IgG subclass distribution in patients with multiple myeloma or with monoclonal gammopathy of undetermined significance

Multiple myeloma provides a unique model for studying factors affecting IgG isotype distribution in humans. Evaluations were made as to whether monoclonal immunoglobulins (M-proteins) of different IgG isotypes are associated with different extents of hypogammaglobulinemia and whether all residual subclasses are decreased comparably. The isotype patterns were analyzed in the context of the gene order of the constant regions of gamma (gamma) heavy chains on chromosome 14. Using monoclonal antibody-based immunoenzymometric assays, IgG subclasses were quantitated in the sera of 50 patients having IgG M-proteins, 38 with multiple myeloma and 12 with monoclonal gammopathy of undetermined significance. Thirty-three (66 percent) patients had IgG1, nine (18 percent) had IgG2, four (8 percent) had IgG3, and four had IgG4 M-proteins, paralleling the normal IgG subclass distribution. The concentration of residual IgG (sum of the evaluatable polyclonal IgG subclasses) was significantly decreased in patient sera (p less than 0.05). However, in only seven (14 percent) of the patients were all three subclasses below the reference range, suggesting some selectivity of immunosuppression. Patients with M-proteins of different IgG subclasses had markedly different patterns of suppression. Patients with IgG2 M-proteins (78 percent) were more likely to have depressed residual IgG than patients with IgG3 (50 percent), IgG1 (27 percent) or IgG4 (0 percent) M-proteins. Some patients had deficits of only one or two IgG subclasses. When considering all sera together, residual IgG1 was disproportionately reduced, followed by residual IgG2, IgG3, and IgG4. Next it was determined whether or not patterns of suppression were predicted by the gamma heavy-chain gene order (5' to 3'): gamma 3, gamma 1, gamma 2, gamma 4, as seen in some other immunologic disorders. Interestingly, the normal isotypes encoded by genes in juxtaposition to that of the M-protein were most often decreased (p less than 0.05). Thus, the patterns of hypogammaglobulinemia in multiple myeloma are heterogeneous. They may be influenced by the M-protein itself, possibly through interactions with regulatory cells. In addition, factors at the gene rearrangement level may contribute.