Autoimmunity: Definition, Criteria, Classification, and Mechanisms

1. Definition

"Pathogenic autoimmunity represents a breakdown in specific immunological tolerance... it may be that tolerance is initially operating effectively but that in genetically predisposed individuals an accumulation of environmental influences, and possibly mutations, eventually leads to uncontrolled pathogenic anti-self responses."

• Roitt's Essential Immunology, p. 528

2. Criteria for Autoimmunity (Rose & Bona's Updated Witebsky Postulates)

• For B-cell-mediated diseases, identifying the autoantigen is relatively easier since B cells react to whole proteins (e.g., anti-AChR antibodies in myasthenia gravis)
• For T-cell-mediated diseases, identifying the autoantigen is harder because T cells recognize processed peptides of 10-20 amino acids; autoreactivity alone in healthy individuals does not confirm disease causality
• Disease transfer by serum or T-cell transfer both confirms autoimmune etiology and proves pathogenic involvement (e.g., myasthenia gravis serum transfer to animals reproduces muscle weakness)
• Bradley and Daroff's Neurology in Clinical Practice, p. 1037
• Janeway's Immunobiology 10e, p. 724

3. Classification of Autoimmune Diseases

A. By Anatomical Scope: Organ-Specific vs. Systemic

"In organ-specific diseases, autoantigens from one or a few organs are targeted... By contrast, SLE is characterized by antibodies against antigens ubiquitous and abundant in every cell of the body, such as chromatin and the proteins of the pre-mRNA splicing machinery."

• Janeway's Immunobiology 10e

B. By Effector Mechanism: T-cell vs. B-cell Mediated

C. Gell & Coombs Classification by Hypersensitivity Type

• Firestein & Kelley's Textbook of Rheumatology, Classification table

4. Mechanisms of Autoimmunity

A. Failure of Central Tolerance

• Self-reactive T cells should be deleted by apoptosis (clonal deletion) in the thymus when they bind self-antigen with high affinity
• If a self-antigen is poorly expressed or absent in the thymus (e.g., cryptic epitopes), autoreactive T cells escape deletion and enter the periphery
• Certain MHC alleles (e.g., HLA-DRB1*1501 in MS) can present self-peptides and fail to induce effective deletion, linking HLA to disease susceptibility

• Self-reactive B cells normally undergo receptor editing (continued V(D)J recombination) to replace self-reactive B-cell receptors
• Failure of this editing allows autoreactive B cells to escape into the periphery

B. Failure of Peripheral Tolerance

• Peripheral autoreactive T/B cells are normally kept in check by:
  • Regulatory T cells (Tregs, CD4+CD25+FoxP3+)
  • Inhibitory co-receptors: CTLA-4, PD-1 binding to their ligands (B7, PD-L1) induces anergy
• Defects in CTLA-4 signaling or Treg function lead to unrestrained autoreactive lymphocyte activation

• Certain antigens (sperm, lens, myelin, cardiac antigens) are normally "hidden" from the immune system (immunological privilege)
• Physical trauma, infection, or tissue injury can release these antigens, activating previously ignorant self-reactive lymphocytes (e.g., sympathetic ophthalmia, post-myocardial infarction autoimmunity)

C. Molecular Mimicry

• Microbial antigens share structural/sequence similarities with self-antigens
• Immune responses against pathogens cross-react with self-tissues
• Examples:
  • Group A Streptococcus M protein → cross-reacts with cardiac myosin → rheumatic fever
  • Campylobacter jejuni (Penner O:19) → cross-reacts with ganglioside Gd1b → Guillain-Barré syndrome
  • Yersinia enterocolitica envelope proteins → share epitopes with the TSH receptor → thyroid autoimmunity
  • EBV → linked to SLE; P. gingivalis → linked to RA via citrullination of bacterial proteins

D. Bystander Activation

• Tissue inflammation from infection activates innate immune cells (macrophages, DCs) that present self-antigens non-specifically
• Local danger signals (PAMPs, DAMPs) provide co-stimulation that would otherwise be absent, breaking peripheral anergy
• Self-reactive T cells in the vicinity are activated not by molecular mimicry, but by the inflammatory environment itself

E. Modification of Self-Antigens

• Post-translational modifications (PTMs) can render self-proteins immunogenic:
  • Citrullination of vimentin, fibrinogen, collagen type II, and alpha-enolase in RA (strongly linked to smoking and HLA-DR shared epitope)
  • Drug-induced haptenization (e.g., alpha-methyldopa modifies RBC surface antigens → autoimmune hemolytic anemia)
• These modified antigens are perceived as "neo-antigens," bypassing existing T-cell tolerance

