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IMMUNOPATHOLOGY AND AIDS

2nd MBBS Pathology - MUHS Exam Notes

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QUESTION 1: HYPERSENSITIVITY REACTIONS

Definition

• Inadequately controlled
• Directed against normally harmless antigens (environmental allergens)
• Inappropriately targeted to host tissues (autoimmunity)

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Causes of Hypersensitivity

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Classification (Gell and Coombs - 4 Types)

┌─────────────────────────────────────────────────────────────────────┐
│           CLASSIFICATION OF HYPERSENSITIVITY REACTIONS              │
├────────┬───────────────┬───────────────┬────────────────────────────┤
│ TYPE   │ MECHANISM     │ MEDIATORS     │ EXAMPLES                   │
├────────┼───────────────┼───────────────┼────────────────────────────┤
│ I      │ IgE-mediated  │ IgE, Mast     │ Anaphylaxis, Asthma,       │
│ (Imm.) │ (Immediate)   │ cells,        │ Allergic rhinitis,         │
│        │               │ Eosinophils   │ Urticaria, Food allergy    │
├────────┼───────────────┼───────────────┼────────────────────────────┤
│ II     │ Antibody vs.  │ IgG, IgM,     │ Autoimmune hemolytic       │
│ (Cyto.)│ cell/tissue   │ Complement,   │ anemia, Goodpasture,       │
│        │ antigens      │ Phagocytes    │ Graves disease, MG         │
├────────┼───────────────┼───────────────┼────────────────────────────┤
│ III    │ Immune complex │ IgG, Comple-  │ SLE, Post-strep GN,        │
│(IC-med)│ deposition    │ ment, Neutro- │ Serum sickness,            │
│        │               │ phils         │ Arthus reaction            │
├────────┼───────────────┼───────────────┼────────────────────────────┤
│ IV     │ T cell-       │ CD4+ (DTH),   │ Contact dermatitis, TB     │
│ (DTH)  │ mediated      │ CD8+ (CTL),   │ granuloma, Type 1 DM,      │
│        │               │ Macrophages   │ Multiple sclerosis         │
└────────┴───────────────┴───────────────┴────────────────────────────┘

• Types I, II, III = Antibody-mediated
• Type IV = Cell-mediated (Delayed-type Hypersensitivity)

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QUESTION 2: TYPE I HYPERSENSITIVITY (IMMEDIATE / IgE-MEDIATED) ⭐⭐

Definition

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Mechanism (Step by Step)

┌─────────────────────────────────────────────────────────────────────┐
│              TYPE I HYPERSENSITIVITY - MECHANISM                    │
└─────────────────────────────────────────────────────────────────────┘

SENSITIZATION PHASE (First exposure):
   Allergen → APC presentation → Th2 cell activation
       ↓
   Th2 cells secrete IL-4 and IL-13
       ↓
   B cell class switching → IgE production
       ↓
   IgE binds to FcεRI receptors on MAST CELLS and BASOPHILS
   (Mast cells become "armed/sensitized")

ELICITATION PHASE (Re-exposure):
   Same allergen re-enters → CROSS-LINKS IgE on mast cells
       ↓
   Mast cell DEGRANULATION (within seconds-minutes)
       ↓
   Release of PRIMARY MEDIATORS from granules:
     • Histamine (vasodilation, increased permeability, smooth muscle spasm)
     • ECF-A (eosinophil chemotaxis)
     • NCF-A (neutrophil chemotaxis)
     • Proteases (tryptase, chymase)
       ↓
   Release of SECONDARY MEDIATORS (newly synthesized):
     • Leukotrienes (LTC4, LTD4, LTE4) - sustained bronchospasm
     • Prostaglandin D2 - bronchoconstriction
     • PAF - aggregates platelets
     • Cytokines (IL-4, IL-5, TNF) - late phase

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Two Phases of Type I Response

• Vasodilation, increased vascular permeability
• Smooth muscle spasm
• Hypersecretion of mucus
• Due to: Histamine, prostaglandins

• Infiltration by eosinophils, basophils, neutrophils, T cells
• Tissue damage, mucosal edema
• Due to: Leukotrienes, cytokines, eosinophil products (MBP)

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Mediators Summary Table

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Clinical Examples

MUHS Exam Tip: Anaphylaxis = most severe systemic Type I reaction. SRS-A (Slow-Reacting Substance of Anaphylaxis) = LTC4 + LTD4 + LTE4.

