Dual recognition of lipid A and DNA by human antibodies encoded by the VH4-21 gene: a possible link between infection and lupus.
The VH4-21 (V4-34) gene segment, a member of the VH4 family, is expressed early in B-cell maturation and is utilized by approximately 6% of normal adult B lymphocytes. This prevalence indicates an importance of VH4-21 in the B-cell repertoire. The gene also encodes certain autoantibodies being mandatory for pathological IgM anti-red cell antibodies directed against the I/i antigen, and also capable of encoding anti-DNA antibodies. Recognition of I/i antigen or DNA appears to be via two distinct sites on VH, with I/i binding mediated by sequences in the framework region, and DNA binding correlating with the presence of positively charged amino acids in complementarity-determining region 3. However, these positively charged residues appear to suppress the ability of the framework region to interact with I/i, rendering a single sequence monospecific for I/i or DNA. The IgM anti-DNA antibodies also recognize bacterial lipid A, whereas the anti-I/i antibodies do not, indicating that CDR3 may be involved in binding the negatively charged lipid A. Structural similarities between the DNA backbone and lipid A provide a possible explanation for this cross-reactivity. This dual recognition of bacterial antigen and autoantigen provides a potential link between infection and autoimmunity.
D000328:Adult; D000595:Amino Acid Sequence; D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology; D000974:Antibodies, Antinuclear / Q000737:chemistry / Q000276:immunology*; D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D003429:Cross Reactions; D004247:DNA / Q000276:immunology*; D005803:Genes, Immunoglobulin; D006384:Hemagglutination; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008050:Lipid A / Q000276:immunology*; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D000974:Antibodies, Antinuclear; D000942:Antigens, Bacterial; D001324:Autoantigens; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D008050:Lipid A; D004247:DNA