Immunopathology

🟢 Lite — Quick Review (1h–1d)

Immunopathology encompasses hypersensitivity reactions (Types I–IV), autoimmunity, immunodeficiency, and transplant rejection. Type I (IgE/mast cell–mediated) causes anaphylaxis and asthma. Type II involves antibody-mediated cytotoxicity (e.g., AIHA, Goodpasture). Type III is immune complex–mediated (SLE, serum sickness). Type IV is T-cell delayed hypersensitivity (TB skin test, contact dermatitis). Autoimmunity results from loss of self-tolerance (Hashimoto, Graves, SLE, RA). Primary immunodeficiencies include Bruton’s agammaglobulinemia (X-linked, ↓B cells), DiGeorge (thymic hypoplasia, 22q11 deletion), and SCID (adenosine deaminase deficiency). HIV/AIDS destroys CD4+ T cells. Autoantibodies like ANA, anti-dsDNA, and anti-Smith are diagnostically crucial. Key structures: immunoglobulins (IgG, IgA, IgM, IgD, IgE) with light chains (κ/λ) and heavy chains.

🟡 Standard — Regular Study (2d–2mo)

Type I Hypersensitivity (Immediate/Anaphylactic)

Type I is IgE-mediated, occurring within minutes of allergen exposure. Prior sensitization produces IgE antibodies that bind Fc receptors on mast cells and basophils. Re-exposure causes cross-linking of IgE, degranulation, and release of histamine, leukotrienes, and prostaglandins. Clinical examples: anaphylaxis (bee sting, penicillin), asthma (allergen-induced bronchoconstriction), allergic rhinitis (pollen), and atopic dermatitis. Treatment includes antihistamines, corticosteroids, and epinephrine.

Type II Hypersensitivity (Cytotoxic/Antibody-Mediated)

Antibodies (IgG or IgM) bind to antigens on cell surfaces, leading to destruction via complement activation, opsonization, or antibody-dependent cellular cytotoxicity (ADCC). Examples include autoimmune hemolytic anemia (AIHA), Goodpasture syndrome (anti-basement membrane antibodies against type IV collagen in kidney and lung), transfusion reactions (ABO incompatibility), hemolytic disease of the newborn, and myasthenia gravis (anti-acetylcholine receptor antibodies). Complement activation generates membrane attack complex (MAC), causing cell lysis.

Type III Hypersensitivity (Immune Complex–Mediated)

Antigen-antibody complexes deposit in tissues, activate complement, and recruit neutrophils, causing inflammation and tissue damage. Classical examples: serum sickness (after antitoxin therapy), Arthus reaction (localized immune complex deposition at injection site), systemic lupus erythematosus (SLE), and post-streptococcal glomerulonephritis. Features include vasculitis, arthritis, and nephritis. Pathology shows neutrophilic infiltration and fibrinoid necrosis.

Type IV Hypersensitivity (Delayed/Cell-Mediated)

T-cell mediated (no antibodies involved). Takes 24–72 hours to develop. Involves sensitized CD4+ Th1 cells releasing cytokines (IFN-γ) and CD8+ cytotoxic T cells. Examples: tuberculin skin test (PPD/Mantoux test — induration at 48–72 hours indicates prior TB exposure), contact dermatitis (nickel, poison ivy), graft rejection (acute and chronic), and granulomatous inflammation (TB, leprosy). Granulomas form when macrophages unable to clear antigen are surrounded by lymphocytes.

Autoimmunity

Loss of self-tolerance leads to immune attack on host tissues. Mechanisms include molecular mimicry, polyclonal B cell activation, epitope spreading, defective apoptosis (Fas mutations), and reduced regulatory T cells. Key autoimmune diseases for INI CET:

Disease	Autoantibody	Target
Hashimoto thyroiditis	Anti-thyroglobulin, anti-microsomal	Thyroid
Graves disease	TSI (thyroid-stimulating immunoglobulin)	TSH receptor
Myasthenia Gravis	Anti-AChR	Neuromuscular junction
SLE	ANA, anti-dsDNA, anti-Smith	Nuclear antigens
Rheumatoid Arthritis	Rheumatoid factor (anti-IgG Fc), anti-CCP	IgG Fc, citrullinated proteins
Goodpasture	Anti-GBM	Type IV collagen (kidney/lung)
Type 1 Diabetes	Anti-GAD65, anti-insulin	Pancreatic beta cells