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QUESTION 3: GRAFT REJECTION - MECHANISM AND ROLE OF HLA ANTIGENS ⭐

Types of Graft Rejection

┌────────────────────────────────────────────────────────────┐
│                    GRAFT REJECTION                         │
├──────────────┬───────────┬─────────────┬───────────────────┤
│ TYPE         │ TIMING    │ MECHANISM   │ MORPHOLOGY        │
├──────────────┼───────────┼─────────────┼───────────────────┤
│ Hyperacute   │ Minutes-  │ Preformed   │ Thrombosis,       │
│              │ hours     │ antibodies  │ ischemic necrosis │
│              │           │ against HLA │                   │
├──────────────┼───────────┼─────────────┼───────────────────┤
│ Acute        │ Days-     │ T cells     │ Tubulointerstitial │
│ Cellular     │ weeks     │ (CD4+, CD8+)│ nephritis,        │
│              │           │ react to    │ vasculitis        │
│              │           │ donor HLA   │                   │
├──────────────┼───────────┼─────────────┼───────────────────┤
│ Acute        │ Weeks-    │ Antibodies  │ Necrotizing        │
│ Humoral      │ months    │ to HLA      │ vasculitis         │
│              │           │ (de novo)   │                   │
├──────────────┼───────────┼─────────────┼───────────────────┤
│ Chronic      │ Months-   │ T cells +   │ Vascular           │
│              │ years     │ Antibodies  │ intimal thicken-   │
│              │           │             │ ing, fibrosis,     │
│              │           │             │ "graft vasculo-    │
│              │           │             │ pathy"             │
└──────────────┴───────────┴─────────────┴───────────────────┘

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Mechanisms of Acute T-Cell Mediated Rejection

1. Direct pathway:
   • Recipient T cells recognize intact donor MHC on donor APCs
   • Responsible for early, acute rejection
2. Indirect pathway:
   • Recipient APCs process donor antigens
   • Present donor peptides (including HLA peptides) to recipient T cells
   • More important in chronic rejection

• CD4+ Th1 cells → secrete IFN-γ → macrophage activation → DTH-type inflammation
• CD8+ CTLs → directly kill graft parenchymal cells (via perforins/granzymes)
• CD4+ Th17 cells → recruit neutrophils

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Role of HLA (MHC) Antigens in Graft Rejection

┌──────────────────────────────────────────────────────┐
│              HLA ANTIGENS IN TRANSPLANTATION         │
├──────────────┬───────────────────────────────────────┤
│ CLASS I      │ HLA-A, HLA-B, HLA-C                  │
│ (HLA Class I)│ Present on ALL nucleated cells        │
│              │ Recognized by CD8+ T cells            │
├──────────────┼───────────────────────────────────────┤
│ CLASS II     │ HLA-DR, HLA-DQ, HLA-DP               │
│ (HLA Class II│ Present on APCs (DC, macrophage, B)   │
│              │ Recognized by CD4+ T cells            │
└──────────────┴───────────────────────────────────────┘

• Each person has a unique set of HLA molecules (except identical twins)
• Donor HLA molecules on graft cells = foreign antigens to recipient
• Recipient immune system mounts both cellular and humoral attack
• Greater the HLA mismatch → greater the rejection risk

• HLA typing done before transplantation (crossmatching)
• Best match = HLA-identical sibling (lowest rejection)
• Immunosuppressants (cyclosporine, tacrolimus) block T cell activation

• Caused by preformed anti-HLA antibodies (from prior transfusion, pregnancy, or transplant)
• Complement activation → thrombosis → immediate graft loss

