Characterization of anti-DNA B cells that escape negative selection

Abstract

One of the challenges in the study of autoimmunity is to understand which autoreactive cells are subject to regulation and what mechanisms of regulation are operative. In mice transgenic for the R4A-gamma2b heavy chain of an anti-double stranded (ds) DNA antibody, the gamma2b heavy chain can pair with the full spectrum of endogenous light chains to produce a multitude of antibodies, including anti-dsDNA antibodies of different affinities and fine specificities. We have previously demonstrated the existence of two populations of anti-DNA B cells in non-autoimmune hosts: a high-affinity population which is rendered anergic in vivo, and a second high-affinity population which is deleted. We have now identified a third population of dsDNA-binding B cells. These cells produce germ-line-encoded antibodies with an apparent affinity for dsDNA that is 1 to 4 logs lower than the apparent affinities of antibodies made by anergic or deleted B cells, and represent a non-tolerized population which escapes regulation. Based on its characterization, we can define a molecular threshold for tolerance induction, and can speculate on the fate of these B cells when they are recruited to an immune response and undergo somatic mutation to become high-affinity anti-DNA B cells.

Natural Autoreactive B Cells in Transgenic Mice Reproduce an Apparent Paradox to the Clonal Tolerance Theory

“…B cells with a very low affinity for self-Ags will not reach the affinity threshold for tolerance induction. The recent description of the different fates of anti-dsDNA B cells in a single tg line is in accord with the notion of a molecular threshold for tolerance induction (36). This notion also questions the potential roles of these nAAb B cells in general, and of natural RF B cells in particular, in adult mice.…”

Prolactin modulates the naive B cell repertoire

“…The anti-dsDNA antibody-producing hybridomas were screened for transgene expression by RNA dot blot using a 32 P-labeled 210-bp DNA fragment that detects all members of the S107 V H family (47). The S107 V H -positive hybridomas were screened for expression of a Vκ1 light chain by RNA dot blot using a 230-bp probe for genes of the Vκ1 family (48).…”

“…In these mice, the R4A-γ2b heavy chain can associate with the endogenous light chain repertoire, creating a variety of transgene-encoded antibodies; some of these bind DNA, whereas others do not. Three distinct populations of anti-dsDNA B cells have been identified (47)(48)(49)(50). The first is an ignorant or indifferent resting B cell population that is not regulated and produces nonpathogenic, low-affinity antidsDNA antibodies (47).…”

“…Three distinct populations of anti-dsDNA B cells have been identified (47)(48)(49)(50). The first is an ignorant or indifferent resting B cell population that is not regulated and produces nonpathogenic, low-affinity antidsDNA antibodies (47). The second is an anergic population that produces high-affinity anti-dsDNA antibodies that acquire a high affinity for DNA by somatic mutation (48,49).…”

Neuroendocrinology and autoimmunity: current aspects

“…В серии других работ (на мышах) также продемон-стрировано, что эстрогены изменяют регуляцию молекул апоптоза (Bcl-2) и активации В-клеток. Данные исследова-ния показали, что низкая реактивность предшественников В-клеток на ранней стадии их созревания способствует развитию иммунокомпетентных клеток в аутоиммунном направлении [70].…”