Diseases to Know

B Cell Diseases
• Case 10: X-linked Agammaglobulinemia
o Caused by a gene defect
 Encodes a cytoplasmic protein tyrosine kinase called Bruton’s
tyrosine kinase (Btk)
• Its activated at different stages of B cell development and is
necessary for survival of mature B cells
o Bcell development is arrested @ pre B stage
o Symptoms include:
 Lack of mature B cells
• Test for cells with CD19 (a B cell marker) using Flow
cytometry
 Succeptible to bacterial infections
 Not succeptible to viral / intracellular bacterial infections
• Th1 (cell mediated response) still functions
o Treat with IVIg

• Case 12: Activation-Induced Cytidine Deaminase (AID) Deficiency

o Caused by a defective AID protein
 Protein involved in Ig class switching
 Results In Hyper IgM syndrome (autosomal, not x-linked)
o Inability of B cells to class switch from IgM or D
o B cells can’t undergo somatic recombination or somatic hypermutation
without AID
o Selective IgA deficiency
 Inability to class-switch to IgA
 DO NOT treat with IVIg
• Can form Ab against IgA
• Case 13: Common Variable Immunodeficiency (CVID)
o Characterized by the inability to produce adequate levels of Ig’s of any
class
 Many different types (different causes)
 Inability to differentiate B cells
o low humeral immune response in general
o treat with IVIg or SCIg (sub cutaneous Ig)

• Heavy Chain Deletions

o Deletion of heavy chain genes
o Results in inability to produce that Ig isotype
 Diseases to Know
T Cell Diseases
• Case 11: X-linked Hyper IgM Syndrome
o Caused by a defect in the gene for CD154 (CD40L)
 Located on the X chromosome @ Xq26
 Involved in B cell Ig class switching, and activation of
macrophages
o Symptoms include:
 Inability of B cells to class switch from IgM or D
 Activated T cells do not express CD154
• CD25 is expressed on actiated T cells
 Effects both humeral and cell mediated responses
• Inability to effectively opsonize with IgG
o Increases bacterial infections (mostly G+)
• Opportunistic infections arise
 Low levels of neutrophils
• due to the inability of T cells to stimulate macrophages to
secrete GM-CSF
• causes sores and blisters in mouth and throat

• Case 22: Wiskott-Aldrich Syndrome

o Inability of T cells to reorganize actin cytoskeleton
 Affects cell to cell interactions
• Th—Bcell
• Tc—Target cell
 Affects ability to target cytokines to the bound cell
 Affects cell movement (diapedsis)
o Xlinked recessive
o Gene encodes Wiskott-Aldrich Syndrome Protein (WASP)
 Protein only found in WBC and megakaryocytes (souce of
platelets)
 Homologous to other proteins associated with cytoskeleton
reorganization in non-wbc’s
o Symptoms include
 Small platelets
• Clotting problems
 Bald Tcells (no surface structures)
• Low Ab levels
• Increased infections of all kinds

• ZAP-70 Deficiency
o CD3/TCR signaling is mediated by ZAP-70
o CD8+ cells are absent (unknown reason)
o Fatal unless treated with BoneMarrow transplant
 Diseases to Know
• CD3 Deficiency
o Mutations in CD3ε CD3γ or CD3δ chains
o Results in reduced # of T cells
o Variable effects on T cell function
o Often CD3 still functions due to ability of other chains to compensate for
the mutation


SCID’s
• Purine Nucleoside Phosphorylase Deficiency (PNPD)
o Similar to ADA Deficiency (case 15)
o Toxic metabolites build up and kills T cells
 Not toxic to B cells (ADAD is toxic to B cells)
o Can treat with PEG-PNP or BM transplant

• JAK3 Deficiency
o Jak-stat signaling is used by cytokine receptors
o Janus Kinase 3

• Case 14: X-linked Severe Combined Immunodeficiency (SCID)

o Defects in cytokine-mediated signals for lymphocyte maturation and
proliferation
 This is the X linked form of the disease
• Gene is for the γ-chain of the IL-2 receptor on T cells
• Found on long arm (Xq11)
• The γ-chain is also a component of:
o IL-4, IL-7, IL-9, IL-15, IL-21
o IL-7 is involved in T-cell development
• Symptoms Include:
o Crippled immune response, both cell mediated and
humeral
 Normal levels of B cells, but low T cells
o Thrush in mouth and throat
o Severe Diaper rash
o Prone to any type of infection
• Needs a bone marrow transplant from an HLA identical
sibling

