Diseases of Immunity

Li Qun
2016.12.
 Contents
• Autoimmune disease
• Immunodefeciency disease
• Organ transplant rejection
 Teaching objective
• Autoimmune disease
• Immunodefeciency disease
• Organ transplant rejection

• Concept
• Mechanism
• Basic morphology &
types
 Concept of Immunity

immunis = excepta from “charges”

immunity = exempt from diseases

The ability of organism to keep homeostasis

by recognizing self or non-self and
eliminating the latter.
Epithelial barriers Effect components
skin, gastrointestinal tract, T lymphocytes
respiratory tract B lymphocytes
Effect components
neutrophils, macrophages , NK cell
complement system
 Cells taking part in Adaptive
Immune System
Cell Function
CD4 （ T Secrete cytokines to orchestrate all immune cells
T H ）

ce TH1 cell-mediated immune by activate Mφ & NK

ll TH2 Promote humoral immune
CD8 （ T Regulatory
Kill target cellT &
cell
Secrete cytokines
c）
Treg Modulate other T cells’ function
B cell Humoral immune (→ plasma cell →antibody)
Dendritic cell APC***
Macrophage APC and phagocytosis
 Chromosome 6
HLA
complex

CD4+ CD8+

Stereo
digram
Ideograph

• On APCs (DC, MΦ ） , • On all nucleated cells

BC • Bind to peptides
• Bind to peptides derived derived from proteins
from proteins synthesized within
synthesized outside the the cell (virus)
 Double Signals for Activation
B7
APC In peripheral blood

5% 95%
B1 C B2C

TH2 cell

CD40
L
CD40

TH CIndication: BC
•Adaptive immune system needs the help from innate
immune system
•The T or B cell will not be activated without signal 2
•B cell activation needsCostimulatory
the help from T H2 cell
molecules
 Immune Function
Allergy Autoimmune diseases

Rejection Defense
Homeostasis Surveillance
of ↓
↓ ↓
transplantation Microbes,
Aging & ill cell Mutant cell
Heterogens

Infection Tumor
 Abnormality of Immune
• Autoimmune diseases Organ/cell-specific
（ civil war ） Systemic

• Immunodeficiency diseases Primary

（ national power fading ） Secondary (AIDS)

• Transplant rejection Host versus graft

（ war against invader ） Graft versus host
Autoimmune Diseases
 Concept of Autoimmune Diseases
• Autoantibody and autosensitive lymphocytes react
to self-antigens ， and injure the self cell or tissue
resulting tissue and even organ dysfunction .

Note:
Autoantibody
Autosensitive T lymphocytes
≠ Autoimmune
disease
 Mechanism of T cell Tolerance

Central
tolerance
of T cells APOPTOSIS

Conclusion:
Normally ， there is no effective T
cell clone against to the self tissue
Peripheral
tolerance
SUPPRESSION
of T cells
ANERGY APOPTOSIS
Mechanism of Autoimmune Diseases
• Failure of tolerance
– Alteration of self-proteins (modification of
the molecule)
• Complex of self-antigens with drugs or micro-
organisms.

Clonal
anergy to React to “foreign
self-antigen antigen”
Mechanism of Autoimmune Diseases
– Imbalance of suppressor-helper T cell function
[T regulatory cell (Treg, CD4+CD25+)]
Mechanism of Autoimmune Diseases
– Hidden antigens exposure (enter blood)
• Isolated zone to immune: brain, eyes, testes, uterus.
• Cause of exposure: Trauma, infection, operation
• Example
– Thyroglobulin→thyroiditis
– Crystallin in eyes→sympathetic ophthalmia
– Sperm cell→male infertility

– Partial degradation of self antigens.

• Injury, infection
Mechanism of Autoimmune Diseases
– Cross-reactions (molecular mimicry)
connective tissue
B in cardiac muscle
Self
protein

streptococcal antigens M Th

Rheumatic fever
Mφ
 Mechanism of Autoimmune Diseases
– Polyclonal lymphocyte activation
(Antigen-independent mechanism)

Bacteria B cell
Anti-DNA Ab
B cell
Endotoxin
(lipopolysaccharide)
(+) Anti thymocyte Ab
B cell
Anti-red cell Ab
B cell
Mechanism of Autoimmune Diseases
• Genetic factors
– Familial clustering:
• SLE
• Autoimmune hemolytic anemia
• Autoimmune thyroiditis
– Linkage of autoimmune diseases with HLA
• HLA-B27—— ankylosing spondylitis
• HLA-DR2, DR3——systemic lupus erythematosus
• HLA-DR1, DR4 ——rheumatoid arthritis
Mechanism of Autoimmune Diseases

