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3rd Year MBBS - Immunology & Pathology

Complete Detailed Notes

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UNIT 1: INNATE (NONSPECIFIC) IMMUNITY

Definition

Components

1. Physical & Anatomical Barriers

• Skin: Keratinized squamous epithelium - impermeable to most pathogens
• Mucosal surfaces: Mucus traps organisms; ciliary action clears them (mucociliary escalator)
• Secretions: Tears, saliva, gastric acid (HCl, pH 2), urine flow
• Normal flora: Competitive exclusion of pathogens

2. Cellular Components

3. Soluble Components

• Complement system (C1-C9): opsonization, lysis, chemotaxis
• Acute phase proteins: CRP, serum amyloid A, fibrinogen, mannose-binding lectin
• Cytokines: TNF-α, IL-1, IL-6, IL-12, type I interferons (IFN-α/β)
• Lysozyme: Degrades bacterial peptidoglycan
• Defensins: Antimicrobial peptides in neutrophil granules

4. Pattern Recognition Receptors (PRRs)

• Toll-like receptors (TLRs): TLR4 recognizes LPS (gram-negative bacteria); TLR3 recognizes dsRNA
• NOD-like receptors (NLRs): Intracellular; activate inflammasome
• RIG-I-like receptors: Detect viral RNA in cytoplasm
• Scavenger receptors, Lectin receptors, Complement receptors

5. Inflammatory Response

• Vasodilators: Histamine, PGE2 → redness, heat, swelling
• Chemokines: IL-8 (CXCL8) → recruit neutrophils
• Pyrogens: IL-1, IL-6, TNF-α → fever via PGE2 in hypothalamus

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UNIT 2: HUMORAL IMMUNITY

Definition

B Cell Activation

1. B cell encounters antigen (via B cell receptor - surface IgM/IgD)
2. T-dependent antigens (proteins): require CD4+ T helper cell co-stimulation via CD40L-CD40 interaction + cytokines (IL-4, IL-5, IL-21)
3. T-independent antigens (polysaccharides, lipids): directly crosslink BCR; no T cell help needed; produce IgM primarily

B Cell Differentiation

• Naive B cell → Germinal center reaction → affinity maturation, somatic hypermutation, class switching → Long-lived plasma cells + Memory B cells
• Primary response: IgM first, then IgG; takes 5-7 days; lower affinity
• Secondary response (memory): Faster (1-3 days), higher titer, predominantly IgG (or IgA/IgE), higher affinity

Antibody Classes & Functions

Antibody Effector Functions

1. Neutralization: Block pathogen-host cell interaction
2. Opsonization: IgG Fc region → Fc receptor on phagocytes → enhanced phagocytosis
3. Complement activation: IgM > IgG1/3 → classical pathway
4. ADCC (antibody-dependent cellular cytotoxicity): IgG binds target → NK cells/macrophages kill via Fc receptor

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UNIT 3: COMPLEMENT SYSTEM

Overview

• Opsonization (C3b coats bacteria)
• Lysis (MAC - membrane attack complex)
• Chemotaxis (C3a, C5a - anaphylatoxins)
• Clearance of immune complexes

Classical Pathway

1. C1q binds Fc of IgM/IgG → C1r + C1s activate
2. C1s cleaves C4 → C4a (anaphylatoxin) + C4b (binds surface)
3. C4b + C2 → C4b2 (with C1s cleaves C2) → C4b2a = Classical C3 convertase
4. C3 convertase cleaves C3 → C3a (anaphylatoxin/chemotaxis) + C3b (opsonin; binds surface)
5. C4b2a3b = Classical C5 convertase
6. C5 → C5a (most potent anaphylatoxin) + C5b
7. C5b + C6 + C7 + C8 + poly-C9 = MAC (C5b-9) → pore in membrane → osmotic lysis

Alternative Pathway

1. C3 tickover: C3 spontaneously hydrolyzes to C3(H2O)
2. C3(H2O) + Factor B → cleaved by Factor D → C3(H2O)Bb = fluid-phase C3 convertase
3. Generates C3b → binds microbial surface
4. Surface-bound C3b + Factor B (cleaved by Factor D) → C3bBb = Alternative C3 convertase (stabilized by Properdin/Factor P)
5. C3bBb3b = Alternative C5 convertase
6. → MAC (same as classical)

