Cold agglutinin activity is common among human monoclonal IgM Rh system antibodies using the V4‐34 heavy chain variable gene segment

Abstract

Anti-I/i reactivity is common among IgM Rh system MoAbs and is shown only by the V4-34-encoded subset. This finding has implications for the use of MoAbs for Rh system typing of blood.

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

“…Four of the identified antibodies were RhD-specific agglutinating IgM antibodies used in blood typing, and indeed the IgM response to foreign RhD is dominated by IGHV4-34*01 antibodies (16,20). Three of the anti-RhD IgM antibodies retain the AVY sequence and are known to retain self-reactivity measured by agglutination of I/i antigen-bearing erythrocytes (20).…”

“…Three of the anti-RhD IgM antibodies retain the AVY sequence and are known to retain self-reactivity measured by agglutination of I/i antigen-bearing erythrocytes (20). Experimentally introduced mutations in the AVY motif that inactivate self-I/i agglutination also abolish RhD-mediated agglutination by an IGHV4-34 IgM antibody (13), indicating that mutation away from self-reactivity would come at the cost of losing foreign RhD reactivity.…”

“…Glycosylated BCRs may also be recognized by lectins on follicular dendritic cells or macrophages in the germinal center to deliver a survival advantage (26). A need for some preimmune antibodies to mutate away from self-reactivity provides an alternative explanation for the phenomenon of repertoire shift during the maturation of antibody responses, when certain antibody specificities that ultimately dominate responses to haptens (52)(53)(54)(55)(56)(57) or RhD alloantigens (16,20) or bind conserved neutralizing epitopes of viruses (58)(59)(60)(61)(62) are minimally represented in the primary wave of plasma cells but gradually emerge after repetitive stimulation by foreign antigen. Inherited defects that prevent hypermutation away from self-reactivity by antimicrobial antibodies may explain the surprising prevalence of autoantibodies in human AICDA deficiency, where GCs are formed but hypermutation is crippled (63).…”

A VH4-34+ myeloma protein with weak autoreactivity

“…15 The M-protein did not bind to erythrocytes in flow cytometry (data not shown). Binding to I/i is determined by a hydrophobic patch in FR1, involving residue W7 and the AVY motif (residues 23-25), identical to the epitope bound by the 9G4 antibody.…”

Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia

“…26, 27 It appears that less malignant Responses of selected mutated CLL samples to anti-IgM, anti-IgD, and anti-CD79␣ determined by induced Syk phosphorylation are shown. ND indicates not determined; ϩ, greater than 2-fold increase in Syk phosphorylation; Ϫ, less than 2-fold increase in Syk phosphorylation.…”