Auto immune disease short question in biochemistry
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autoimmune disease mechanisms tolerance breakdown diagram
Here is a complete, exam-focused set of short notes on Autoimmune Disease - Molecular/Immunological Mechanisms for MBBS/MD exams.
Autoimmune Disease - Mechanisms (Short Notes for MBBS/MD)
Definition
Autoimmune disease is a condition in which the immune system mounts a destructive response against self (host) antigens (autoantigens), resulting in tissue damage. Paul Ehrlich called this "horror autotoxicus." - Janeway's Immunobiology 10e
Q1. What is Self-Tolerance and how is it normally maintained?
Self-tolerance = the immune system's ability to recognise self-antigens but NOT attack them.
1. Central Tolerance (in primary lymphoid organs)
| Cell | Site | Mechanism |
|---|---|---|
| T cells | Thymus | Negative selection - strongly self-reactive T cells are deleted (clonal deletion) |
| B cells | Bone marrow | Deletion + receptor editing (replacement of self-reactive BCR) |
- AIRE gene (Autoimmune Regulator) in thymic medulla drives expression of peripheral tissue antigens (e.g., insulin) in the thymus, so self-reactive T cells can be deleted before they exit.
- Loss of AIRE → APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) - Janeway's Immunobiology 10e, p.719
2. Peripheral Tolerance (in secondary lymphoid organs and tissues)
| Mechanism | How it works |
|---|---|
| Clonal anergy | Autoreactive T cells that encounter self-antigen WITHOUT costimulation (signal 2) become unresponsive/anergic |
| Regulatory T cells (Treg / CD4+CD25+FoxP3+) | Suppress autoreactive effector T and B cells via IL-10, TGF-β, CTLA-4 |
| Activation-induced cell death (AICD) | Fas-FasL interaction induces apoptosis in repeatedly stimulated autoreactive lymphocytes |
| Immunological ignorance | Low-affinity self-reactive lymphocytes do not get activated because they never encounter co-activating signals |
| Antigen sequestration | Some self-antigens (e.g., lens proteins, sperm, myelin) are physically hidden behind barriers - not normally seen by the immune system |
| Immune-privileged sites | Brain, eye, testis, uterus suppress lymphocyte activation via TGF-β and FasL |
- Janeway's Immunobiology 10e (Fig. 15.1)
Q2. What are the mechanisms by which self-tolerance breaks down?
1. Molecular Mimicry
- Pathogen antigens structurally resemble self-antigens.
- Immune response against the pathogen cross-reacts with host tissue.
- Example: Streptococcal M-protein → anti-cardiac antibodies in Rheumatic Fever
- Goodman & Gilman's Pharmacological Basis of Therapeutics
2. HLA/MHC Association
- Certain HLA alleles present self-peptides more "efficiently" to T cells, increasing risk of autoreactive activation.
- Examples:
- HLA-DR3/DR4 → Type 1 Diabetes (T1DM)
- HLA-B27 → Ankylosing Spondylitis
- HLA-DR4 → Rheumatoid Arthritis
- HLA-DR2/DR3 → SLE
- HLA-DQ2/DQ8 → Celiac Disease
- Goodman & Gilman's, p.782
3. Altered Thymic Selection
- Infections (e.g., viruses) elevate Type I IFNs, which disrupt thymic negative selection, allowing autoreactive T cells to escape into the periphery.
4. Immunological Ignorance Broken
- Low-affinity autoreactive lymphocytes normally ignored can become activated if:
- Tissue inflammation provides strong co-stimulatory signals during infection
- Autoantigens act as ligands for TLRs (e.g., TLR-9 binds CpG DNA in SLE - nuclear self-DNA drives anti-dsDNA response)
- Janeway's Immunobiology 10e, p.719
5. Bystander Activation
- During infection, non-specific inflammation activates APCs in tissue; these present self-antigens with full co-stimulation, activating previously ignorant autoreactive T cells.
6. Epitope Spreading
- Initial immune response against one self-antigen destroys tissue → releases new self-antigens → more autoreactive clones activated → disease amplifies over time.
7. Loss/Dysfunction of Treg Cells
- Reduced FoxP3+ Treg activity → loss of suppression of autoreactive clones.
