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

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 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.

IL-21 o IL-7 is involved in T-cell development • Symptoms Include: o Crippled immune response. 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 • 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. both cell mediated and humeral  Normal levels of B cells. IL-9. IL-7. IL-15.

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 • .

Enteropathy Xlinked 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 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.

33. 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 34: Atopic Dermatitis o Type I hypersensitivity ***Cases 32. they just differ based on the way the antigen is introduced: (32 = injested. 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. and 34 are all the same. 33 = inhaled.

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 • 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.

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). because it upregulates MHC expression on recipient’s native cells. causes the degeneration of neural function Case 45: Hemolytic Disease of the Newborn o Occurs when Rh. TNFa. which via some unknown path. IL-2 .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.  Donor T cells also secrete IFN-γ which makes the situation worse. so they are not educated in the thymus for self-CNS antigen o Th1 cells infiltrate the brain and cause inflammatory response. • • • 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.

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. 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 • • • . E.

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