Autoantibody Patterns

• ANA (antinuclear antibody): Screening test for SLE; positive in >95% of SLE cases
• Anti-dsDNA: Highly specific for SLE; correlates with disease activity (lupus nephritis)
• Anti-Smith: Most specific for SLE (but low sensitivity)
• Anti-centromere: Limited systemic sclerosis (CREST syndrome)
• Anti-Scl-70 (anti-topoisomerase I): Diffuse systemic sclerosis
• Anti-Ro/SSA and Anti-La/SSB: Sjögren syndrome
• Anti-Jo-1: Polymyositis/dermatomyositis with lung fibrosis
• p-ANCA (MPO-ANCA): Microscopic polyangiitis, Churg-Strauss
• c-ANCA (PR3-ANCA): Granulomatosis with polyangiitis (Wegener’s)

Immunodeficiency Disorders

Primary Immunodeficiencies:

Disorder	Defect	Key Features
Bruton’s X-linked agammaglobulinemia	BTK gene mutation → No mature B cells	Recurrent pyogenic infections after 6 months (maternal IgG wanes); absent tonsils, lymph nodes
DiGeorge syndrome	22q11.2 deletion → Thymic hypoplasia	CATCH-22 (Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia); T-cell deficiency
SCID (Severe Combined Immunodeficiency)	ADA deficiency (autosomal recessive) or IL-2Rγ chain (X-linked)	Absent T cells + B cells; fatal within 1 year without bone marrow transplant; no graft-versus-host disease due to absent immunity
Common Variable Immunodeficiency (CVID)	Unknown; failure of B cell maturation	Low IgG, IgA, IgM; recurrent infections; autoimmune disease association
Wiskott-Aldrich syndrome	WAS gene mutation (X-linked)	Thrombocytopenia (small platelets), eczema, recurrent infections; triad
Hyper-IgM syndrome	CD40L mutation on T cells	Normal IgM but very low IgG, IgA, IgE; cannot class-switch

Secondary Immunodeficiency:

• HIV/AIDS: Retrovirus targeting CD4+ helper T cells via CCR5/CXCR4 co-receptors. CD4 count <200 cells/µL defines AIDS. Opportunistic infections (Pneumocystis jirovecii pneumonia, oral candidiasis, toxoplasmosis, cryptococcal meningitis) and malignancies (Kaposi sarcoma, NHL) define AIDS. Key markers: ELISA (screening), Western blot (confirmation), and viral load/CD4 count for monitoring.
• Other causes: Malnutrition, chemotherapy, corticosteroids, immunosuppressive drugs, splenectomy.

HIV/AIDS Pathology

• Acute stage: Mononucleosis-like syndrome (fever, lymphadenopathy, rash)
• Chronic latency: Asymptomatic; viral replication continues
• AIDS: CD4 <200; opportunistic infections (Pneumocystis jirovecii pneumonia — most common AIDS-defining illness; Candida esophagitis; CMV retinitis; Cryptococcus; TB)
• Kaposi sarcoma: HHV-8–associated vascular tumor; seen in AIDS patients
• HIV encephalopathy (AIDS dementia): Direct CNS infection by HIV
• Gynecological malignancy: HPV → Cervical cancer

Transplant Rejection

• Hyperacute rejection (minutes-hours): Preformed antibodies against donor antigens → complement activation → thrombosis → graft necrosis. Prevented by crossmatching.
• Acute rejection (weeks-months): T-cell mediated (CD8+ killing of graft cells; CD4+ Th1 cytokine response) and/or antibody-mediated (donor-specific antibodies). Classified as cellular vs humoral.
• Chronic rejection (months-years): Both cellular and humoral mechanisms; vascular changes (intimal fibrosis — transplant vasculopathy), interstitial fibrosis. Major cause of long-term graft loss.
• Graft-versus-host disease (GVHD): Donor T cells attack recipient tissues; seen after bone marrow/stem cell transplant; targets skin, liver, GI tract.