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QUESTION 4: AUTOIMMUNITY ⭐

Definition

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Mechanisms of Self-Tolerance (Normal)

1. Central tolerance:
   • In thymus (T cells) and bone marrow (B cells)
   • Clonal deletion of self-reactive lymphocytes (negative selection)
   • AIRE gene controls expression of tissue antigens in thymus
2. Peripheral tolerance:
   • Clonal anergy: Self-reactive T cells encounter antigen without co-stimulation → become unresponsive
   • Regulatory T cells (Tregs): CD4+CD25+FoxP3+ cells suppress self-reactive T cells
   • Activation-induced cell death (AICD): Repeated antigenic stimulation → apoptosis via Fas-FasL

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Pathogenesis of Autoimmunity

┌──────────────────────────────────────────────────────────────────┐
│              PATHOGENESIS OF AUTOIMMUNITY                        │
└──────────────────────────────────────────────────────────────────┘

    GENETIC FACTORS               ENVIRONMENTAL FACTORS
    • HLA genes (HLA-DR2,         • Infections (molecular mimicry)
      HLA-DR3, HLA-B27)           • Polyclonal B cell activation
    • Non-HLA genes               • Tissue injury releasing
    • PTPN22, CTLA4, FoxP3          sequestered antigens
    • AIRE mutations              • UV light (SLE)
              ↓                              ↓
         FAILURE OF SELF-TOLERANCE
         • Escape of autoreactive T cells from thymus
         • Loss of peripheral anergy
         • Deficient Treg function
         • Molecular mimicry
         • Bystander activation
              ↓
     AUTOIMMUNE DISEASE
     (organ-specific or systemic)

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Mechanisms in Autoimmune Disorders

Key concept: Molecular mimicry - Streptococcal M protein mimics cardiac myosin → rheumatic fever. EBV, CMV, and HIV cause polyclonal B cell activation → autoantibodies.

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QUESTION 5: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) ⭐⭐

Definition

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Pathogenesis of SLE

┌─────────────────────────────────────────────────────────────────┐
│                    PATHOGENESIS OF SLE                          │
└─────────────────────────────────────────────────────────────────┘

GENETIC PREDISPOSITION:
HLA-DR2, HLA-DR3 → Susceptibility
C1q, C2, C4 deficiencies → Impaired clearance of apoptotic material

TRIGGER:
UV light, Estrogen (F:M = 9:1), Drugs (hydralazine, procainamide)

DEFECTIVE CLEARANCE OF APOPTOTIC CELLS:
↓ Apoptotic bodies release nuclear fragments (dsDNA, histones, RNA)
↓ Normally cleared; in SLE → persist and stimulate TLRs
↓ TLR activation in pDCs → excessive type I IFN production

LOSS OF SELF-TOLERANCE:
↓ Autoreactive B cells and T cells escape elimination
↓ CD4+ T cell help → B cell hyperactivation
↓ Production of ANA (Antinuclear Antibodies)

KEY AUTOANTIBODIES IN SLE:
• Anti-dsDNA (highly specific for SLE, correlates with disease activity)
• Anti-Sm (Smith antigen - highly specific)
• Anti-histone (drug-induced lupus)
• Anti-Ro/SSA, Anti-La/SSB (neonatal lupus, Sjogren's)
• Antiphospholipid antibodies (thrombosis, recurrent miscarriage)
• ANA (screening test - sensitive but not specific)

TISSUE INJURY:
• Immune complexes (IC) deposit in basement membranes
  → Complement activation → Inflammation → Organ damage
• Direct antibody attack on cells (anemia, thrombocytopenia)
• T cell-mediated tissue injury

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Morphology of SLE

• Butterfly (malar) rash - erythema over cheeks and nose
• Hematoxylin bodies (LE bodies) - characteristic nuclear debris in tissue
• Vasculitis, fibrinoid necrosis

