The different mechanisms through which immune tolerance to antigens can occur, and their relative importance in preventing the development of allergic disease

Table of Contents

Allergy

Central Tolerance
T-cell tolerance
B-cell Tolerance

Peripheral Tolerance
Anergy
Deletion
B cell antibody production

Immune Deviation

Regulatory Lymphocytes
Regulatory T cells: Treg, Tr1, Th3
Regulatory B cells: Breg, Br1, Br3

Innate Immune System: Dendritic cells

Immune Privilege

Tolerance in Pregnancy

Induced Tolerance

Conclusion

References

The different mechanisms through which immune tolerance to antigens can occur, and their relative importance in preventing the development of allergic disease

Leahy, C 2014

Immune tolerance is the inhibition or absence of an immune response leaving only protective and beneficial immunity intact. Tolerance reduces response to both self and non-self antigens, which are substances which stimulate antibody production.

Tolerance breakdown causes immune disease; failed self-tolerance causes incorrect identification of self as foreign, causing autoimmune disease¹. Failure of induced tolerance causes overzealous identification of harmless foreign substances as a threat, causing hypersensitivities².

Allergy

Allergy occurs when a harmful immune response develops to an otherwise harmless foreign substance (the ‘allergen’); mainly type I hypersensitivity, although it can be mixed with type IV³. Type I is immediate hypersensitivity reaction, mediated by IgE. Antigens are presented to specific Th2 cells that release IL-4 and IL-13, stimulating B cell production of antigen-specific IgE. The atopic immune system has a polarised Th2 population⁴.

Initial exposure causes sensitisation and allergen-specific IgE formation. During acute reactions, mediators such as prostaglandins and histamine are released by mast cells (figure 1) leading to allergy symptoms.

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Figure 1: Mechanism of tolerance taken from Li et al 20084

After dendritic cells (DCs) encounter the allergen they promote Th2 cell proliferation. Th2 cells produce IL-4 and IL-13. These cytokines help switch mature B cell to IgE isotype. IgE binds to FcεR1 on mast cells and cross-links them causing degranulation of allergy mediators. Allergic asthma pulmonary iNKT cells are activated by glycolipid antigens and can amplify Th2 response. Eosinophils also contribute to allergic response, particularly in the lungs.

Type IV delayed type hypersensitivity (DTH) is cell-mediated chronic inflammation driven by macrophage IL-12 and allergen-specific T cell IFN-γ cross-talk and TNF release³. It is often a skin reaction, eg to nickel, driven by Th1 cells inducing tissue cell apoptosis.

Central Tolerance

Central tolerance, first theorised in 1959 by Joshua Lederberg⁵, is the induction of lymphocyte apoptosis or anergy within primary lymphoid organs; bone marrow for B cells and the thymus for T cells. It prevents self-reactive lymphocytes entering the circulation.

T-cell tolerance

T-cells respond to antigens in the context of major histocompatibility complex (MHC) on antigen presenting cells (APCs). Activation requires co-stimulation of both the cell-surface T cell receptor (TCR) and CD28 by the MHC and B7 on the APC, with lack of co-stimulatory CD28 engagement causing anergy⁶.

Within the thymus, cells are retained or excluded according to their receptor affinity for peptide antigen, leaving a pool of functionally useful T-cells (figure 2), with ~98% dying during selection⁷. Firstly, pluripotent haemopoietic stem cells from the bone marrow produce precursor CD4-CD8-T-cells which seed in the thymus from week eight of development⁸. β-repertoire selection ensures thymocytes with a functional TCR β-chain survive and divide, with TCRα gene rearrangement and differentiation to CD4+CD8+ αβ+ cells.

Positive selection of thymocytes which have self-MHC binding, during MHC presentation by thymic DCs, occurs and thymocytes which fail die ‘by neglect’. Negative selection occurs during overly strong responses to MHC, resulting in apoptosis, ensuring self tolerance.

Autoimmune regulator (AIRE) is a transcriptional control element which promotes central tolerance during negative selection by enhancing antigen-presentation by thymic DCs⁹. When AIRE is absent autoimmunity overwhelms the body.

The resulting mature cells are either CD4+ in response to MHC class II or CD8+ to MHC class I. Thymic DCs also drive regulatory T cell formation, which has a large role in peripheral tolerance.

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Figure 2: Mechanisms of central tolerance of T cells in the thymus, taken from Takahama et al, 20067

Positive selection to ensures survival of CD4+ and CD8+ T cells capable of recognising MHC classes. Negative selection prevents unwanted strong immune response to the body’s own tissues and prevents autoimmunity. “Death by neglect” is where positive selection has failed due the no recognition of MHC and peptide.

