Lupus IgG VH4.34 Antibodies Bind to a 220-kDa Glycoform of CD45/B220 on the Surface of Human B Lymphocytes

Abstract

Anti-lymphocyte autoantibodies are a well-recognized component of the autoimmune repertoire in human systemic lupus erythematosus (SLE) and have been postulated to have pathogenic consequences. Early studies indicated that IgM anti-lymphocyte autoantibodies mainly recognized T cells and identified CD45, a protein tyrosine phosphatase of central significance in the modulation of lymphocyte function, as the main antigenic target on T cells. However, more recent work indicates that lupus autoantibodies can also recognize B cells and that CD45 may also represent their antigenic target. In particular, IgM Abs encoded by VH4.34 appear to have special tropism for B cells, and strong, but indirect evidence suggests that they may recognize a B cell-specific CD45 isoform. Because VH4.34 Abs are greatly expanded in SLE, in the present study we investigated the antigenic reactivity of lupus sera VH4.34 IgG Abs and addressed their contribution to the anti-lymphocyte autoantibody repertoire in this disease. Our biochemical studies conclusively demonstrate that lupus IgG VH4.34 Abs target a developmentally regulated B220-specific glycoform of CD45, and more specifically, an N-linked N-acetyllactosamine determinant preferentially expressed on naive B cells that is sterically masked by sialic acid on B220-positive memory B cells. Strikingly, our data also indicate that this reactivity in SLE sera is restricted to VH4.34 Abs and can be eliminated by depleting these Abs. Overall, our data indicate that VH4.34 Abs represent a major component of the lupus IgG autoantibody repertoire and suggest that the carbohydrate moiety they recognize may act as a selecting Ag in SLE.

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

“…6,[9][10][11] Increased titers of IGHV4-34 antibodies have been found in individuals infected by various pathogens, especially CMV, EBV and M. pneumoniae, 10-13,38-40 which engage in superantigeniclike interactions with a conserved motif in the HFR1 of IGHV4-34 Abs. 3-5 Indeed, it has been proposed that the IGHV4-34 gene may have been selected during evolution for its ability to encode protective antibodies, as indicated by the fact that the immune response to pathogens carrying NAL epitopes selectively targets IGHV4-34 B cells.…”

“…7 In contrast, it has been demonstrated that IGHV4-34 antibodies are secreted in high level in patients with systemic lupus erythematosus (SLE) and closely related to tissue damage and disease activity. [8][9][10] IGHV4-34 G-switched (IgG) antibodies have been shown to constitute a substantial fraction of SLE anti-DNA antibodies and target CD45 either on T cells or the corresponding isoform on B cells. [8][9][10] A rise in IGHV4-34 Abs is also observed in the serum of otherwise healthy individuals in response to acute infections with herpesviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and in acute Mycoplasma pneumoniae infections.…”

“…[8][9][10] IGHV4-34 G-switched (IgG) antibodies have been shown to constitute a substantial fraction of SLE anti-DNA antibodies and target CD45 either on T cells or the corresponding isoform on B cells. [8][9][10] A rise in IGHV4-34 Abs is also observed in the serum of otherwise healthy individuals in response to acute infections with herpesviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and in acute Mycoplasma pneumoniae infections. [10][11][12][13] The immunoglobulin gene repertoire expressed by chronic lymphocytic leukemia (CLL) malignant B cells is biased and notable for the existence of subsets with quasi-identical (stereotyped) B-cell receptors (BCRs), [14][15][16][17][18][19][20][21][22][23][24] implying the recognition of structurally similar epitopes, likely selecting the leukemic clones.…”

The Immunoglobulin genes and Chronic Lymphocytic Leukemia (CLL)

“…In the mutated group, restricted usage of the V H 3-07 gene and the V H 4-34 gene has been demonstrated (5,41). The latter V gene has been associated with both self and non-self antigens as well as has been found overrepresented in both autoimmune disease and different lymphomas (58)(59)(60)(61)(62). In the unmutated CLL group, biased usage of the V H 1-69 gene has been reported by a number of groups with V H 1-69 representing a large proportion of the unmutated V H gene rearrangements (5,42,56,63,64).…”

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

“…It is therefore conceivable that auto-reactive precursors to the subset #4 CLL clones could arise early in B cell development and subsequently undergo positive selection by DNA, nucleosomes or surface structures of apoptotic cells (38,39).…”