• "Wire loop" lesion - immune complex deposits thicken capillary wall
• Hyaline thrombi in glomerular capillaries
• IF: granular ("lumpy-bumpy") deposits of IgG, IgM, C3
• EM: subendothelial deposits

• Sterile, small, warty vegetations on BOTH sides of mitral valve
• Due to immune complex deposition + fibrin
• Pathognomonic of SLE

• Fibrinoid necrosis of vessel walls (acute vasculitis)
• "Onion skin" (concentric fibrosis) in chronic cases - especially in spleen (perivascular fibrosis = "onion skin lesion")

• Splenomegaly
• "Onion skin" perivascular fibrosis (pathognomonic)
• Lymphoid hyperplasia

• Pleuritis (50%), lupus pneumonitis
• Pulmonary fibrosis

• Non-erosive synovitis (vs. RA which is erosive)

• Vasculitis, infarcts, diffuse microangiopathy

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Diagnosis of SLE (ACR/EULAR Criteria - 2019)

1. Constitutional (fever)
2. Hematologic (hemolytic anemia, leucopenia, thrombocytopenia)
3. Neuropsychiatric (seizures, psychosis)
4. Mucocutaneous (malar rash, oral ulcers, photosensitivity, alopecia)
5. Serosal (pleuritis, pericarditis)
6. Musculoskeletal (arthritis)
7. Renal (proteinuria > 0.5 g/day, biopsy findings)
8. Immunology (anti-dsDNA, anti-Sm, complement levels, antiphospholipid antibodies)

MUHS Exam Tip: LE cells = Neutrophil that has engulfed nuclear material opsonized by anti-histone antibodies. LE cell phenomenon = hallmark, but now replaced by ANA testing.

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QUESTION 6: HIV - LIFE CYCLE, ETIOPATHOGENESIS, LAB DIAGNOSIS, CLINICAL STAGES OF AIDS, NEOPLASMS ⭐⭐

HIV Genome (Easy to Draw)

• gag: Encodes core proteins (p24 capsid, p17 matrix, p7 nucleocapsid)
• pol: Encodes enzymes - reverse transcriptase (p66/51), integrase (p32), protease (p10)
• env: Encodes envelope glycoproteins gp160 → cleaved to gp120 (binds CD4) + gp41 (fusion)
• LTR: Long terminal repeats - contain NF-κB, NFAT, Sp1 binding sites; required for transcription
• tat: Transcriptional activator (essential for replication)
• rev: Regulates export of viral mRNA
• nef: Downregulates CD4, MHC-I on infected cells; enhances viral infectivity
• vif: Degrades APOBEC3G (cellular antiviral enzyme)

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HIV Life Cycle (EASY TO DRAW)

┌─────────────────────────────────────────────────────────────────────┐
│                    HIV LIFE CYCLE                                   │
└─────────────────────────────────────────────────────────────────────┘

STEP 1 - ATTACHMENT/ENTRY:
  HIV gp120 → binds CD4 receptor (T cells, macrophages, DCs)
       ↓ Conformational change in gp120
  gp120 → binds coreceptor CCR5 (M-tropic, macrophages - early) 
                           or CXCR4 (T-tropic, T cells - late)
       ↓ Conformational change in gp41
  gp41 fusion peptide inserts into cell membrane
       ↓ Membrane fusion
  HIV RNA genome enters cytoplasm

STEP 2 - REVERSE TRANSCRIPTION:
  HIV RNA → (Reverse Transcriptase) → dsDNA (proviral DNA)

STEP 3 - INTEGRATION:
  Proviral DNA → (Integrase) → integrates into HOST genome
  → LATENT INFECTION (may persist for months/years)

STEP 4 - TRANSCRIPTION (Activation required):
  Cell activation (cytokines, infections) → NF-κB activation
  → Transcription of HIV genes via Tat protein
  → HIV mRNA → cytoplasm

STEP 5 - TRANSLATION:
  HIV proteins synthesized (Gag, Pol, Env)
  → Core proteins assemble