• DAF (CD55): Displaces Bb from C3 convertase
• CD59 (Protectin): Blocks MAC formation on self cells
• Factor H & Factor I: Cleave C3b on self surfaces
• C1-inhibitor: Inhibits C1r/C1s (deficiency = hereditary angioedema)

Lectin Pathway

• MBL (Mannose-Binding Lectin) recognizes mannose on microbes → MASP-1/2 act like C1r/C1s → joins classical pathway at C4

Common Final Pathway (all 3 pathways)

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UNIT 4: ADAPTIVE (ACQUIRED) IMMUNITY

Characteristics

Phases of Adaptive Immune Response

1. Recognition: T/B cells recognize specific antigen
2. Activation: Clonal expansion of antigen-specific cells
3. Effector phase: Cytotoxicity, antibody production, cytokine secretion
4. Contraction: 90% of effector cells undergo apoptosis
5. Memory: Long-lived memory cells persist

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UNIT 5: LYMPHOCYTES

T Lymphocytes

Thymic Education

• Positive selection: TCR must recognize self-MHC → survival; if not → apoptosis (death by neglect)
• Negative selection: TCR must NOT react strongly to self-peptide/MHC → autoreactive cells deleted (clonal deletion)

T Cell Subsets

CD4+ T Helper Subsets

T Cell Activation - Two-Signal Model

1. Signal 1: TCR recognizes peptide-MHC complex on APC
2. Signal 2 (co-stimulation): CD28 (T cell) + B7 (CD80/CD86 on APC)
   • Without Signal 2 → Anergy (T cell unresponsiveness)
3. Signal 3: Cytokines determine differentiation (IL-12 → Th1; IL-4 → Th2)

B Lymphocytes

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UNIT 6: NEUTROPHILS

Origin

Structure

• Multilobed nucleus (2-5 lobes; >5 = hypersegmented in B12/folate deficiency)
• Primary (azurophilic) granules: Myeloperoxidase (MPO), defensins, elastase, lysozyme, cathepsins
• Secondary (specific) granules: Lactoferrin, collagenase, B12-binding proteins
• Tertiary granules: Gelatinase, alkaline phosphatase

Functions

1. Phagocytosis (see Phagocytosis section)

2. Degranulation

• Primary granules fuse with phagosome → MPO + H2O2 + Cl- → HOCl (bleach) = most potent ROS

3. Oxidative Burst (Respiratory Burst)

• NADPH oxidase converts O2 → superoxide (O2•-) → H2O2 → HOCl (via MPO)
• Chronic Granulomatous Disease: NADPH oxidase defect → recurrent catalase-positive organism infections (Staph, Aspergillus)

4. Neutrophil Extracellular Traps (NETs)

• Chromatin + granule proteins extruded → trap pathogens (NETosis)

Neutrophil Recruitment Steps

1. Margination: Slowing in postcapillary venules (leukostasis)
2. Rolling: Selectin-PSGL-1 interaction (P-selectin, E-selectin, L-selectin)
3. Firm adhesion: Integrin (LFA-1/Mac-1) + ICAM-1 (upregulated by IL-1, TNF)
4. Transmigration (diapedesis): Through endothelial junctions via PECAM-1 (CD31)
5. Migration: Along chemokine gradient (C5a, IL-8, LTB4, fMLP)

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UNIT 7: ANTIGEN PRESENTING CELLS (APCs)

Definition

Professional APCs

MHC Presentation Rules

• MHC Class I (on all nucleated cells): Presents endogenous peptides (intracellular, viral, tumor) to CD8+ T cells
• MHC Class II (on professional APCs only): Presents exogenous peptides to CD4+ T cells
• Cross-presentation: DCs can present exogenous antigens on MHC I to CD8+ T cells

Antigen Processing

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UNIT 8: EOSINOPHILS

Origin

Granule Contents

• Major basic protein (MBP): Toxic to helminths and host tissues
• Eosinophil cationic protein (ECP): Anti-parasitic, neurotoxic
• Eosinophil peroxidase: Generates ROS
• Eosinophil-derived neurotoxin (EDN)
• Charcot-Leyden crystals: Lysophospholipase; found in asthmatic sputum

