Hypersensitivity & Immune Disorders

• Type I (immediate) – IgE–mast cell/basophil mediated
• Cross‑linking of IgE → FcεRI → degranulation
• Mediators: histamine, heparin, ECF‑A, LTB₄, PGD₂, PAF, LTC₄/LTD₄
• Eosinophil influx amplifies late‑phase response
• Systemic: anaphylaxis (e.g. bee sting, drugs)
• Local: atopy, asthma, food allergy
• Type II (antibody‑mediated) – IgG/IgM against cell/tissue
• Complement‑dependent lysis / opsonization
• Examples: autoimmune hemolytic anemia, transfusion reaction, erythroblastosis fetalis
• ADCC (antibody‑dependent cell‑mediated cytotoxicity)
• Example: pernicious anemia
• Antireceptor antibodies (agonist or antagonist)
• Graves disease (TSH receptor activation)
• Myasthenia gravis (AChR blockade)
• Type III (immune complex) – Ag–Ab complexes deposit in tissues
• In situ or circulating complexes → complement activation → inflammation
• Examples: serum sickness, SLE, glomerulonephritis
• Type IV (cell‑mediated) – T‑lymphocyte driven
• Delayed‑type (CD4⁺ Th1) – granuloma formation
• PPD skin test, tuberculosis
• Cytotoxic (CD8⁺) – direct target cell killing
• Type 1 diabetes, virus‑infected cells, tumor antigens, graft rejection

• SLE (systemic lupus erythematosus)
• F:M = 9:1; peak 20–45 yr; more common in African Americans
• Mixed type II & III hypersensitivity
• Autoantibodies: ANA (>95%), anti‑dsDNA (40‑60%), anti‑Sm (20‑30%), antihistone, anti‑Ro/SS‑A
• Organ involvement:
• Hematologic (type II): hemolytic anemia, thrombocytopenia, neutropenia, lymphopenia
• Skeletal (type III): polyarthralgia, synovitis (no deformity)
• Skin (type III): malar rash, maculopapular, ulcerations
• Serosal (type III): pericarditis, pleuritis, effusions
• CNS (type III): seizures, psychosis, focal deficits
• Cardiac (type III): Libman‑Sacks endocarditis (nonbacterial verrucous)
• Renal (type III) – ISN/RPS classes:
• I: minimal mesangial
• II: mesangial proliferative
• III: focal (<50%)
• IV: diffuse (>50%)
• V: membranous
• VI: advanced sclerosing
• Treatment: steroids + immunosuppressives
• Prognosis: 10‑yr survival ~85%; death from renal failure or infection
• Sjogren syndrome (sicca)
• Destruction of lacrimal & salivary glands → dry eyes (keratoconjunctivitis sicca), xerostomia
• Associated with RA and other autoimmune diseases
• Autoantibodies: anti‑SS‑A (Ro), anti‑SS‑B (La)
• ↑ risk of non‑Hodgkin lymphoma
• Scleroderma (progressive systemic sclerosis)
• Fibroblast activation (IL‑1, PDGF, FGF) → collagen deposition
• Diffuse: anti‑Scl‑70 (topoisomerase I), widespread skin + early visceral (esophagus, GI, lung fibrosis, heart, kidney)
• Localized (CREST): anti‑centromere, face/hands, late visceral, benign course
• CREST: Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia
• Mixed connective tissue disease – overlap SLE/scleroderma/polymyositis; anti‑RNP positive