STEP 6 - BUDDING AND MATURATION:
  Immature virus buds from cell membrane
  → Viral Protease cleaves polyproteins
  → Mature infectious HIV virion released
  → CD4+ T cell dies

• Entry: Maraviroc (CCR5 antagonist), Enfuvirtide (fusion inhibitor)
• Reverse transcriptase: NRTI (Zidovudine), NNRTI (Nevirapine)
• Integrase: Raltegravir
• Protease: Lopinavir

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Etiopathogenesis of AIDS

• Family: Retroviridae, genus Lentivirus
• Types: HIV-1 (worldwide), HIV-2 (West Africa)
• Transmission: Sexual, parenteral (blood/needles), mother-to-child (vertical)

┌─────────────────────────────────────────────────────────────────┐
│            MECHANISMS OF CD4+ T CELL DEPLETION                  │
└─────────────────────────────────────────────────────────────────┘

DIRECT EFFECTS:
• Productive viral replication → cell lysis
• Accumulation of unintegrated viral DNA → toxic
• HIV-induced apoptosis (via gp120 cross-linking of CD4)
• Formation of syncytia (gp120 on infected cell binds CD4 on uninfected cell)

INDIRECT EFFECTS:
• Immune-mediated killing of HIV-infected T cells by CD8+ CTLs
• Chronic immune activation → activation-induced cell death (AICD)
• Destruction of CD4+ T cell precursors in thymus and bone marrow
• Macrophage and DC dysfunction → impaired antigen presentation

ROLE OF MACROPHAGES AND DCs:
• HIV infects macrophages via CCR5 (early in infection)
• Macrophages are RESERVOIRS of HIV (not killed, virus persists)
• Infected DCs carry virus to lymph nodes → amplify infection

VIRAL LOAD AND CD4 COUNT:
• Normal CD4 = 500-1500 cells/μL
• AIDS defined as CD4 < 200 cells/μL OR AIDS-defining illness
• Viral load correlates with rate of disease progression

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Laboratory Diagnosis of HIV

SCREENING TESTS (highly sensitive):
┌─────────────────────────────────────────────────────────┐
│  ELISA (4th generation = detects HIV Ag + Ab together)  │
│  • Detects HIV p24 antigen + anti-HIV antibodies        │
│  • Window period: ~18 days for 4th gen                  │
│  • Sensitivity: >99.9%                                  │
└─────────────────────────────────────────────────────────┘

CONFIRMATORY TESTS:
┌─────────────────────────────────────────────────────────┐
│  WESTERN BLOT                                           │
│  • Gold standard confirmatory test                      │
│  • Detects antibodies to specific viral proteins        │
│  • Positive if bands at: p24, gp41, gp120/160          │
└─────────────────────────────────────────────────────────┘

MONITORING TESTS:
• CD4+ T cell count: Immunological status, when to start ART
• HIV RNA viral load (RT-PCR): Treatment response, infectivity
• HIV resistance testing: Guide drug selection
• p24 antigenemia: Early infection, infants

TESTS FOR INFANTS (<18 months):
• HIV DNA PCR or HIV RNA PCR (maternal antibodies persist, ELISA unreliable)
• Positive at 4 weeks → confirmatory test at 4 months

RAPID TESTS:
• Point-of-care, result in 20-30 min
• Used in resource-limited settings, labor/delivery

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Clinical Stages of HIV Infection / AIDS

STAGE 1: ACUTE HIV INFECTION (2-4 weeks after exposure)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
• Acute retroviral syndrome (mononucleosis-like illness)
• Fever, lymphadenopathy, pharyngitis, rash, myalgia
• High viral load, transient CD4 fall
• Lasts 2-4 weeks, resolves spontaneously
• Anti-HIV antibodies appear (seroconversion)

STAGE 2: CHRONIC ASYMPTOMATIC PHASE (Clinical Latency)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
• Typically asymptomatic (may have persistent generalized lymphadenopathy)
• Low-level viral replication in lymph nodes
• Gradual CD4 decline (~50 cells/μL/year)
• Duration: Untreated = 8-10 years (without ART)
• Persistent Generalized Lymphadenopathy (PGL)

