Anti-DNA antibodies

Introduction

Elevated anti-double-stranded (ds) DNA antibody titers are diagnostic and prognostic markers of systemic lupus erythematosus (SLE), and their presence is well documented to correlate with lupus nephritis. These antibodies are often deposited in the glomeruli and can be eluted from the kidneys of SLE patients and lupus mice. Moreover, passively transferring anti-dsDNA antibodies into mice can induce proteinuria. The observation that a subset of anti-dsDNA antibodies cross-reacts to the N-methyl- d -aspartate receptor (NMDAR) on neurons has led to the discovery of another pathogenic role for these antibodies in neuropsychiatric lupus. Finally, these antibodies form immune complexes, and, in so doing, facilitate the entry of DNA, a toll-like receptor (TLR)-9 ligand, into the cell to activate downstream inflammatory pathways.

Cellular source of anti-DNA antibodies

There are two B-cell lineages in mice; one gives rise to B1 cells and one to marginal zone and follicular B cells. Presumably, these same two lineages are present in humans. B1 cells originate in the fetal liver, self-renew, produce germline-encoded antibodies, have a limited repertoire of immunoglobulin (Ig) genes, and respond to antigen without cognate T-cell help. B1 cells usually produce IgM or IgA antibodies. Marginal zone and follicular B cells arise from hematopoietic stem cells in the bone marrow continuously throughout adult life. Marginal zone B cells, like B1 cells, have a relatively limited repertoire and are able to respond to antigen and differentiate into plasma cells (PC) without a requirement for cognate T-cell help. Many autoreactive B cells that are present in healthy individuals and produce the antibodies that help clear apoptotic debris have a marginal zone phenotype. Follicular B cells express the most diverse repertoire and require both antigen and cognate T-cell help to differentiate into either short-lived PCs through an extrafollicular (EF) reaction or to form a germinal center (GC) and become memory cells or long-lived PCs, which are usually class-switched.

In mice, it is clear that B1 cells, marginal zone, or follicular B cells can each be the source for pathogenic anti-DNA antibodies. In patients, most data suggest that follicular B cells are the source of pathogenic anti-DNA antibodies, as the antibodies are encoded by a diverse set of Ig genes, are of the IgG isotype, and exhibit evidence of somatic hypermutation (SHM), as discussed later. The presence of high levels of interferon (IFN) in many SLE patients may skew activated follicular B cells to a short-lived PC phenotype, rather than a GC response, and so lead to relatively rapid alterations in anti-dsDNA antibody titers.