Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Abstract

Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5–15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.

Sites and Stages of Autoreactive B Cell Activation and Regulation

“…Regardless of the origins of autoreactive cells, they must be stimulated to divide and differentiate in order to generate Murakami et al, 1992;Nemazee and Burki, 1989;Wang and Shlomchik, 1998 Receptor editing anti-MHCII Tg, 3H9/Vk4 anti-dsDNA Tg, 3H9 or 56R site-directed Tg, HEL site-directed Tg with mHEL cells express an endogenous V L rather than the Tg-encoded one, or cells express a limited repertoire of L chains that veto autoreactivity Gay et al, 1993;Hippen et al, 2005;Li et al, 2001;Tiegs et al, 1993 Allelic inclusion anti-MHC II site-directed Tg, 3H9 56R cells coexpress an endogenous V L with the Tg-encoded one, or cells express two L chains, including one that vetoes autoreactivity Li et al, 2002b;Liu et al, 2005 Anergy anti-HEL Tg with sHEL, anti-DNA (3H9/Vl 1 ), anti-Sm Tg (2-12), ArsA1 cells have variably reduced sIgM expression, shortened life span, and localize to the T-B interface; variably impaired response to LPS and reduced response to BCR ligation Erikson et al, 1991;Goodnow et al, 1988;Merrell et al, 2006;Santulli-Marotto et al, 1998 Clonal ignorance anti-IgG (RF) AM14 Tg, anti-La cells assume a normal follicular B cell phenotype Aplin et al, 2003;Hannum et al, 1996;Shlomchik et al, 1993 autoantibodies. Clues to the nature of this process derive from autoantibody-secreting clones recovered from diseased mice and humans.…”

“…B cells expressing receptors that are weakly crosslinked by self will emerge from the bone marrow (BM) and appear in the periphery (provided that their ligand remains unavailable) as normal non-self-reactive B cells (Aplin et al, 2003;Hannum et al, 1996;Liu et al, 2007a;Nemazee et al, 1991;Shlomchik et al, 1993). This has been termed ''clonal ignorance.…”

Deconstructing B cell tolerance to basement membranes

“…Soluble oligovalent and low-affinity self antigen crosslink less effectively, generating weaker signals that are more likely to functionally incapacitate the cell [20,34]. Antigen that fails to effectively engage receptors does not induce tolerance [3,4,6,23,37,68]. Antigen sequestration, T cell tolerance, and additional mechanisms provide protection in this setting.…”

Autoantigen-B Cell Antigen Receptor Interactions That Regulate Expression of B Cell Antigen Receptor Loci

“…In addition, evidence is accumulating to suggest that a significant percentage of autoreactive B cells that enter the periphery and are exposed to autoantigen is not anergic. Such B cells are said to be "ignorant" of or "indifferent" to self Ags (11,24).…”