SN5 SHORT NOTE 5M ★ High-yield

Describe immunological tolerance and the mechanisms by which it is lost.

Pathology · 2nd Professional — Para-Clinical

Definition

Immunological tolerance is the state of unresponsiveness to an antigen induced by prior exposure to it; self-tolerance is the tolerance of one’s own antigens, whose failure causes autoimmune disease.

Central Tolerance

Cell	Site	Mechanism
T lymphocytes	Thymus	Negative selection — thymocytes binding self antigen too strongly undergo apoptosis. Self antigens from all over the body are expressed in the thymus under the control of the AIRE gene
B lymphocytes	Bone marrow	Strongly self-reactive B cells either edit their receptor (receptor editing) or are deleted

Mutation of AIRE causes autoimmune polyendocrine syndrome type 1, because self antigens are never displayed in the thymus and the corresponding clones are never deleted — direct proof of the mechanism
Some autoreactive CD4 cells become regulatory T cells instead of dying

Peripheral Tolerance

Mechanism	Explanation
Anergy	A T cell meeting antigen without the second (co-stimulatory) signal from B7–CD28 becomes permanently unresponsive
Regulatory T cells (Treg)	CD4+ CD25+ FOXP3+ cells actively suppress other lymphocytes through IL-10 and TGF-beta, and by CTLA-4
Deletion (activation-induced cell death)	Repeated stimulation triggers apoptosis through Fas–Fas ligand
Immune privilege	Some sites are hidden from the immune system — eye, testis, brain, and the fetus

FOXP3 mutation causes IPEX syndrome — severe multi-organ autoimmunity in infancy, showing how essential regulatory T cells are

CLINICAL PEARL

Two signals are needed to activate a lymphocyte, and that requirement IS peripheral tolerance. Antigen alone (signal 1) without co-stimulation (signal 2) produces anergy rather than activation. Since co-stimulatory molecules appear on antigen-presenting cells only during infection or tissue damage, self antigens encountered in a quiet tissue silence the cell instead of arming it.

Mechanisms of Breakdown

Failure of central or peripheral tolerance — defects in AIRE, FOXP3, Fas or CTLA-4
Molecular mimicry — a microbial antigen resembles a self antigen; rheumatic fever after group A streptococcal infection is the classic example
Release of sequestered antigen — sympathetic ophthalmia after penetrating eye injury; anti-sperm antibodies after vasectomy
Polyclonal activation by superantigens
Genetic susceptibility, chiefly HLA, and a strong female preponderance in most autoimmune disease

Applied Aspects

Rh isoimmunisation is prevented by inducing tolerance artificially — anti-D immunoglobulin removes fetal cells before the mother can respond to them
Desensitisation (allergen immunotherapy) induces regulatory T cells and blocking IgG, and is the only treatment that modifies the natural history of allergy
Checkpoint inhibitors in cancer block CTLA-4 and PD-1 to deliberately break tolerance against tumours — and predictably cause autoimmune colitis, thyroiditis and hepatitis as a consequence
The fetus is a natural allograft tolerated for nine months, through trophoblast lacking classical MHC, local regulatory T cells and immunosuppressive factors
Inducing tolerance rather than suppressing immunity remains the goal in transplantation, and would remove the need for lifelong immunosuppression

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