (PAMPs) microbial agents
-2 important examples of PAMP
-endotoxin and MBL
-endotoxin:

-a LPS (lipopolysaccharide) found on surface
of most gram neg bacteria (BUT NOT ON
HUMAN CELLS)
-lipid A portion of LPS is most important
cause of septic shock and death
-LPS when released from bacteria lsurface,
LPS combine with LPS binding protein ( a
normal component of plasma)
-LPS +LPS binding protein -> transfer LPS to
receptor on surface of macrophages CD14
*** -> THUS STIMULATE TLR4 (toll like
receptor 4) -> transmit signal to nucleus of
cell
-nucleus of cell -> production of cytokines
(e.g IL1, IL6, IL8, TNF) + induce costim
protein B7 (B7 activate helper t cell)

mannan
-polysach o nbacteria and yest not on uman
cell
-pattern recognition receptor (mannan
binding lectin MBL) -> bind to mannan on
surface of microbe -> activate complement -
> death of microbe
-MBL is ormal serum protein whose
conectration in plasma increase during
acute phase reponse
Diversity Limited high
Memory No yes
Self reactivity No no
Components
Anatomic and physiologic barrier Skin, mucosa, normal flora, temperature, Lymph nodes, spleen ,mucosal associated
ph, antimicrobials,cytokines lymphoid tissues
Blood proteins complement antibodies
Cells Phagocytes, granulocyte, nk cells B lymphocyte, T lympocoyte


origin of cells:
notes:
in general,
(1) start with pluripotent stem cells in bone marrow
(2) divie into common lymphoid stem cell or myeloid stem cell
(3) common lymphoid stem cell -> T progenitor or B progenitor
(4) myeloid stem cell -> Granulocyte progenitor, eosinophil progenitor, basophil progenitor, megakaryocyte, erythroid progenitor

different cells:

Leukocyte : Granulocyte (nuetohil, eosinophil, basophil, mast NLMEB
cell), mononuclear (monocyte, lymphocyte) From highest count to lowest
Neutrophil, lymphocyte, monocyte, eosinophil, basophl

Neutrophil acute infl response cell
increase in bacterial infection
phagocytic, relase degrading enzymes enzymes
multilobed nucleus
specific granules contain: LAP (leukocyte alkaline
phosphatase), collagenase, lysozyme, lactoferin
lysosomes contain proteinase, acid phosphatase,
myeloperoxidase, beta glucorinadase
structure:
cd 14
cytoplasmic grnaules that stain a pale pink (neutral) colour with
blod stain such as wright stain (in contrast to eosinophisl and
basophils)(whose granule stain red and blue respectivitely)
NOTE: DO NOT display class 2 mhc on surface THUS DO NOT
present antigen to helper t cell

clinical:
hypersegmented neutrophil (> 6 lobes) seen in vit b12/folat def
increase band cells (immature neturophils) = increase myeloid
prolif (bact infection or cml)
important neutrophil chemotactic agents (c5a, IL8, LTB4,
kallikrein, platelet activating factor)
Monocyte Fct: diff into macrophage in tissue

Structure:
Large, kidney shaped nucleus, frosted glass cytoplasm, found
in blood

Macrophage Fct:
phagocyte bacteria ,cellular debris, senescent rbc

-macrophage ingest bacteria etc
-macrophage have surface Fc receptors -> interact with -> fc
portion of IgG thus enhance uptake of opsonized organisms
-also have receptor for c3b (opsonin)
Granuloma formation
(lipid A from bacterial LPS bind CD14 on macrophage to initiate
septic shock)
antigen presentation
-foreing material ingest -> froegin antigen present on cell
surface with class 2 mhc with TCR of cd4
cytokine production
-e.g IL1 nad TNF
-iL1 is fever

structure:
CD 14
agranlocyte with a ruffled cytoplasmic membrane and cytoplasmic
vacuoles and e sicules

Note
Diff from circulating blood moocyte
Activated by gamma IFN
Can function as apc via mhc 2

Macrophage activation:
(1) macrophage activiated initially by substances e.g
LPS (bacterial lipopolysaccharide, endotoxin) OR
bacterial peptidoglycan OR by bacterial DNA
(bacterial dna is unmethylated, human dna is
methylated)
these -> interact with-> TOLL LIKE RECEPTORS on
macrophage
(2) macrophage ecna also be activated by gamma
IFN by helper t cell (Gamma IFN increase syntehssi of
class 2 MHC -> enhance antigen presentation thus
increase microbial acivity of macropahges)

Fct:
Eosinophils: Defend against helminthic infection (major basic protein)
Highly phagocytic for antigen antibody complexes
Produce histaminase, major basic protein (MBP:
helminthotoxin), eosinophil peroxidase, eosinophil cationic
protein, eosinophil derived neurtoin

Structure
Bilobate nucleus
Packed with large eosinophilic granules of uniform size
Granulocyte with bilobed nucleus and large pink cytoplasmic
granules
STAIN RED WITH wright stain (sue to negatively charged eosin
dye bind to positive charged major baiscp ortein in granules)

Note:
Causes of eosinophilia NAACP
Neoplasia, asthma, allergic, parasite (esp by neomatodes), chronic adrenal
insuff
Basophils fcT:
mediate allergi reaction,
type 1 hypersenstivity,
-have receptors on their surface for Fc portion of the jeavu
cjaom pf Ige
- when adjacent IgE molecules are cross linekd by antigen ->
cause release of mediators such as histamine and enzymes (.g
peroxidase and hydrolase) -> thus infl -> thus severe immediate
hyperssentivity reaction (e.g systemic anaphylaxis)
eliminate large extracellular parasite

structure:
densely basophilic granules
contain heparin (anticoagulant), histamine (vascodilator)
granulocyte with bilobe nucleus and large blue cytoplasmic
granules
-STAin BLUE with wright stain (due to positively charged methyl
blue dye bind to negative charge molecuels in grandules)

note:
stain with basic stain
can be sign of myeloprolif diease e.g cml
Mast cell Fct:
Mediate allergic reaction I local tissues

Structure
Contain basophilic granules
Fc proteion of IGE to membrane
-IgE crossl ink upo antigen bind -> degranulation -> release of histamine,
heparin, trypase, eosinophil chemotactic facture

note:

invive in type 1 Hypersentivity reaction
cromolyn sodium prevent mast cell degrandulation (use for asthma
prophylaxis)
Dendritic cell Locate: epi ttissuee

Constituivey expresss MHC class 2 + costim B7 cell surface receptor

From myeloid
granolyte monocyte progenitor -> dendritic

Structure:
Long cytoplasmic arm
Cd14 postiive
RAQUET SHAPEED intracytoplasmic granule (birbeck granudle) (UWORLD)

Function: antigen caputer, transport remnstaiton, infl

Innate cellular response:

NK cells
Member Innate immunity
Note: -a large granular lymphocyte

Natural = active without prior exposure to virus, not enhanced by exposure and not specific for any virus
-can kill without antibody (but IgG enhances it)(process called ADCC antibody depdent cellular cytotoxicity)

-essentially lymphocyte with some t cel markers
-DONT HAVE TO pas sthrough thyus to mature
-NO memoery, NO t cell repceptor, NO NEED recognition of MHC proteins (just detect number of HM1 )
-viral and tumour cell has dereased number of MHC1 protei thus killed
-ALSO detect MICA (protein on cancer cell)

-clinical: If lack of NK cell, predisposed to infection with varicella zoster and cmv

fct Kill virus infected cells + tumour cells**
Marker CD 16 (FCR), CD 56 ( CAM )
Effector Cytotoxins: Perforin + granzymes
(to induce apoptosis of virally infected cells + tumour eclls)

OR
Antibody depdent cell mediated cytotoxicity (e.g CD16 vubds Fc region of bound Ig, activating the NK cell)
(FAS-FAS ligand mediated apoptosis***)
Enhanced by IL2, IL12, INF alpha, IFN beta
Receptor Killer activating receptor (KAR)

-if only KAR engaged then target cell will be destroyed
+

-detect MICA (MIC proteins) (stress proteins*** expressed by cells infected or undergoing tramsformation
(TUMOUR CELLS)
-kills cells if expressed MICA
Killer inhibitor receptor (KIR)
-if both KIR and KAR are ligated ,target cell lvies
-KIR activiate protein tyrosine phsophatse -> inhibit-> intracellular signal and activation via REMOVING
TYROSINE RESIDUES fROM SIGNAL MOLCULE
-KIR -> binds to HLA-E (special type of MHC 1)
-HLA-E amount fo expression = overall wellbeing of the cell
-during viral infection, HLA E decreases thus susceptible to NK cell killing
Induced to kill (1)Exposed to non specifc acitviation signal on targe cell
OR
(2) Absence of MHC1 on target cell surface
-
do not require the thymus for maturation and are present in athymic patients .
have no antigents-specific activities, do not require exposure to antigen for activation, and do not possess
antigen memory ability.
are activated by interferon-y and IL-12.
.........
Natural killer cells are derived from lymphoid stems cells and comprise approximately 10% of all circulating
lymphocytes.

T cells

Notes:
Fct: Regulatory + effector
Regulatory:
-via helper T cell (CD4)
-secretion of IL 4, IL10 -> help B cell produce antibody (by becoming antibody producing plasma cell)
-IL2 -> activated CD4 + CD8 cell
-gamma IFN -> activate macrophage

effector:
CYTOTOXIC OR DELAYED HYPER SENSITIVTY
DELAYEd HYPERSENSITVITY:
-via cd8 cytotic t cell
-e.g leprosy or intracellular microorganism

CYtOTOXIC:
-destroying virus infected cell and tumour cell, and graft rekjection
-e.g ag ainst virus infected cell:
(1) CD4 postive cell -> recognize viral antigen on MHC2
(2) CD4-> secrete IL2 -> activate CD8+ cytotxic t cell
(3) cytoxic CD8 cell kill via insert perforins + granzymes into infected cells
-perforins: form chanel through membrane, cell content lost and cell dies
-granzymes: protease that degrade protein in elcell membrane thus lea d to loss of cell contents + activate caspases that initate
apotosis
(4) cytotic cd8 can also activate Fas Fas ligand (fAsL) interaction
-FAS is also a protein displayed on surface o many cell
-when cytotoxic t cell recgonzie an antigeon on surface of targe cell, FasL is induced in cytotixic t cel thus interact between fas and FAsL hus
aptosis
uworld fas ligand:

apoptosis can be triggered by number fo mechanism incl deprivation of growth factors, dna damage, intarcellualr acc of
musfiolded protein, mediation by cytotoxic t lymphocyte, activation of recetpors in TNF receptor family such as FAS
fas receptors initate the extrinsic pathway of apoptosis through cytoplasmic component known as death domain
upon binding FAs lingang (FASL), the receptor trimerize thus allow death domain to form a binding site for adaptor protein
cauled fas aw death tdomain (FADD)
receptor bound FADD then stimulate activation of iniator caspases (8 and 10) that begin an activation cascade culminating in the
activation of executioner caspases (3 and 6)
these intiate the terminal process fo apoptosis incl cleavage of dna, fragmentation fo ncuelus, organelle autodigest, plasma
membrane blebbing
FAS receptor is expressed on t lymphocyte and play role in pathogensis of numerous disease incl cancer and autoimmune
Once activated, t lymphocyte begin t oexpress FASL which can bind to FAS on the same cell or adjacent lymphocyte
During intial clonal expansion, activated t lymph are resittant to fas induced apoptosis but after constat stimulation of self
antigen, activated t lymph undergo apoptosis via activation induced cell death
(mutation involve fas or fal impairs this thus result in excess acc of autoreactive t cell and develop of autoimmune diease such as
SLE)

e.g graft reject
-cytotixic t cell recognize foregin mhc1 thus attack

Only recognize polypeptide antigens + in association with MHC protein (AKA mhc restriction)
MHC1 present endogenously synthesized antigen (e.g viral) while MHC2 presnt extracelllar mcorgram (bacterial)
Can bind to sheep erythrocyte (sheep erythrocyte receptor) ** (used as mean of idtnfiyint t cell)

TH cells (subdivision of CD4):