• Infection with autoimmunity

– Change self antigen
– Activate polyclonal lymphocyte
– Injury promotes the hidden antigen releasing

Note the effect of infection

on autoimmune diseases
Basic Characters of Autoimmune Diseases

1. High level autoantibody or autosensitive T

lymphocyte in blood;
2. The injury extent depends on the distribution of
autoantigen recognized by autoantibody or
autosensitive T lymphocytes;
3. Chronicity and recurrent attacks;
4. The turnover intimately related with the degree
of individual autoimmnue reaction;
5. Female patients are more than males.
 Types of Hypersensitivity and Effect
Involved Hyersensitivity Effect
elements Type
IgE Immediate I Vasopermeability ↑
antibody-depedent
bronchiospasm cell-mediated cytotoxicity
~
Mucous
complement-mediated secretion ↑
cytotoxicity
IgM Antibody- Ⅱ Target cell lysis （ CDC ）
IgG Mediated （ ADCC ）
Diseases Organ/cell dysfunction
IgG Immune Ⅲ Vasculitis Arthus reaction
Complement Complex Systemic immune complex diseases
s Diseases
NK
T cell T-Cell- IV Delayted hypersensitivity
Mediated (Granulomatous inflammation)
CDC
Autoimmune hemolytic anemia

MΦ
ADCC NK
Perforin
granzyme

Anti-
receptor
antibody

Hyperthyroidism
(Graves diseaes) Myasthenia gravis
CDC (complement-mediated cytotoxicity)

Autoimmune hemolytic anemia

The favored sites of
deposition:
Kidney
(Glomerulonephritis)
Jonits (Arthritis)

Fibrinoid necrosis

Vasculitis
Tuberculin reaction

Skin reaction
Rejection of
solid-organ
transplants

Type 1 diabetes
Classification of Autoimmune Diseases

• Organ/cell specific:
Special autoantigen in certain organ /cell

• Systemic:
Common component in many organs as autoantigen
 Examples of Organ/Cell Specific
Autoimmune Diseases
Disease Autoantigen Typ Clinical
e
Autoimmune Membrane protein of II Hematolysis
hemolytic anemia erythrocyte
Autoimmune Membrane protein of II Thrombocytopenia
thrombocytopenia platelet
Chronic lymphocytic Follicular epithelium IV Thyroiditis
thyroiditis * of thyroid
Graves disease * TSH receptor II* Hyperthyroiditis
Autoimmnue Microsome of II Pernicious anemia
atrophic gastritis * parietal cell
Chronic ulcerating Adenocyte of colon II Colonic ulcer, polyp
colonitis *
Type Ⅰ diabetes * Islet cell IV, II Hyperglycemia
Myasthenia gravis Acetylcholine II, IV Myasthenia
Systemic Autoimmune Diseases
• Concept: the autoantigen (nucleus or
mitochondria) exists in many organs or
tissues, the Ag-Ab complex deposit
extensively in vessel wall ( type Ⅲ ) of
involved tissues, result in inflammation
in multiple organs.
---- collagen disease
---- connective tissue disease (CTD)
Examples of Systemic Autoimmue Diseases
Disease Autoantigen Type Clinical
Systemic Lupus Nucleus, others Ⅲ,Ⅱ Mutiple organs
Erythematosus damage
Rheumatoid arthritis Synovium Ⅲ Multiple small
arthrositis
Sjogren‘s syndrome Glandular epithelium Ⅲ Dryness of eyes
& mouth
Multiple myositis Nucleus Ⅲ Myoasthenia
Dermatosclerosis Skin Ⅲ Skin atrophy &
fibrosis
Polyarteritis nodosa Vessel Ⅲ Arteriolitis
Systemic Lupus Erythematosus
 General features
• Multisystem disease
• F : M = 9 ： 1, young female preponderance
• Wide array of autoantibodies, ANA predominant
• Extensive vasculitis anti-nuclear antibody
• Progressive chronic course with repeat remitting
and relapse
• Pessimistic prognosis
 Etiology