Functions

1. Anti-parasitic immunity: Kill helminths (too large for phagocytosis) via ADCC - IgE coats parasite → eosinophil Fc receptor → degranulation
2. Allergy/Asthma: MBP damages airway epithelium; contributes to late-phase allergic response
3. Phagocytosis: Limited; mostly extracellular killing

Causes of Eosinophilia (>0.5 × 10^9/L)

• Allergy (asthma, allergic rhinitis, eczema)
• Parasitic infections (especially tissue-invasive helminths)
• Drug reactions
• Loeffler syndrome (transient pulmonary eosinophilia)
• Hypereosinophilic syndrome
• Addison disease (loss of cortisol)

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UNIT 9: NATURAL KILLER (NK) CELLS

Origin

Key Concept: "Missing Self" Hypothesis (Karre)

• Normal healthy cells express MHC I → inhibitory signal to NK cells via KIR (Killer Ig-like Receptors) and NKG2A/CD94 → NK cell spared
• Virus-infected/tumor cells downregulate MHC I → NK cell activates and kills
• Activated cells upregulate NKG2D ligands (MICA, MICB) → activating signal

Activation/Inhibition Balance

Killing Mechanisms

1. Perforin/Granzyme pathway: Perforin forms pores; Granzyme B enters → activates caspases → apoptosis
2. Fas-FasL: Apoptosis of Fas-expressing targets
3. Cytokine secretion: IFN-γ (activates macrophages), TNF-α

NK Cell Role

• Viral infections (especially herpes group)
• Tumor surveillance
• Missing self-detection
• ADCC: Kill IgG-coated cells via CD16

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UNIT 10: BASOPHILS

Origin

Structure

• Bilobed nucleus
• Large basophilic granules containing: histamine, heparin, proteases, PAF (platelet activating factor)
• Surface: high-affinity IgE receptor (FcεRI)

Function

• In Type I hypersensitivity: IgE crosslinking by antigen → degranulation → release of:
  • Preformed: Histamine, heparin, proteases
  • Newly synthesized: Leukotrienes (LTC4, LTD4), PGD2, PAF
• Histamine → vasodilation, increased permeability, bronchospasm, smooth muscle contraction
• Similar to mast cells but found in blood (mast cells are tissue-resident)

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UNIT 11: MAST CELLS

Origin

Subtypes

Activation

• IgE-dependent: Antigen crosslinks 2 IgE molecules bound to FcεRI → degranulation
• IgE-independent: Complement (C3a, C5a), trauma, cold, opioids, contrast media

Mediators

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UNIT 12: MONOCYTES & MACROPHAGES

Monocyte

• Circulates in blood (5-10% of WBC); half-life ~1-3 days in blood
• Recruited to tissues by MCP-1 (CCL2)
• Differentiates into macrophages (resident) or dendritic cells

Macrophage (Mononuclear Phagocyte System)

Tissue-specific Names

Macrophage Activation

• Triggered by: IFN-γ + LPS (or TNF-α)
• Produces: TNF-α, IL-1, IL-6, IL-12, ROS, NO
• Function: Killing intracellular pathogens, inflammation

• Triggered by: IL-4, IL-13
• Produces: IL-10, TGF-β, arginase (makes ornithine → collagen)
• Function: Tissue repair, fibrosis, anti-inflammatory

Macrophage Functions

1. Phagocytosis and killing of pathogens
2. Antigen presentation (MHC II) to CD4+ T cells
3. Cytokine secretion: IL-1, IL-6, IL-12, TNF-α
4. Granuloma formation: Epithelioid cells + Langhans giant cells
5. Wound healing: M2 macrophages produce growth factors
6. Foam cells: Macrophages ingest oxidized LDL → atherosclerosis

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UNIT 13: DENDRITIC CELLS

Types

Life Cycle of Conventional DC

1. Immature state in tissues: High phagocytic capacity, low co-stimulatory molecule expression
2. Capture antigen → mature → migrate to draining lymph node
3. Mature state in lymph node: ↓ phagocytosis, ↑↑ MHC II, ↑↑ B7 (CD80/86), CCR7+ for lymph node homing
4. Present antigen to naïve T cells → initiate primary immune response