8. Polyclonal Activation
- Bacterial superantigens or viral products activate large numbers of T cells non-specifically, including autoreactive clones.
Q3. What are the effector mechanisms of autoimmune tissue damage?
Autoimmune tissue injury follows the same patterns as hypersensitivity reactions:
| Type | Mechanism | Example Disease |
|---|---|---|
| Type II (Antibody-mediated cytotoxic) | Autoantibodies bind cell-surface antigens → complement activation, ADCC, opsonization | Autoimmune hemolytic anemia, Myasthenia gravis (anti-AChR Ab), Graves' disease (anti-TSH-R Ab) |
| Type III (Immune complex) | Autoantibodies form immune complexes that deposit in tissues → complement + neutrophil activation | SLE (anti-dsDNA complexes in glomeruli, vessels) |
| Type IV (T cell-mediated) | Autoreactive CD4+ TH1/TH17 or CD8+ CTL cells directly kill self tissue | Type 1 Diabetes (CTL kill β cells), Multiple Sclerosis (TH17 cells cross BBB), Rheumatoid Arthritis |
- Goldman-Cecil Medicine; Cellular and Molecular Immunology
Q4. Key Autoimmune Disease Examples with Mechanisms
Rheumatoid Arthritis (RA)
- TH17 autoreactive cells activated (HLA-DR4 association)
- Anti-citrullinated protein antibodies (ACPA/anti-CCP) and Rheumatoid Factor (anti-IgG IgM)
- IL-17, IL-1, TNF-α → synovial inflammation → pannus formation → cartilage/bone erosion
- Janeway's Immunobiology 10e, p.737
Multiple Sclerosis (MS)
- Autoreactive TH17 cells against myelin antigens (MBP, PLP) cross the blood-brain barrier
- Microglial activation + macrophages + complement → demyelination
- Relapsing-remitting course
- Janeway's Immunobiology 10e, p.736
SLE (Systemic Lupus Erythematosus)
- Nuclear antigens released from apoptotic cells → self-DNA stimulates TLR-9 → anti-dsDNA antibodies
- Type III hypersensitivity → immune complex deposition in glomeruli, skin, joints
Type 1 Diabetes
- CD8+ CTL destroy insulin-producing β cells
- T cell-mediated (Type IV) + some autoantibodies (anti-islet cell)
- HLA-DR3/DR4 linkage; AIRE gene failure
- Robbins & Kumar Basic Pathology
Q5. Summary Table: Layers of Self-Tolerance (Exam Favourite)
| Type | Mechanism | Site |
|---|---|---|
| Central tolerance | Deletion, receptor editing | Thymus, bone marrow |
| Antigen sequestration | Physical barrier | Thyroid, pancreas, eye |
| Peripheral anergy | No co-stimulation → unresponsiveness | Lymph nodes |
| Regulatory T cells | IL-10, TGF-β suppression | Lymph nodes, tissues |
| AICD | Fas-FasL apoptosis | Lymph nodes |
| Immunological ignorance | Low-affinity, no activation | Peripheral tissues |
| Immune privileged sites | TGF-β, FasL | Brain, eye, testis |
- Janeway's Immunobiology 10e (Fig. 15.1)
Key One-Liners for MCQs
- AIRE defect → APECED (multiple endocrine organ autoimmunity)
- FoxP3 defect → IPEX syndrome (Immunodysregulation Polyendocrinopathy Enteropathy X-linked)
- Molecular mimicry = best example for Rheumatic Fever (Strep → cardiac)
- Graves' disease = stimulatory autoantibody (against TSH receptor) → Type II HS
- Myasthenia gravis = blocking autoantibody (against AChR) → Type II HS
- SLE = prototype Type III HS autoimmune disease
- T1DM, MS, RA = Type IV (T cell-mediated) dominant mechanism
- TH17 cells = key driver in RA and MS
- TLR-9 + self-DNA = key pathway in SLE pathogenesis
Sources: Janeway's Immunobiology 10e (Ch. 15), Goodman & Gilman's Pharmacological Basis of Therapeutics, Robbins & Kumar Basic Pathology, Goldman-Cecil Medicine, Cellular and Molecular Immunology
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