Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process

Abstract

Anti-single stranded DNA (ssDNA) and anti-double stranded DNA (dsDNA) B cells are regulated in non-autoimmune mice. In this report we show that while both anti-ssDNA and anti-dsDNA B cells are blocked in their ability to differentiate into antibody-secreting cells, other phenotypic and functional characteristics distinguish them from one another. Splenic anti-ssDNA B cells are found distributed throughout the B cell follicle, and are phenotypically mature and long-lived. On the other hand, splenic anti-dsDNA B cells are short-lived, exhibit an immature and antigen-experienced phenotype, and localize to the T-B interface of the splenic follicle. Functionally, anti-ssDNA B cells proliferate, albeit suboptimally, in response to anti-IgM, lipopolysaccharide (LPS) and CD40L/IL-4 + anti-IgM stimulation, and tyrosine phosphorylate intracellular proteins upon mIgM cross-linking. Anti-dsDNA B cells, on the other hand, are functionally unresponsive to anti-IgM and LPS stimulation, and do not phosphorylate intracellular proteins, including Syk, upon mIg stimulation. Importantly, anti-DNA B cell anergy is maintained in the absence of T cells since both anti-ssDNA and anti-dsDNA B cells are as efficiently regulated in RAG2(-/-) mice as in their RAG2(+/+) counterparts. Interestingly, the severely anergic state of anti-dsDNA B cells is partially reversible upon stimulation with CD40 ligand and IL-4. In response to these signals, anti-dsDNA B cells remain viable, up-regulate cell surface expression of B7-2 and IgM, and restore their ability to proliferate and phosphorylate Syk upon mIg cross-linking. Collectively, these data suggest that anti-DNA B cell anergy encompasses distinct phenotypes which, even in its most severe form, may be reversible upon stimulation with T cell-derived factors.

Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis

“…14 Thus, it has been shown that anergic B cells can be drawn into proliferation if T helper (Th)-related signals are present. 41,42 It is therefore interesting to note that numerous MZ B cells (possibly some CII-specific) have left the MZ after CII immunization and migrated into the follicles forming clusters in the B-cell zone where germinal centres normally are located. The MZ B cells may shuttle the CII into the follicle where they deposit the Ag on FO dendritic cells 27,43 and/or present CII to T cells.…”

Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

“…Negatively selected B cells exhibit one or more of a variety of features. These include elevated expression of activation markers (30 -33), unresponsiveness to LPS and T cell-derived factors (32, 34 -36), and deficiencies in BCR signaling (31,34,36,37). However, in contrast to negatively selected cells, 6-1/V 1A B cells express normal levels of multiple activation markers (Fig.…”

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…Anergic B cells fail to secrete Ab in response to LPS or Ag immunization due to receptor unresponsiveness (17,18,20). Some anergic B cells exhibit reduced surface IgM levels (21,22), decreased lifespan (20,23), and exclusion from the lymphoid follicle (23,24).…”