Case Studies in Immunology

2008

(13) CVIDTACI 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-Hodgkin’s 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

(14) X-Linked SCIDIL-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

(16) Omenn Syndromemissense 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

(22) Wiskott-Aldrich Syndromedefective 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

(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)

(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 Treg 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

(28) Mixed Essential Cryoglobulinemiachronic 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, Waldenstrom’s macroglobulinemia

(30) Lepromatous LeprosyMycobacterium 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• Virchow’s foam cells• No response to delayed

hypersensitivity tests

• Tx: dapsone, clofazamine, rifampin

• Colonizes macrophages, grow best at 30⁰C at extremities, defective TH1 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

(31) AIDShuman 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

(33) Allergic Asthmatype 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)

(34) Atopic Dermatitisimpaired 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 TH2 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

(35) Drug-Induced Serum Sicknesstype 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

(36) Celiac DiseaseGluten

• 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, TH1 cells secrete IFN-γ

(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 Addison’s 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

(41) Pemphigus Vulgarisautoantibody 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)

(42) Rheumatoid Arthritisrheumatoid 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

(44) Multiple SclerosisT-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

(45) Hemolytic Disease of the NewbornRh 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

(46) Kidney Graft and IDDMT-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

(47) Graft vs Host Diseasegraft 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

• Doesn’t 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