• Case 15: Adensine Deaminase Deficiency

o A type of SCID
o ADA gene is on C20
 Condition is autosomal recessive
 Diseases to Know
o Due to build of adenosine and deoxy adenosine
 Toxic to lymphocytes B and T
o Symptoms include:
 No thymic shadow
 Abnormal rib structure
 Crippled immune system
• Thrush
• All types of infections
o Can treat with:
 PEG-ADA
 Bone marrow transplant

• Case 16: Omenn Syndrome

o A type of SCID
o Defective RAG proteins
 Responsible for VDJ rearrangements in Ig’s and TCR’s
o Sometimes RAG proteins are partially functional
 They can rearrange only to a specific Isotype
o Typical SCID symptoms:
 Crippled Immune system
 Opportunistic infections

Naked Lymphocyte Syndrome

• Case 17: MHC Class I Deficiency (Naked Lymphocyte Syndrome I)
o Results in mutated TAP gene
 Antigen could not be loaded onto MHC I in the ER
 Symptoms are”
• High level of viral infections
• Low level of CD8 T cells
o Because of the abscense of MHC I during T cell
development

• Case 18: MHC Class II Deficiency (Naked Lymphocyte Syndrome II)

o Due to defects in the Txpn factors that govern the expression of the HLA
genes
 Symptoms include
• Decreased Th1 and 2 responses
• Low # of CD4 T cells
• Normal # of CD8 T cells
• No graft rejection
o Because the patient never had a MHC II to cause
the rejection
• Patient needs a bone marrow transplant
 Diseases to Know
Cancer
• Case 19: Multiple Myeloma
o Caused by a cancerous Plasma cell
o Symptoms Include:
 Bence-Jones Proteins
 Bone Lesions
 High mAb levels

• Case 20: T cell Lymphoma

o Caused by a Double positive Tcell precursor tumor
o The tumor occurs in the thymus
o High levels of IL-4 are produced by the tumor
 Causes Eosinophils to differentiate from marrow
 Causes IgE to be secreted in high levels

Overactive Immune Diseases

• Case 24: Autoimmune Lymphoproliferative Syndrome (ALPS)
o Mutated FasL gene (this is a dominant inheritance pattern)
 Heterozygous individuals have the disease
o T and B cells accumulate, because they can’t enter apoptosis
 Caused by a nonfunctioning Fas / Fas ligand interaction
o High levels of Ab result
o Enlarged spleen and lymphnodes due to excessive T and B cells
 Large # of DN CD3+ Tcells
o Prone to autoimmune problems due to high levels of Ab

• Case 25: Immune Dysregulation, Polyendocrinopathy, Enteropathy X-

linked Disease (IPEX)
o Characterized by an overactive immune system
 Caused by a mutated Foxp3 gene
• A txpn factor that is only found in Treg cells
 Treg cells are unable to down regulate Tcell immune responses
• Can’t secrete IL-10 or TGF-β

• Case 32: Acute Systemic Anaphalaxis

o Type I hypersensitivity rxn
 mast cell bound IgE binds antigen
 mast cell degranulates
 blah blah blah blah

• Case 33: Alergic Asthma

o See above
 Diseases to Know
• Case 34: Atopic Dermatitis
o Type I hypersensitivity

***Cases 32, 33, and 34 are all the same, they just differ based on the way the antigen is
introduced: (32 = injested, 33 = inhaled, 34 = skin surface)

• Case 35: Drug-induced Serum Sickness

o Kid received large intravenous injection of penicillin and ampicillin
 Type III Hypersensitivity rxn
 IgG bound to the antibiotic and formed small complexes
 The complexes travel to various tissues and induce complement
mediated inflammatory responses

