Immune Tolerance & Autoimmunity
A Step 1 high-yield walkthrough of immune tolerance — central (thymic positive/negative selection, AIRE; B-cell receptor editing) and peripheral (anergy, FOXP3+ Tregs, CTLA-4, Fas–FasL) — linked to the monogenic tolerance-failure diseases (APS-1, IPEX, ALPS, complement-deficiency SLE) and to the HLA associations, molecular-mimicry mechanisms, and signature autoantibodies the boards test.
Overview: Self-Tolerance vs Autoimmunity
Immune tolerance is the acquired failure to mount a destructive response against self-antigens. It operates in two arms. Central tolerance happens in the primary lymphoid organs — the thymus (T cells) and bone marrow (B cells) — where strongly self-reactive lymphocytes are deleted or edited before they mature. Peripheral tolerance happens in secondary lymphoid tissue and the periphery, restraining the autoreactive clones that inevitably slip through.
Autoimmunity usually requires more than one tolerance mechanism to fail. Because central tolerance is inherently leaky, low-affinity autoreactive lymphocytes routinely reach the periphery in everyone; clinical disease emerges when peripheral tolerance also fails to restrain them (the autoreactive clone must be both generated and activated). The boards test this as a chain — a defined molecular/genetic defect → a specific tolerance mechanism that fails → a stereotyped autoimmune disease. Susceptibility is polygenic (HLA alleles are the strongest common risk) and is commonly triggered by infection (classically via molecular mimicry).
- T cells mature in the thymus through two sequential checks.
- Positive selection (thymic CORTEX): thymocytes whose TCR binds self-MHC with low/moderate affinity survive; those that cannot engage self-MHC die by neglect. Ensures MHC restriction.
- Negative selection (thymic MEDULLA): thymocytes whose TCR binds self-peptide–self-MHC with HIGH affinity are deleted by apoptosis (clonal deletion); some intermediate-affinity clones are instead diverted into regulatory T cells.
- AIRE (AutoImmune REgulator): transcription factor in medullary thymic epithelial cells that drives ectopic "promiscuous" expression of tissue-restricted self-antigens (e.g., insulin) so organ-specific autoreactive T cells can be displayed as self and deleted. Loss of AIRE → APS-1 / APECED.
- B cells mature in bone marrow: immature B cells binding self-antigen with high avidity first attempt receptor editing (re-express RAG, rearrange a new light chain); if that fails → clonal deletion or anergy.
- Anergy: a lymphocyte receiving signal 1 (antigen/TCR–MHC) without signal 2 (costimulation, B7[CD80/86]–CD28) becomes functionally unresponsive. B cells anergize when they bind antigen without T-cell help.
- Regulatory T cells (Tregs): CD4+ CD25+ FOXP3+. Suppress autoreactive cells via CTLA-4, secreted IL-10 and TGF-β, and consumption of IL-2 (CD25 = high-affinity IL-2Rα). Loss of FOXP3 → IPEX.
- CTLA-4 (CD152): binds B7 with higher affinity than CD28 and delivers an inhibitory signal (competes away costimulation). PD-1/PD-L1 is a second inhibitory checkpoint. Both are targets of cancer checkpoint-inhibitor drugs — whose characteristic adverse effect is iatrogenic autoimmunity.
- Peripheral clonal deletion: strongly/repeatedly stimulated T cells undergo apoptosis via Fas (CD95)–FasL. Defect → ALPS.
- Immune-privileged sites (eye, testis, brain, placenta) sequester self-antigens behind barriers; trauma releasing them can trigger autoimmunity (e.g., sympathetic ophthalmia).