Immunoglobulin Structure

• Basic unit: 2 heavy chains + 2 light chains (κ or λ)
• Heavy chain classes: γ (IgG), α (IgA), μ (IgM), δ (IgD), ε (IgE)
• IgG: Most abundant; crosses placenta; fixes complement; opsonization; 4 subclasses (IgG1–4)
• IgM: Largest (pentamer); first antibody in primary response; fixes complement efficiently; does NOT cross placenta
• IgA: Dimeric (secretory IgA in secretions — saliva, tears, breast milk, respiratory/GI secretions); protects mucosal surfaces
• IgD: Surface receptor on naive B cells; co-stimulatory
• IgE: Least abundant; mediates Type I hypersensitivity; binds Fc receptors on mast cells/basophils; important in parasitic infections

⚡ INI CET Exam Tips:

• Gell and Coombs classification: Remember Types I (IgE, immediate, minutes), II (antibody, cytotoxic), III (immune complex), IV (T-cell, delayed, 48-72 hrs) — classic table-based questions
• SLE autoantibodies: Anti-dsDNA = specific + correlates with nephritis; Anti-Smith = most specific; ANA = most sensitive
• CD markers: CD19/CD20 (B cells), CD3 (T cells), CD4 (helper T — HIV target), CD8 (cytotoxic T), CD34 (stem cells), CD56 (NK cells)
• HIV:gp120 binds CD4 + CCR5/CXCR4; primary target = CD4+ T cells and macrophages
• Immunoglobulin cross-placenta: IgG only; IgM does NOT cross placenta (if elevated in newborn = intrauterine infection)

🔴 Extended — Deep Study (3mo+)

Type I Hypersensitivity — Detailed Mechanisms

Type I hypersensitivity represents the classic immediate allergic response and is the most common hypersensitivity mechanism encountered in clinical practice. The reaction proceeds in two phases: sensitization and effector phase.

During sensitization, an individual is first exposed to an allergen (e.g., pollen, peanut protein). Antigen-presenting cells (dendritic cells) process and present the allergen to naive CD4+ Th2 cells, which produce IL-4 and IL-13. These cytokines promote class switching in B cells to produce allergen-specific IgE. IgE then binds to the FcεRI receptor on mast cells and basophils, “sensitizing” the individual. There is NO clinical response during sensitization.

Upon reexposure, the allergen cross-links IgE molecules on the surface of mast cells, triggering immediate degranulation within minutes. Preformed mediators released include histamine (causing vasodilation, increased vascular permeability, bronchoconstriction, itching), tryptase (mast cell specific — useful as a biomarker for anaphylaxis), heparin, and proteases.

Within 2–6 hours, de novo synthesis of lipid mediators occurs: leukotrienes (LTC4, LTD4, LTE4 — the “slow-reacting substance of anaphylaxis”) cause prolonged bronchoconstriction and increased vascular permeability (far more potent than histamine), and prostaglandins (PGD2) cause bronchoconstriction and vasodilation.

Cytokines (TNF-α, IL-4, IL-5, IL-13) are also released, recruiting eosinophils and perpetuating inflammation. Eosinophils release major basic protein, eosinophil cationic protein, and eosinophil peroxidase — all toxic to parasites but also cause tissue damage in allergic conditions.

Clinical manifestations: Anaphylaxis (systemic, life-threatening: hypotension, bronchospasm, angioedema), allergic asthma (IgE-mediated bronchial smooth muscle constriction + airway inflammation), allergic rhinitis (hay fever — sneezing, rhinorrhea, congestion), atopic dermatitis (eczema — chronic pruritic skin rash), and food allergies.

Diagnosis: Skin prick test (immediate wheal-and-flare), serum specific IgE (RAST), total IgE levels, and mast cell tryptase (elevated in acute anaphylaxis).

Treatment: Avoidance, antihistamines (H1 blockers), corticosteroids, bronchodilators (β2-agonists), and allergen immunotherapy (desensitization). Epinephrine is first-line for anaphylaxis (IM).

Type II Hypersensitivity — Cytotoxic Mechanisms

Type II reactions involve antibodies directed against antigens expressed on the cell surface or extracellular matrix, leading to cellular destruction or dysfunction through multiple mechanisms:

1. Complement activation → MAC formation (cell lysis). Classic example: transfusion reactions (ABO incompatibility).
2. Opsonization and phagocytosis (IgG coating the cell surface makes it easy prey for macrophages with Fc receptors).
3. ADCC (Antibody-Dependent Cellular Cytotoxicity): NK cells recognize IgG-coated target cells via FcγRIII (CD16) and kill without complement. Important in tumor surveillance and certain autoimmune cytopenias.
4. Receptor modulation: Antibodies block or stimulate receptors. Graves disease (TSI stimulates TSH receptor → hyperthyroidism), Myasthenia Gravis (antibodies block AChR → muscle weakness), and insulin resistance (antibodies against insulin receptors).