Key Concept

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UNIT 14: PHAGOCYTOSIS

Steps of Phagocytosis

1. Recognition: Phagocyte surface receptors recognize opsonized particles
   • Fc receptors (FcγRI, II, III): Bind IgG Fc
   • Complement receptors (CR1, CR3): Bind C3b/iC3b
   • Lectin receptors: Bind mannose, glucan
2. Engulfment: Pseudopod extension → zipper mechanism → phagosome formation
3. Phagolysosome formation: Phagosome + lysosome fuse
4. Killing mechanisms:
   • Oxygen-dependent: NADPH oxidase → O2•- → H2O2 → MPO converts to HOCl
   • Oxygen-independent: Lysozyme, defensins, lactoferrin, elastase, low pH

Opsonins

• IgG (most important)
• C3b
• Fibronectin, CRP, Serum amyloid A (acute phase proteins)

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UNIT 15: CYTOKINES

Definition

Key Cytokines Table

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UNIT 16: HISTOCOMPATIBILITY ANTIGENS (MHC)

HLA (Human Leukocyte Antigen) System

• Encoded on chromosome 6p21 (short arm of chromosome 6)
• Most polymorphic gene complex in the human genome
• Codominant expression: Both alleles expressed

MHC Class I (HLA-A, B, C)

• Structure: α chain (polymorphic, chromosome 6) + β2-microglobulin (chromosome 15)
• Expression: All nucleated cells + platelets (NOT RBCs)
• Function: Present endogenous peptides (8-10 aa) to CD8+ T cells
• Antigen groove: Formed by α1 + α2 domains

MHC Class II (HLA-DR, DP, DQ)

• Structure: α + β chain (both encoded on chromosome 6)
• Expression: Professional APCs only (DCs, macrophages, B cells) + thymic epithelium; can be induced on other cells by IFN-γ
• Function: Present exogenous peptides (13-25 aa) to CD4+ T cells
• HLA-DR is the most important - most allelic variation

MHC Class III

• Complement components (C2, C4, Factor B), TNF-α, heat shock proteins
• Not directly involved in antigen presentation

Clinical Significance of HLA Associations

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UNIT 17: HYPERSENSITIVITY REACTIONS (Gell & Coombs Classification)

Type I - Immediate (IgE-mediated)

• First exposure to allergen → Th2 response → B cells switch to IgE → IgE binds FcεRI on mast cells and basophils (sensitization; no symptoms)

• Allergen crosslinks 2+ IgE on mast cells → degranulation
• Early phase (0-30 min): Histamine, tryptase, PAF → vasodilation, edema, bronchospasm, itching
• Late phase (2-24 hrs): LTC4/D4/E4, IL-4, IL-5, TNF → eosinophil recruitment, sustained inflammation

Type II - Cytotoxic (IgG or IgM-mediated)

1. Complement activation: C3b opsonization + MAC lysis
2. ADCC: NK cells via FcγRIII
3. Phagocytosis: Fc receptor-mediated

Type III - Immune Complex-mediated

Type IV - Delayed-Type (Cell-mediated, T cell-mediated)

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UNIT 18: AUTOIMMUNITY

Mechanisms of Tolerance Failure

1. Release of sequestered antigens: Lens protein, sperm (behind blood-testis barrier)
2. Molecular mimicry: Streptococcal M protein mimics cardiac myosin → rheumatic fever
3. Failure of peripheral tolerance: CTLA-4, PD-1, Treg deficiency
4. Epitope spreading: Immune response broadens to adjacent epitopes
5. Polyclonal B cell activation: EBV activates B cells non-specifically
6. Genetic predisposition: HLA genes + other susceptibility genes

General Features

• More common in females (2-9:1 ratio)
• Often multisystem
• ANA (anti-nuclear antibody) common marker
• Fluctuating course: Flares and remissions

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Systemic Lupus Erythematosus (SLE)

Pathogenesis

• Failure to clear apoptotic debris → nuclear antigens (dsDNA, histones, Sm) exposed → autoantibodies formed → immune complex deposition

ACR Criteria (SOAP BRAIN MD - 11 criteria, ≥4 required for diagnosis)

