STEPTRACKERIMMUNOLOGY + GENETICS | AUTOIMMUNITY | HIGH-YIELD REVIEW

Tolerance & Mechanisms of Autoimmunity

Autoimmunity happens when the safeguards against self-reactive lymphocytes fail — usually a genetic tilt (HLA and immune genes) plus an environmental trigger.

FOCUS ON
Central tolerance: thymic negative selection (AIRE), B-cell receptor editing/deletion in marrow. Peripheral tolerance: anergy (no costimulation), Tregs (FOXP3, IL-10, TGF-β, CTLA-4), activation-induced cell death (Fas–FasL), immune privilege (eye, testis, brain). Triggers: molecular mimicry (GAS M protein → rheumatic fever; Campylobacter → Guillain-Barré), bystander activation, release of sequestered antigen (sympathetic ophthalmia), epitope spreading, drugs (procainamide, hydralazine, isoniazid → drug-induced lupus). Women are affected more often (SLE ~9:1). Monogenic examples: AIRE (APS-1), FOXP3 (IPEX), Fas (ALPS), CTLA-4 haploinsufficiency, early complement deficiency (SLE). Checkpoint inhibitors unmask autoimmunity.
MECHANISM
HOW IT WORKS
FAILURE → DISEASE
CLUE
Thymic negative selection
AIRE shows tissue antigens; strong binders die
AIRE mutation → APS-1: chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency
Autoantibodies to IL-17/IL-22 explain the Candida
B-cell central tolerance
Receptor editing, deletion in marrow
Defective editing ↑ autoreactive B cells
—
Anergy
Signal 1 without B7–CD28 → unresponsive T cell
Infection-induced B7 on APCs can break anergy
Abatacept restores it
Regulatory T cells
FOXP3⁺CD25⁺; IL-10, TGF-β, CTLA-4, IL-2 consumption
FOXP3 → IPEX; CD25 deficiency; CTLA-4 haploinsufficiency
Enteropathy, type 1 diabetes, eczema in infant boys
Activation-induced cell death
Fas on activated lymphocytes binds FasL → apoptosis
Fas/FasL mutation → autoimmune lymphoproliferative syndrome
Lymphadenopathy, splenomegaly, autoimmune cytopenias, ↑ double-negative T cells
Immune privilege
Barrier and local suppression (eye, testis, CNS, fetus)
Trauma releases antigen → sympathetic ophthalmia, autoimmune orchitis
Injury to one eye → uveitis in the other
Molecular mimicry
Microbial antigen resembles self
Rheumatic fever (GAS M protein ↔ myosin), Guillain-Barré (Campylobacter LOS ↔ gangliosides), reactive arthritis
Weeks after infection
Bystander activation · epitope spreading
Inflammation activates nearby self-reactive cells; response broadens to new self-epitopes
Progression of MS, type 1 diabetes
—
Drug-induced autoimmunity
Altered self proteins, slow acetylation
Drug-induced lupus (procainamide, hydralazine, isoniazid, TNF inhibitors) · anti-histone antibodies, spares kidney and CNS
Resolves after stopping drug
Checkpoint blockade
Removes CTLA-4/PD-1 brakes
Colitis, hepatitis, thyroiditis, hypophysitis, pneumonitis, type 1 diabetes, myocarditis
Steroids for severe reactions
Sex and hormones
Estrogen enhances B-cell activity; X-chromosome genes (TLR7)
SLE, Sjögren, Hashimoto more common in women
Flares in pregnancy (SLE) vary
Shared risk genes
HLA class II, PTPN22, CTLA4, IL2RA, STAT4
Clusters of autoimmune disease in families and individuals
Type 1 diabetes + celiac + thyroiditis together

Mechanism — molecular mimicry

InfectionGAS pharyngitis
→
Antibodies / T cells to M protein
→
Cross-react with cardiac myosin, valves
→
Rheumatic carditisWeeks later

Monogenic autoimmunity

GENE
SYNDROME
SIGNATURE
AIRE
APS-1
Candida, hypoparathyroid, Addison
FOXP3
IPEX
Enteropathy, diabetes, eczema
FAS
ALPS
Nodes, spleen, cytopenias
C1q, C2, C4
SLE-like
Immune-complex disease

How it's tested

COMMON CONFUSIONDrug-induced lupus (anti-histone, no renal or CNS disease, resolves) vs SLE (anti-dsDNA, nephritis, low complement).
THE TRAPNew hypothyroidism, colitis or adrenal crisis in a patient on cancer immunotherapy is an immune-related adverse event, not metastasis.
YOUR APPROACHWhich safeguard failed (central, Treg, Fas, privilege) or what trigger (mimicry, drug, checkpoint) → disease pattern → key antibody.

If you see… think…

Thymic gene allowing negative selection to tissue antigens → AIRE
Infant boy with diarrhea, diabetes and eczema → IPEX (FOXP3)
Lymphadenopathy, splenomegaly and autoimmune cytopenias → ALPS (Fas)
Uveitis in the healthy eye after injury to the other → sympathetic ophthalmia
Carditis weeks after strep throat → molecular mimicry (rheumatic fever)
Ascending paralysis after Campylobacter → mimicry with gangliosides
Lupus on hydralazine with anti-histone antibodies → drug-induced lupus
Colitis after starting ipilimumab → checkpoint inhibitor toxicity
T cell given signal 1 without signal 2 → anergy
Lupus-like disease from early complement deficiency → poor immune-complex clearance