Th 1 Th 2 Th17 T reg
Pathogens Intracellular infections: viruses + Parasitic infections or Extra cellular (arise from Th0)
intracellular bacteria allergens bacteria and fungal
infections
-due to inability to pahgcyte
such pathogen, There is no
significant macrophage or NK
cell stimuatlion
expresses T-Bet GATA-3 ROR-gamma-T Fox P3
transcription factor
(to induce activation)
Secretes IFN gamma + IL 2 IL 2,4,5,6,10,13 IL7, IL22 Inflamatory
-IL2: activate antigen specific t -IL4,5,10: activate b cell inhibitory
helper t cell to produce a clone + -IL4: cause B cell to istype cytokes IL10,
activate cytotixic t cell switch to IgE (Which will bind TGFbeta
-IL2 ALSO stimulate helpter t cell to mast cell, eosinophil +
to multiply into a clone of antigen basophils)
specific helper t cell OR be come -IL13, IL4: enhance
memory cell (capable of rapidly alternative macrophage
activated upon exposure to activation fro tissue repair +
antigen at later time) muscus secretion +
-IFN gamma: activate macrophage peristalissi
+ amplify Th1 response by

increasing MHC class 2 proteins -IL4, IL10, IL13: promote Th2
on APC+ inhibit th2 response + response while inhibit th1
enhance isotype switching to IgG respponse
-IL5: mature and activate
eosinophils
Activates Macrophages + cytotoxic cells Recruits eosinophils for
parasitic defeces + promote
IgE production by B cell
Differentiation IFN gamma, IL12 IL2, IL4 TGF beta, IL6, IL23 TGF-beta
induced by IL12 secreted by
macrophage*** (thus
increase TH1 thus host
defece against
organisms that are
controlled by a delayed
hyper senstitivity
respne)
IFN gamma from NK cell
Inhibited by IL4, IL10 (from th2) IFN gamma (from th1)
Enhance cell YES NO
mediated immunity
and delayed
hypersentivity
primarily
Enhance antibody NO YES
production primarily

Clinical relevance Kaplan:

Leprosy
Progression of Mycobacterium leprae depends on: balance of th1 and th2
Tuberculoid leprosy
-lipprotein of a certain leprosy -> stimulate toll like receptor on macrophage -> cell to synthesize IL12
IL12 -> cause increase prolif of strong th1 -> which eradicate intracellular pathogen by granuloma formation + secrte IFN gamma
-> which activate macrophage -> thus idisease progress slowly and patient survive
Lepromatous leprosy:
-strong th2 -> AND DUE TO RECIPRICOAL INHIITON THUS CELL MEDIATED RESPONSE IS DEPRESSED (e.g IL10 from th2)-> progress
to lots of infection

Th1 and Th2 development (after thymus and bone marrow)

Th 1:
(1) microorganisms -> ingested by macrophage -> macrophage release IL12
(2) IL12 -> induces nave TH- cells to -> become Th1 cells
(3) Th1 cells -> gamma IFN (activate macrophage) + IL2 (active cytotoxic t cell) -> THUS CELL MEDIATED IMMUNITY OCURS
TH2:
(1) Microorganism -> ingest by unknown cell
(2) Unknown cell -> release IL4 induce nave th cell to -> become th2 cells
(3) Th2 cell -> secrete IL 4,5 -> activate b cell to -> become plasma cells -> THUS antibodies are pdocued -> ANTIBODY MEDIATED
RESPONSE
(4) TH2 also secrete IL10 -> which inhibit macrophages thus drive ystem toward antbody response and waway from cell mediated
response

Cytokines functions:
Hot T-bone steak
Hot (1), stimulate T cell (2), stimulate bone marrow (3), stimulate IgE (4), stimulate IgA (5), simulate aKute phase protein IL6

Cytokines Major source Important functions
IL1 macrophage Activate helper t cell, cause fever (endogenous pyrogen that act on hypothalamus)
-activate endothelium to express adhesion molecules**
-induces chemokine secretion to recruit WBC

nbme>>>1,2,15>>>impaired snthesis of IL-1>>>impaired function of T lymphocytes
when antigenic peptide (on MHC 2 of macrophages) binds the T-cell receptor on CD4
helper T cells, the macrophages secretes IL-1.
IL-1 stimulates the helper T-cells to proliferate and/or secrete lymphokines
526
IL2 All t cell (th1 also) Activate and stimulate growth of helper + cytotoxic T cell + reg cell, also activate b cell and nk
cell
-*T CELL growth factor

Interleukins-2 (IL-2) receptor is transmembrane protein complex that acts via a

multipathway system, including a JAK-STAT signaling component, a MAP kinase
pathway, and phosphoinositide 3-kinase
function in an autocrine manner whereby activated T-lymphocytes (Th1 )provide
costimulus to themselves by secreting IL-2 and producing IL-2 receptors

increased activity of T cells and NK cells is responsible for IL-2 antitumors ability
(aldesleukin)
nbme>>>4,2,15
activation of cytotoxic T cells to eliminate virus infected cell require>>>>MHC class 1
and IL-2, NOT interferon-gamma.
explanation
Once activated, the TC cell undergoes clonal expansion with the help of a cytokine
called Interleukin-2 (IL-2) that is a growth and differentiation factor for T cells.
IL3 Secreted by ALL t cell Support growth and diff of bone marrow stem cells
-fincutions like GM-CSF
IL4 Th2 subset of helper th Stimulate B cell growth, increase isotype switching to igE*** (thus increase acute immediate
hypersensitivity) and IgG****
Increase th2 subset of helper t cell
IL5 Th2 Stimulate b cell diff, increase eosinophils + igA**
IL6 Macrophage Fever + production of acute phase protein
IL8 Macrophage Major chemotactic factor for neutrophil

acc of pus****
(pus is a thin protein rich fluid made of dead leukocyte and neutrophils)
(during infection, macrophage and surroudnign enotheia l cell release cytokine such as IL8
that trigger neutrophil to enter the site of infection via chemotaxis)(il8 alos induce
phagocytosis in neutrophil when they arrive)
Il10 Th2 (also secreted by reg t -attenuates infl response
cell) -decrease expression of MHC class 2 +Th1 cytokines
-inhibits activated macrophage + dendritic cell

besides Th2 also produced by macrophages.
limits the production of proinflammatory cytokines (eg gamma interferon, IL-2,IL-3 and
TNF-alpha), also has immunomodulatory roles
...........
effects of IL-10 results in the attenuation of cellular-mediated immunity with some
enhancement of the humoral response, leading to a protective effect in crohns
disease.
IL12 Macrophages - Induce differentiation of T cells -> Th1 cells
- Activates NK cells
-IL12-gamma interferon axis:
-important for intracellular pathogens (e.g M tuberculosis)
-IL12 increase th1 and th1 produce gamma interferon that activate macrophage to kill
intracellular bacterial pathogen
IL13 Th2 - Mediator of allergic airway disease (e.g asthma)
- Made by th2 and bind to receptor
- Involve in airway hyperesponsive in ashtam BUT NOT increase igE
Gamma Th1 subset of th Stimulate phagocytosis + killing by macropahges + nk cells
interferon -also secreted by NK cell + Increase class 1 and 2 mhc protein expression by all cells
IFN T cell in response to -inhibits diff of Th2 ell
gamma antigen or IL12 from
macrophages jak-STAT pathway.
is a type II interferon produced mainly by T-cells and NK cell..

promotes Th 1 differentiation, increases expression of MHC class II molecules on
antigen presenting cell, and improves intracellular killing ability of macrophages.
(macrophage infect with mycobacteriaproduce Il12 -> stim t cell and nk cell to produce
IFN gamma -> which nthen bind to its receptor thus lead to receptor dimerization and
activate of janus kinase 1 + 2 -> result in neuclear signal via STAT 1 and transcription of
IFN gamma reg gene which promote mycobact kill by phagocyte)(also enhances viral
and parasitic resitance by inc expression of MHC and intrinsic dfefece actor)
Tumor Macrophage -activates endothelium
necrosis -cause wbc recruitment + vascular leak
factor -causes cachexia in malignancy
alpha -maintian granuloma in TB
(TNF -mediate sepsis (IL1, IL6, TNF alpha)
alpha)
Tnf Macropahges Low conetration: activate neutrophils + increase adhesion to endothelial cell
High concentration: mediates septic shock, act as cahectin, causes necrosis of tumour

Other:

IFN alpha + beta Most human cells in response to viral Fct:
infectios Bind to type 1 IFN receptor on infected +
neighboring cells (autocrine/paracrine
signaling) -> transcription of antiviral enzymes
capable of halting protein synteshis
-note: antiviral enzyems active ONLY in
presence of ds RNA (forms in infected cell as
result of viral replication)


Interleukin by sources

Macrophage IL 1,6,8,12, TNF alpha
All t cells IL 2,3
Th1 cells INF gamma
Th2 cells IL 4,5,10 ,13

Leukocyte Migration (Extravasation)
Note:
First step in acute inflammatory response is activation of vascular endothelium in breached epithelial barrier
Cytokines + other infl mediators released in area as result of tissue damage induce expression of slectin type adhesion molecule on
endothelial cell
Neutrophils are the FIRST cell to bind to infl endothelium and extravasate into tissues, peaking at within 6 hours
Monocyte, macrophage eosinophils may arrive 5-6t hours later in reponse to neutrophil released meidates
Molecule on vascular/stroma Leukocyte

MARGINATION AND ROLLING E-selectin, Sialyl-Lewisx Note:
-leukocyte become redistributed -upreg by TNF + IL1 Sialyl lewis -def in leukocyte adhesion def type 2 (decrease
closer to vessel wall(from central axial P selectin L selectin sialyl lewis x)
column to periphery -released by Weibel Palade -AR***
**))(margination) bodies -LAD type 1: def of CD11aLCD18 (beta 2 integrin)
GlyCAM-1, CD34 -LAD type 2: def of selctin that bind neutorphils
rolling: -px:
-due to activation of selectin -delayed separation of umbilical cord**** (>1
adhesion molecule on surface of month)(neutrophil enzymes are important in cord
neutrophil and endothelial cell separation)
-neutrophil bind loosely to selectin -esevere genetiivis, poor wound healing,
and roll along endothelial peripheral blood neutorphilic leukcoytsiis
Tight binding /adhesion ICAM1 (CD54)(intracellular CD11/18 integrin Leukocyte adhesion def (LAD) type 1
adhesion meolcule) (all beta 2 -(decrease cd 18 integrin subunit)
VCAM1 (CD106)(vascular cell integrin) (LFA-1, -px:
adhesion mcule) MAC-1) -omphalitis (swell and red around stalk of umbilical cord)
VAL4 integrin -not more suscpetibal to viral infections than are normal
-both bidn to integrin on surface controls but suffer RECURRENT CHORNIC BACTERIAL
of neutrophil INFECTIONS
-activate by IL1 and TNF

-abd high numbers of grannulocytes in their circulation 9but
migration into istes of infection not possible so abscess and
pus formation DO NOT OCCUR)

pus defintino: thin protein rich fluid with dead uekocyte
primarily neutrophils**

-adheision molecule of neutrophil activation is mediated by
c5a and leuktroiene B4 (LTB4)
-catecholamine, corticosteroids and lithium INHIBIT
activation of adhesion meolcules (thus cause an increase
inperipehral blood neutrophil count) (neutrophilic
leukocytosis)

-endotoxins enhance activation of adhesion meoclue (thus
casue a decrease in peripheral blood neutrophil count
neutropenia)

(note:
LAD type 3: similar type 1: aw sever recurrent bact infection,
delay sepration of umbilical cord, bleed complication du to
affected beta 3 integrins on paltelts)
Dipaedesis PECAM-1 (CD31) PECAM-1 (CD31)
-wbc travel between endothelial cell
and exist blood vessel
-neturophil dissolve basement
membrane and enter interstitial
tissue
-THUS fluid rich in protein and ecell
(Exudate) acc in interstitial tissue
-fct of exudate: dilute bacteria ltoxin
+ providing opsonins( assist in
phagocytosis) natbodies and
compelemnt
Migration Chemotactic prdocuts: c5a, IL8,
-wbc travel through intersitum to site LTB4, kallikrein, platelet
of injury or infection guided by activating factor
chemotactic singals
After neutrophil extravasation:

