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Case Studies in Immunology 2008. (13) CVID TACI mutation 40 yo F w/ recurrent respiratory and GI infections Lower than normal levels of all Ig-subtypes.

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Presentation on theme: "Case Studies in Immunology 2008. (13) CVID TACI mutation 40 yo F w/ recurrent respiratory and GI infections Lower than normal levels of all Ig-subtypes."— Presentation transcript:

1 Case Studies in Immunology 2008

2 (13) CVID TACI mutation 40 yo F w/ recurrent respiratory and GI infections Lower than normal levels of all Ig-subtypes Normal B/T-cell count Unable to respond to pneumococcal vaccine Hx: Giardia infection, thyroid insufficiency (antithyroid Ab) Family Hx: CVID, GI cancer, non-Hodgkins lymphoma Mutation in TACI Tx: IVIg 35g q 2wks Most common primary immunodeficiency BAFF, APRIL in follicles (peripheral lymphoid) activate BAFF-R, TACI, BCMA receptors on B-cells to class switch to IgA and IgG and promote B-cell survival Mostly sporadic cases, 10% TACI mutation Unable to respond to APRIL, susceptible to pneumo-coccus, H. influenza Increased autoimmune, gastric carcinoma, lymphoma

3 (14) X-Linked SCID IL-2Rγ mutation 6 mo M has thrush, RSV, Pseudomonas aeruginosa No T-cells, low Ig levels Normal B-cell count, did not react to IL-2Rγ Unresponsive to PHA, ConA, PWM, immunizations Complete non-random X- chromosome inactivation Tx: IVIg, ribavirin, TMP-STX, maternal marrow graft SCID: Thrush, persistent cough, intractable diarrhea X-linked is different because B-cell count is normal Mutation in IL-2Rγ (Xq11) is also part of IL-7 involved in T-cell development Successful bone marrow graft yields normal life with Ig-therapy

4 (16) Omenn Syndrome missense RAG-1/2 mutation 1 mo M papular rash over body, palms, soles, purulent conjunctivitis Eosinophilia, high IgE No B-cells, little T-cells, no thymic shadow Hypoglobulemia 90% cells express MHC-II Missense RAG-1 mutation No Tx, died of P. carinii pneunomia Missense mutation in RAG allows partial ability for V(D)J recombination resulting in no B-cells, and few oligoclonal T- cells Can also be IL-7Rα chain deficiency, DNA repair, or V(D)J recombination protein Artermis Treat with bone marrow transplantation

5 (22) Wiskott-Aldrich Syndrome defective WASP protein 2 yo M with recurrent infections, eczema, asthma, bloody diarrhea Low, small platelet count Decreased IgM, increased IgA, IgE No immune response to PCV, PRP, TDaP, no T-cell response to ConA, PHA No Ab to blood group Ag Tx: Splenectomy, IVIg Abnormally small platelets Defective WASP on X- chromosome expressed in WBC and megakaryocyte do not initiate nucleation of actin affecting T-cell movement, cell division, Ag receptors, lose microvilli (bald T-cells) Little anti-polysacchride Ab Platelets destroyed in spleen Susceptible to pyogenic, opportunistic infections

6 (23) X-Linked Lymphoproliferative (XLP) SAP loss of fxn deletion (SH2D1A) 5 yo M with persistent unexplained fever, neck lymphadenoapathy High atypical lymphocytes, EBV infection Hepatomegaly Hx: recurrent otitis media, bacterial pneunomia Family hx of lymphomas, thrombocytopenia Tx: Acyclovir, IVIg, dexamethasone EBV infection w/ family hx SH2D1A gene (Xq25) encoding protein SAP have uncontrolled T-cell activation (inflammatory cytokines, hepatocyte Fas expression) Reduced capacity to kill EBV-infected B-cells leading to fulminant infectious mono by not activating SLAM family of receptors in NK cells when activated by infected B-cells (no killing)