STAGE 3: SYMPTOMATIC HIV DISEASE
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
• Constitutional symptoms: Weight loss, fever, night sweats, diarrhea
• CD4 200-500 cells/μL
• Minor opportunistic infections
• Oral candidiasis, oral hairy leukoplakia (EBV), shingles (VZV)
• Bacterial pneumonias (recurrent)

STAGE 4: AIDS (Full-blown AIDS)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
• CD4 < 200 cells/μL OR AIDS-defining illness
• Major opportunistic infections (see below)
• Constitutional: Wasting syndrome (HIV wasting > 10% weight loss)

WHO STAGES: 1 → 2 → 3 → 4 (correlates with CDC classification)
CDC: Category A (acute/asymptomatic) → B (symptomatic) → C (AIDS)

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AIDS-Defining Opportunistic Infections by CD4 Count

CD4 < 500: Candida (oral), Kaposi sarcoma, TB reactivation
CD4 < 200: PCP (Pneumocystis jirovecii pneumonia) - MOST COMMON OI
           Toxoplasma encephalitis, Cryptococcal meningitis
CD4 < 100: Cryptosporidiosis, Microsporidiosis
CD4 < 50:  CMV retinitis, Disseminated MAC (Mycobacterium avium complex)
           PML (Progressive Multifocal Leukoencephalopathy - JC virus)

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Neoplasms in AIDS Patients ⭐⭐

┌──────────────────────────────────────────────────────────────────────┐
│                  NEOPLASMS IN AIDS PATIENTS                          │
├──────────────────┬───────────────┬─────────────────────────────────  ┤
│ TUMOR            │ VIRUS/CAUSE   │ FEATURES                         │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ KAPOSI SARCOMA   │ HHV-8 (KSHV) │ MOST COMMON tumor in AIDS;       │
│ ⭐ (KS)          │               │ Vascular tumor; purple/red skin  │
│                  │               │ plaques; also visceral           │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ HIGH-GRADE       │ EBV           │ 2nd most common; diffuse large   │
│ B-CELL LYMPHOMA  │               │ B cell or Burkitt lymphoma;      │
│                  │               │ CNS lymphoma (primary)           │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ CERVICAL CANCER  │ HPV (16, 18)  │ In HIV+ women; aggressive course │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ ANAL CANCER      │ HPV           │ In HIV+ men (MSM)                │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ PRIMARY CNS      │ EBV           │ Ring-enhancing lesion; must      │
│ LYMPHOMA         │               │ distinguish from toxoplasma      │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ PRIMARY          │ HHV-8 + EBV   │ Pleural/peritoneal effusion;     │
│ EFFUSION         │               │ Body cavity lymphoma             │
│ LYMPHOMA         │               │                                  │
├──────────────────┼───────────────┼──────────────────────────────────┤
│ MULTICENTRIC     │ HHV-8         │ B-cell lymphoproliferative;      │
│ CASTLEMAN'S      │               │ systemic lymphadenopathy         │
│ DISEASE          │               │                                  │
└──────────────────┴───────────────┴──────────────────────────────────┘

• Most common neoplasm in AIDS patients
• Caused by HHV-8 (human herpesvirus 8 = Kaposi's Sarcoma Herpesvirus, KSHV)
• Morphology: Spindle-shaped cells expressing endothelial + smooth muscle markers; slit-like vascular spaces; mixed inflammatory infiltrate
• Lesions: Purple-red skin plaques (face, extremities, genitals) → disseminates to lungs, GI, lymph nodes
• Incidence fell dramatically with antiretroviral therapy (ART)
• Polyclonal or oligoclonal in early stages (not a true malignant tumor)
• HHV-8 encodes: viral cyclin D homologue, inhibitors of p53 → promotes spindle cell survival

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QUICK REVISION SUMMARY FOR MUHS

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