• Serositis (pleuritis, pericarditis)
• Oral ulcers (painless)
• Arthritis (non-erosive, ≥2 joints)
• Photosensitivity
• Blood disorders (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia)
• Renal disease (proteinuria >0.5g/day, cellular casts)
• ANA positive
• Immunologic markers (anti-dsDNA, anti-Sm, aPL antibodies)
• Neurological (seizures, psychosis)
• Malar (butterfly) rash
• Discoid rash

Important Autoantibodies in SLE

Lupus Nephritis (WHO/ISN-RPS Classes)

• Class I: Normal light microscopy; mesangial deposits only by IF
• Class II: Mesangial proliferative
• Class III: Focal proliferative (<50% glomeruli)
• Class IV: Diffuse proliferative (>50% glomeruli) - Most severe; worst prognosis; "wire loop" lesions
• Class V: Membranous - nephrotic syndrome; subepithelial deposits
• Class VI: Advanced sclerosing

Treatment

• Mild: NSAIDs, hydroxychloroquine, low-dose steroids
• Moderate: Higher dose corticosteroids, azathioprine
• Severe nephritis: Cyclophosphamide or mycophenolate mofetil
• Antiphospholipid syndrome: Anticoagulation (warfarin)

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Rheumatoid Arthritis (RA)

Pathogenesis

1. Genetic predisposition: HLA-DR4/DR1 (shared epitope hypothesis)
2. Environmental trigger (e.g., smoking, Porphyromonas gingivalis): Citrullination of proteins
3. Activated CD4+ Th1/Th17 cells in synovium → IL-1, IL-6, IL-17, TNF-α
4. Synovial hyperplasia → pannus formation (invasive granulation tissue)
5. Pannus destroys cartilage (collagenases) and bone (RANKL-mediated osteoclast activation)

Autoantibodies

• Rheumatoid Factor (RF): IgM anti-IgG; present in ~70-80%; not specific (also in SLE, Sjögren, infections)
• Anti-CCP (anti-citrullinated protein/peptide): >95% specific for RA; appears early; predicts severity

Joint Pathology

• Symmetric small joint arthritis (PIP, MCP, wrists, knees, ankles)
• Pannus: Granulation tissue from inflamed synovium; destroys cartilage and bone
• Radiograph: Periarticular osteopenia → joint space narrowing → erosions → joint deformity

Extra-articular Features

Treatment Pyramid

1. NSAIDs + hydroxychloroquine
2. DMARDs (disease-modifying): Methotrexate (anchor drug), sulfasalazine, leflunomide
3. Biologics: Anti-TNF (infliximab, etanercept, adalimumab), anti-IL-6 (tocilizumab), anti-CD20 (rituximab), CTLA-4-Ig (abatacept)

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Ankylosing Spondylitis (AS)

Key Facts

• HLA-B27 association: >90% of patients
• Predominantly affects males (M:F = 3-5:1); onset <40 years
• Seronegative spondyloarthropathy (RF negative)

Pathogenesis

• HLA-B27 presents arthritogenic peptide? Misfolded HLA-B27? Gut dysbiosis?
• Inflammation at entheses (insertions of tendons/ligaments into bone)
• New bone formation → syndesmophytes → bamboo spine

Clinical Features

• Inflammatory back pain: Insidious onset, worse at rest/early morning, improved with exercise, >3 months
• Bilateral sacroiliitis: Hallmark; detected on X-ray or MRI
• Progressive ankylosis: Spine fuses → rigid bamboo spine
• Reduced chest expansion (<2.5 cm in Schober's test)
• Extra-articular: Anterior uveitis (25-30%), aortitis/aortic regurgitation, pulmonary fibrosis (upper lobes), IgA nephropathy

X-Ray Findings

• Bilateral sacroiliitis (earliest)
• Squaring of vertebral bodies
• Syndesmophytes (ossification of annulus fibrosus)
• "Bamboo spine" (advanced)
• "Shiny corner sign" (Romanus lesion)

Treatment

• NSAIDs (first-line), physiotherapy
• Anti-TNF agents (etanercept, adalimumab) for NSAID-refractory cases
• Anti-IL-17 (secukinumab, ixekizumab)