Phagocytosis:
-multistep: opsnization, ingestion, killing
Opsonization:
-opsonins attach to bacteria
-Opsonins: include IgG, C3b fragment of complemenet and others (e.g CRp etc)
-neutrophils have membrane receptors for IgG + C3b
-fct: enhance neutrophil recognition and attachment to bacteria
-clincal: brutons agammagloieua is an opsonizatino defect

Ingestion:
-neutrophils engulf (phagocytosis) and then trap bacteria in phagocytic vacuoles
-pirmary lysosomes empty hydrolytic enzymes into phagocytic vacuoles -> producing phgolysosomes
-clincal: chediak higashi syndrome (defect in membrane fusion preventing phagolysome formation)

Bacteria killing
-via o2 dependent myeloperoxidase*** MPO
- Only present in neutrophils and monocytes (NOT macrophage)
- Macrophage lose this ability when they coneted from monocyte and they use lysosome to kill
Steps:

(1) O2 -> (NADPH oxidase)(+ NADPH) -> oxygen free radicals (O2 dot)
(2) O2 dot + NADP -> (superoxide dismutase) -> H2O2 (hydrogen peroxide )
(3) hydrogen peroxide H2O2 + chloride CL- -> (myeloperoxidase) -> HOCL (hydrogen peroxide bleach)

note:
side oxidative reaction with oxidative burst:
oxidative:
G6P -> (G6PD) -> 6 Phosphoglucolactone -> Ribulose 5P + 2 NADPH + 1 CO2 -> nucleotide puien and pyrimide biosynthesis**** [PRPP]
While G6PD: NADP -> 2 NADPH
NADPH + oxidized glutathione GSSG -> (glutathione reductase) -> NADP + GSH (reduced)
Reduced glutathione (GSH) + H2O2 hydrogen peroxide -> (glutathione peroxidase OR CATALASE***)-> oxidized GSSG + H2O water
Clinical Goljan:
-chornic granulomatous disease, MPO def
-Chronic granulomatous disease (CGD):
-x linked recessive
-def NADPH oxidase in cell memebrane of neutrophils and monocyte THUS reduced produce of surpoxide THUS absent respiratory burst
-dx:
nitroblue tetrazolium test (NBT)
-organisms are incubated with a colorless NBT dye which is convereted to blue IF RESPIRATORY IS INTACT
-Myeloperodixase MPO def


-AR disorder
-both super oxide and H2O@ are produced BUT ABSENT OF MPO prevent synthesis of HOCL
-Catalse positive organisms:
-e.g staph aureas, aspergillus
-catalse degrades H2O2
-G6pd def:
-THUS no NADPH THUS less glutathione THUS more free radicals which damage blood cells and also cause redisposition to infection

note:
o2 indepdent bacterial killing:
e.g lactoferrin (bind iron neccaary for bacterial reproduction) and major basic protein (eosinophil product that is cytotoxic to helminth)

T cell development
initially produced in the bone marrow, but they migrate from that location to mature during the first trimester of gestation in the
thymus.
(1) T cell precursor (or other immature lymphocyte -@ bone marrow
destined to be t cell) leave bone marrow to thymus -first primary lymphoid organ

(2) initially arrive thymus: -@ Thymus
- the T cell precursor -> become -> double negative T -the second primary lymphoid organ
lymphocyte (DO NOT EXPRESS CD4 or CD8 on surface) -bilobed organ consist of: outer cortex (immature cells) +
inner medulla (maturing cells)
(3) double neg T cell travel from thymus cortex ->
medulla

(4) AT CORTEX:
-double neg t cell rearrange the beta + alpha chain of TCR
(t cell receptor) + coexpress CD3 + CD4 + CD8 co receptor
THUS FORM -> double positive T cell
@ cortex:
double neg T -> double positive T (CD3 + CD4 + CD8)

SELECTION PROCESS: SELECTION PROCESS:
(5) MHC1 + MHC2 each loads with NORMAL self- -note: to remove t cells that would bind to normal self
peptide and presented to double positive T cell antigen and cause autoimmunity OR those with no attraction
-will result in 3 outcomes: at all to APC
Positive selection:
- Where TCR capable of binding with low
affinity to self peptide***
- These T cell will receive signal to divide
and mature into medulla

Failure of positive selection
-those that FAIL to receognize slf MHC
-will not be encouraged to mature

Negative selection
-the T cell that bind too strongly to self MHC
and self peptide will be induced to undergo
apoptosis** (due to potential to cause
autoimmune disease)

(6) - As part of selection in positive selection, those that
bind to MHC1 will be directed to express only CD8 ->
THUS become T helper cell
- those that bind to MHC 2 wil be directed
to express only CD4 -> ths become
cytotoxic t cell
-THUS FORM SINGLE POSTIVE T CELL

minor note kaplan:
-some self reactive t cell -> form T reg cell
-fct t reg cell: inhibit self reactive t cell
-identify self reactive t cell by: CD25, Fox P3
(transcription facor)
-T reg cell release: IL 10 + TGF beta to inhibit
inflammation


-T reg:
-has exoression of cd3, cd4, cd25, fox p3

-clincal kapalnan:
IPEX (immune dysregulation
polyendocrinopathy enteropathy x linked
syndrome):
-genetic def of FOX P3 -> thus autoimmunity
-Px: enteropathy, endocrinopathy, nail
dystrophy, dermatitis, autoimmuene
dermatological condtion,
-aw diabetes in male infants
(7)

Activation of T cell

(1) dendritic cell samples antigen -> process antigen -> migrate to lymph node
SIGNAL 1:
(2) antigen carrying dendritic cell -> carried on dendritic cell surface by MHC 1 or 2
-Ag-MHC1 or 2 on DENDRITIC CELL-> (interact with) -> TCR + CD4 or 8 on T cell respectively
-IL1 *** from machrogphage required for activation of thcell

signal 2:
(3) B7-1/2 protein (CD80/86) ON DENDRITIC CELL -> interact with CD28 ON T CELL
-IL2 from t helper cell (CD4) to help activate itself***
-under normal condition, B7 is under expressed on APC, but in infection ro infl, expression increase thus enhance activation of the mature
nave t cell (THEN ATERWARDS< preferentially bind to CTLA4 to turn off t cell response)

Note:
If ag presented by signal 2 is not -> state of anergy*

After activation of t cell
(4) CD28 on T cell displaced by -> CTLA protein**
-CTLA protein of T cell -> bind to B7 protein of dendritic cell
- this interaction (of B7 w/ CTLA) -> result in INHIBITION of TCELL -> by BLOCKING IL2 synthesis
-THUS -> RESULT IN T CELL to a quiescent state ******** (homeostasis tcelll)

clinical relevance:
-cells without CTLa-4 THUS CANNOT be deactivated -> resulting in increased freq in autoimmune reaction *** (+ CTLA4 can be
used in treating rejection of organ transplant)
-CTLA4 fct: downreguate th cell response by competitive binding to B7-1 and B7-2 on APC

Agonist CTLA4 Abatacept Use in RA
Belatacept Renal transplant
Antagonist to CTLA4 Ipilumamb melanoma

Clinical relevance number 2:

Super antigen:
e.g staphylococcal enterotoxins, toxic shock syndrome toxin-1 (TSST-1), streptococcal pyrogenic exotoxins


Definition: viral or bacterial proteins -> that cross link variable beta domain of a t cell R -> AND -> aLpha chain of a
class 2 MHC
Cross link-> result in bypass normal peptide binding grove
THUS activate tcell -> increase IFN gamma -> activate macrophage -> overexpress pro inflammatory cytokeines (IL1,
IL6, TNF alpha) -> thus syteic toicity

Clincia relevance 3:

Normal CD4: CD8 ratio >1.5
(reduced in AIDS/HIV)(where CD4 destroyed by HIV and cD8 increase)

T cell receptor

Structure Alha + beta polypeptide + aw CD3
Recognition of antigen ONLY in conjunction with MHC protein

B CELL

Function:
Humoral immunity
Recognize antigen (undergo somatic hypermutation to optimize antigen specifity)
Produce antibody (differentiate into plasma cells to secrete specific immunoglobins)
Maintain immunologic memory (memory b cells persist and accelerate future response to antigen)

Lifecycle:

Origin: -B cell DO NOT REQUIRE thymus for maturation
(1) B cell precursors start in fetal -B cell precusors:
liver -has u (micro) heavy chain in cytoplasm
st
(2) Migrate to bone marrow (1 - LACK surface IG + lack Light chains
location in adult life)
(3) Maturation of b cell:
- has 2 phases: -B cell surface IgM: serve as receptor for circulating antigen
-antigen independent phase: -surface IgM: monomer
-consist of: stem cell, pre b -circulating igM: pentamer
cell+ b cell
-antigen dependent phase:

-cellls arise subsequent to
interaction of antigen (e.g
activated b cell and plasma
cell)
-mature b cell: surface IgM
(receptor for antigen) or IgD

B cell activation
(4) Th cell activated first
(5) B cell receptor mediated
endocytosis
-antigen bind to surface IgM
or IgD of B cell -> then
endocytosis of capped
material -> then presented as
MHC2
-> recognized by TCR on Th
cell
(6) CD40 receptor on B cell -> bind to ->
CD40ligand (CD40L) on Th cell
-fct: required for class switching form
IgM to IgG and other ig
(7) CD28 on T cell -> interact with B7 on
B cell ***
-req for activation of T cell to produce
IL2

(8) -Th cell secrete cytokines (IL2, IL4,
IL5)(fct: stimulate growth and diff of
Bcell) that determine Ig class switching
of Bcell
-B cell activate and undergo class
switching, affinity maturation + antibody
production
(8.1) Affinity maturation process occurs
-defintion: B cell strengthen response to
already known Ag (achieved through
somatic hypermutation)
-involves:
-formation of germinal centers in follicls
of secondary lymphoid tissues (clones of
proif antigen specific cells)
-random mutation (somatic
hyerpmuation) -> create single point
mutation in antibody diotype -> if
altered idiotype have increaee affinity fo
antigen then cell will be at slecetive
advanctage in competing to bind to that
antigen
-because binding antigen to cell serve as
first signal for prolif, over time clones of
cells with higher receptor affinity will
begin to predominate in the germinal
center *** (CLONAL
SELECTION***)(AFFINITY MUTURATION)

(8.2) Isotype switching DNA:
-after IL 2,4,5 from t helper cell
-change the heavy chain constant DNA for heavy chain :
domains -> to classes of antibodies Variable (VDJ) + constant region (the rest)
-activate switch region -> excise dna->
rearranging the dna encoding the
constant region of the heavy chain


-initally, all B cell carry IgM specific for
antigen + produce IgM antibody in
response to exposure to that antigen
-later, gene rearrangement -> allows
elaboration of antibodies of same
antigenic specificity BUT of different
immunoglobin class
(antigen specificity remain the same for (1) recombination in variable region (VDJ)
the lifetime of the b cell and plasma cell +
because the specificity is determined by (2) recombination in constant region
variable region genes (V,D, J genes on
the heavy cahin and V and J genes on
the light chain) no matter which heavy
chain constant region is being utilized
-class switching occurs only with heavy DNA for light chain:
chains
-light chains DO NOT UNDERGO class
switching
-(catalized by switch recombinase):
catalyze rearrangement of vDJ genes
during class switching
-Note: once a B cel has clas switched Variable region (VJ) + constant region (the rest)
pass a certain H-chain gne, it can no
longer make that class of H chain
because the intervening DNA is excised
and discarded

Humoral immunity timeline
(note:
influenza vaccine:
-works by induce neutralizing ab against hemagluttin ag in selct viral strain -> upon subsequent rexposure to influenza virus through natural
infection these ab inhibit binding of hemaglutin to sialyylated eceptor on host cell membrane thus prevent live virus from etner cell via
endocytosis)