Hemolytic Disease of the Newborn (Erythroblastosis Fetalis): Maternal IgG anti-RhD antibodies cross the placenta and attack fetal RBCs (Rh-negative mother, Rh-positive fetus). RhoGAM (anti-D IgG) prevents this. ABO incompatibility can also occur but is less severe because many fetuses lack strong A/B antigens.

Goodpasture Syndrome: Autoantibodies against the α3 chain of type IV collagen in basement membranes of glomeruli and pulmonary alveoli. Presents with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage. Linear IgG deposits on immunofluorescence (pathognomonic). More common in young male smokers.

Autoimmune Hemolytic Anemia (AIHA): Warm AIHA (IgG, extravascular hemolysis in spleen —Coombs test positive) vs Cold AIHA (IgM, complement-mediated, worse in cold — seen in Mycoplasma and EBV infections).

Type III Hypersensitivity — Immune Complex Disease

Immune complexes (antigen-antibody aggregates) form normally during infections but are cleared by phagocytes. When produced in excess or poorly cleared, they deposit in blood vessel walls, glomeruli, joints, and other tissues.

Serum Sickness: Classic model — injection of foreign protein (e.g., horse antitoxin for diphtheria). Immune complexes deposit in vessel walls 7–14 days later. Features: fever, urticaria, arthralgia, lymphadenopathy, proteinuria. Historically important as the first described immune complex disease.

Arthus Reaction: Localized immune complex deposition at site of repeated antigen injection (e.g., booster vaccines). Within 4–10 hours: edema, hemorrhage, necrosis. Leukocytoclastic vasculitis with neutrophilic infiltration on histology.

Systemic Lupus Erythematosus (SLE): Prototypical systemic immune complex disease. Autoantibodies (anti-dsDNA, anti-Smith, ANA) form immune complexes that deposit in kidneys (lupus nephritis — WHO classes I–VI), skin (butterfly rash), joints (non-erosive arthritis), serosa (pleuritis, pericarditis), and CNS. Lupus band test: IgG, IgM, C3 deposits at dermal-epidermal junction on immunofluorescence of non-lesional skin.

Post-Streptococcal Glomerulonephritis (PSGN): Occurs 1–3 weeks after Group A streptococcal pharyngitis or 3–6 weeks after skin infection. Immune complexes “starry sky” pattern on immunofluorescence (lumpy-bumpy), subepithelial “humps” on EM. Typically resolves with treatment but some cases progress.

Type IV Hypersensitivity — Cell-Mediated Immunity

Type IV is unique among hypersensitivity reactions because it is antibody-independent and T-cell mediated. It takes 24–72 hours to develop (delayed-type hypersensitivity — DTH).

Mechanism: Sensitized CD4+ Th1 cells recognize antigen presented by APCs (macrophages, dendritic cells) and release IFN-γ and TNF-α. These cytokines activate macrophages (increasing their microbicidal activity), increase expression of adhesion molecules on endothelium, and recruit more inflammatory cells. CD8+ cytotoxic T cells directly kill graft cells presenting foreign MHC.

Tuberculin Skin Test (TST/PPD/Mantoux): Intradermal injection of purified protein derivative (PPD) from Mycobacterium tuberculosis. In previously sensitized individuals (active or latent TB), memory T cells migrate to the site and release IFN-γ within 48–72 hours, causing induration (not erythema). ≥10mm induration is positive in healthcare workers, immigrants from endemic areas; ≥15mm in low-risk individuals. A positive test indicates prior TB exposure/infection (not active disease) — requires clinical and radiographic correlation.

Contact Dermatitis: Hapten (small chemicals like nickel, poison ivy urushiol, formaldehyde) binds to skin proteins → processed by Langerhans cells → presented to T cells in lymph nodes → on re-exposure, sensitized T cells migrate to skin and release cytokines → eczematous dermatitis (pruritic, vesicular rash in acute phase; lichenified in chronic).

