peripheral tolerance

**Definition:** Peripheral tolerance prevents autoimmunity against self-antigens that were not presented in the thymus (tissue-restricted antigens not covered by AIRE) or against low-affinity self-reactive clones that escaped negative selection. It also limits responses to harmless foreign antigens (food, commensals) and fetal antigens.

**Contrast with central tolerance:** - Central: thymus (T cells: positive selection in cortex, negative selection in medulla; AIRE drives expression of tissue-specific antigens) and bone marrow (B cells: receptor editing, clonal deletion, anergy). - Peripheral: occurs in secondary lymphoid organs and tissues, after the cells have matured.

**Mechanisms of T-cell peripheral tolerance:** 1. **Anergy (functional inactivation):** TCR engagement (signal 1) without costimulation (signal 2, e.g., B7 binding CD28) makes the cell unresponsive. Self-antigens presented by APCs that are not activated (low B7) cause anergy. 2. **Regulatory T cells (Tregs):** CD4+ CD25+ FOXP3+. They suppress other T cells via IL-10, TGF-β, IL-35, CTLA-4 (which outcompetes CD28 for B7), and IL-2 consumption (CD25 = IL-2Rα). FOXP3 mutation causes **IPEX** (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked): autoimmune diabetes, enteropathy/diarrhea, eczema. 3. **Clonal deletion (activation-induced cell death):** Repeated stimulation upregulates Fas (CD95) and FasL, triggering caspase-mediated apoptosis. Defects in Fas or FasL cause **autoimmune lymphoproliferative syndrome (ALPS)**: lymphadenopathy, splenomegaly, autoimmune cytopenias, elevated double-negative (CD4-CD8-) T cells. Also via BIM-mediated (intrinsic) apoptosis. 4. **Inhibitory (checkpoint) receptors:** CTLA-4 (competes with CD28 for B7) and PD-1 (binds PD-L1/PD-L2) deliver inhibitory signals. Blocking them with drugs (ipilimumab, anti-CTLA-4; pembrolizumab/nivolumab, anti-PD-1) enhances antitumor immunity but causes immune-related adverse events (colitis, hepatitis, thyroiditis, hypophysitis, pneumonitis). CTLA-4-Ig (abatacept, belatacept) uses this pathway therapeutically (RA, transplant). 5. **Immune privilege / sequestration:** Sites such as the eye, testis, brain, and placenta have limited immune access and express FasL. Release of sequestered antigen after trauma can trigger autoimmunity (e.g., sympathetic ophthalmia, autoimmune orchitis). 6. **Ignorance:** Low-affinity or low-concentration self-antigen is not recognized.

**B-cell peripheral tolerance:** - Self-reactive B cells that encounter antigen without T-cell help become anergic or undergo apoptosis (they lack CD40-CD40L co-stimulation from helper T cells). Anergic B cells have reduced surface IgM, and are excluded from follicles and die faster (limited BAFF survival signals). - Lack of T-cell help is the main safeguard, so T-cell tolerance indirectly protects against autoantibody production.

**Clinical correlations:** - Failure of peripheral tolerance → autoimmune disease: IPEX (FOXP3), ALPS (Fas/FasL/caspase-10), CTLA-4 haploinsufficiency, SLE (defective clearance of apoptotic material, loss of B-cell tolerance), and immune checkpoint inhibitor toxicity. - Therapeutic exploitation: oral tolerance, allergen immunotherapy (induces Tregs/IgG4), and tolerance induction in transplantation. - Note: APS-1 (APECED, AIRE mutation) is a defect of **central** tolerance, a frequent board distractor. Mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency are its classic features.

**High-yield pearls:** - Signal 1 without signal 2 → anergy. - FOXP3 → Tregs → IPEX; Fas/FasL → ALPS; AIRE → central tolerance (APS-1). - CTLA-4 and PD-1 are "brakes" on T cells; checkpoint inhibitors release them.