• Primary (congenital)
• X‑linked agammaglobulinemia (Bruton) – BTK mutation → no mature B cells; recurrent pyogenic infections after 6 mo (H. influenzae, S. pneumoniae, S. aureus)
• Common variable immunodeficiency – B‑cell maturation defect; low IgA/IgG; recurrent sinopulmonary + Giardia; ↑ autoimmunity, NHL, gastric cancer
• DiGeorge syndrome – 3rd/4th pouch failure → absent thymus/parathyroids; hypocalcemia, tetany, T‑cell deficiency; viral/fungal infections
• SCID – combined T‑cell & B‑cell defect
• X‑linked: γ‑chain mutation (IL‑2,‑4,‑7,‑9,‑15,‑21 receptors)
• Autosomal recessive: ADA deficiency → deoxyadenosine accumulation
• Susceptibility: Candida, CMV, Pneumocystis; fatal without HSCT
• Wiskott‑Aldrich – X‑linked WASP mutation; triad: infections, thrombocytopenia, eczema; ↑ NHL; treat with HSCT
• Complement deficiencies
• C3: recurrent pyogenic + immune complex disease
• C5‑C8: recurrent Neisseria (meningococcal/gonococcal)
• C1q/C1r/C1s/C2/C4: immune complex disease + pyogenic
• Factor B / properdin: Neisseria
• C1‑INH deficiency: hereditary angioedema (low C2, C4)
• MHC class II deficiency – few CD4⁺ T cells; mutations in CIITA etc.
• Hyper‑IgM syndrome – CD40L mutation (X‑linked); normal/elevated IgM, low IgA/IgG/IgE
• Selective IgA deficiency – undetectable IgA; sinopulmonary infections, diarrhea, transfusion reactions; association with autoimmunity
• Secondary (acquired) – more common; caused by DM, collagen vascular disease, chronic alcoholism, etc.

• HIV biology
• Enveloped RNA retrovirus; reverse transcriptase
• Targets CD4⁺ cells: T‑cells, macrophages, follicular dendritic cells, Langerhans
• Entry: gp120 binds CD4; gp41 + coreceptors CCR5 (M‑tropic) or CXCR4 (T‑tropic)
• Transmission – sexual (most common), parenteral (IVDU, blood products, needlestick), vertical
• Diagnosis – CDC algorithm: Ag/Ab combo immunoassay → confirmatory HIV‑1/2 antibody differentiation; if negative → HIV‑1 NAT
• Clinical phases
• Acute: viremia, mononucleosis‑like symptoms, lymphadenopathy, seroconversion
• Latent (avg 10 yr): asymptomatic or persistent generalized lymphadenopathy; low blood virus; minor OIs (oral thrush, herpes zoster)
• AIDS: CD4 <200 cells/µL; viremia; AIDS‑defining conditions
• Opportunistic infections (common sites)

• AIDS‑defining diseases (regardless of CD4)
• Hairy leukoplakia (EBV) – white tongue plaques
• Kaposi sarcoma (HHV‑8) – most common AIDS neoplasm
• Non‑Hodgkin lymphoma (high‑grade B‑cell, extranodal CNS)
• Cervical cancer, HIV‑wasting syndrome, AIDS nephropathy, AIDS dementia complex

• Hyperacute – minutes to hours; pre‑formed antibodies (cross‑match prevents)
• Acute – first 6 months; cellular (CD8⁺ T‑cells) or antibody‑mediated
• Chronic – months to years; cell‑ or antibody‑mediated; vasculopathy; organ‑specific changes
• Immunosuppressants (calcineurin inhibitors, corticosteroids, antiproliferatives) used for prevention/treatment

• Type II: anti‑receptor antibodies → Graves (TSH‑R) / myasthenia (AChR)
• Type III: serum sickness, SLE, post‑streptococcal GN
• SCID – absence of thymic shadow on CXR; ADA deficiency → ↑ dATP
• DiGeorge – hypocalcemia + congenital heart defects + absent thymus
• Wiskott‑Aldrich – eczema, thrombocytopenia, infections (X‑linked)
• HIV coreceptors: CCR5 (macrophage) → M‑tropic; CXCR4 (T‑cell) → T‑tropic
• Kaposi sarcoma – HHV‑8; most common AIDS malignancy
• Chronic rejection – vascular intimal thickening (transplant vasculopathy)