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Systemic Sclerosis (Scleroderma)

Pathogenesis - Three Key Abnormalities

1. Fibroblast dysfunction: Excessive collagen production (Types I & III)
2. Vascular damage: Endothelial injury → intimal proliferation → Raynaud's → ischemia → fibrosis
3. Immune dysregulation: T cell activation → TGF-β → fibrosis

Types

Organ Involvement

• Skin: Thickening, tightening, loss of wrinkles, "hide-bound" skin, salt-and-pepper pigmentation
• GI: Esophageal dysmotility (most common; lower 2/3 = smooth muscle); malabsorption
• Lung: Interstitial fibrosis (most common cause of death in diffuse); pulmonary hypertension (limited)
• Kidney: Scleroderma renal crisis (malignant hypertension + thrombotic microangiopathy); treat with ACE inhibitors
• Heart: Myocardial fibrosis, pericarditis
• Raynaud's phenomenon: Vasospasm of digital arteries → white → blue → red (triphasic)

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UNIT 19: TRANSPLANT REJECTION

HLA Matching Importance

• Most important loci: HLA-DR > HLA-B > HLA-A
• Blood group ABO compatibility also required
• Crossmatch: Recipient serum + donor lymphocytes → if positive → pre-formed antibodies → hyperacute rejection

Types of Rejection

Hyperacute Rejection

• Timing: Minutes to hours
• Mechanism: Pre-formed antibodies (ABO incompatibility or anti-HLA antibodies from prior sensitization) → antibody + complement → microvascular thrombosis → ischemic necrosis
• Histology: Neutrophil infiltration → fibrinoid necrosis of vessels → thrombosis
• Treatment: None; must remove graft
• Prevention: Crossmatch testing before transplant

Acute Rejection

Acute Cellular Rejection

• Timing: Days to months (usually 1 week - 3 months)
• Mechanism: T cell-mediated
  • CD4+ T cells recognize allogeneic MHC II (direct) or processed peptide on self-MHC II (indirect) → cytokine secretion → macrophage activation
  • CD8+ CTL recognize allogeneic MHC I (direct) → perforin/granzyme → graft cell death
• Histology: Dense mononuclear infiltrate (lymphocytes, macrophages) + "tubulitis" (lymphocytes infiltrating tubular epithelium in kidney)
• Treatment: High-dose corticosteroids; if steroid-resistant → anti-thymocyte globulin (ATG)

Antibody-Mediated Rejection (Acute)

• Timing: Days to months
• Mechanism: Donor-specific antibodies (DSA) against HLA antigens → fix complement → endothelial injury
• Histology: Neutrophils in capillaries; C4d deposition in peritubular capillaries (marker)
• Treatment: Plasmapheresis, IVIG, rituximab

Chronic Rejection

• Timing: Months to years
• Mechanism: Both immune (T cell + antibody) and non-immune factors (hypertension, drug nephrotoxicity); intimal proliferation of arteries; progressive fibrosis
• Histology: "Obliterative arteritis" (intimal smooth muscle proliferation → luminal narrowing); interstitial fibrosis; tubular atrophy
• Treatment: No effective treatment; immunosuppression slows progression; eventually re-transplant

Immune Recognition of Allograft

Direct Pathway

• Recipient T cells recognize intact allogeneic MHC (with or without peptide) on donor APCs
• Dominant in acute rejection
• Large numbers of T cells react (since ~1-10% of T cells react to any given allogeneic MHC)

Indirect Pathway

• Donor MHC antigens shed → processed by recipient APCs → presented as peptides on self MHC to recipient T cells
• Dominant in chronic rejection
• Smaller number of T cells react

T Cell Mediated Rejection (Mechanism)

1. Direct/indirect recognition of alloantigens
2. CD4+ T cell activation → IL-2 → clonal expansion
3. Th1 → IFN-γ → macrophage activation → tissue damage
4. CD8+ CTL → perforin/granzyme → graft cell death
5. B cells (with T cell help) → anti-donor antibody → antibody-mediated rejection

Graft-vs-Host Disease (GvHD)

