Oligodendrocyte-reactive 01, 04, 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 01, 04, A2B5, and HNK-1 IgM kappa monoclonal antibodies are natural autoantibodies by sequencing immunoglobulin (Ig) cDNAs and comparing these with published germline sequences. 01 V-H was identical with unrearranged V-H Segment transcript A1 and A4. 04 V-H had three and HNK-1 V-H had six nucleotide differences from germline V(H)101 in the V-H coding region. The D segment of 01 was derived from germline SP2 gene family. The D segments of 04 and HNK-1 were derived from DFL16 gene family. 04 J(H) and HNK-1 J(H) were encoded by unmutated germline J(H)4, whereas 01 J(H) was encoded by germline J(H)1 with one silent nucleotide change. 01 and 04 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. 01 J(kappa), 04 J(kappa) and HNK J(kappa) were encoded by unmutated germline J(kappa)2. In contrast, A2B5 V-H showed seven nucleotide differences from germline V1, whereas no germline sequence encoding A2B5 V-kappa was identified. 01 and 04, but not A2B5 were polyreactive against multiple antigens by direct ELISA. Therefore, 01, 04 and HNK-1 Igs are encoded by germline genes, and have the genotype and phenotype of natural autoantibodies.