Aging is associated with enhanced production of IgM autoantibodies. Also, aged persons frequently develop gammopathies of IgM autoantibodies with rheumatoid factor (RF) or other autoantibody-like activity. Paradoxically, this enhanced tendency to generate self reactive antibodies generally occurs in the setting of depressed humoral immunity to exogenous antigens. We have characterized cross reactive idiotypes (CRIs) and supratypic CRIs (sCRIs) on such IgM RF paraproteins and IgM autoantibodies from healthy aged individuals. Molecular studies on normal or neoplastic B cells reveal that a given CRI or sCRI may be a serologic marker for expression of a conserved Ig variable region gene (V gene) or a sub-subgroup of Ig V genes, respectively. B cells that express these serologic markers predominate during early fetal B cell development, are found preferentially in the mantle zone of secondary B cell follicle's and apparently increase in frequency in the PBL from young adulthood to old age. In addition, CRI+ B cells are enriched for cells that express the CD5 surface antigen. The latter cells, designated CD5 B cells, also are found at increased frequency in the PBL of the aged and possibly may constitute a separate B cell lineage of autoantibody-producing cells deficient in their ability to undergo Ig V gene somatic hypermutation. Conceivably, the age related increase in IgM autoantibodies and gammopathies may reflect senescence in the subpopulation of B cells able to participate in the secondary immune response to antigen and/or relative oligoclonal expansions of such """"""""CD5 B cells"""""""" unable to respond appropriately to exogenous antigenic stimulation. This proposal: 1) seeks to define the molecular basis for CRI or sCRI expression at various developmental stages; 2) follow-up on preliminary observations that tentatively define the anatomic distribution and surface antigen phenotype of human primary B cells; 3) take advantage of the serologic specificities of defined CRIs to monitor for induced Ig V gene somatic hypermutation in vitro; 4) extend recent studies on the structural basis of IgM autoantibodies that suggest that self-reactivity is a somatically selected specificity. Through these studies we may better appreciate factors influencing development and maintenance of the primary humoral immune repertoire, the physiology of IgM autoantibodies, the age-associated decline in humoral immunity and the etiopathogenesis of age-associated gammopathies, autoimmunity and lymphoproliferative disease.