Notes:
humoral (antibody mediated) immunity:
-directed primarily against:
-(1) exotoxin mediates disease (E.g tetanus + diphtheria)
(2) infection in which virulence is related to polysaccharide capsules (e.g pneumococci, menigococci, hemophilus influenza)
(3) certain viral infection
evaluation of huoral immunity:
-consist of:
-measuring the amount of each ofh te important ig (ie igG, IgM, IgA) in patient serum
-done by radial immunodiffusion or immunoelectrophoresis

PRIMARY RESPONSE
(1) when antigen is first encountered, -during first encounter, antibodies are detectable In
(2) small clone of B cells + plasma cells specifc for antigen is formed serum after a longer lag period than secondary response
(3) serum antibody coentration rise for several weeks -> then -lag period 7-10 days but can be longer depdening on nature + dose
declines of antigen + route of administration
-FIRST antibody to appear are: IgM
-then: IGG or IgA
-IgM levels decline earlier than igG levels

Secondary response: -when there is second encounter with same antigen OR a closely
(1) second encounter with same antigen related (or cross reacting) one
(2) RAPID antibody response
-lag period = 3-5 days -with each succeeding exposure to the same antigen, antibodies
-DUE to persistence of antigen-sepcific memory cells tend to bind antigen more firmly
after first contact

-memory cells proliferate to form a large clone of specific -antibody binding improves due to mutations occur in the DNA that
B cells + plasma cells encodes the antigen-binding site (somatic hypermutation)
(3) IgM produced (similar amount) + IgG (LARGER amount of igG
produced + permist much longer than primary response) -some mutations result in insertion of different amino acids in the
hypervariable region that result in better fit thus cause antigen to
bound more strongly
-subset of plasma cells with these improved hypervaraible regions
are more strongly and more freq selected by antigen and therefore
cotnitute an increasingly larger part of population of antoibody
producing cels THUS affinity maturation
-affinity maturation occur in the germinal center of follicles in the
spleen and lymph nodes
-follicle dendritic cells capture antigen antibody complexes on their
surface via Fc receptor
-these complex then interact with an activated b cell bearing the
immunoglobin that best fit the antigen and it is that ba cell that is
stimulated to form a clone of many b cells capable of synthesizing
the improved antibody

clinical:
-one effect of booster dose of vaccine is to improve antibody
binding by enhacing the affinity maturation process

Antibody

definition:
-globular proteins (immunoglobins) that react specifically with the antigen that stimulated their production
-monoclonal (homogenous) if arise from one clone of plasma cell (a single clone of cells)
-polyclonal if arise to typical antigen (thus formed by several different clones of plasma cell)
3 types globulins***:
-alpha, beta, gamma (antibody is GAMMA globulins)
-(types depend on electrophoretic migration rate )
5 types of antibody:
-IgG, IgM, IgA, IgD, IgE
-subdividied based on difference sin HEAVY CHAINS

fct:
neutralize toxins, viruses
opsonize microbes to make it more easily phagocytosed
-occur by two reactions:
-(1) the Fc portion of IgG interacts with its receptor on phagocyte surface to facilitate ingestion
-OR
-(2) IgG or IgM -> activate complement -> to yield c3b -> c3b interact with receptors on the surface of phagocyte
activate complement

prevent attachment of microbes to mucosal surfaces
catalytic (enzymatic) capability

structure
glycoproteins made of LIGHT (L) and HEAVY (H) polypeptide chain
-L or H refer to molecular weight

e.g Y shape:
-consist of 4 polypeptide chain: 2 H and 2 L
4 chains linked by disulfide bond** (SS)
(any antibody always consist of: identical H chains + identical L chains)
and subdivided into VARIABLE + CONSTANT region
-variable fct: antigen binding (@ amino terminal portion of each L and H chain**)
-antigen antibody binding: involve electrostatic + van der waals fores + hydrogen bond + hydrophobic bonds **
-constant region: various biologic function (E.g complement activation nand bind to cell surface receptor)
each region has DOMAINS
-L region: 1 variable (VL) + 1 constant (CL) domains
-H region: 1 variable (VH) + 3 constant (CH) domains

or
consist of Fab region + hinge + Fc region
fab: 2 fab: antigen binding site
1 fc fragment: placental transfer, complenet fixation,a ttachemnet for various cells etc
Differences Between Antibody Regions
Feature Antibody Binding (Fab) Constant (Fc)
One heavy and one light Two heavy chains
chain Linked by disulfide bonds
Composition
Linked by disulfide bonds Attached to carbohydrate chains
N-terminus of protein
C-terminus of protein chains
Terminus chains
Binds to complement proteins

Binds to antigen in specific
manner Binds to effector regions of innate
Function
immune cells
Site of idiotype diversity Site of isotype diversity

Changed in affinity Changed in isotype switching
Variability maturation 5 types that are shared among all
Unique for every antibody antibodies


nbme>>>2,4,18
The immature B cells whose B cell Receptors (BCRs) bind too strongly to self antigens will not be allowed to mature. If B cells
are found to be highly reactive to self, three mechanisms can occur.
1.Clonal deletion: the removal, usually by apoptosis, of B cells of a particular self antigen specificity.
2.Receptor editing: the BCRs of self reactive B cells are given an opportunity to rearrange their conformation. This process
occurs via the continued expression of the Recombination activating gene (RAG). Through the help of RAG, receptor editing
involves light chain gene rearrangement of the B cell receptor. If receptor editing fails to produce a BCR that is less
autoreactive, apoptosis will occur. Note that defects in the RAG-1 and RAG-2 genes are implicated in Severe Combined
Immunodeficiency (SCID). The inability to recombine and generate new receptors lead to failure of maturity for both B
cells and T cells.
3.Anergy: B cells enter a state of permanent unresponsiveness when they bind with weakly cross-linking self antigens that are
small and soluble.
TCR DNA rearrangement is an exceeedingly complex process that results in excess of 10'5 different possible antigen binding
sites.
the process is similar to that of immunoglobulin gene rearrangement in that it involves joininh of V, D, J and C regions of the
TCR gene and the process of junctional flexibility, N and P-region nucleotide addition, alternative joining of genes, and
multiple peptides combining to form the intact receptor.
the mature TCR is formed from joining of an a and a b protein segement, and these proteins are membrane-bound in close
association with either CD4 or CD8 as well as the costimulatory CD28 and CD 45
..............
this TCR gene rearrangement occur in thymic cortex

immunoglobin isotype
(-most nave mature B cell prior to activation express either IgM or IgD on surface)
(-later differentiate in germinal centers of lymph nodes by isotype switching/gene rearrangement mediated by ctyokines
+ CD40L into plasma cells that secrete IgA, E or G)
definition:
-antigenic (amino acid) differences in their CONSTANT REGION of H-chain***

IgG Structure: Notes:
- monomer -most abundant IG in serum
-consist of 2 L and 2 H chain linked by disulfide bond -main AB in 2ndary (delayed) response* to
-divalent**: 2 identical antigen binding site an antigen
-gamma heavy chain -produced in response to IFN gamma
Fct: produced by th1
complement fixation,
-IgM can do activate complement too
transplacental passage (giving infant passive immunity),
-ONLY antibody that cross the placenta
-ONLY its Fc poertion bind to receptors on surface of placenta
opsonization,
-definition: enhance phagocytosis*
-NOT directly, but via
(1) activate complement -> creating C3b

(2) C3b can opsonize phagocyte**
neutralize bacterial toxins and viruses

IgA Fct: Incdue by secretion of TGF beta by infected
-in secretions (e.g saliva, tears, resp, intestinal, genital tract) cell
-prevent attachemtn of microganism to mucous membrane
found in: colostrum, mucosa, saliva, breast milk first Classical pathway:
- activated by antigen-
structure: antibody complex
-dimer
-two H2L@ units + 1 J chain + secretory component (polypeptide) MALT:
-secretory compoenent: synthesized by epi cell to provide for IgA passage to -mucosal assocaied lymphoid tissue
mucosal surface, protect from being degraded in intestinal tract -a collection of th2 cells dedicated to
providing help for class switching to IgA +
IgA secreting blmphocyte and plasma cell
notes: found here
association of ten distinct protein molecule.
4 IG light chain note:
4 IG heavy chain HSP:
1 J chain (protein) pathogeneiss IgA immune
1 secretory compoanent (protein) complex med
IgA class switching is induced by stimulaiotn of the B-lymphocytes with vasculitis
TGF-beta aw urti
-type 3 HS
mechanism of live oral vaccine (e.g polio): -deposit of thes
upon intestinal exposure to a novel antigen , B cells found in payers complex in walls
patches and mesenteric lymph nodes become activated and preferentially of small vesels
migrate to lamina propia underlying the intestinal mucosa, there they and renal
become fully differentiated plasma cell and begin to synthsize IgA dimers. mesangium ->
these IgA dimer then bind to polymeric immunoglobulin receptor lead to
(PIgR) found on basolateral surface of intestinal epithelial cell and recruitment of
undergo trancytosis. neutrophil and
as linked IgA dimer is released onto intestinal lumen, a portion of PIgR lymphocyte and
remain attached to the antibody (secretory component) forming the activation of
complete secretory IgA molecule complement via
nbme 7,2,37 alternate lectin
movement of dimeric IgA molecules through polarized epithelial cells to pathway -> lead
reach the ductal lumen is>>>transcytosis not endocytosis not to organ
pinocytosis. dysunfction and
explanation. palpabe purpura
Transcytosis is the process by which various macromolecules are

transported across the interior of a cell. Vesicles are employed to intake
px palpable purrua,
the macromolecules on one side of the cell, draw them across the cell, and
arthralgia,
eject them on the other side. While transcytosis is most commonly
abdominal pain,
observed in cells of an epithelium, the process is also present elsewhere.
intussuception,
Blood capillaries are a well-known site for transcytosis, though it occurs in
renal disease
other cells, including neurons, osteoclasts and intestinal cells.
similar to iga
Eg : Insulin and Antibodies
nephropathy
igA protease: (hematuria)
secreted by neisseira and strep pneumonia and h influenza: ft to cleave at dx confirm by skin
hinge ojint of igA and binds and inhibit action of PILLI*** and other cell biopsy showing
surface antigen that normally mediate mucosal adherence and subseqenet iga deposit in
penetration
blood vessels
IGM Fct: antigen binding receptor -primary response
-present as monomer on surfaeo f all B cells
Structure:
-pentamer* (secreted form), MONOMER (if on cell surface) -IgM is the antibody made with the gratest
- 5 H2L2 units + 1 J chain amount in the fetus
-10 antigen binding site ** HTUS most efficient immunoglobin in agglutination, -note: hoever, fetus has more total IgG than
complement fixation, etc IgM because maternal igG pases the
placenta in great amounts

-the first isotype of IG that can be produced
by a B cell DUE to coding for the constant
domains of the heavy chain of IgM (u or

micro chain) are the first sequences
downstream from the coding for the
idiotype of the molecule

clinical Kaplan:
X-linked hyper IgM syndrome
-characterized by def of IgG, IgA
and IgE and ELEVATED igM
-reach to 2,000mg/Dl (norm 45-
250mg/dl)
-DUE to def in gene encoding
CD40L (in X chr) THUS th cell fail
to express functional CD40L on
membranin THUS fail to give
costim singal needed for the B
cell response to T depdent
antigen THUS only IgM
antibodies produced
-most commonly x linked or
acquired
-dx:
-peripehral blood of patients ahs
high numbers of igM secreting
plasma cells as well as
autoantibodies to neutrophils,
paltlets, rbc
-patients fail to make germinal
centers duringa humoral immune
response
-THUS children suffer resp infect
esp pneumocytitis jiroveci

IgD
IGE Fct: Structure: epsilon heavy chain
-
-bind mast cell, basophils, cross ink when expose to allergen,
-
mediate immediate/anaphlactic (type 1 hyeprsentivity through
relaease of inflamtory mediates eg histamein
- Fc region of IGe binds to the surface of mast cell and basophils ->
THUS bound igE serve as receptor for allergen antigen
- Contribute to immunity to worms by activating eosinophils
- Worms too big to be ingested by phagocyte THUS killed by osinophils
that release worm destroying enzyme + ADCC (antibody depdent
cellular cytotocity)
- Lowest concentration in serum
UWORLD CLINICAL:

Eosinophils fct:
Parasitic defence: when parasite enter blood, coated
by igG and igE ab that bind to the
Fc receptors on eosinophil cell
surface
- Th2 + mast cell ->
increase IL5 -> increase
eosinophils
- Eosinophis degranulate
-> release cytotoxic
proteins (e.g MAJOR
BASIC PRTEIN) and
reactive o2 > thus
destroy antibody bound
parasite
- HEHNCE ANTIBODY
DEPENDENT CELL
MEDIATED
CYTOTOXICITY ADCC
*****

Type 1 hypersensitivity rxn: eospinphils synthesize =>
prostaglandin, leukotrienes,
cytokines -> late phase type 1
hypersensitivyt

-

-

Immunoglobin allotype
Definition:
-additional antigenic feature that vary due to genes that code for L and H chain are polymorphic

idiotype:
definition: antigenic determinants formed by specific amino acids in the hypervariable region
-each is unique for the immunoglobni produced by specific cone of antibody producing cells

immunoglobin genes
roughly compose of gene segments: V, D,J,C
Involves specifc genetic mechanism e.g dnarearrangement + rna splicing
Via recombinases (e.g RAG-1, RAG-2)(recombination activation genes)
(clinical: mutatin in RAG1 or Rag2: arrest development of lymphocyte -> SCID**)
ANTIBODY DIVERSITY:
-depends on:
-(1) multiple gene segemnts
-(2) rearrangement into different sequences
-(3) combining of different L and H chains in assembly of IG molecules
-(4) mutations
-(5) junctional diversity (applies to antibody heavy chain)(occur sby adddtion of new nucleotides at splice junctions between genes)

clinical:
Severa lymphoid cancer manifest chromosomal translocations involving VDJ recgion + cellular oncogene
E.g Burkit lymphoma:
-c-myc oncogene on chr 8 is TRANSLOCATED to position adjacent to VDJ region of a heavy chain gene
-the active promoter of the heavy cah in gene increase transcription of c-myc oncogene thus predispose to makginacy

Complement system
Notes:
-made in liver
-heat labile (inactivatd by heating serum at 56 degrees c for 30 min) (Immunoglobins ARE NOT INACTIVATED at this temperature)
Consist of:
-20 proteins that are present in normal human serum
-can COMPLEMENT (ie ability to augment the effects of other componenets of immune system for example antibody)
-important for innate

3 main effects:
-(1) lysis of cells (e.g bacteria, allografts, tumor cells)
-works by insertion of complex on cell membrane result in disturption fo membrane and entry of water and electrolyte into cell
-(2) generation of mediators that participate in inflammation and attract neutrophils
-(3) opsonization (ie. Enhancement of phagocytosis)
- microbes (e.g bacteria + viruses) are phagocytizied much better in presence of c3b because there are c3b receptors on the surface
of many phagocytes

other:
(3) chemotaxis
-c5a, c5,6,7 complex attract neutrophils
-c5a also enhance the adhesive to endotheliam

(4) anaphylatoxin
-c3a, c4a,c5a -> cause degranulation of mast cell
-leads to increase vascular permeability + smooth msucel contraction esp contraction of bronchioles -> bronchospasm
-c5a most potent anaphylatoxins

(5) enhancement of antibody rpdocution
-binding of c3b to its receptor on surface of activated b cell -> enhance antbody production ***
-clincal: patient def in c3b prodce less ab than those with normal amount of c3b

ebg

3 Pathways for activation of complement:
notes:
-all 3 lead to-> production of C3b (the central molecule of complement cascade)
-c3b on surface of molecule marks it as foreign and targets it for destruction
-c3b fct:
-combines with other complement component to -> generate C5 convertase (enzyme that lead to production of the membrane attack complex)
-opsonizes the bacteria because phagocytes have receptors for c3b on their surface


(1) classical pathway
(1) antigen-antibody complex activates C1 -> to C3a, c5a: anaphylatoxin
form a C1 protease
(2) C1 Protease cleave C4 + C2 -> to form-> C4b +
C2b complex (which is C3 convertase)
(3) C4b + C2b complex (C3 convertase) -> cleave C3
-> to form-> c3a + c3b
(4) C3b + form a complex with c4b2b -> to form C5
convertase (c4b2b3b)
(5) C5 convertase (c4b2b3b) -> cleave c5 -> to form
-> c5a + c5b
(6) C5b -> bind to -> c6 +c7 -> to form a complex
that ineract with c8 + c9 -> to produce
membrane attack complex (c5b, 6,7,8,9)****

(2) alternative pathway

(1) many unrelated cell surface substances (E.g bacterial
lipopolysaccharides (endotoxin), fungal cells wals ,viral
envelopes -> initate by binding c3 (H2O) factor B -> thus
C3+B complex
(2) C3+B complex -> (cleaved by factor D protease)-> form->
c3b Bb
(3) C3b Bb -> become c3 convertase -> to cleave more c3 to
form more c3b

(3) lectin pathway

(1) mannan-binding lectin or mannose binding protein (MBL) -NOTE:
-> bind to surface of microbes bearing manna (a polymer Lectin bypass antibody requiring step
of the sugar mannose) THUS protective early in infection before antibody is
(2) MBL a citvates proteases aw with MBL -> cleaves C2 + C4 formed
-> to actviiate CLASSIC PATHWAY

Regulation of the complement system:
First regulatory step in classic pathway:
-at antibody itself
-the complement binding site on the heavy chain of IgM + IgG is unavaibale to the c1 componenet of complement if antigen is not
bound to these antibodies***
-after antigen is bound to its specific antbody, a conformation change occurs and the c1 componeent can bind and initiate the
cascade
Other:
-@ classic pathway:
(1) c1 inhibitor: important regulator of the classic pathway
-inactivates protease activity of c1
-activation of classic pathway proceed past this point by generating sufficient c1 to overwhelm the inhibitor
-@ alternative pathway
- factor H
-binding of factor H to c3b -> H + c3b complex -> then cleaage by factor I (apreatease) THUS reduce amount of c5 convertase around
-can proceed past if enough c3b created and attach to cell membrane (attachemenet of c3b to cell membrane protect it fro
degradating by factor H and I)

-properidin
-protect c3b and stabilize the c3 convertase

-decay accerlating factor (DAF)
-a glycoprotein located on surface of human cells

-DAF acts by destabilizing c3 convertase + c5 convertase
-prevents the formation of membrane attack compelx

CLINICAL complement:
Note:
In transfusion mismatch, AB oincompatibiltiy, e.g when type A blood given to mistake to person with type B blood, antbody to type
A antigen in reciepent bind to A antigen on the odnor red cell thus complement is activated thus large amround of anaphylatoxin
and membrane attack complexes are generated and caus red cell hemolysis

In immune comple disease, immune complex bid complement thus compelemnt levels are low in immune complex disease (e.g
acute glomerulonephritis + sle

Pateitn with severe live siease (e.g alcoholic cirrhsos ior chornic hep b thus cannto synthesize sig live ruction and compelenet protein
thus pyogen bacteria infection
Complement protein def
C3 def Increase risk of severe, recurrent pyogenic sinus + resp tract
infection
-increase susceptible to type 3 hyper snestiity reaction
C5-c9 def Terminal complement def -> increase risk to recurrent
Neisseria bactermia
Complement regulatory protein def
C1 esterase inhibitor def Causes hereditary angioedema due to unrega ctivation of
kallikrein -> increase bradykinin
-characteried by decrease c4 level
CI: ACEI
Cd55 def Aka DAF def
Causes complemenet mediated lysis of RBC, + PNH
paroxysmal nocturnal hemogloninura ****

Note:
Eculizumab: prevent conversion of c5 to c5a THUS reduce hemolysis and transfusion req for PNH

PASSIVE vs ACTIVE immunity

Passive Active
Means of acquisition Resistance based on receiving Exposure to foreign antigens
preformed antibodies (antibodies -e.g
preformed in another host) clinical or subclincal infecitons
immunization with lvie or killed
infectious agent or their antigens
or exposure to mircrobial prodcuts (e.g
toxins and toxoids)
Onset Rapid Slow

-
Mediators Antibodies + T cell (hyper and cytotxic)
Duration Short span of antibodies (half life = 3 Long lasting protection (memory)
weeks)

Examples IgA in breast milk, maternal IgG crossing Natural infection, vaccines, toxoid
placenta, antitoxin (diphtheria, tetatnus,
botuism, rabieis, heap a and b virus),
humanized monoclonal antibody

Toxoid vaccines:
-made from exotoxins from toxigenic
bacteria
-prevent disease, NOT infection
-seen in:
-DTaP: diphertia, tetanus, acellular
pertussu

component vaccine:

-composed of immunodominant protein
from virus that is grown on yeast cell
-e.g
-HBV (hbv surface antigen)
OR
-HPV:
-quadrivalent vaccine with serotype
6,11,16,18
OR
-9 valent vaccine (garasil 9_ ot prevent:
serotype 6,1,,16,18,31,33,45,52,58

Live vs inactivated vaccines FOR VIRAL VIRUSES ****

Live vaccines Killed or inactived
vaccine
notes -composed of LIVE organism which lost capacity to cause disease but still -pathogen inactivated
replicate in the host by head or chimicel
-induces cellular + humoral responses -maintains epitope
structure on surface
antigen important for
immune response
-mainly induces a
humoral response
Examples (In babies, SMALL YELOW VIRUS OR MMR) PAIR
Polio (Salk)
influzna (intranasal), bcg, small pox, yellow fever, varicella, OPV (sabin), Hep A virus
rota virus measule mump rubella Influenza (injection)
Rabies
Pro Induce strong often lifelong immunity Safer than live vaccine
Con May revert to virulent form Weaker immune
Often ci to preg and immunodef response, booster shot
req
Note INDUCES prolonged mucosal IgA secretion
-live vacc colonize natural site of viral entry and produce a greater and
more prolonged immune response there

-pathoegensis U WORDL QUESTION:
-upon intenstinal exposure to novel antigen, B cell in peyers patches +
esetneric lymph node activate and migrate to laminia proprier underlying
intestinal mucosa
-B cell -> diff to plasma cells -> sntehsize IgA dimers (linked by J chain)
-these IgA dimers bind to polymeric immunoglobulin receptor (pIgR)
found on basolateral surface of the intestinal epitheali cell -> undergo
transcytosis
-as linked igA dimer relased into intestinal lumen, oteion of pIgR
(immunoglobulin receptor) remain attached to antbody (secretory
compeonet) THUS forming complete secretory igA

molecule

Bacterial vaccination
-invovlve administration of characteristic protein:
e.g inactivated toxin (toxioid)
-coat protein from capsule
e.g
DTap: dipheria toxid, tetani toxoid, pertussis toxid
OR
H influenza capsular type B (Hib)
OR
Strep pneumonia: 23 capsular type for adult PPV, 7 capsule type for pediatric PCV
OR
N mengitis with 4 capsular protein (MCV-4, MPSV4)

Extra notes:
CI:
People with egg allergies should avoid: eyellow fever vaccine or other made in eggs
Pregnant owmen: avoid rubella
Immunocompromised: avoid all lvie vaccines

Vaccine schedule:
At birth BE smart: HBV
@ 2,4,6 Dont put her baby at pneumonia risk
Dtap, Polio, hib, HBV, PCV, rota
@ 1 1 monther had passed vaccination
MMR, HAV, Polio, varicella
@ 16 And HID
Hib, Ipv, dtap
4 years DMV inquiry

Dtap, MMR, varicella, IPV

Hep B:....... 0, 2, 6
HiB: ......... 2, 4, 6, 12 - 15
Pneumo: ... 2, 4, 6, 12 - 15
DTaP:....... 2, 4, 6, 15 - 18, 4 - 6 yrs, Td X 10 yrs
IPV: ........ 2, 4, 6,............ 4 - 6 yrs
Varicella:.............. 12 - 15
MMR: .................. 12 - 15, 4 - 6 yrs
Hep A: ..... 2 yrs
Mening: ... 11 - 12 yrs (or school)

1. are vaccines given according to the gestational age or chronological age? Whats the exception?
2. allergic to neomycin, which vaccines are CI?
3. dirty wound, last tetanus booster was 8 yrs ago. how do you treat?
4. CI to rotavirus vaccine?