Transplant Rejection:

• Hyperacute: Minutes to hours; preformed antibodies (from prior transfusion, pregnancy, previous transplant) against donor MHC antigens; thrombosis of graft vessels; macroscopically hemorrhagic and cyanotic
• Acute cellular: Days to weeks; CD8+ T cells directly attack graft endothelial and parenchymal cells; tubulitis (lymphocytes in tubular basement membrane) on kidney biopsy
• Acute humoral/antibody-mediated: Donor-specific antibodies; C4d deposition in peritubular capillaries (kidney)
• Chronic: Months to years; transplant vasculopathy (foam cell arteriopathy — accelerated atherosclerosis), interstitial fibrosis, tubular atrophy

Granulomatous Inflammation: When macrophages cannot destroy phagocytosed material, they transform into epithelioid cells and fuse to form giant cells (Langhans-type with peripheral nuclei). T cells surround these aggregates, forming granulomas. Types: caseating (TB — central cheese-like necrosis) and non-caseating (sarcoidosis, Crohn’s disease, foreign body).

Autoimmunity — Deep Dive

Self-tolerance mechanisms:

1. Central tolerance: Negative selection in thymus (autoreactive T cells die by apoptosis — “clonal deletion”). Autoimmune regulator (AIRE) gene promotes self-antigen expression in thymus.
2. Peripheral tolerance: Anergy (functional inactivation of autoreactive T cells in periphery), regulatory T cells (Tregs — CD4+CD25+ with FOXP3 transcription factor), and activation-induced cell death.

Mechanisms of autoimmunity (breakdown of tolerance):

• Molecular mimicry: Pathogen antigens that resemble self (e.g., Streptococcus pyogenes M protein mimics cardiac myosin → rheumatic fever)
• Polyclonal B cell activation: Viruses/mitogens activate multiple B cell clones including autoreactive ones (e.g., EBV in SLE)
• Epitope spreading: Initial immune response to one epitope expands to include other epitopes on the same protein or related proteins
• Defective apoptosis: Fas (CD95) or FasL mutations → autoimmune lymphoproliferative syndrome (ALPS); failure to delete autoreactive lymphocytes
• Bystander activation: Inflammation releases sequestered self-antigens and provides danger signals (LPS, cytokines) that break tolerance
• Hormonal factors: Female predominance in most autoimmune diseases (estrogen effect)

Hashimoto Thyroiditis: Most common cause of hypothyroidism in iodine-sufficient areas. Anti-thyroglobulin and anti-thyroid peroxidase (anti-microsomal) antibodies cause thyroid destruction. Lymphocytic infiltration with germinal centers, Hürthle cell metaplasia, and fibrosis. Presents with goiter and hypothyroidism.

Graves Disease: Autoantibodies (TSI) that bind and activate TSH receptors → hyperthyroidism. Characterized by diffuse toxic goiter, exophthalmos (anti-TSH receptor antibodies cross-react with orbital tissues), pretibial myxedema, and thyroid acropachy.

Systemic Lupus Erythematosus: Prototypical systemic autoimmune disease. Classic features: malar (butterfly) rash, photosensitivity, oral ulcers, arthritis (non-erosive), serositis, nephritis, CNS involvement, hematologic abnormalities (cytopenias). Anti-dsDNA correlates with nephritis; anti-Smith is most specific. HLA-DR2 and HLA-DR3 associated.

Rheumatoid Arthritis: Chronic inflammatory disease primarily affecting synovial joints. Rheumatoid factor (IgM anti-IgG Fc) and anti-CCP (anti-cyclic citrullinated peptide — more specific) in serum. Pannus formation (synovial hyperplasia + inflammatory infiltrate) erodes cartilage and bone. HLA-DR4 associated.

Sjögren Syndrome: Lymphocytic infiltration of exocrine glands (especially salivary and lacrimal) → dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Anti-Ro (SSA) and Anti-La (SSB) antibodies. Often associated with other autoimmune diseases (RA, SLE).

Autoimmune Hepatitis: Type 1 (ANA, anti-SMA) and Type 2 (anti-LKM1). Female predominance. Interface hepatitis (“piecemeal necrosis”) on liver biopsy.

Primary Immunodeficiency — Detailed

Bruton’s Agammaglobulinemia: X-linked recessive (defect in Bruton tyrosine kinase — BTK). Affected males have NO mature B cells (pre-B cells present in bone marrow but cannot mature). Recurrent bacterial infections begin at ~6 months when maternal IgG wanes. Absent germinal centers, tonsils, lymph nodes (no B-cell zones). All immunoglobulin classes severely decreased. Treatment: IVIG.