Central vs Peripheral Tolerance
| Feature | Central tolerance | Peripheral tolerance |
|---|---|---|
| Location | Thymus (T cells); bone marrow (B cells) | Secondary lymphoid organs & tissues |
| Timing | During lymphocyte development | After mature lymphocytes exit |
| T-cell mechanism | Negative selection (clonal deletion); AIRE self-antigen display; Treg generation | Anergy, Treg suppression, Fas–FasL apoptosis |
| B-cell mechanism | Receptor editing → deletion/anergy | Anergy (antigen without T-cell help) |
| Key molecules/genes | AIRE, RAG | FOXP3, CTLA-4, IL-10, TGF-β, Fas/FasL |
| Failure example | APS-1 (AIRE) | IPEX (FOXP3), ALPS (Fas) |
Molecule / Gene → Function → Disease When Defective
| Molecule / gene | Normal tolerance role | Defect → disease (key features) |
|---|---|---|
| AIRE | mTEC display of tissue-restricted self-antigens for negative selection | APS-1 / APECED (AR): chronic mucocutaneous candidiasis + hypoparathyroidism + adrenal insufficiency |
| FOXP3 | Master transcription factor of Tregs | IPEX (X-linked): autoimmune enteropathy + type 1 diabetes + thyroiditis + eczema, ↑IgE |
| Fas (CD95) / FasL | Apoptotic peripheral deletion of autoreactive lymphocytes | ALPS: lymphadenopathy + hepatosplenomegaly + autoimmune cytopenias; ↑ CD4−CD8− "double-negative" T cells |
| CTLA-4 | Inhibitory checkpoint outcompeting CD28 for B7 | Haploinsufficiency → autoimmune cytopenias/enteropathy/lymphoproliferation; blockade (ipilimumab) → immune-related adverse events |
| Early classical complement (C1q, C4, C2) | Clearance of immune complexes & apoptotic cells | Deficiency → SLE (C1q deficiency = highest-penetrance genetic risk) |
1. AIRE → APS-1 (APECED). A child has recurrent oral thrush (chronic mucocutaneous candidiasis), then perioral numbness and tetany from hypoparathyroidism (low Ca²⁺), and later fatigue, hyperpigmentation, and hypotension from adrenal insufficiency (Addison). Autosomal recessive; failed thymic negative selection.
2. FOXP3 → IPEX. A male infant in the first months of life has intractable watery diarrhea (autoimmune enteropathy), neonatal type 1 diabetes, thyroiditis, and an eczematous rash with elevated IgE. X-linked; absent functional Tregs.
3. Fas/FasL → ALPS. A child has chronic non-malignant lymphadenopathy and splenomegaly with autoimmune hemolytic anemia and thrombocytopenia; flow cytometry shows expanded double-negative T cells (CD3+ TCRαβ+ CD4− CD8−). Defective Fas-mediated apoptosis; increased lifetime lymphoma risk.
- Molecular mimicry (most tested): a microbial epitope resembles self.
- Rheumatic fever — S. pyogenes M protein ↔ cardiac myosin.
- Guillain–Barré — Campylobacter jejuni ↔ peripheral-nerve gangliosides.
- Release of sequestered self-antigen: sympathetic ophthalmia (eye trauma), post-MI/Dressler syndrome.
- Superantigens (TSST-1, staph/strep exotoxins): cross-link MHC II to TCR Vβ outside the peptide groove → massive polyclonal T-cell activation.
- HLA associations:
- HLA-B27 → PAIR (Psoriatic, Ankylosing spondylitis, IBD-associated, Reactive arthritis).
- HLA-DR3 & DR4 → type 1 diabetes; DR4 → RA; DR3 → SLE, Graves.
- HLA-DQ2/DQ8 → celiac disease.
- HLA-DR2 → multiple sclerosis, Goodpasture, SLE.
- HLA-B47 → 21-hydroxylase deficiency; HLA-A3 → hemochromatosis.
- Signature autoantibodies: anti-dsDNA / anti-Smith (SLE), anti-CCP (RA), anti-Scl-70 (diffuse scleroderma), anti-centromere (CREST/limited scleroderma), anti-Jo-1 (polymyositis/dermatomyositis), anti-mitochondrial (PBC), anti-TPO (Hashimoto), TSI (Graves), anti-AChR (myasthenia gravis).
- PAIR — HLA-B27 diseases: Psoriatic arthritis, Ankylosing spondylitis, IBD-associated (enteropathic) arthritis, Reactive arthritis.
- Selection direction: Positive selection = your TCR passes because it recognizes self-MHC; Negative selection = you're deleted for being too self-reactive.
- The disease acronyms encode the phenotype: IPEX = Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked. APECED = Autoimmune PolyEndocrinopathy–Candidiasis–Ectodermal Dystrophy.
- ALPS → "double-negative" (CD4−CD8−) T cells — the buzzword that nails the diagnosis.
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