F. Epitope Spreading

• An initial autoimmune response to one epitope of a self-antigen causes tissue destruction, releasing new epitopes that were previously "cryptic" (unexposed)
• These new epitopes activate additional autoreactive clones, broadening and perpetuating the autoimmune response
• Explains why many autoimmune diseases progress and diversify over time (e.g., multiple autoantibodies in SLE)

G. Polyclonal Lymphocyte Activation / Superantigens

• Superantigens (e.g., Staphylococcal toxins) can cross-link MHC II molecules with the V-beta region of T-cell receptors, causing non-specific mass T-cell activation
• This polyclonal activation may activate autoantigen-specific clones among the broad repertoire
• Bystander B-cell activation by LPS or viral products can similarly induce non-specific autoantibody production

H. Genetic and Hormonal Factors

• HLA associations are the strongest genetic risk factors: HLA-DR2 (MS), HLA-DR3 (MG, SLE, Sjögren), HLA-DR4 (RA, Type 1 DM)
• Non-HLA genes: PTPN22, CTLA-4, STAT4, IRF5, BLK polymorphisms affect T-cell/B-cell signaling thresholds
• Sex: Women are disproportionately affected (ratio 9:1 in SLE), implicating sex hormones (estrogen promotes, testosterone suppresses immune responses) and X-chromosome dosage effects
• Epigenetics: DNA methylation and histone modification changes in lupus T cells activate genes like ITGAL (CD11a), contributing to autoreactivity

Summary Diagram of Mechanisms

Self-tolerance → maintained by:
├── Central: Clonal deletion (thymus/BM) + Receptor editing
└── Peripheral: Treg suppression + Anergy (CTLA-4/PD-1) + Apoptosis

Breakdown of tolerance (Autoimmunity) caused by:
├── Genetic factors (HLA, non-HLA genes)
├── Environmental triggers
│   ├── Infections → Molecular mimicry / Bystander activation
│   ├── Drugs/Chemicals → Antigen modification
│   └── UV radiation → Increased nuclear antigen exposure (SLE)
├── Failure of central tolerance (thymic negative selection defects)
├── Failure of peripheral tolerance (Treg dysfunction, CTLA-4/PD-1 defects)
├── Release of sequestered antigens
├── Epitope spreading
└── Post-translational modification of self-antigens

• Robbins & Kumar Basic Pathology (Robbins Pathology), p. 210
• Roitt's Essential Immunology, pp. 528-529
• Janeway's Immunobiology 10e, pp. 724-725
• Firestein & Kelley's Textbook of Rheumatology - Classification, Mechanisms and Models of Autoimmune Diseases
• Bradley and Daroff's Neurology in Clinical Practice, p. 1037
• Tietz Textbook of Laboratory Medicine, 7th Edition - Triggers of Autoimmunity

SECTION A - Question 4 (10 Marks)

a) Pathophysiology of Myocardial Infarction (6 Marks)

Step-by-Step Pathophysiology:

• Exposed collagen activates platelets → platelet adhesion, activation, aggregation
• Tissue factor (from the lipid core) triggers the coagulation cascade → fibrin clot forms
• The resultant thrombus occludes the coronary artery lumen

• Within seconds: Cessation of oxidative phosphorylation → switch to anaerobic glycolysis → ATP depletion
• Within minutes: Loss of contractile function; intracellular acidosis; K+ efflux (→ arrhythmias); Na+/Ca²+ pump failure → intracellular Ca²+ overload
• 20-40 minutes: Point of irreversible cell injury (coagulative necrosis begins in subendocardium)
• 3-6 hours: Transmural necrosis progresses (wavefront phenomenon - from endocardium outward)
• ST elevation on ECG reflects transmural injury current (injury current of Pardee)

• 0-24 hrs: Neutrophil infiltration
• 1-3 days: Macrophage-mediated removal of necrotic debris
• 1-2 weeks: Granulation tissue with neovascularization
• 4-6 weeks: Dense fibrous scar (non-contractile)

• Reduced cardiac output → cardiogenic shock
• Arrhythmias (most common early cause of death)
• Cardiac rupture (day 3-7 - risk at softened wall)
• Papillary muscle dysfunction → mitral regurgitation
• Pericarditis (Dressler syndrome)

b) Role of Atherosclerosis in MI Development (4 Marks)