DiGeorge Syndrome (22q11.2 deletion syndrome): Thymic hypoplasia → T-cell deficiency (especially CD4+). Also: parathyroid hypoplasia → hypocalcemia (neonatal tetany), cardiac defects (conotruncal — truncus arteriosus, tetralogy of Fallot, interrupted aortic arch), abnormal facies, cleft palate. CATCH-22 mnemonic. T-cell deficiency leads to viral and fungal opportunistic infections.

Severe Combined Immunodeficiency (SCID): Most severe PID. Multiple defects in T and B cell development. Adenosine deaminase (ADA) deficiency (autosomal recessive): accumulation of deoxyadenosine and dATP is toxic to lymphocytes. IL-2Rγ chain deficiency (X-linked SCID): impaired IL-2 signaling. Presents in first months of life with persistent infections (bacterial, viral, fungal, opportunistic — including Pneumocystis jirovecii). Failure to thrive. Graft-versus-host disease can occur from maternal T cells or blood transfusions (because the infant has no T cells to reject them). Treatment: Bone marrow transplant (before infections) or gene therapy. Without treatment, fatal by 1–2 years.

Wiskott-Aldrich Syndrome (WAS): X-linked triad: Wiskott (thrombocytopenia with small platelets), Aldrich (eczema), Syndrome (recurrent infections). WAS protein (WASP) is important for cytoskeletal reorganization in hematopoietic cells.

Hyper-IgM Syndrome: Defect in CD40 ligand (CD40L/CD154) on activated T cells. T cells cannot signal B cells to undergo class switching (T-B cell interaction via CD40-CD40L is essential for switching from IgM to IgG, IgA, IgE). Therefore: Normal or elevated IgM but absent/low IgG, IgA, IgE. Presents with recurrent pyogenic infections and opportunistic infections (Pneumocystis, Cryptosporidium). X-linked.

HIV/AIDS — Comprehensive Pathology

Virology: HIV-1 (pandemic) and HIV-2 (West Africa). Envelope glycoprotein gp120 binds CD4 on host cells plus CCR5 (macrophage-tropic/R5-tropic strains in early infection) or CXCR4 (T cell-tropic/X4 strains in late infection). gp41 mediates membrane fusion. Reverse transcriptase converts viral RNA to DNA. Integrase integrates proviral DNA into host genome. Protease cleaves viral polyproteins.

Transmission: Sexual (homosexual and heterosexual), blood products (IVDU, contaminated needles, clotting factor concentrates), perinatal (vertical transmission — breastfeeding, in utero, peripartum).

Stages of HIV Infection:

1. Acute infection (2–4 weeks): High viral load, widespread dissemination. Mononucleosis-like syndrome (fever, lymphadenopathy, pharyngitis, rash, arthralgias). High infectivity.
2. Clinical latency (8–10 years average): Asymptomatic or persistent generalized lymphadenopathy. Viral replication continues at low level. CD4 count gradually declines.
3. Symptomatic HIV/AIDS: CD4 <200 cells/µL. Opportunistic infections and malignancies define AIDS.

AIDS-Defining Conditions (CDC classification — Category C):

• Pneumocystis jirovecii pneumonia (PJP/PCP): Most common AIDS-defining illness. Presents with subacute onset of fever, non-productive cough, dyspnea, hypoxia. Chest X-ray: bilateral interstitial infiltrates. Diagnosis: induced sputum or BAL showing cysts with methenamine silver stain.
• Candidiasis: Oral thrush (pseudomembranous — white plaques; erythematous; angular cheilitis) and esophageal candidiasis (odynophagia)
• Cryptococcal meningitis: Subacute meningitis; India ink stain shows encapsulated yeast; cryptococcal antigen very sensitive
• Toxoplasmosis: Reactivation of latent infection; ring-enhancing brain lesions (encephalitis); CD4 <100
• CMV disease: CMV retinitis (most common — “pizza pie” or “cottage cheese and ketchup” appearance on fundoscopy), CMV colitis, CMV esophagitis
• Disseminated Mycobacterium avium complex (MAC): CD4 <50; fever, weight loss, lymphadenopathy, hepatosplenomegaly
• TB: Reactivation; can occur at any CD4 count but disseminated disease is AIDS-defining
• Cryptosporidiosis: Chronic watery diarrhea; untreatable in AIDS
• Kaposi sarcoma: HHV-8–associated angioproliferative tumor; violaceous skin/nodal/GI lesions; associated with HIV itself (can occur at higher CD4 counts than other opportunistic infections)
• Primary CNS lymphoma: EBV-associated; ring-enhancing brain lesions; CD4 <50
• Cervical cancer: HPV-associated; squamous cell carcinoma of cervix