5. Which vaccine is indicated for travelers going to
a. Mecca
b. Subsahara
c. Egypt
6. which live vaccines are ok in HIV? at what CD4 count?
7. An egg allergy may cause a reaction with which vaccines?
8. Who is eligible for HPV?
9. Dog bite in patient with Pn allergy. treatment?
Report Abuse
* Re:Vaccinations all in one spot
#3159928
penelope24 - 11/17/14 14:22
1. are vaccines given according to the gestational age or chronological age? Whats the exception?
They are given according to chronological age except in Hep B do not give dosage at birth if they are less
than 2 kg.
2. allergic to neomycin, which vaccines are CI?

sorry not contraindicated but neomycin is found in MMR, IPV and varicella. So its not contraindicated but if
allergic then watch for rash.
3. dirty wound, last tetanus booster was 8 yrs ago. how do you treat?
Tetanus toxoid given to dirty would if booster was more than 5 years ago
4. CI to rotavirus vaccine?
SCID, intussusception, severe allergy to rotavirus components
5. Which vaccine is indicated for travelers going to
a. Mecca- meningitis
b. Subsahara- yellow fever
c. Egypt- Hep A, B, typhoid, polio
6. which live vaccines are ok in HIV? at what CD4 count?

MMR only if CD4 is more than 200
7. An egg allergy may cause a reaction with which vaccines?

Influenza and yellow
8. Who is eligible for HPV?

men and women between the ages of 9 and 26
9. Dog bite in patient with Pn allergy. treatment?

Doxycycline is an option but not in kids less than 8 so TMP SMX is another option.

Summary of all vaccines
Bacteria Vaccine Vaccine type
C diphertheria, B pertussis, Ctetanni DTAP Toxioid, toxoid plus filamentous
hemagluttin, toxoid
H influenza Hib Capsular polysaccharide and protein
S [pneumonia PCV pediatric 13 capsular serotype

PPV adult 23 capsular serotype

N mengitis MCV 4 4 capsular serotype (Y,W-135,C,A) and
protein

Viral
Rota virus RV Live
Polio IPV Killed (salk)
OPV Live (sabin)
Influenza IIV Inactivated (killed)
LAIV LIVE
Varicella zoster virus VAR Live
HEp HepA Inactivated (killed)
HPV HPV Component
Hep b virus Hepb Componenet
Measles MMR Live
Mumps MMR LIVe
Rubella MMR Live

Hypersensitivity
Note:
Definition: when an immune response results in exaggerated or inappropriate reactions that is harmful to the host
4 types: ACID (anaphylactic/atopic, cytotxic, immune complex, delayed
Humoral Cellular Examples
Type 1 igE Basophils, mast cells Anaphylaxis, allergies
Type 2 IgG, IGM NK cell, eosinophil, neutrophil, Autoimmune hemolytic anemia,
Atoab, complement activation macrophage good pasture syndrome
Type 3 Deposit o fAB ag complex Neutrophils Serum sickness
Compelemnt activation Lupus nephritis
PSGN
type 4 None T cell, macrophage Contact dermitits, tuberculin
skin test

Typ Immune mechanisms Manifestation Notes
e
1 Steps: Px: Asthma (primarily IL13 mediated via th2 cells)
Sensitiziation: Edema,
(1) antigen (allergen) -> induce erythema (wheal Anaphylactic: ige mediated
formation of IGE antibody and falre) and
(2) igE bind via Fc portion to Fc itch (uritaria) Anaphylactoid (usually drugs or iodinated
receptors on the surface of rhnitits contrast media): induce mast cell and basophils
baosphils and mast ell conjuitviits without ige
asthma
when exposed to allergen again: IMMEDIATE systemic
PHASE anaphylaxis (severe
bronchroconstirctio IgE antibodies become crosslinked and
(3) allergen bind to IgE on surface of n and hypotension) receptor aggregation occur after interaction
presensitized mast cells -> with of IgE with multivalent antigen>>>>>this
clumping of receptors leads to non-
receptor tyrosine kinases>>>triggering an

consequent release of several intracellular cascade that ultimately result in
mediators (e.g histamine) mast cell and basophil degranulation and
reelease of preformed mediators...........
(NOTE: location of presentizied mast cell the strength of IgE-FcRe1 is the result of
determine px. IF I nnose then rhinitis etc) sum of many weak noncovalent forces.;it
is not associated with the formation of
LATE PHASE (6 hours after exposure to covalent bonds (eg disulfide or peptide) ;
antigen) most of total IgE in the body is bound to the
(4) synthesis of mediators (e.g surface of mast cells and basophils and not
leukotrienes (SRS-A)) after cell circulating freely.
degranultes ...........
(5) meidators -> infulux of infl cells medications such as beta-lactam and
(e.g neutrophils, eopsinpheils) sulfonamides antibiotics>>>>these 2 drugs
also has serum sickness type 3 reactions
important mediators:
histamine
-location: granules of mast cells and
basophils
-fct: vasodilation, increase capillary
permeability, smooth muscle
contraction
-clinical:
-allergic rhinitis (ahy fever), urticarial,
angioedema

slow reacting substance of
anaphylaxis (SRS-A)
-consists of several leukotrienes that
DO NOT EXIST in preformed state
-formation from arachidonic acid -> to
form leukotrienes
-fcT: increase vascular permabiltiy and
smooth muscel contraction
-px: bronchoconstriction in asthma

eosinophil chemotactic factor of
anaphylaxis (ECF-A)
serotonin (hydroxytryptamine)
-preformed in mast cell and blood
platelet
-fct: capillary dilation, increased
vascular permeability ,smooth
smucle contraction
-nto important in human
anaphylaxis

prostaglandin + thromboxanes
-related ot leukotrienes
-drived from arachidonic acid via
cyclooxygenase pathway
fct: dilation and increase
permeability of capiliaries and
bronchoconstriction, aggregate
platelets (thromboxanes)

extra notes from LEVINSON:
acute desensitization
-involves the administration of very
small amount of antigen at 15 min
interval
-antigen-IgE complex form o nsmal
lscale -> small amout nfo mediator
released
-small reaction

-this permit admintratino fo drug or
foreign protein to a hypersentivie
person but hypersenstivei state returns
because IgE continue to be made
chronic desensitization
-involve the long term weekly administration
of an antigen to which person is
hyerpsenstive -> s timulate production of IgA
BLOCING and IgG BLOCKIN antibodies ->
prevent subsequent antigen from reaching
IgE on mast cells THUS preventing a reaction

note uworld:
HIGH AFFINITY IGE receptor (FceRI):
-found on mast cells and basophils and play
role in mediating alleric response
-receptor normally bidns the Fc protion of
circulation IgE coating the ecll with various
antigen specific IgE mocleules
-when a multivalent antigen come in contact
with cell, multiple IgE ab become cross
linked thus result in aggregation of the FCERI
receptor on mast cell surface
-thus clumping fo receptor lead to activation
of non receptor tyrosine kinase thus trigger
an intracellular cascade thus mast cell and
basophil degranulation

2 definition: Dx: direct comb test (detect antibody
-cytotoxic hyper sensitivity occur when attachedirectly to rbc surface)
antibody directed at antigens of the c ell
membrane activates complement -> Indirect comb test: detect presence of unbound
generate attack complex antibody in serume

(1) antibody (IgG or IgM)s Fc region-> attach ntibody-dependet cellular cytoxicity (type
to antigen via its Fab region II hypersensitivity) is part of the bodys
(2) THUS complement mediated lysis: defense against viral and parasitic
hemolytic enmia, abo transufion reaction, rh infections. antibodies bound to antigens on
hemolytic disease the surface of infected cells are recognized
by the Fc receptors on effector cells (eg
(3) cause damage via: natural killer cells, neutrophils,
- opsonizatio esinophils) hat then destrpy the infected
n fo cells cells by releasing cytolytic granules
- OR
- Activate nbme>>>5,1,31
compeleme blood group O receive blood group A. Ab-
nt which RBC complex trigger "classic complement
recruit pathway", mechanism of hemolysis is
neutrophils >>>action of C5-9 complex of
or complememnt(which make hole in RBCs).
macrophag mechanism of shock in this patient
es that is>>>release of histamine by the action of
cause tissue C5a
damage
- Cellular
dysfunction
via block
normal
cellular
function
3 Definition:
Immune complex occurs when
antigen-antibody complex induce
an infl response in tissues

-normally, immune complex are
promoptly removed by the
reticuloendothelial system but
occasionally deposited in tissue ->
lead to activate complement
-typical exam are arthus reaction
+ serum sickness*

Arthus reaction:
-infl caused by deposition of
immune complexes at a localized
site (LOCALIZED IMMUNE
COMPLEX REACTION)
-> cause antigen + antibody +
complement -> result in
polymorphonculear cell
infiltration + intravascular clump
of platelet -> vascular occusion +
necrosis
-px:
-hypersenstivity pneumonitis
(Allergic alveolitis) aw with
inhalation of thermophilic
actinomycetse growing in plant
material such as hay
-other causes also include site of
tetanus immunization (if give nat
same site with too short an
interval between
immunization)(mimum interval =
4 years)
most pateitns with
hypresensotivity
pneumonitis have specific
serum IgG antibodies whihc
precipitate actinomyces
species antigens, consisting
with a type III hypersensitivity
mechanism producing
intersticial alveolitis and
broncholitis via immune
complex and complememnt
depostition in vessel walls.
serum sickness
-example: nephritis, arthritis,
vasculitis
-definition: systemic infl response
to the presence of immune
complex deposited in many areas
of body
-> antibody production starts ->
presence of antigen + antibody
leads to -> immune complex
-px:
-fever, urticarial, arthralgia,
lymphadenopathy,
splenomegaly, eosinophilia
-serum sickness can occur following
administration of antigenic heterologous
proteins such as chimeric monoclonal
antibodies (eg rituximab and infliximab)
or non-human immunoglobulins (eg
venom antitoxin). a serum sickness like
reaction is also associated with the use of
certain non-protein drugs (eg penicillin,
cefaclor, and TMP-SMX)....

the most common manifestation include
fever, pruritic skin rash, and arthralgias
that begin 7-14 days after exposure to an
antigen..lymphadenopathy and
proteinurua may also occur in some
patients..
histologic examination of affected tissue
typically show small vessel vasculitis with
fibrinoid necrosis and intense neutrophil
infiltration.
deposition of IgG/IgM complement fixing
antibodies results in localized
complement consumption and
hypocomplementemia (decreased serum
C3 levels)
serum sickness causes release of the
C5a complement fragment (a neutrophil
chemoatractant) at sites of immune
complex deposition.. this leads to
neutropenia and due to extensive
neutrophil margination and and tissue
infiltration..in addition infliximab and other
TNF-alpha inhibitors can also cause
neutropenia.
mild thrombocytopenia due to
platelet consumption at the site
of the active vascular
inflammation.
4 Definition: Dx: ppd, patch test
-sensitized by t cells *
-delayed response*** t cell
transplany
-via: tb
direct cell cytotoxicity Cd* or delayed cd4 touching oak and sumac all
(contact produce urushiol>>>a
contact hypersensitivity dermatitis) small allergenic
tuberculin type hypersensitivity substance that causes
-when a patient is previously an immune response
exposed to mycobacterium when attached to
tuberculosis and injected with protein (ie hapten)..
small amount of tuberculin (PPD) mediated by CD8 T
intradermal cell
-induration reach peak in 48-72 cytotoxicity>>>directl
hours y destroy keratinocytes
-a positive skin test indicate that expressing heptenated
the person has been infected with protein.
agent BUT DOES NOT COIFRM
PRESENCE OF CURRENT DISEASE
-if test convert from neg to depending on
positive, then recently infected etiologic agent can be
-false negative: overwhelming mediated primarily by
infection, disorders that suppress the cytotoxic CD8 T
cell mediated immunity, or cell or CD4 Th 1 cell
immunosuppressive drugs (that cause indirect
damage by activating
macrophages....
..............
in urushiol-induced
contact dermatitis, CD8
T cells are the primary
effector cells and
directly destroy
keratinocytes
expressing haptenated
proteins

the pathogenesis of
contact dermatitis
predominantly involves
repeated binding of
small foreign
molecules (haptens)
applied tot he skin
surface to proteins on
the surfaces of
cutaneous cells,
including antigen
presenting
langerhans cells.
LCs with bound
hapten migrate to
local draining lymph
nodes where they
generate circulating
Th1 type memory
cells.
upon cutaneous
reexposure to the
hapten these, Th1 cells
release inflammatory
cytokines at the site of
exposure. the result ia
a type IV, cell mediated
hypersensitivity
immune response in
the dermis and
epidermis.

