Immune Tolerance & Mechanisms of Autoimmunity
How the immune system learns to spare self, and how it forgets
Overview: two layers of tolerance
Why tolerance is needed. Random V(D)J recombination inevitably produces receptors that recognize self. Tolerance is the set of mechanisms that removes or silences these lymphocytes. Autoimmunity results when a genetically susceptible person meets an environmental trigger that overrides them.
Central tolerance acts on developing lymphocytes: strongly self-reactive T cells are deleted in the thymus, and self-reactive B cells in the marrow undergo receptor editing or deletion. Peripheral tolerance catches the clones that escape, through anergy, regulatory T cells, inhibitory receptors, Fas-mediated deletion and the sequestration of antigens in immune-privileged sites. Self-reactive cells that never meet their antigen simply remain ignorant.
Central tolerance and APS-1
Thymic selection. In the cortex, positive selection keeps T cells that can bind self-MHC at all. In the medulla, negative selection removes those that bind self-peptide-MHC too tightly; some intermediate-affinity cells are diverted into thymic (natural) Tregs instead of dying.
AIRE. The autoimmune regulator is a transcription factor in medullary thymic epithelial cells that switches on thousands of tissue-restricted antigens, such as insulin and thyroglobulin, so that T cells reactive to peripheral organs can be deleted before they leave the thymus.
APS-1 (APECED). Autosomal recessive AIRE mutations let organ-specific T cells escape. The classic triad is chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency, often with ectodermal dystrophy of enamel and nails. Candidiasis usually appears first in childhood and reflects neutralizing autoantibodies against IL-17 and IL-22, cytokines required for mucosal antifungal defense.
Peripheral tolerance
Anergy. A naive T cell needs two signals: TCR engagement of peptide-MHC and CD28 binding B7 (CD80/CD86) on a professional APC. TCR signaling without costimulation leaves the cell functionally unresponsive. Because most tissue cells never express B7, self-antigen displayed on them tolerizes rather than activates. Abatacept (CTLA-4-Ig) exploits this rule by binding B7 and blocking signal 2 in rheumatoid arthritis.
Regulatory T cells. Tregs are CD4+ CD25+ FOXP3+. They arise in the thymus or are induced in the periphery by TGF-β and IL-2. They suppress other lymphocytes by secreting IL-10 and TGF-β, by using surface CTLA-4 to strip B7 from APCs, and by consuming IL-2 through their high-affinity CD25 (IL-2Rα) receptor.
IPEX. X-linked FOXP3 mutation eliminates functional Tregs: immune dysregulation, polyendocrinopathy, enteropathy, X-linked. Infant boys develop intractable watery diarrhea with villous atrophy, neonatal type 1 diabetes, eczematous dermatitis, thyroiditis and high IgE. Hematopoietic stem-cell transplant is the definitive treatment.
Inhibitory receptors. CTLA-4 and PD-1 turn activated T cells down and keep responses to self in check.
| Feature | CTLA-4 | PD-1 |
|---|---|---|
| Ligand | B7 (CD80/CD86), with higher affinity than CD28 | PD-L1, PD-L2 |
| Main site and phase | Lymph nodes, during priming | Peripheral tissues, effector phase |
| Blocking drugs | Ipilimumab | Nivolumab, pembrolizumab (PD-L1: atezolizumab) |
Deletion by Fas. Lymphocytes stimulated repeatedly by persistent self-antigen co-express Fas (CD95) and Fas ligand. Fas engagement recruits FADD and caspase-8 and triggers extrinsic apoptosis, called activation-induced cell death.
ALPS. FAS mutations cause autoimmune lymphoproliferative syndrome: chronic childhood lymphadenopathy, splenomegaly and autoimmune cytopenias (Coombs-positive hemolytic anemia, thrombocytopenia), with expanded CD4−CD8− double-negative TCRαβ T cells and increased lymphoma risk.
| Syndrome | Gene, inheritance | Mechanism lost | Hallmarks |
|---|---|---|---|
| APS-1 (APECED) | AIRE, autosomal recessive | Thymic negative selection | Candidiasis, hypoparathyroidism, adrenal insufficiency |
| IPEX | FOXP3, X-linked | Regulatory T cells | Enteropathy, neonatal diabetes, eczema, high IgE |
| ALPS | FAS (most often) | Activation-induced apoptosis | Lymphadenopathy, splenomegaly, cytopenias, double-negative T cells |
Immune privilege
Privileged sites. The eye, brain and testis limit immune attack through blood-tissue barriers, low MHC expression, local Fas ligand that kills entering lymphocytes, and TGF-β-rich fluids. Antigens there are sequestered rather than tolerated, so exposure can provoke autoimmunity.
Sympathetic ophthalmia. Penetrating trauma or surgery to one eye releases uveal antigens that prime T cells, producing a bilateral granulomatous uveitis weeks to months later that threatens the uninjured eye. Classic prevention is early enucleation, within about 2 weeks, of a blind and severely injured eye; established disease needs systemic immunosuppression.
Vasectomy can similarly expose sperm antigens and induce antisperm antibodies.
How tolerance breaks
| Mechanism | What happens | Classic example |
|---|---|---|
| HLA susceptibility | Alleles shape which self-peptides are presented | B27 spondyloarthritis; DR4 RA; DR3/DR4 type 1 diabetes; DQ2/DQ8 celiac |
| Molecular mimicry | Antimicrobial response cross-reacts with a similar host structure | Strep M protein → cardiac myosin (rheumatic fever); Campylobacter lipooligosaccharide → GM1 ganglioside (Guillain-Barré) |
| Bystander activation | Inflammation raises B7 and cytokines, activating ignorant or anergic self-reactive cells | Autoimmunity flaring after infection |
| Epitope spreading | Tissue damage exposes new self-epitopes, broadening the response | Progressive diversification of autoantibodies |
| Neoantigen formation | Modified self-proteins look foreign | Smoking-induced citrullination in RA |
| Sequestered antigen release | Hidden antigens meet lymphocytes | Sympathetic ophthalmia |
Molecular mimicry. Rheumatic fever follows untreated group A streptococcal pharyngitis by about 2-4 weeks, as antibodies and T cells against M protein cross-react with cardiac myosin and valve tissue. HLA genes load the gun; environmental triggers like these pull it.
Citrullinated neoantigens. Cigarette smoke activates peptidylarginine deiminase in the lung, converting arginine residues in self-proteins to citrulline. In carriers of HLA-DR4 shared-epitope alleles these neoantigens provoke anti-CCP antibodies years before rheumatoid arthritis appears in the MCP and PIP joints.
Female predominance. Most autoimmune diseases favor women. Estrogen enhances B-cell survival and antibody production, and the X chromosome carries immune genes (TLR7, CD40L, FOXP3), some of which escape X-inactivation and are expressed at a higher dose.
Men with Klinefelter syndrome (XXY) have lupus rates approaching those of women, supporting an X-chromosome dose effect.