• In bone marrow/stem cell transplantation: Donor T cells attack recipient tissues
• Organs: Liver (↑ bilirubin), skin (rash), gut (diarrhea)
• Acute GvHD: <100 days; Th1/Th17 T cells
• Chronic GvHD: >100 days; fibrosis, resembles autoimmune disease

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UNIT 20: IMMUNODEFICIENCY

Primary (Congenital) Immunodeficiency

B Cell Deficiencies

T Cell Deficiencies

Combined (T + B) Deficiencies

Phagocyte Deficiencies

Complement Deficiencies

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Secondary (Acquired) Immunodeficiency

Causes

• HIV/AIDS (most important)
• Malnutrition (most common worldwide)
• Immunosuppressive drugs (corticosteroids, chemotherapy, biologic agents)
• Malignancy (lymphoma, leukemia, myeloma → B cell dysfunction)
• Diabetes mellitus (↓ phagocyte function)
• Burns (loss of physical barrier)
• Splenectomy (↑ encapsulated bacteria)
• Extremes of age

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AIDS (Acquired Immunodeficiency Syndrome)

HIV Biology

• Virus: HIV-1 (pandemic) and HIV-2 (West Africa, milder)
• Family: Retroviridae; Lentivirus genus
• Genome: Two copies of ssRNA(+); diploid
• Enzymes: Reverse transcriptase (RNA→DNA), Integrase (integrates into host genome), Protease (cleaves polyproteins)
• Envelope glycoproteins: gp120 (binds CD4) + gp41 (fusion with membrane)

HIV Entry Mechanism

1. gp120 binds CD4 receptor on T cell (or macrophage/DC)
2. gp120 changes shape → binds co-receptor (CCR5 on macrophages = M-tropic; CXCR4 on T cells = T-tropic)
3. gp41 mediates membrane fusion → viral RNA enters cell
4. Δ32 mutation in CCR5 → resistance to HIV-1 infection (found in ~1% Europeans)

HIV Life Cycle

1. Attachment: gp120-CD4-CCR5/CXCR4
2. Fusion: gp41
3. Reverse transcription: ssRNA → dsDNA (by reverse transcriptase - error-prone → mutations)
4. Integration: dsDNA → host genome (by integrase) = provirus
5. Transcription/translation
6. Assembly + budding
7. Maturation: Protease cleaves polyproteins

Drugs Targeting HIV Life Cycle

Natural History of HIV

1. Acute phase (2-4 weeks post-infection): "Flu-like" illness; high viremia; CD4 ↓; HIV p24 antigen positive; seroconversion
2. Chronic/latent phase (years): Clinical latency but viral replication continues; CD4 slowly declines; CD4 count ~500-200 cells/μL; minor opportunistic infections
3. AIDS: CD4 <200 cells/μL OR AIDS-defining illness

AIDS-Defining Conditions

Pathogenesis - CD4+ T Cell Depletion

• HIV directly kills CD4+ T cells (lysis, apoptosis)
• CTL destroy infected CD4+ T cells
• Follicular dendritic cell reservoir
• Progressive decline in CD4 → profound immunosuppression
• Functional defects appear before numerical decline

Laboratory Markers

Treatment

• ART (Antiretroviral therapy): HAART = 2 NRTIs + 1 INSTI (preferred) or NNRTI or PI
• Goal: Undetectable viral load; restore CD4 count
• Start in all patients regardless of CD4 count
• PCP prophylaxis: TMP-SMX when CD4 <200
• MAC prophylaxis: Azithromycin when CD4 <50

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UNIT 21: AMYLOIDOSIS

Definition

Properties of Amyloid

• Congo red stain: Pink/red color; apple-green birefringence under polarized light - diagnostic!
• Electron microscopy: Non-branching fibrils, 7.5-10 nm width
• X-ray diffraction: Cross-β pattern (β-pleated sheet)
• All amyloids share: β-pleated sheet structure, Congo red birefringence, fibrillar appearance

Amyloid P Component (SAP)

• Glycoprotein derived from serum amyloid P protein (SAP)
• Pentameric; found in all amyloid deposits
• Not the fibrils themselves; binds to fibrils; protects from degradation