in scabies has
type 4 against
mite, its egg
and feces
.....
sarcoidosis is a
type IV
hypersensitivity
.
.......
dress
syndrome also

has type 4

Uworld notes:
URUSHIOL INDUCED CONTACT DERMATITIS

note:
puritic skin rash following wilderness exposure is consistent with poison ivy dermatitis
poison ivy, oak, poison sumac all produce -> URUSHIOL (small allergenic substance that causes an immune response hne attached t
oproteins (ie. A hapten)
-following contact with these plants, patient develop a highly pruritic erythematous rash cosnsit of papules, vesicles, bullae that may show
signs of excoriation

rash most freq affect exposed skin and o ften linear streaks as patient walk past the plant,dragging it along the skin

contat dermatitis is a type 4 delayed type occurs in 2 distinct phases

can be either cd 8+ T cell or CD 4 + t h1


in urushio induced contact dermatitis, cd8 are primary effector cells and destroy keratinocyte express haptenated proteins

(1) sensitization lead to creation of hapten specific t cell and takes 10-14 days
pahse cutaneous dendritic cell take up the haptens and express them on MHC1 and MHC2 molecules as hpaten
conjugated peptides
these dendritic cells travel to the drainging lymph nodes and interact with hapten sensitive cd 4+ and cd 8+ T
cells -> cause activation and clonal expansion
(2) elicitation occur within 2-3 days following REXPOSURE to same antigen (or following sensitization after first exposure to a
phase highly antigenic antigen such as urashiol)
in this phase, hapten is taken up by skin cells and cause ac tivation of hapten sensitized t cell in the dremis and
epidermis
this results in infl response and clinical manifestiation of contact dermatitis


Immunodeficiency

B cell

B cell T ell Granulocyte Complement def
Bacteria Please SHINE my ks Sepsis Staph, burkhodleria Encap with early

cepacia, component def
Pseudomonas pseudomonas
Strep pneumonia aergoinosa, serratia Late component def
Hemophilus influenza type B nocardia (c5-9) get nesseria
N menigits
E coli
Klebsiella pneumonia
Group b strep
Virsues Enteroviral encephalitis CMV, EBV, JC, VZV, n/a
Polio virus (lvie vaccine ci) chronic infection with
respiratory G ivirsues
Parasite Giardiasis ( iga def) Candida (local), pcp, Candida (Systemic),
cryptococus aspergilus, mucor

B cell disorder XSC Defect Presentation Finding tx
X linked (Bruton) Defect in BTK recurrent bacterial + Absent mature B Pooled gamma
agammaglobulinemia (tyrosine kinase enteroviral infection cell in peripheral globulin (IVIG
gene)-> no b cell after 6 months blood monthly)
maturation (decrease maternal Decrease IG of ALL
-x linked recessive IgG) class
(boys only)(female Absent scant lymph
carriers are node and tonsils
immunologically Live vaccines
normal) contraindicated

absence of germinal
center and primary
lymphoid follicle in
the lymph node.
outer cortex which
contain primary and
sencondary lymphoid
fillicle also contain
prominent number of
CD4 T-cells within
interfollicular regions
(allowing for T-B cell
interaction).
in patients with
agammaglobulinemia
,the outer cortex is
present but
diminshed.
1134

Selective IgA def Unknown Asymp -B cell fail to (NOT TREAT WITH
Can see airway or gi differentiate into GAMMA GLOBULIN AS
infection IgA producing MAY FORM AB
otitis media, plasma cell AGAINSt FOREGN IGA
sinusitus, Decrease IgA with by CROSS REACTION
bronchitis, normal IgG , IgM THUS DEPLETE IGA)
pneumonia by lelves
encapsulated Increase ab as needed,
bacteria due to suspeecitbility to immunization, blood
absence of giardiaisis transfuio from igA def
secretory IgA. donor
Autimmune often form IgG
disease(celic diease) antibodies directed
Atopy (allergy, against IgA ( eg anti-
asthma,a atopic IgA

dermitis)anaphylaxis antibodies)>>>when
to igA containing transfused with blood
products which contain small IgA
they develop
anaphylactic reaction.
gamma-globulin
preperation should
not be used for
treatment of these
patients as it may
increase the
synthesis of anti-IgA
antibodies.
..........
ABOVE
EXPLANATION IS
WRONG>>now uworld
say its IgE antiboides
against IgA which
causes analphylaxis
1130
Common viarable immunodef Defect in b cell diff -Present after age 2 Decrease plasma Tx
CVID and may be delayed cells IVIG, antibiotics
-increase risk of Decrease
autoimmune immunoglobins
disease,
bronchiectaisis,
lymphoma,
sinopulm infection

nbme,11,3,50
Common variable
hypogammaglobuli
nemia, unknown
molecular defect,
onsets in late
teens, early
tewnties, B cells
presents in
peripheral blood,
immunoglobulin
levels decreased
with time,;
increased
autoimmunity, the
albumin can be
normal or low, but
the gamma globulin
always is low, this
curve is the same
for
Lymphoproliferative
disorders,
inflammatory bowel
disease, congenital
immunodeficiencie
s
T cell disorders T12EC
Thymic aplasia (digeorge 22q11 deletion Tetany Decrease T cells, Thymus fetal
rd
syndrome) fail to develop 3 and (hypocalcemia) decrease PTH, transplant
th
4 phayrgeal pouches Recurrent decrease Ca
Catch 22 -> absent thymus and viral/fungal Absent thymic NOT 14 weeks older
(cardiac, abdnormal faceies, parathyroid infections (t cel ldef) shadow on CXR thymus used as graft
thymic absence, cleft palate, Conotruncal vs host can occur
hypoca, chr 22) abnormalities (e.g
immunodeficiency wanes

tetralogy of allot as patient ages due to
,truncus arteriosus) maturation of T cell other
than thymus

Cardiac defects
associated with this
syndrome are Tetralogy
of Fallot and
interrupted aortic arch.
..........
aberrant formation
of mandible and
palalate (frequently
associated with
cleft palate) and
low set ear
IL 12 receptor def Decrease TH1 Disseminated non tb Decrease IFN
response (thus cant mycobacterial and gamma
(IL12 fct: cell med immunity limit mycobacterial fungal infection
(maturation of t cell into th1, infect), AR May present after
stim macrophage to secret IFN administration of bcg
gamma, activate NK cell) vaccine
Autosomal Def of TH17 cells due FATED Increase iGE
dominant hyper IgE syndrome to STAT3mutation Course facies Decrease IFN
(job syndrome) (abd JAK STAT Cold staph gamma
pathway) -> impaired abscess(non infl Increase eosinophls
recruitment of abscess on body that
neutrophil to site of is coo lto touch)
infection Retained primary
teeth ( 2 rwos of
teeth)
Increase igE
Dermatologic
problems (eczema)
Chronic mucutaneous T cell dysfunction Non invasive candida Absent in vitro t
candidiasis specifically for albicans infection fo cell prolif in
candidia skin and mucous response to candida
membrane antigens
Absent cutaneous
reactions to
candida antigens
B and T cell disorder SAMW
Severe combined immunodef Several type including Failure to thrive Decrease T cell treatment with retro viral
defective IL-2R Chronic diarrhea receptor excision gene therapy>>>transfer
gamma chain (most Thrush circules (TREC) geentic code for
commn, x linked) Recurrent viral, Absence of thymic adenosine deaminase.
OR bacteria, fungal, shadow (CXR), ..........
-lack gamma chain in protozoalinfections germinal centers ( retroviral vesctor are used
IL2 receptor on T cell lymph node becasie of the ability of
essential for Infections early at 3 biopsuy), retroviridae to
development of T cell months of age incorporate their
because both b and t Absent of t cell ( genome directly into the
Adenosine deminase c ells are defective flow cytometry) genome of infected
def (AR) human cells by the
-cause acc of dATP -> Other: action of the enzyme
inhbit ribonucelotide Eczematous integrase.
reductase -> thus dermatitis, sever
decrease deoxy seborrheic
Triphosphate ofor dna dermatitis, diffuse
aloepica, absent
also defect in MHC lymphatic tissue e.g
class II tonisils and thymus
.......
Null mutations in

rag1 or rag2 genes Tx: avoid live
No rag enzyme vaccines, give
activity. antimicrobial
AUTOSOMAL prophylaxis + IVIG
RECESIVE Bonem marrow
transplant curative
(no concern for
rejection )
Ataxia telangetisa Defect in ATM gene -> Triad: cerebellar Increase AFP
fail to repair ddna defect (Ataxia, spider Decrease IGA , IgG,
double strand breaks - angioma IGE
> cell cycle arrests (telangctsia), IgA def Lymphopenia,
cerebellar atrophy
autosomal Increase risk of
recessive. lymphoma and
DNA is leukemia
hypersensitive to
ionizing radiation
(X-RAYS) which
causes multiple
chormosomal
breaks
defect in DNA repair

enzyme>>>increase
risk of hematological
malignancies and
causes an immune
deficiency consisting
of both humoral and
cell-mediated
dysfunction.these
immune deficiency
primary manifests
as an IgA
deficiency.
Hyper igM syndrome Most commonly due Severe pyogenic Normal or increase Tx pooled gamma
to defective CD40L on infection, early in igM globulins
th cells -> clas switch lfie, opportunistic Decrease IgG, IgA,
dfect, x lnk recessive infection with IgE
pneumocytsiis, Fail to make
cryptosporidium, germinal centers
CMV
Wiskott ladrich syndrome Mutation in WASp WATER Decrease to normal
gene, leukocyte and Wiskott ladrich igG, IgM, increase
platlets unable to Thrombocytopenia igE, IgA
reorgniaze with Eczema recurrent Fewer and smaller
cytoskeleton -> pyogenic infections platelets
defective antigen Increase irsk of
presnation, x linked autoimmune dis ease
recessive and malig

onset of disease early
in
life>>>thrombocytopenia
present at birth, with
eczema and repeated
infection (encapsulated
org particularly) at 6-12
months of age.
........
recurrent infections that
worsen with age.
.........

treatment>>>HLA-
matched bone
marrow transplant
Phagocyte dyfunction
Leukocyte adhesion def type 1 Defect in LFA1 integrin Recurrenet skin and Increase neturophils
(CD18) protein on mucosal bact infection, Absence of neutrophisl at
phagocyte absent pus, impaired infection site
Impaired migration wound healing, delayed >
and chemotaxic 30 days separation of
AR umbilical cord
Chediak higashi syndrome Defect in lysosomal Recurrent pyogenic Giant granules in
traffing regulator gene infection by staph and granulocyte and platlets
(LYST) dstrep Pancytopenia
Microtubule Partial albimsim Mild coag defects
dysfunction in Peripheral neuropathy
phagosome lysosome Progressive neurodegen
fusion Infiltrative
AR lymphohistocytosis
Chronic granulomatous disease Defect of NADPH Increase susceptibility to Abd dihydrorhodamine
oxidase -> decrease catalase positive organism (flow cytometry) test
reactive oxygen (decrease green
speciesthese fluorescence)
oxidants has direct Nitro blue tetrazolium
microbicidal activity dye reduction test
and also function to (obsolete) fail to turnb
activate granule blue (DD: normal in MPO
proteases (eg def)
elastase and
cathepsin G) that Cytochrome c reduction
destroy engulfed test
pathogen. and (measure production fo
decrease resp burst in reactive oxygen specifes)
neutrophils

nd macrophage
phagolysosome.>>>
>increased risk of
fungal and bacterial
infection.
normal response to
virus and parasites.