Pathogenesis of Atherosclerosis (Response-to-Injury model):

• Hypertension (endothelial shear stress)
• Obesity (dyslipidemia, insulin resistance, systemic inflammation)
• Age and male sex

• Fuster and Hurst's The Heart, 15th Edition
• Robbins & Kumar Basic Pathology

SECTION B - Short Notes (6 × 5 = 30 Marks)

B1. T and B Lymphocytes (5 Marks)

T Lymphocytes

• Origin: Bone marrow stem cells → mature in the Thymus (hence "T")
• Surface marker: T-cell receptor (TCR) + CD3; Helper T cells are CD4+; Cytotoxic T cells are CD8+
• Function:
  • Helper T cells (CD4+/Th): Recognize antigen via MHC class II; secrete cytokines (IL-2, IFN-γ, IL-4) that activate B cells, cytotoxic T cells, and macrophages. Further subdivided into Th1, Th2, Th17, and Treg subsets.
  • Cytotoxic T cells (CD8+/Tc): Recognize antigen via MHC class I on any nucleated cell; kill virus-infected cells and tumor cells by releasing perforin and granzymes
  • Regulatory T cells (Tregs, CD4+CD25+FoxP3+): Suppress excessive immune responses and maintain self-tolerance
• Memory T cells: Long-lived; enable rapid secondary responses upon re-exposure to antigen

B Lymphocytes

• Origin and maturation: Bone marrow (hence "B"); mature in bone marrow
• Surface marker: B-cell receptor (BCR = surface immunoglobulin); also CD19, CD20, CD21
• Function:
  • Recognize intact antigens via BCR (no MHC processing required)
  • Activated by T-cell help (CD4+ Th cells) or T-independent antigens
  • Differentiate into plasma cells that secrete specific antibodies (IgM, IgG, IgA, IgE, IgD)
  • Differentiate into memory B cells for long-term humoral immunity
• Antibody functions: Neutralization, opsonization, complement activation (IgG, IgM), ADCC

• Roitt's Essential Immunology

B2. Penicillin Hypersensitivity - Type & Mechanism (5 Marks)

Gell & Coombs Classification - Type I:

1. Penicillin acts as a hapten - it is too small to be immunogenic alone, but its reactive beta-lactam ring binds covalently to self-proteins (carrier) forming a hapten-carrier conjugate
2. This conjugate is processed by APCs and presented to CD4+ T helper (Th2) cells
3. Th2 cells secrete IL-4 and IL-13, driving B cells to undergo class switching to IgE production
4. IgE antibodies bind to high-affinity FcεRI receptors on mast cells and basophils throughout the body (sensitization)
5. Patient is now sensitized - no symptoms yet

1. On re-exposure, penicillin-protein conjugate cross-links two adjacent IgE molecules on the mast cell surface
2. This triggers mast cell degranulation - release of:
   • Preformed mediators (immediate - within minutes): Histamine (→ vasodilation, bronchoconstriction, urticaria), heparin, tryptase
   • Newly synthesized mediators: Leukotrienes (LTC4, LTD4 → sustained bronchoconstriction), prostaglandins, PAF
3. Cytokines (TNF-α, IL-4) are also released, perpetuating the reaction

• Skin rash/urticaria - histamine-mediated vasodilation and increased vascular permeability
• Bronchospasm - histamine + leukotrienes cause smooth muscle contraction in airways
• Severe reaction = anaphylactic shock (hypotension, laryngeal edema, cardiovascular collapse)

B3. Allograft Rejection - Definition & Pathophysiology (5 Marks)

Types and Pathophysiology:

• Mechanism: Pre-formed anti-donor antibodies (against HLA or ABO blood group antigens) exist in the recipient (from prior transfusions, pregnancy, or transplant)
• These antibodies bind to donor endothelium → activate complement → immediate endothelial injury → platelet aggregation → intravascular thrombosis → irreversible graft ischemia
• Graft turns blue/black immediately on the operating table
• Not reversible - graft must be removed
• Prevented by pre-transplant crossmatch testing

• Host T cells recognize donor HLA antigens via:
  • Direct pathway: Host T cells recognize intact donor MHC on donor APCs (dendritic cells in the graft)
  • Indirect pathway: Host APCs present processed donor HLA peptides to host T cells
• CD8+ cytotoxic T cells directly lyse graft cells; CD4+ Th1 cells activate macrophages → tissue destruction
• Pathology: Lymphocytic infiltration of tubules, interstitium, and vascular structures (tubulitis, interstitial nephritis)