•Hydralazine
hydrochloride
apoptotic •Procainamide
cells ？
•30% monozygotic •Estrogen
twins suffer from SLE •Ultraviolet
•Familiar aggregation
•HLA-DR2, DR3 Polyclonal B-cell
hyperactivity→
multi-autoantidies
Types of Autoantibodies in SLE
• ANA ( ＞ 95%)
– Ab to DNA (ds-DNA) (40-60%) ***
– Ab to histone (50-70%)
– Ab to nonhistone proteins bound to RNA
– Ab to core proteins of small nuclear ribonucleoprotein
particles (Smith Ag) (20-30%)
***
• Ab to blood cell
– Ab to granular leukocytes
– Ab to platelet
– Ab to erythrocytes
• Ab to smooth muscle
 Mechanism of tissue injury
•Type Ⅲ lupus body neutrophile

Antinuclear
antibody

Degenerative cell macrophage Lupus cell

complements

endothelial cell in glomerulus Vasculitis

•Type Ⅱ erythrocyte
Anemia

Lysis Granulocytopenia
Autoantibodies neutrophile
Thrombocytopenia
platelet
 • Lupus body
Big round like, violet blue

• Lupus cell
 Morphology
• Immune globulin, DNA
• Complement fragments
• Fibrin

Acute necrotizing vasculitis

Vessel wall fibrinoid necrosis
Perivascular leukocytic infiltration
↓
Thick wall & narrow lumen
↓
Tissue ischemia → Necrosis
 Morphology
• Skin (80%) ：
Vasculitis in dermis
↓
Erythema on skin
(epiderm atrophy,
hyperkeratesis,
liquefactive degeneration of
the basal layer)
↓
Erythema anywhere

“butterfly pattern” erythema on face

 Morphology
• Immune fluorescence
Dermoepidermal
IgG, IgM deposit at
junction
junction of derma
and epiderm
(granules or
clumping) Squamous
epithelium
—lupus band

Derm
 Morphology
• Kidney (50-60%) ： lupus nephritis
– Mesangial glomerulonephritis (10~15%)
– Focal proliferative glomerulonephritis (10~15%)
– Diffuse proliferative glomerulonephritis
(40~50%)
– Membranous glomerulopathy (10~20%)
↓
Chronic glomerulonephritis (Sclerosing GN)
 Focal glomerulonephritis
Two necrotizing lesions(↓)

Diffuse proliferative
glomerulonephritis

HE IMFL
 Morphology
• Heart (50%)
• Pericarditis
– Non-specific serous or
sero-fibrinous
inflammation
• Non-bacterial verrucous
endocarditis (libman-
Sacks endocarditis)
– 1~3mm warts on the
either surface of leaflets
of mitralis or tricuspid
Fibrin
Necrotic debris
Inflammatory cells
 Morphology
• CNS (50%) Vasculitis→ischemia→
– Focal neurologic deficit multifocal cerebral
– Neuropsychiatric symptoms microinfarcts
• Joints (90%)
– serous inflammation Ab to phospholipid
– Few with joint deformity Ab to synaptic
• Spleen membrane protein
– Follicular hyperplasia
– Numerous plasma cell (→IgG 、 IgM) in red pulp ；
– Central penicilliary arteries fibrosis ----onion-skin lesions
↓
– Moderately enlarged with thick capsule
 Clinical manifestations
• Laboratory diagnosis:
– ANA + (100%)
– Low serum complements levels
• Butterfly rash on the face
• Arthritis
• Hematuria & Proteinuria
• Nerve or psychiatric symptom
Principle of Therapy & Prognose
• Steroid & immunosuppressant.
• Survivals: 90% 5-year, 80% 10-year
• Major causes of death :
– Renal failure
– Intercurrent infection
– Diffuse central nervous system involvement
Rheumatoid Arthritis (RA)
 General features
• Predilection population: 25-55 y, F:M=3-5:1.
• Etiology: unclear.
Genetics / Autoimmune / Infection
• Characters of morphology:
– Symmetricly, mainly affecting the small joints.
– Chronic nonsuppurative proliferative synovitis
 Mechanism & Morphology
Antigen→APC B cell → plasma cell →autoantiboies
Macrophage
↓ (+) Neutrophiles
CD4+ T cell
↓
↓ Dense inflammatory cell infiltration
Cytokines Synoviocyte proliferation
Angiogenesis
Fibrosis &
Calcification Cartilage eroded→loss
Subarticular bone eroded
Permanent ankylosis
 Thick and
inflammatory
synovium

