Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene

Abstract

Although the Ig H chains of anti-nuclear Abs (ANA) have been described to possess certain shared molecular signatures, it remains unclear whether the L chains of these Abs also possess distinctive molecular features. The present study examines this by generating and analyzing two comprehensive murine Ig L chain databases, one consisting of 264 monoclonal ANAs and the other consisting of 145 non-ANAs, drawn from previously published work. Importantly, clonal replicates were represented only once each, so as to minimize bias. ANAs and non-ANAs did not differ in Vκ family or Jκ gene usage, nor in their mutation frequencies. Interestingly, the L chains of ANAs exhibited differential usage of certain complementarity-determining region residues, arising almost entirely from the increased usage of certain Vκ germline genes, notably, Vκ ai4 among anti-dsDNA ANAs, Vκ23–45 among anti-ssDNA ANAs, and Vκ21–12 among non-ANAs. Finally, prompted by the increased prevalence of a particular Vκ1 family sequence among ANAs, we proceeded to clone a novel New Zealand Black Vκ1 germline gene, named bb1.1, which appears to be frequently used to encoded anti-ssDNA Abs. Collectively, these studies underline the potential contribution of particular Vκ germline genes in promoting or thwarting DNA binding.

Rap1 Signal Controls B Cell Receptor Repertoire and Generation of Self-Reactive B1a Cells

“…Because the immature BM B cells also showed enhanced expression of the Vk4 gene, the characteristic Vk gene repertoire involving both peripheral B cell populations was suggested to reflect the primary repertoire of the immature BM B cells. A database analysis indicates that Vk4 is the most frequently utilized Vk gene among anti-dsDNA and ANA in mice (Liang et al, 2003), and, thus, enhanced Vk4 gene usage may favor the generation of immature B cells reactive to the nuclear autoantigens. It was also Figure 6.…”

Self-Antigen-Driven Thymic B Cell Class Switching Promotes T Cell Central Tolerance

“…The Vκ5-43 and 5-45 genes are rarely detected in non-autoimmune mice, but their over-representation is common among anti-DNA antibodies in different autoimmune mice (Brard et al, 1999; C. Chen et al, 2006; Liang et al, 2003; Moisini et al, 2012; Roark et al, 1995; Tillman et al, 1992). While a common property of editor light chains is the presence of negatively charged residues within CDR1 and 2, Vκ5-43 and 5-45, in contrast, have positively charged arginines in these regions, leading to the suggestion that they may confer a selective advantage to anti-DNA antibodies in diseased mice when cognate T cell help is present in autoimmune-prone genetic background (C.…”

Receptor editing and receptor revision in rheumatic autoimmune diseases

“…Remarkably, Spa-1 À/À mice exhibit an expansion of autoreactive B cells, produce anti-dsDNA Abs, and develop a lupus-like syndrome [51]. Importantly, their immature B cells show ineffective receptor editing of V k genes as well as a significantly altered repertoire, in which the frequency of usage of the V k 4 gene, the most frequently utilized V k gene among murine anti-dsDNA and antinuclear Abs [52], is markedly increased. This enhanced V k 4 gene utilization might favor the generation of immature B cells that are reactive with nuclear autoantigens.…”