Classification by Protein Precursor

1. Primary (AL) Amyloidosis

• Protein: AL (Amyloid Light chain) - derived from immunoglobulin light chains (κ or λ; λ more common)
• Associated disease: Plasma cell dyscrasias (Multiple myeloma, Waldenström macroglobulinemia, monoclonal gammopathy)
• Systemic distribution: Heart, kidneys, GI, liver, spleen, nerves, skin, tongue (macroglossia)
• Kidney: Nephrotic syndrome (most common presentation), later renal failure
• Heart: Restrictive cardiomyopathy; "sparkling" pattern on echo; low voltage on ECG
• Tongue: Macroglossia - pathognomonic for AL amyloidosis

2. Reactive Systemic (AA) Amyloidosis

• Protein: AA (Amyloid Associated) - derived from SAA (Serum Amyloid A), an acute phase reactant
• Associated disease: Chronic inflammatory conditions:
  • Rheumatoid arthritis, SLE, Crohn's disease
  • TB, leprosy, osteomyelitis, bronchiectasis
  • Familial Mediterranean fever (FMF)
  • Hodgkin lymphoma
• Systemic distribution: Kidneys (most common; nephrotic syndrome), liver, spleen, adrenals
• NOT heart or brain (differs from AL)
• Kidney: Glomerular mesangial + subendothelial deposits → nephrotic syndrome

3. Familial (Hereditary) Amyloidosis

• Protein: ATTR (mutated transthyretin/TTR) or Apolipoprotein A1, fibrinogen, gelsolin, lysozyme
• Most common type: Familial amyloid polyneuropathy (FAP) - mutated TTR (Val30Met mutation)
• Features: Peripheral and autonomic neuropathy; cardiomyopathy; vitreous opacities
• Other familial: Familial Mediterranean Fever → AA amyloidosis (not ATTRm)

4. Amyloid of Aging (Senile/Wild-type ATTR)

• Protein: Normal (wild-type) transthyretin (TTR) - also called senile systemic amyloidosis
• Age: Elderly (>70 years); predominantly males
• Features: Restrictive cardiomyopathy (most prominent; cardiac amyloid); carpal tunnel syndrome
• No light chain component; no plasma cell dyscrasia

5. Endocrine Amyloidosis

• Protein: Amyloid derived from locally produced hormones/peptides
• Examples:

  Tissue	Protein precursor	Disease
  Pancreatic islets	IAPP (Islet Amyloid Polypeptide = amylin)	Type 2 Diabetes Mellitus
  Thyroid	Calcitonin	Medullary carcinoma of thyroid
  Pituitary	Prolactin	Pituitary adenoma

6. Localized Amyloidosis

• Amyloid deposits restricted to a single tissue/organ without systemic spread
• Examples:
  • Alzheimer's disease: Aβ (beta-amyloid from APP) protein in brain (senile plaques) + tau (neurofibrillary tangles)
  • Prion disease (CJD): PrP^Sc
  • Type 2 Diabetes: IAPP in islets (localized if not systemic)
  • Bladder, trachea: Local deposits of AL or other proteins
  • Amyloid in orbit, conjunctiva

Summary Table of Amyloid Types

Diagnosis of Amyloidosis

1. Tissue biopsy: Abdominal fat pad biopsy (safest, ~80% sensitivity in systemic), rectal biopsy, kidney biopsy
2. Congo red staining: Apple-green birefringence under polarized light
3. Immunohistochemistry: Type the amyloid (anti-λ/κ for AL; anti-SAA for AA; anti-TTR for ATTR)
4. SAP scintigraphy: ^123I-labeled SAP → quantify body burden
5. Echocardiography: "Sparkling" pattern + thickened walls + diastolic dysfunction

Treatment

• AL: Treat underlying plasma cell dyscrasia; bortezomib-based regimens; autologous stem cell transplant
• AA: Treat underlying inflammatory disease; Colchicine for FMF (prevents AA amyloidosis)
• ATTR: Tafamidis (TTR stabilizer); patisiran/inotersen (RNA interference - reduce TTR production)
• General: Supportive (renal - dialysis; cardiac - diuretics, anti-arrhythmic)

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UNIT 22: IMMUNE DEFICIENCY - QUICK REVIEW

How to Remember Which Infections Suggest Which Deficiency

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Quick Reference: Key Markers

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