• De novo donor-specific antibodies → complement activation → C4d deposition in peritubular capillaries (diagnostic hallmark)
• Treatment: High-dose IV corticosteroids, antilymphocyte globulin, plasmapheresis

• Slow progressive loss of graft function
• Both cellular and humoral mechanisms contribute
• Characterized by obliterative vasculopathy (intimal thickening of graft vessels), fibrosis, and tubular atrophy
• No effective treatment; leads to eventual graft failure

• Goldman-Cecil Medicine

B4. Air Pollution & Health Hazards of Smoking Tobacco (5 Marks)

Air Pollution

• Respiratory: Chronic bronchitis, asthma exacerbations, reduced lung function, COPD, lung cancer (PM2.5 classified as Group 1 carcinogen by IARC)
• Cardiovascular: Particulates enter systemic circulation → endothelial dysfunction → accelerated atherosclerosis → increased MI and stroke risk
• Neurological: PM2.5 crosses blood-brain barrier → neuroinflammation → increased dementia risk
• Carcinogenesis: Polycyclic aromatic hydrocarbons (PAHs) cause DNA adduct formation

Health Hazards of Smoking Tobacco

• Chronic bronchitis (mucous gland hypertrophy, excess secretions)
• Emphysema (elastase-antielastase imbalance → alveolar wall destruction)
• COPD (irreversible airflow limitation)
• Lung cancer (squamous cell and small cell carcinoma - most strongly linked)

• Nicotine → catecholamine release → tachycardia, hypertension, vasospasm
• CO → carboxyhemoglobin → reduced oxygen delivery → ischemia
• Endothelial injury → atherosclerosis → IHD, MI, peripheral vascular disease, stroke
• Promotes thrombosis (increased platelet aggregation, fibrinogen)

• Oral cavity, pharynx, larynx, esophagus, stomach, pancreas, bladder, cervix cancers
• Nitrosamines and PAHs cause p53 mutations and DNA damage

• Infertility, spontaneous abortion, low birth weight, placenta previa
• SIDS (sudden infant death syndrome) in babies of smoking mothers

• Peptic ulcer disease (reduced mucosal prostaglandins)
• Osteoporosis, cataracts, impaired wound healing

B5. Dopamine Deficiency in the Pathophysiology of Parkinsonism (5 Marks)

Neuroanatomical Basis:

Pathology:

• Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta
• Lewy bodies (intraneuronal inclusions of misfolded alpha-synuclein) are the pathological hallmark
• Symptoms appear when >60-80% of dopaminergic neurons are lost (or striatal dopamine falls below 20% of normal)

Role of Dopamine Deficiency - Basal Ganglia Circuit Disruption:

• Dopamine acts on D1 receptors in the direct pathway (striatum → GPi → thalamus) → facilitates movement (Go)
• Dopamine acts on D2 receptors in the indirect pathway (striatum → GPe → STN → GPi) → inhibits the indirect pathway → further facilitates movement

• Direct pathway: D1 stimulation absent → striatum fails to inhibit GPi → GPi becomes overactive → excessive inhibition of thalamus → reduced thalamocortical output → bradykinesia/akinesia
• Indirect pathway: D2 inhibition absent → indirect pathway becomes overactive → STN overactivates GPi → further thalamic suppression → rigidity
• Net effect: Thalamus is excessively inhibited → motor cortex cannot initiate smooth voluntary movements

Clinical Features Due to Dopamine Deficiency:

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Stahl's Essential Psychopharmacology

B6. Acute Renal Failure vs. Chronic Renal Failure - Differentiation with Clinical Features (5 Marks)

Definitions:

• Acute Kidney Injury (AKI): Sudden (within hours to days) decline in kidney function with rise in serum creatinine ≥0.3 mg/dL within 48 hrs, or ≥1.5× baseline within 7 days, or urine output <0.5 mL/kg/hr for ≥6 hrs
• Chronic Kidney Disease (CKD): Persistent (>3 months) structural or functional abnormality of the kidneys, defined by GFR <60 mL/min/1.73 m²

Comparison Table:

• History of sudden insult (contrast, sepsis, NSAID use, obstruction) → AKI
• Long-standing diabetes/hypertension + small kidneys + anemia + renal osteodystrophy → CKD
• Broad waxy casts on urinalysis are pathognomonic of CKD (reflect dilated, scarred tubules)
• Goldman-Cecil Medicine; Brenner and Rector's The Kidney