Oligodendrocyte-reactive O1, O4, and HNK-1 monoclonal antibodies are encoded by germline immunoglobulin genes.

Natural or physiologic autoantibodies are present normally in serum, are polyreactive, are frequently of the IgM subtype, and are encoded by unmutated germline genes. We tested whether the oligodendrocyte-reactive O1, O4, A2B5, and HNK-1 IgM kappa monoclonal antibodies are natural autoantibodies by sequencing immunoglobulin (Ig) cDNAs and comparing these with published germline sequences. O1 VH was identical with unrearranged VH segment transcript A1 and A4. O4 VH had three and HNK-1 VH had six nucleotide differences from germline VH101 in the VH coding region. The D segment of O1 was derived from germline SP2 gene family. The D segments of O4 and HNK-1 were derived from DFL16 gene family. O4 JH and HNK-1 JH were encoded by unmutated germline JH4, whereas O1 JH was encoded by germline JH1 with one silent nucleotide change. O1 and O4 light chains were identical with myeloma MOPC21 except for one silent nucleotide change. HNK-1 V kappa was identical with germline V kappa 41 except for two silent nucleotide changes. O1 J kappa, O4 J kappa and HNK J kappa were encoded by unmutated germline J kappa 2. In contrast, A2B5 VH showed seven nucleotide differences from germline V1, whereas no germline sequence encoding A2B5 V kappa was identified. O1 and O4, but not A2B5 were polyreactive against multiple antigens by direct ELISA. Therefore, O1, O4 and HNK-1 Igs are encoded by germline genes, and have the genotype and phenotype of natural autoantibodies.