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Mechanism of immune tolerance Robbins based md pathology exam answer

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Robbins Basic Pathology immune tolerance central peripheral mechanisms

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Mechanisms of Immune Tolerance

Immune tolerance is a state of specific immunologic unresponsiveness to an antigen. Self-tolerance prevents immune reactions against the body’s own antigens. Loss of self-tolerance results in autoimmune disease.
Mechanisms are divided into:
  1. Central tolerance: occurs in primary lymphoid organs
  2. Peripheral tolerance: acts on self-reactive lymphocytes that escape central tolerance

1. Central tolerance

A. T-cell central tolerance - thymus

Immature T cells recognizing self-antigen with high affinity in the thymus undergo:

i. Negative selection or clonal deletion

  • Strong recognition of self peptide-MHC by immature thymocytes activates apoptosis.
  • It deletes potentially harmful high-affinity self-reactive T cells.

ii. Development of regulatory T cells

  • Some self-reactive CD4+ T cells differentiate into FOXP3+ regulatory T cells (Tregs) instead of dying.
  • Tregs migrate to peripheral tissues and suppress immune responses to self antigens.

Role of AIRE

  • AIRE (autoimmune regulator) in medullary thymic epithelial cells induces expression of many tissue-restricted self antigens in the thymus.
  • This permits deletion of T cells reactive to antigens normally present only in peripheral organs, such as endocrine tissues.
  • Defect of AIRE causes failure of central tolerance and autoimmune polyendocrine syndrome.

B. B-cell central tolerance - bone marrow

When immature B cells strongly recognize multivalent self antigens, they may undergo:

i. Receptor editing

  • The B cell reactivates light-chain gene rearrangement.
  • A new B-cell receptor is produced that is no longer self-reactive.
  • This is an important mechanism unique to B cells.

ii. Clonal deletion

  • If receptor editing fails, strongly self-reactive B cells undergo apoptosis.

iii. Anergy

  • Recognition of certain soluble self antigens may make immature B cells functionally unresponsive.

2. Peripheral tolerance

Central tolerance is incomplete. Mature self-reactive T and B cells may enter peripheral lymphoid tissues; they are controlled by the following mechanisms.

A. Peripheral T-cell tolerance

i. Anergy

Anergy is long-lasting functional unresponsiveness.
It occurs when a T cell recognizes antigen but does not receive adequate co-stimulation.
  • Signal 1: TCR recognition of peptide-MHC
  • Signal 2 absent: lack of B7 on APC binding to CD28 on T cell
Self antigens are often presented by resting APCs without co-stimulation, leading to anergy rather than activation.
Inhibitory receptors:
  • CTLA-4 binds B7 with higher affinity than CD28 and inhibits T-cell activation.
  • PD-1 binds PD-L1/PD-L2 and inhibits activation, proliferation, and survival of T cells.

ii. Suppression by regulatory T cells

Tregs are generally CD4+ CD25+ FOXP3+ cells. They maintain peripheral self-tolerance by:
  • Secreting inhibitory cytokines: IL-10 and TGF-beta
  • Expressing CTLA-4, which reduces co-stimulatory capacity of APCs
  • Consuming IL-2, thereby limiting effector T-cell proliferation
  • Directly suppressing activation of T cells and APCs

iii. Deletion or apoptosis

Repeated or persistent stimulation of self-reactive T cells, or antigen recognition without survival signals, causes apoptotic cell death.
Important pathways:
  • Intrinsic mitochondrial pathway: increased pro-apoptotic proteins such as BIM
  • Fas-Fas ligand pathway: activation-induced cell death

B. Peripheral B-cell tolerance

Self-reactive mature B cells are normally prevented from producing autoantibodies by:

i. Anergy

  • Encounter with soluble self antigen without appropriate T-cell help makes the B cell unresponsive.
  • Such cells may have reduced surface IgM and impaired signaling.

ii. Deletion

  • Persistent self-antigen stimulation can lead to apoptosis of autoreactive B cells.

iii. Inhibitory receptors

  • Co-ligation of BCR and inhibitory receptors, especially FcγRIIB, suppresses B-cell activation.
  • Complement receptor-related inhibitory signals may also contribute.

iv. Lack of T-cell help

  • Most high-affinity antibody responses require helper T cells.
  • If autoreactive helper T cells are tolerant, autoreactive B cells do not receive CD40L and cytokine signals needed for activation, class switching, and affinity maturation.

Other protective mechanisms

Sequestration of self antigens

Some self antigens are hidden from the immune system in immune-privileged sites, such as:
  • Eye
  • Testis
  • Central nervous system
Trauma or inflammation may expose these antigens and trigger autoimmune responses.

Flowchart for exam

Self-reactive lymphocyte
→ Central tolerance
  • T cells in thymus: deletion or Treg formation
  • B cells in bone marrow: receptor editing, deletion, anergy
→ Cells escaping to periphery
→ Peripheral tolerance
  • Anergy due to absent co-stimulation or CTLA-4/PD-1 signaling
  • Treg-mediated suppression
  • Apoptotic deletion
  • In B cells: inhibitory receptors and absence of T-cell help
→ Failure of these mechanisms leads to autoimmunity.

One-line conclusion

Immune tolerance is maintained by deletion, receptor editing, anergy, suppression by Tregs, and apoptosis of self-reactive lymphocytes.
This structure is consistent with the standard Robbins approach. The parallel textbook summary describes central T-cell deletion/Treg formation, B-cell receptor editing/deletion, and peripheral anergy, Treg suppression, and apoptosis in the same framework: Cellular and Molecular Immunology, pp. 958-959, 1026.
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