Diagnosis:

• Screening: 4th generation ELISA (detects anti-HIV antibodies + p24 antigen — “combined antibody/antigen test”); window period ~2 weeks
• Confirmation: Western blot (detects antibodies to specific HIV proteins)
• Point of care: Rapid antibody tests
• Viral load: RT-PCR for HIV RNA (monitoring disease progression and treatment efficacy)
• CD4 count: Main clinical indicator of immune status
• Resistance testing: Before initiating ART and on treatment failure

Treatment (HAART/ART): Combination of at least 3 drugs from 2+ classes:

• NRTIs (nucleoside reverse transcriptase inhibitors): Tenofovir, emtricitabine, zidovudine, lamivudine
• NNRTIs (non-nucleoside RTIs): Efavirenz, nevirapine
• Integrase inhibitors: Raltegravir, dolutegravir (first-line)
• Protease inhibitors: Ritonavir (boosted)
• Entry/CCR5 inhibitors: Maraviroc

Post-exposure prophylaxis (PEP): 28-day ART regimen after high-risk exposure.

Immunoglobulin Structure and Classes

Basic structure: All immunoglobulins have a monomeric basic unit of 2 identical heavy chains + 2 identical light chains (κ or λ; each immunoglobulin has either κ or λ, not both). Light chains have 2 domains (VL + CL); heavy chains have 4–5 domains (VH + CH1 + CH2 + CH3 [+ CH4 in IgM and IgE]).

Domains: Variable (V) domains at N-terminus show hypervariability (CDR regions — complementarity determining regions) responsible for antigen binding. Constant (C) domains are relatively conserved.

Fab fragment: Antigen-binding fragment — contains entire light chain + VH + CH1 of heavy chain. Each basic unit has 2 Fab arms (bivalent).

Fc fragment: Crystallizable fragment — contains CH2 and CH3 (and CH4 in IgM/IgE). This is where effector functions are determined (complement binding, Fc receptor binding, placental transfer).

Hinge region: Flexible region between CH1 and CH2 allowing Fab arms to move independently (important for antigen binding to closely spaced epitopes).

Immunoglobulin Classes:

Class	Heavy Chain	Structure	Key Features
IgG	γ	Monomer	Most abundant (75%); crosses placenta; 4 subclasses; fixes complement; long half-life; opsonization
IgA	α	Monomer (serum) / Dimer (secretory)	Secretory IgA in secretions; J chain; secretory component protects from proteolysis
IgM	μ	Pentamer (can also be monomer on B cell surface)	First antibody in primary response; most efficient complement activator; does NOT cross placenta; largest immunoglobulin
IgD	δ	Monomer	Surface Ig on naive B cells (BCR); co-stimulatory signaling with BAFF
IgE	ε	Monomer	Least abundant; binds FcεRI on mast cells/basophils; Type I hypersensitivity; anti-parasitic immunity; elevated in allergic diseases and hyper-IgE syndrome (Job syndrome)

Class Switching: B cells initially produce IgM. Upon antigen stimulation and T cell help (CD40L binding to CD40 + cytokine signals), B cells undergo class switch recombination (CSR) — same antigen specificity (V region unchanged) but different heavy chain constant region → IgG, IgA, or IgE. This process requires CD40-CD40L interaction (defect in Hyper-IgM syndrome).

