Naturally Occurring Anti-I/I Cold Agglutinins May be Encoded by Different VH 3 Genes as Well as the VH 4.21 Gene Segment

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In the current study, we wished to determine if the V regions encoding the naturally occurring anti-i/I Cold Agglutinins (anti-i/I CA) differ from pathogenic anti-i/I CA that are exclusively encoded by the VH 4.21 gene. After EBV transformation of B lymphocytes, we generated one anti-I secreting clone from each of two individuals; clone 4G (individual CM, PBL) and clone Sp1 (individual SC, spleen). Clone 4G expresses a VH 3 gene sequence that is 92% homologous to the germline gene WHG26. Clone Sp1 also expresses a VH 3 gene that is 98% homologous to the fetally rearranged M85/20P1 gene. Another clone, Sp2 (anti-i specificity), from individual SC is 98% homologous to the germline gene VH 4.21. For correlation, we studied anti-i/I CA fractions purified from 15 normal sera and found no or relatively small amounts of 9G4 (VH 4.21 related idiotype) reactive IgM. Five cold agglutinin fractions contained large amounts of VH 3-encoded IgM (compared to pooled normal IgM) by virtue of their binding to modified protein Staph A (SPA), and absorption of three CA fractions with modified SPA specifically removed anti-i/I binding specificity entirely. Collectively, the data indicate that naturally occurring anti-i/I CA may be encoded to a large extent by non-VH 4.21-related genes, and that the V (H) 4.21 gene is not uniquely required for anti-i/I specificity. (J. Clin. Invest. 1993. 92:2821-2833.) Key words: immunoglobulin. autoantibody. red blood cell. cold agglutinin. autoimmunity

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