7 (25) IPEX* missense mutation FOXP3 6 mo M with atopic dermatitis, diarrhea, diabetes, failure to thrive Brother died with diarrhea, low platelets Total villous atrophy, plasma, T-cell infiltrate Lack of CD4CD25 cells Tx: Immunosuppression, bone marrow transplant Mutation in FOXP3 causes loss of fxn in T reg cells which breaks self- tolerance, uninhibited T- cell activation and induces autoimmune disease Diarrhea, dermatitis, autoimmune diabetes, thrombocytopenia, anemia, hepatitis, hyper/hypo-thyroidism, food allergies *Immune Dysregulation, Polyendocrinopathy, Enteropathy X-Linked Disease

8 (28) Mixed Essential Cryoglobulinemia chronic hepatitis C infection 42 yo M with fatigue, hepatomegaly, multiple purpuric spots on legs Blood transfusion 20y ago Hepatitis C infection Positive for blood cryoglobulins Cyroglobulin are immune complexes can deposit on b.v. walls and activate compliment causing vasculitis, purpura; can deposit in joints and cause arthritis Can also be caused by multiple myeloma, Waldenstroms macroglobulinemia

9 (30) Lepromatous Leprosy Mycobacterium leprae 18 yo F hypopigmented lesions over both arms Family, home location history of leprosy Nosebleeds, loss of sensation in periphery Acid-fast bacilli in lesions Virchows foam cells No response to delayed hypersensitivity tests Tx: dapsone, clofazamine, rifampin Colonizes macrophages, grow best at 30C at extremities, defective T H 1 response leads to ineffective Ab response and no macrophage activation, dissemination leads to extensive tissue damage Neurological damage from Schwann cell infection and loss of myelin sheath Nosebleeds common

10 (31) AIDS human immunodeficiency virus 48 yo M diagnosed with HIV Tx: TMP/SMX for prophylaxis against P. carinii while CD4 T-cells are low, HAART therapy Caused by HIV-1, HIV-2 CD4 T-cells drops to 200-400 cells/uL level

11 (33) Allergic Asthma type I hypersensitivity rxn – iNK T-cells 14 yo M with persistent wheezing Hx: chronic asthma, rhinitis Family hx of asthma, allergic rhinitis Tx: albuterol, Intal, disodium cromoglycate, steroid, antihistamine Family history of allergies (atopy) iNK T-cells express NK receptors and TCR/CD3 with invarient antigen receptor that recognize glycolipid Ag presented by MHC-1b to generate cytokines (IFN-γ, IL-3, IL-13, TNF-α, IL-2)

12 (34) Atopic Dermatitis impaired cell-mediated immunity 2 yo M with worsening eczema Hx: numerous allergies Skin cultured S. aureus, S. pyogenes Family hx of allergy, actopic dermatitis Tx: oxacillin, anti-histamines, steroids, coal tar, avoid allergens Chronic itchy inflammatory skin disorder (10% children) Increased IgE levels (IL-4, IL- 13, influx of eosinophils) Impaired cell-mediated immunity (increased T H 2 CD4 cells) Defective skin barrier (mutations in FLG encoding fliaggrin essential to integrity of skin) Dendritic cells secrete IL-12 on IgE cross-linking inducing T- cells to secrete IFN-γ causing chronic lesions

13 (35) Drug-Induced Serum Sickness type III hypersensitivity rxn – penicillin 12 yo M with lobar pneunomia, treated with ampicillin Replaced with penicillin Developed puffy eyes, uticaria (hives), swollen face, wheezing Decreased serum complement components Tx: discontinue penicillin, give Benadryl, albuterol, naproxen, prednisone Antibiotics are the most common cause for serum sickness Large amounts of antigen and rapid IgG response form immune complexes (antigen excess) which are deposited in tissue and activate complement, also forming C3a and C5a and localized inflammatory responses