• Case 36: Celiac Disease

o Caused by a reaction to Gluten
o Gluten is injested and digested into small peptides
 One specific peptide is immunogenic (it remains long enough)
o In the small intestine the peptides pass through the intestinal wall, where
they are phagocytized and presented on MHC II to Tcells
o The then cause an inflammatory response in the small intestine near the
duodenum

• Case 37: Contact Sensitivity to Poison Ivy

o Type IV hypersensitivity
o Caused by active compound in poison ivy (catechol)
o Catechol alters the structure of surface proteins on skin cells
o These cells are phagocytized and presented on MHC II to T cells
o T cells then circulate until they are stimulated by the altered surface
proteins
o Then start a inflammatory response
o Takes about 2 days
o Can occur on first exposure

• idiopathic Thrombocytopenic Purpura

o type II hypersensitivity
o caused by antibodies against platelets

• GoodPasture’s syndrome
o Antibodies against kidney cells
 Glomerular basement membrane
o Type II hypersensitivity

Autoimmune Diseases
 Diseases to Know
• Case 38:Autoimmune Polyendocrinopathy-candidiasis-Ectodermal
Dystrophy (APECED)
o AIRE (stands for AutoImmune REgulator) gene is mutated
 This gene is a txpn factor that up regulates txpn of many organ
specific genes in the medulla of the thymus
 Functions in educating Tcells in self-tolerance
o Autosomal recessive
o Results in many autoAb’s being formed to various different self-antigen
o Also succeptible to candidiasis and ectodermal abnormalities
 Abnormal fingernail growth

• Case 39: Autoimmune Hemolytic Anemia

o Type II hypersensitivity rxn
o Molecular mimicry ab against mycoplasma also binds to RBC
o Ab bind to rbc’s and initiate complement
 Lysis of RBC’s = Anemia

• Case 40: Myasthenia gravis

o Caused by production of antibodies to the acetylcholine receptor at the
neuromuscular junction
 Blocks acetylcholine from binding
 Causes impared muscle movement
o Symptoms include:
 Impared eye movement

• Grave’s Disease
o Autoimmune disease where ab are targeted against the tyroid

• Case 41: Pemphigus Vulgaris

o Autoimmunity against desmoglein-3 (structural protein of epidermal skin
cells)
 Causes skin cells to come apart
 Formation of blisters and eventual destruction of cells
o Complement is not activated, because the disease is IgG4 mediated
 IgG4 doesn’t fix complement
o It is thought that Ig binding causes an upregulation of serine proteinase
 Serine proteinase digests desmoglein-3

• Case 42: Rheumatoid Arthritis

o Type IV hypersensitivity attack
 T cell mediated
o Caused by immune attack on synovial tissues of joints
o Unknown antigen

• Case 43: Systemic Lupus Erythematosus

o Caused Autoimmunity to dsDNA or snRNP’s
 Diseases to Know
o Ab complexes get trapped in synnovial fluid and in the kidney
 Joint pain and kidney glomerunephritis result
• Mediated by complement activation by ab complexes
o Symptoms include:
 Joint pain
 glomerunephritis
 butterfly rash on face
• due to UV damage to cells
o UV damage releases dsDNA so Ab can access it

• Case 44: Multiple Sclerosis

o Tcell mediated attack of microglia of the brain/CNS
 Previous injury (trauma) causes the release of CNS antigen to the
Blood (usually Tcells do not go into the CNS, so they are not
educated in the thymus for self-CNS antigen
o Th1 cells infiltrate the brain and cause inflammatory response, which via
some unknown path, causes the degeneration of neural function

• Case 45: Hemolytic Disease of the Newborn

o Occurs when Rh- mother has Rh+ baby
o Mothers anti-D IgG crosses the placenta and binds to baby RBC’s and
sequesters complement
 Must be the 2nd Rh+ baby

• Case 46: Kidney Transplant from Type I Diabetis meilitis

o Type I diabetis caused by autoimmine tcell mediated killing of beta cells
in the islets of langerhans of the pancrease
 Antigen unknown

• Case 47: Graft-Versus-Host Disease

o Donated marrow has competent T cells in it
o The recipient’s leukocytes have been destroyed so as to avoid graft
rejection
o The donated T cells proceed to attack any cells that express MHC
molecules (they interpret them as foreign).
 Donor T cells also secrete IFN-γ which makes the situation worse,
because it upregulates MHC expression on recipient’s native cells.