High-Yield Associations for INI CET

• Anaphylaxis: Type I; IgE; mast cells; histamine; epinephrine is treatment
• Hemolytic transfusion reaction: Type II; complement; ABO incompatibility
• Goodpasture syndrome: Type II; anti-GBM; linear IF pattern
• Myasthenia Gravis: Type II; anti-AChR; receptor modulation
• Serum sickness: Type III; immune complexes; 7–14 days after antigen exposure
• Arthus reaction: Type III; localized; 4–10 hours
• SLE: Type III (also Type II); ANA, anti-dsDNA, anti-Smith
• TB skin test: Type IV; delayed (48–72 hrs); PPD/PPD
• Contact dermatitis: Type IV; nickel, poison ivy; hapten-carrier complex
• Graft rejection: Type IV (cellular); Type II (antibody-mediated — hyperacute)
• Bruton’s agammaglobulinemia: X-linked; BTK; no mature B cells; no tonsils
• DiGeorge: 22q11; CATCH-22; thymic hypoplasia; hypocalcemia
• SCID: Adenosine deaminase deficiency; fatal in 1 year without transplant
• HIV: gp120; CD4+ T cells; CCR5/CXCR4; opportunistic infections
• PCP: Most common AIDS-defining illness; CD4 <200
• Kaposi sarcoma: HHV-8; HIV-associated malignancy
• Wiskott-Aldrich: Triad — thrombocytopenia (small platelets), eczema, infections
• Hyper-IgM: CD40L defect; cannot class switch
• CVID: Low IgG; recurrent infections; autoimmune associations
• IgA deficiency: Most common PID; selective IgA deficiency; anti-IgA antibodies (transfusion reaction)
• IgG: Only immunoglobulin that crosses placenta
• IgM: Does NOT cross placenta; pentamer; first antibody
• Secretory IgA: Dimer; J chain; secretory component; protects mucosae
• IgE: Type I hypersensitivity; anti-parasitic; elevated in allergies
• ANA: Most sensitive for SLE (but not specific — also positive in RA, scleroderma, Sjögren, drug-induced lupus, hepatitis C)
• Anti-dsDNA: Specific for SLE; correlates with nephritis
• Anti-Smith: Most specific for SLE (but low sensitivity)
• Anti-CCP: Specific for RA (more specific than rheumatoid factor)
• Anti-centromere: Limited systemic sclerosis (CREST)
• Anti-Scl-70: Diffuse systemic sclerosis
• C3 and C4: Low in SLE (consumed via complement activation)
• Donath-Landsteiner test: Paroxysmal cold hemoglobinuria (PCH) — anti-P antibodies
• Coombs test: Direct (DAT) detects IgG/complement on RBCs; Indirect (IAT) detects serum antibodies
• C1q binding assay: Detects immune complexes
• gp120/CD4: HIV entry mechanism
• CCR5: Coreceptor for macrophage-tropic HIV
• NRTIs + NNRTIs + Integrase inhibitors: HAART combination
• gp210 and p62: Nuclear pore complex proteins — antibodies in primary biliary cholangitis (PBC)

⚡ Critical INI CET Success Factors:

1. Gell and Coombs table is a must-memorize: know Type, antibody/cell involved, timing, examples, and mechanisms for each of the 4 types
2. Autoantibody table: Anti-dsDNA = SLE + nephritis; Anti-Smith = most specific SLE; Anti-CCP = RA; Anti-AChR = MG; TSI = Graves
3. PID syndromes: Bruton’s (X-linked, B cells), DiGeorge (22q11, T cells), SCID (T+B cells), Wiskott-Aldrich (triad), Hyper-IgM (CD40L, no class switching), CVID (B cell maturation failure)
4. HIV: gp120-CD4 mechanism; CD4 count and opportunistic infections; PCP = most common AIDS-defining illness; Kaposi = HHV-8
5. Transplant rejection: Hyperacute (minutes, antibodies), Acute (weeks, T cells), Chronic (months-years, both)
6. Immunoglobulin characteristics: Who crosses placenta (IgG), which is pentamer (IgM), which is in secretions (IgA dimer), which mediates Type I (IgE)
7. ANA pattern interpretation: Homogeneous = SLE; Peripheral/rim = SLE (anti-dsDNA); Speckled = mixed connective tissue, SLE, Sjögren; Nucleolar = systemic sclerosis; Centromere = CREST
8. Complement in SLE: Low C3 and C4 (consumed); anti-C1q antibodies in active disease
9. TB skin test interpretation: ≥10mm for healthcare workers/endemic areas; ≥15mm for low-risk; induration (not erythema) is measured at 48–72 hours
10. Lupus nephritis: WHO Classification (Class I–VI); diffuse proliferative (Class IV) is most severe