14 (36) Celiac Disease Gluten 1 yo F with distended abd, foul-smelling stool Positive for anti-gliadin IgA and IgG Ab Total villous atrophy Tx: Gluten-free diet Abd distension, diarrhea, malabsorp- tion, weight loss Gluten are modified by tissue transglutamase (TTG) making it antigenic, T H 1 cells secrete IFN-γ

15 (38) APECED* AIRE gene mutation 18 mo M with dry skin and lethargic movements, dx hypothyroidism Sister has parathyroidism, Graves disease Thickened fingernails with longitudinal notches and ridging, alopecia areata Developed Addisons disease and idiopathic thrombocytopenic purpura Autoimmune polyglandular syndrome Autosomal recessive inheritance AIRE protein is a transcriptional activator in the thymus, defect causes lack of self-antigen expression and increase in self-reactive T-cells Increased susceptibility to Candida albicans *Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

16 (41) Pemphigus Vulgaris autoantibody to desmoglein-3 55 yo M Ashkenazi Jew Numerous erosions and ulcers in mouth, skin Biopsy shows antibody against desmoglein-3 (pemphigus antibody) Tx: Prednisone, cyclophosphamide Autoantibodies (IgG4) binds to desmoglein-3 upregulates proteinase which digests desmoglein-3 and the epidermis loses integrity, blistering, septicemia Associated with Ashkenazi Jews (HLA-DR4 haplotype DRB1*0402)

17 (42) Rheumatoid Arthritis rheumatoid factor, TNF-α Morning stiffness >1 hr Arthritis of 3+ joints Arthritis in hand joints Symmetrical arthritis of the same joint areas Rheumatoid nodules Serum rheumatoid factor Radiographic changes Tx: MAb against TNF-α Strong association with HLA-DRB1*0404 and HLA- DRB1*0401 Female > male Thick synovial membrane, increased b.v. growth, inflammatory cells infiltrate TNF-α dominant cytokine

18 (44) Multiple Sclerosis T-cell mediated autoimmunity 29 yo F with sudden loss of vision in one eye Family hx of MS Developed CNVII weakness, L arm and leg weakness, nystagmus, ataxia, slurred speech Tx: IFN-β, corticosteroids, cyclophosphamide Multiple sclerotic (hard) plaques in white matter of CNS 10x female > male CNS Ag are presented in peripheral lymphoid activating auto-reactive T- cells initiating inflammation in the CNS Demylenation, interference with neuronal function

19 (45) Hemolytic Disease of the Newborn Rh antigen Mother: Blood A, Rh- Fetus: Blood A, Rh+ Indirect Coombs titer 1:8 and 1:16 Amniotic fluid bilirubin increasing, hemocrit from umbilical vein low Tx: Infuse type O, Rh- blood into umbilical vein Maternal IgG cross into placenta during second trimester, hemolyze fetal red blood cells Bilirubin in amniotic fluid corresponds with hemolysis in fetus All Rh- women given Rhogam at 28 wk and within 72 hr of delivery

20 (46) Kidney Graft and IDDM T-cell mediated autoimmunity - β islet cells 12 yo M frequent urination, thirst, weight loss, dx diabetes mellitus 35 yo develops renal complications, HTN, extensive diabetic glomerulosclerosis Kidney transplant, given cyclosporin, azathioprine, methylprednisolone, CD3 MAb when rejected Type 1 diabetes mellitus, IDDM, is T-cell mediated autoimmune attack on β islet cells of the pancreas If poorly controlled, kidneys are irreversibly damaged and requires dialysis, ultimately kidney transplantation

21 (47) Graft vs Host Disease graft T-cells attack foreign host 7 yo M with severe anemia, dx aplastic anemia Bone marrow transplant from brother 24 days later, skin rash, watery diarrhea, dx acute GVHD, tx tacrolimus Doesnt resolve, tx anti- CD3, anti-CD2 Bright red rash involving palms and soles, GI involvement leads to watery diarrhea Mature graft CD4 T-cells are activated and produce cytokine storm Test for alloreactive T- cells with mixed lymphocyte reaction Treat by eliminating the graft T-cells


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