X link recessive
bare lymphocyte syndome >>>immunodeficienc
y result from defect
in expression of
HLA class II
antigens on the
surface of antigen
presenting cell. MHC
class II is needed to
present foreign
antigen to T-cells to
elicit a cell mediated
and humoral
mediated response

Acq phagocyte dysfunction
Neutropenia Cause: Tx: ciprofloxacin
Cytoxic drug,
leukemia,
autoimmune
destruction of
neutorphils
Chronic fatigue s7dnrome

Complement def:
Hereditary Def of C1 inhibitor
angioedema
C1 -> act on C4 to gerneate c4a ->
Leads to capillary permeability and edme,a then laryngeal edema

Tx: e.g oxymetholone, danazol (increase concetriation of c1 inhibitor(
Recurrent infection Def in c1, c3 or c5 or c678

C3 def: susceptible to sepsis with pyogenic bacteria e.g s aureus

C6,7,8: prone to bacteria nwith n mengitis or n goneorrhea

NOTE:
Suprifecia candida in HIV: T lymphocyte ****
Systemic candida in HIV: NEUTROPHILS*

Blood transfusion reaction : AFAT

Pathogenesis Px Timing
Allergic/anaphylactic Type 1 hypersenstivity against Urticarial Within minutes to 2-3hour
plasma protein in transfused Prurtisis
blood Fever
Wheeze
IgA def indivudals must receive Hyptension
blood products without IgA Arrest
Shock
Febrile non hemolytic Type 2 hypersensitivity reaction Fever, headache, chill flushing Within 1-6 hour s
transfusion reaction
Host antibodies aginst donor
HLA atigens + WBC
Acute hemolytic transfusion Type 2 hypersensitivity reaction Fever, hypotension, tachypnea Within 1 hour
reaction tachycardia, flank pain,
Intra vascylar hemolysis (ABO hemoglobinuria (intravascular
blood group incompatibility) or hemolysis), jaundice
extra vascular hemolysis (host (extravascular)
antibody rxn a gainst foreign
antigen on donor rbc)
Tranfsuio nrelated acute lung Donor anti leukocyte ab against Resp distress and non Within 6 hours
injury receipeient neutrophils and cardiogenic pulm edema
pulm endothelial cell

ABO blood group/ftransfusion reactions:
Note:
All human erythrocyte contain: alloantigens (Antigen that vary among individual members of a species)
A and B genes:
Codominant genes: so people who inherit both are AB
Inherit either homozygous AA or heterozygous Ao are type A
Homozygous BB or heterozygous BO are type B
encode enzymes that add specific sugar to the end of a polysaccharide chain on the surface of man ycells incl red cells
erythrocyte have 3 terminal sgars in common: N acetylglucosamine + galactose + fucose -> all 3 form the H ANIGEN
type A: have N acetylglucosamine added to the galactose of the H antigen
B have galactose added to galactose of the H antigen
Type O DONT HAVE such genes and only have the H antigen

In summary
4 combinations of the A and B antigen:
A, B, AB, O
Determine by mix persons blood with antiserum against A antigen on ONE AREA, antiserum against B antigen on OTHER
If agglutination occur only with A antiserum then blood goru p is A
If it occurs with only B anti serum then blood group is B
If it occurs with btoh and b antisera, the blood group is AB
If occurs with neither A nor b anisero then O

Transfusion reaction noccurs when:
- Incompatiable blood donor (eg group A blood transfuse to group B BECAUSE anti A ab present -> thus red cell
antibody complex- > activate compelemnt -> thus reaction -> shock caused by large amounts of c3A, C5a,
c5,c6,c7,c8,c9 membrane attack compelx


TO AVOID TRANSFUSION REACITON,

- MATCH:
-defintion: erythrocyte are typed for their surface antigen by specific sera

NOTE:
maternal blood type A and B, isoimmunization does NOT occur as the naturally occurring antibody (ant A and B) are of IGM type which
cannot cross the placenta
type O mothers have ab that are igG type which can cross palcenta and cause hemolsys i
HOWEVER< ABO disease CAN occur with first preg because anti A and anti B ab are formed early in life from exposure to A or B like antigen
present in food bacteria, virus

RH blood type and hemolytic disease of the new born
type 2 hypersenstivity
Definition: destruct of fetal rbc by maternal anti rh (d antigen) igG ab that cross pplacenta
st
1 pregnancy:
-mother is Rh-, fetus is Rh +
-mother exposed to fetal blood at some point during preg or delivery and generate anti rh igG ab

nd
2 pregnancy
mother is RH- and fetus is RH+
maternal anti RH IgG corss placenta and ttach to fetal rbc
fetal splenic macrophage phocytose igG coated rbc

px:
severe eatal anemia after birth
jaundice (kernicterius(
generalized eema (hydrops fetalis due to hypoxic lvier and cardiac injury)
severe anemia (stim release of immature nucleated erythrocyte and lead to persistent extramedullary hematopeosis in liver, spleen,
hepatospelneomgy)

dx:
positive idriect and indirect comb test on cord blood

tx
prevent of initial rh exposure:
th
-rh neg mothers receive anti D globulin during 28 week of pregnancy + at delivery

-anti D globulin hemolzyes fetal RBC that enter maternal iruclation efore an immune eaction can be mounted against the Rh antigen thus
prevent form of anti rh IgG in mother

note uworld:
rhesus rh antigen is a group of non glycosylated transmembrane protein on surface of rbc
-d antigen is the most immunogenic of the roup and present on erythrocyte of rh positive
-when rh neg mother become pregnant with rh positive, fetal rbc can etner mat circulation and elicit a maternal igG ab response with form
of memory b lymphocyte (rh alloimmunization)
-risk of transplacental fetomaternal blood exchange inc with gestainoal age and higest during delivery

-to prevent mat rh alloimmunize, rh neg mother must be prevented from mounting an immune response against D antigen
-anti RH dD immune globilin is a polyclonal ab product consit of IgG anti D ab collect from pooled donor plasma
-it is routinely administered to Rh neg women at 28 weeks gestatino and in the immed post partum period
-it is administered to rh neg women at 28 weeks gestation and in immediate post partum period
-once gien, anti rhd ab bind to rh positive fetal ertyrhocyte that enter maternal cicurlcation thus preent their interaction with mat immune
system via sequesteration and elimaintino by mothers spleen
-administer of anti D igG ab during preg does not cause sig transplacental fetal hemolysis because the quantitiy of anti rh d admister is very
small compared to that produced in typical immune reaction

Immunosuprresntas

Cyclosporine

Mechanism Use: Toxcity
-Bind to calciphillin Transplant, psoriasis, RA, short and long 5H
-(cytosolic protein) term suppression of organ rejection in hirsutisim , hyperpplsia of gums,
-cyclosporin-cyclophillin complex -> bind transplant of kidney liver heart ( harm to kidney, ht, hyperglycemia
calcineurum inconbination with glucorticoid)
-(calcineurum fct: calcium depddent phosphatase,
activate transcription for il2 via transport NFAT to
nucleus by cleaving phosphate from NFAT-P) -> THUS
inhibit transport to nucleus of the transcription
factor NFAT
-> THUS block IL2

Tacrolimus

Mechnisim
Calcineurin inhibitor Organ rejection transplant (liver) Dm, neurotoxitiy

Bind FK 506 binding protein (FKBP) -> which NO gingivial hyperplasia or hirstuitism***
inhibit calcineurun-> prevent IL2
transcirption

Sirolimus (Rapamune/RAPAMYCIN)

Mechanism
M tor inhibitor Renal transplant only Pancytopenia
(as prophylaxis***) Insulin resistiance
Mtor (mammalian target of rapamycin) + Hyperlipid
bind to FKBP -> interfere with protein
biosynthesis -> delay G1-S transition -> NOT nephrotoxic
block t cell and b cell diff by preventing
response to IL2

Basiliximab/ daclizumab

mechanism
Block CD25 of IL-2R (Expressed on activated NOT FOR ACUTE REJECTION Edema, ht, tremor, sob, hypersenstiviity
t cell) For use as KIDNEY TRANSPLANT REJECTION
PROPHYLAXIIS NLY


Azathiopirine
Extra note:
-sphase specific
-supress t cell more than b cell, suppres marrow activity
-precusor for mercaptopurine (which is immunosuppressive)

mechanism use
Antimetabolite precursor of 6MP RA, chron, glmeurloenprhtis, autoimmne Pan cytopenia
condition
(6MP degraded by xo)
(toicity increase by allopurinol which
inhibit XO and requires decrease dosage )

Mycohenolate mofetil
Aw invasvive cmv infection
Mech
Inhibit imp dehydrogenase thus prevent Lupus nephritis Gi upset, pancytopenia, ht, hyperglycemia,
purine synthesis of b and t cells less nephrotoxic and less neurotxic

Corticosteroids

Inibit nf kappa B (protein complex that Cusjngoid Cushingoid
control transcritoin of dna, cytokine Cataract
production ) Ulcer
Striae
Hirsutism
Infection
Necrosis fo femoral head
Glucose elevate
Op
Psychosis
Diabetes

Recombinant cytokine and clinical use

Aldesleukin (IL2) Renal cell ca, metastatic melanoma Mechanism:
Inhibit IL2 thus inhibit nk, t, b, cells

Epoeitin alfa (erythropeotin) Anemia (esp renal failure)
Filgrastim (GCSF) Recovey of bone marrow and wbc count by
granulocyte stimulation
Sargramostim GM CSF

Recovery of bone marrow + wbc count y
granulocyte and monocyte
IFN alpha Cytokines which interfere with viral dna HBV, HCV, Kaposi , malig melanoma, hairy
rna synthesis + induce ribonuclease activity cell iekma, rcc, condyloma accuminata
to degrade viral mrna

Part of innate immune repsosne
Beta Ms
Gamma Chronic granulomatous disease
Romiplostim Thrombocytopenia
Eltrombopag Thrombopoetin receptor agaonist
Oprelyekin (IL11) Thrombocytopenia

Therapeutic ab
alemtuzumab Cd52 Cll, MS
Bevacizumab VEGF Colorectal cancer
Rcc
Non small cell lung cancer
Cetuximab EGFR Stage 4 colorectal cancer,head and neck
cacner

Rituximab Cd 20 B cell non Hodgkin lymphoma, cll, ra , itp
Transtuzumab Her2 neu Breast cancer, gastric cacner

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Immunology Usmle Hsu Notes PDF

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Hsu

notes usmle immunology

-region of cortex between follicle and medulla

-immunologic part of spleen

Antigen RER Acidified endosome**

DQ2, DQ8 Celiac disease I 8 2 much gluten at DQ

- CMV is the most significant opportunistic infection in lung transplant recipients

Azathioprine Inhibitor of dna synthesis and block growth of t cell

Receptor Killer activating receptor (KAR)

IL8 Macrophage Major chemotactic factor for neutrophil

Molecule on vascular/stroma Leukocyte

-chornic granulomatous disease, MPO def

-Chronic granulomatous disease (CGD):

nitroblue tetrazolium test (NBT)

-Myeloperodixase MPO def

-Catalse positive organisms:

-e.g staph aureas, aspergillus

-catalse degrades H2O2

Binds to complement proteins

Site of idiotype diversity Site of isotype diversity

2. allergic to neomycin, which vaccines are CI?

6. which live vaccines are ok in HIV? at what CD4 count?

7. An egg allergy may cause a reaction with which vaccines?

8. Who is eligible for HPV?

9. Dog bite in patient with Pn allergy. treatment?

2. allergic to neomycin, which vaccines are CI?

5. Which vaccine is indicated for travelers going to

6. which live vaccines are ok in HIV? at what CD4 count?

7. An egg allergy may cause a reaction with which vaccines?

8. Who is eligible for HPV?

9. Dog bite in patient with Pn allergy. treatment?

S [pneumonia PCV pediatric 13 capsular serotype

Bacteria Please SHINE my ks Sepsis Staph, burkhodleria Encap with early

defect in DNA repair

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