Normal joint Rheumatoid

joint
Low power:
Synovium
proliferation forming
villus

High power:
Synoviocyte hyperplasia
with abundant
lymphocytes ， macrop
hage, plasma cell &
vessels in interstitium
Arthrentasis Radiolgraphic hallmarks:
（ Chronic & progressive • joint fusions
• juxta-articular osteopenia
inflammation → joints
• loss of articular cartilage.
fused & deformity by • joint space narrowing
fibrosis)
 Clinical manifestations
• Repeated relapse of arthralgia→ankylosis
• General signs: weakness, malaise, low-grade
fever
• Laboratory diagnosis: Rheumatoid Factor
(+)
 Extra-articular changes
• Subcutaneous nodules (1/4 patients)
– oval / round, 2 cm in diameter, often be seen at
extensor of forearm.

Fibrinoid necrosis

Macrophages

Palisade-like rank
Granulation tissue
 Summary of Autoimmune Diseases
• All autoimmune diseases result from broken of
immunological homeostasis.
(autoantigen variation / cross-immune reaction / self-tolerance
loss→autoantibody & sensitive T cell →injury ）
• Chronic & repeat relapse.
• Most organ/cell specific autoimmune diseases refer to
typeⅡ (cytotoxicity ) or Ⅳ hypersensitivity
• Most systemic autoimmune diseases refer to type Ⅲ
(Ag-Ab complex deposit) or Ⅱ hypersensitivity
 Mini-test
• Once the autoantibody be detected in blood,
can the autoimmune disease be diagnosed.（ F ）
• The autoimmune diseases can be classified as
organ/cell and systemic ones. （T）
• Autoantigen specific exists in a certain organ
will cause either organ/cell or systemic
autoimmune diseases. （F）
• The mechanism of most systemic autoimmune
diseases is type Ⅲ hypersensitivity. （ T ）
Immunodeficiency Diseases
 Concept & Grouping
• Concept: the diseases caused by inherited
defects of immune system development
or by secondary effects of other diseases.
• Grouping:
– Primary (innate) immunodeficiencies
– Secondary (acquired) immunodeficiencies

humoral -
cellular -
combined -
 Manifestations of Different
Property of Immnodeficiency
• Humoral immunodeficiency ：
– Low production of antibody→ repeat bacterial infection
– No germinal centers in lymph tissue, also no plasma cell
– Low level of serum immunoglobulins

• Cellular immunodeficiency:
– Severe virus, fungi, endophyte and protozoon infection
– Poorly developed lymphoid tissue →weak / no delayed
allergies
– High incidence of autoimmune diseases & malignant tumors
 Primary Immunodeficiency
• Rare. Inherited, occur in infant, repeat
infected.
– Humoral immunodeficiency (50%)
– Cellular immunodeficiency (10%)
– Combined immunodeficiency (30%)
– Complements defect (4%)
– Phagocyte defect (6%)
 (adenosine deaminase) TH cell
activate B cell

(severe combined
immunodeficiency )

(common variable
immunodeficiency)
Secondary (Acquired) Immunodeficiency
• A little bit common
• Temporary or permanent
• No characteristic morphology
• Causes
– Infection (virus, bacterium)
– Malignant tumor (HL, Leukemia, myeloma)
– Autoimmune diseases (SLE, Rheumatoid arthritis ）
– Dystrophia (Immunoglobulin synthesize less or lose more)
– Lymphocytopenia
– Immunosupressive therapy
• Consequence ： opportunistic infection →death
Acquired Immunodeficiency
Syndrome (AIDS)
Organ and Bone Marrow
Transplantation
• Concept: implant the healthy cell, tissue or
organ into the body to replace the
irreversible organ injury.
• Types:
– Autotransplantation
Transplant organ/tissue
– Allogeneic graft in two individuals from
different animal species
– Heterotransplantation
 Autotransplantation

monozygotic twins

Allogeneic graft

Donator/receptor
HLA zygosity get closest

Transplant Rejection
 Types of Allogeneic Transplant Rejection
GVHD HVGR
(graft versus host disease) (host versus graft reaction)

Donator’ white blood cell Receptor’ white blood cell

HLA-A2 HLA-A1
Mechanism of Transplant Rejection

• One way rejection theory: natural pattern

– HVGR （ host versus graft reaction ）
(Solid organ graft)