B-cell Tolerance

B cells are part of the humoral immune response, primarily making antibodies against specific antigens. In the context of allergy they are stimulated by Th2 cells producing IL-4 to switch immunoglobulin classes to IgE.

During the transitional phase in B cell maturity, induction of tolerance occurs that helps shape the final B cell receptor (BCR) repertoire. Immature B cells encounter self antigens in the bone marrow and negative selection ensures that the cells which are self-reactive undergo apoptosis or anergy⁹. Where BCR has limited cross-linking to self-antigens, anergy occurs. Where multivalent self-antigens cause extensive BCR cross-linking the B cell undergoes maturational arrest and receptor editing. Unsuccessful receptor revision leads to cell apoptosis and successful revision results in a pool of mature B cells which are not self-reactive.

Whilst central tolerance is vital for preventing autoimmune disease and some hypersensitivities it does not have an obvious role allergy, other than the production of regulatory T cells (Tregs).

Peripheral Tolerance

Central tolerance is not foolproof and antigens from peripheral tissues do not circulate within the primary lymphoid tissues. This can lead auto-reactive lymphocytes circulating in the body, with T cells and B cells being modulated or deleted to ensure no auto-reactivity and to suppress response to harmless external antigens.

Peripheral tolerance of T cells is regulated by intrinsic and extrinsic mechanisms. Intrinsic mechanisms involve T cell anergy, phenotype skewing and deletion and extrinsic mechanisms involve regulatory T cells, cytokines and APCs. Impairment of these mechanisms can lead to allergy.

Anergy

T cell anergy is induced by antigen recognition leading to functional inactivation, where the cell remains alive in a hyporesponsive state¹⁰. There are two types of anergy; clonal anergy and adaptive tolerance (table 1).

Clonal anergy arises from incomplete T cell activation, inhibiting cell cycle progression and IL-2 secretion. Anergy can be broken by exogenous IL-2¹¹. It is induced in CD4+ T cells about 6–12 h after strong TCR signal in the absence of costimulation, or by a low-affinity ligand with inhibitory costimulation, blocking the Ras/MAP kinase pathway with indirect blockage of the cell cycle and inhibiting IL-2 production¹². The CD28/B7 costimulation is vital in blocking anergy, although other costimulation pathways have roles, such as ICAM-1/LFA-1¹³.

Adaptive tolerance anergy occurs when cells down-regulate proliferation and differentiation functions due to persistent antigens and can be reversed in antigen absence¹⁰. It involves a block in tyrosine kinase activation and IL-2 receptor signalling. Both anergic states can be found in Tregs, preventing them from dominating and suppressing immune responses prematurely. B cell suppression is another mechanism by which inflammatory response is reduced¹⁴.

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¹ Van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science (New York, N.Y.) 1998;280(5361): pp. 243-248.

² Akdis M. Immune tolerance in allergy. Current opinion in immunology 2009;21(6): pp. 700-707.

³ Akdis CA. Allergy and hypersensitivity: mechanisms of allergic disease. Current opinion in immunology 2006;18(6): pp. 718-726.

⁴ Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance. The Journal of allergy and clinical immunology 2004;113(3): pp. 395-400.

⁵ LEDERBERG J. Genes and antibodies. Science (New York, N.Y.) 1959;129(3364): pp. 1649-1653.

⁶ Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annual Review of Immunology 2009;27: pp. 591-619.

⁷ Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature reviews.Immunology 2006;6(2): pp. 127-135.

⁸ Haynes BF, Heinly CS. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. The Journal of experimental medicine 1995;181(4): pp. 1445-1458.

⁹ Mathis D, Benoist C. Aire. Annual Review of Immunology 2009;27: pp. 287-312.

¹⁰ Schwartz RH. T cell anergy. Annual Review of Immunology 2003;21: pp. 305-334.

¹¹ Powell JD. The induction and maintenance of T cell anergy. Clinical immunology (Orlando, Fla.) 2006;120(3): pp. 239-246.

¹² Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunological reviews 2003;192: pp. 161-180.

¹³ Saeki K, Iwasa Y. T cell anergy as a strategy to reduce the risk of autoimmunity. Journal of theoretical biology 2011;277(1): pp. 74-82.

¹⁴ Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. Journal of immunology (Baltimore, Md.: 1950) 2005;175(7): pp. 4180-4183.