Adaptive tolerance: Protection through self‐recognition

Abstract

The random nature of immunoglobulin gene segment rearrangement inevitably leads to the generation of self‐reactive B cells. Avoidance of destructive autoimmune reactions is necessary in order to maintain physiological homeostasis. However, current central and peripheral tolerance concepts fail to explain the massive number of autoantibody‐borne autoimmune diseases. Moreover, recent studies have shown that in physiological mouse models autoreactive B cells were neither clonally deleted nor kept in an anergic state, but were instead able to mount autoantibody responses. We propose that activation of autoreactive B cells is induced by polyvalent autoantigen complexes that can occur under physiological conditions. Repeated encounter of autoantigen complexes leads to the production of affinity‐matured autoreactive IgM that protects its respective self‐targets from degradation. We refer to this novel mechanism as adaptive tolerance. This article discusses the discovery of adaptive tolerance and the unexpected role of high affinity IgM autoantibodies.

Medical Geography and Ecology of Autoimmune Hashimoto Thyroiditis and Related Disorders

“…В Москве и на Орловщине носительство аутоантител к ЩЖ увеличивается с возрастом, достигая у пожилых женщин 15-30%. Обнаружение у индивида проявлений аутоиммунитета к ЩЖ, даже если придерживаться разделяемых нами представлений о существовании естественного регуляторного аутоиммунитета [12], не следует, тем не менее, оставлять без тактических медицинских последствий, так как подобные аутоантитела, даже сами не будучи патогенными, могут быть свидетелями начавшихся и еще не дошедших до стадии явной болезни иммунопатологических процессов [13]. Таких лиц (особенно пожилых женщин) важно наблюдать с определением сывороточного уровня тиротропного гормона (ТТГ) хотя бы раз в год.…”

“…Нас заинтересовала медицинская география описанных случаев ЭХ. Было проанализировано 133 публикации из баз данных PubMed (121) и РИНЦ (12), в которых суммарно представлено за последнее десятилетие 163 клинических случая ЭХ. Распространенность описаний ЭХ по странам отражена на рисунке 1 и в таблице 1.…”

Immune Tolerance vs. Immune Resistance: The Interaction Between Host and Pathogens in Infectious Diseases

“…Central immune tolerance is majorly performed in the thymus and bone marrow parts (organs and tissues of CIT) of the host body. During the development of an embryo and neonate stages, the T cells and immature B cells obtain tolerance against self-antigens by the selection processes, which may be positive or negative at the maturation time ( 38 ). During the process, the self-antigen receptors possessing cells are eliminated.…”

“…T cells that do not recognize either major histocompatibility complex (MHC)-I and MHC-II molecules degenerate through apoptosis and are known as “positive selection” ( 38 ) ( Figure 1 ). The high-affinity binding of T-cells to Major Histocompatibility complexes I, II, or I/II self-peptide complex are also directed to programmed cell death and are known as “negative selection” ( 38 ). A similar negative selection process has been observed during B cell development in the bone marrow.…”

Inborn errors of immunity and immunodeficiencies: Antibody‐mediated pathology and autoimmunity as a consequence of impaired immune reactions

“…Clonal deletion or receptor editing of self-reactive B cells are not the only mechanisms suggested to control primary repertoire self-reactivity. In new concept of adaptive tolerance [6], affinity-matured autoreactive IgM generated by activation of B cells by polyvalent autoantigen complexes can bind the autoantigen and protect it from degradation and consequent presentation to T cells. In adaptive tolerance, the complexity of the antigen (monovalent vs. multivalent) can influence generation and expansion of pathogenic autoantibodies.…”