– GVHD （ graft versus host disease ）

T-cell mediated rejection

Antibody mediated rejection
 DIRECT PATHWAY INDIRECT PATHWAY

Example:
HVGR
host CD28-B7 CD28-B7

graft

←graft→
• Two way rejection theory: manual intervention
pattern （ under continue immunosuppressant ）

Host Graft
HVGR GVHR
• Microchimerism: anergy of WBCs from both donor
& host (weak rejection to each other) →coexist of
donor/ host -- transplantation tolerance.
• Mechanism: immature dendritic cell (MHC±,B7-) →
T-cell apoptosis.
• What is the problem of transplantation
tolerance by using immunosspressant
continually?
– Repeat infection
– Malignant tumor
• What is the way to solve this problem?
– Stem cell engineering
 Pathological changes of entity
organ-graft rejection (eg. Kidney )
 Hyperacute rejection: Fast & Severe
• Time ： a few minutes to a few hours
• Precondition ：
– antibody-HLA to donator has exist in circulation of
receptor (repeat blood transfusion )
– inconsistant ABO blood groups (donator / receptor)
• Mechanism & morphology:
– Type Ⅲ (Ag-Ab complex deposit) → acute arteritis and
arteriolitis→ tissue ischemic necrosis
 Immune Frank acute Graft kidney
inflammation arteriolitis is eliminated
in kidney in short time

Complement

Ag graft
Ab Tissue ischemia

Neutrophile Endothelial cell injury Multiple

Thrombosis small
Fibrinoid necrosis cagulative
necrosis
Endothelial damage, platelet
and thrombin thrombi in a
glomerulus

Immune complex
vasculitis, many leucocytes
in lesion

Gross: dark red, mottled,

enlarged, soft
Clinic: anuria/hemoturia
 Acute rejection: Common.
• Time ：
– after some days (without immunosuppressant)
– months or years later (with immunosuppressant)
• Mechanism:
– Cell-mediated immunity
– Humoral immunity
• Morphology:
Type Ⅳ
Extensive interstitial monocytes
infiltration with edema & mild
interstitial hemorrhage.
Type Ⅲ
vasculitis →proliferating
fibroblasts & foamy
macrophages block the
lumen

Glomeruli (◆) & tubules (▲) degeneration or necrosis.

Gross view:
Enlarged kidney,
spots of bleeding
& infarction,
many clots in the
renal calices and
pelvis

Oliguria → Anuria
Poor effect of
immunosuppressant
 Chronic rejection:
• Time: months to years late.
• Mechanism: an ongoing healing response
• Morphology:
– Microscope:
• Arteries & arterioles narrow or blocked by intimal
smooth muscle cell proliferation and extracellular
matrix synthesis ;
• Interstitial fibrosis;
• Loss of renal parenchyma.
 Interstitial fibrosis

Vessel intima
proliferation
& fibrosis, the
lumen nearly
closed.

Monocytes
infiltration in
interstitium &
vessel walls

Tubular atrophy Hyalinized glomerulus

 – Gross view ：
• Atrophic kidney with more or less small scars
• Thick and accretion capsule
• Clinical:
– Progressive rise in serum creatinine
(progressive renal dysfunction concordant
with worse morphology)
 Pathological changes of marrow
graft rejection
• GVHD graft versus host disease ***
• HVGR host versus graft reaction

Deplete all Transfuse

bone graft bone
marrow marrow
cells of host stem cells
 GVHD
T-cell Donor marrow stem cell B –cell

CTL , Cytokines Host cells Antibodies

with host (Humoral
(Cell-mediated
HLA immunity)
immunity)

• Fever , Weight loss

• Exfoliative dermatitis
• Intestinal malabsorption
• Pneumonia
• Splenohepatomegalia
 HVGR
Host
T-cell NK cell

HLA
Donor marrow stem cell

Marrow transplantation failure

Summay for Transplant Rejection
• Transplant rejection happens based on the host
normal immune function.
• Both donor & host immune system aim at other
side HLA antigen.
• Transplant rejection involves to the type Ⅲ, Ⅳ
hypersensitivity.
• Allogeneic graft in different cases may cause
different outcomes.
Host Donor
immunocompetence cell immunocompetence cell

HVGR GVHD

Graft survival
(microchimerism)
Different outcomes after allegic transplatation