Secondary Immune Diseases

• Case 26: Toxic Shock Syndrome
o Caused by super antigens
 Stimulate CD4 Tcells (~10-20%)
• Causes a unregulated amount of cytokines to be released
o IL-1, TNFa, IL-2
 Diseases to Know
 All cause acute phase response
 Secreted by many G+ bacteria
o Symptoms Include:
 Rapid onset fever
 rash
 organ failure
o Typically associated with a localized S. aureus infection

• Case 27: Acute Infectious Mononucleosis

o Facilitated By Epstein-Barr virus
 Virus infects B cells and causes them to divide
• Binds to CD21
 Promotes the secretion of IL-10
• Inhibits Th1 response
o Symptoms Include:
 Swollen secondary lymphoid tissues
 Loss of apetite
 Presence of atypical lymphocytes in the blood
• Known as Downey-McKinlay cells
o Large cells w/ foamy basophilic cytoplasm and
fenestrated nuclei.

• Case 29: Rheumatic Fever

o Autoimmune disease triggered by streptococcal infection
o Molecular mimicry causes immune response
 M proteins from Strep have identical aa sequences to myosin and
tropomyosin of cardiac muscle.
o Casues cardiac inflammation via immune attack

• Case 30: Lepromatous Leprosy

o Caused By Mycobacerium leprae
o Can result in 2 different clinical manifestations
 Tuberculoid leprosy
• Present along with a vigorous cell-mediated response
• Milder clinical symptoms
 Lepromatous leprosy
• Presents with a strong Th2 response
• Causes skin lesions and much more severe clinical
symptoms
o Due to the fact that M. leprae is an intracellular
pathogen
o Therefore Ab are not effective
o Neurological damage due to M. leprae infected
schwan cells (insulators on axons)
 Diseases to Know
Complement Diseases
• Hereditary Angioedema
o Caused by C1 inhibitor deficiency
o Autosomal dominant
o Results in swelling of hands feet and face
 Swelling is mainly the result of bradykinin release
 Reduced levels of C4

• Paroxysmal Nocturnal hemoglobinuria

o Caused by mutated GPI (glycosylphosphatidylinositol) tail
 GPI tail is involved with DAF (decay accelerating factor) and
CD59 (Protectin) in the inhibition of complement activation
against host cells
• GPI tail links CD59 & DAF to cell surface
o Results in RBC Lysis via complement

Other Immune Diseases

• DiGeorge Syndrome
o Abnormal Development of 3rd and 4th pharyngeal pouches
 Results in abnormal Thymus Development
 Caused by deletion on 22 chromosome
• Responsible gene is unknown
o Symptoms include:
 Facial abnormalities
 Severity of symptoms can vary

• Ataxia Telangiectasia
o Inability to Repair Damaged DNA
o Caused by mutated ATM gene
 Gene product is involved in DNA repair
o DNA damage in the Ig genes and TCR genes is common
 Due to somatic recombination events
o Symptoms include:
 Multisystem disorders
• Neurologic impairment
• Dialated vessels in the Eye
o Spider veins
• Sensitivity to X-Rays
 Immine system disorders
• T cells are decreased
 Diseases to Know
• B cells are normal
o But low IgA, E, G levels

• Job’s Syndrome
o Cause Unknown (likely mutation in STAT3)
o Characterized by:
 Lack of Th17 cells
• Involved in Neutrophil recruitment
 Linked to a lack of IFN-γ

• Leukocyte Adherence Deficiency

o Inability of phagocytes to enter the site of infection
o Lack of adhesion molecules necessary for diapedesis

• Cronic Granulomatous Disease

o caused by mutations in proteins responsible for producing ROI’s
 results in the inability to kill pathogens
 Granulomas form due to chronic inflammation

• Chediak-Higashi Syndrome
o Autosomal recessive
o Mutation in LYST gene = involved in intracellular protein transport
 Causes an inability to form phagolysosome
 Results in hypopigmentation
• Defect in melanization of melanosomes
o Often results in death at early age
 Due to infection