The primary antibody repertoire of normal, immunodeficient and autoimmune mice is characterized by differences in V gene expression
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abstract
During the last decade, the structure and organization of the immunoglobulin heavy and light chain locis have been defined in mice and humans. Studies on VH gene expression at different stages of development, in different organs and disease states have provided useful insight into the construction of a primary antibody repertoire in mice. Clearly, 3'VH genes 7183, Q52 and Vh11, which are conserved during evolution, are preferentially expressed during early development of the B-lymphocyte repertoire. A preferential use for the V kappa 4 gene family is evident during early B-cell development. The initial development of the primary antibody repertoire is therefore influenced by a restricted set of VH and V kappa gene elements. The restricted B-cell repertoire is subsequently normalized in the periphery, as revealed by stochastic VH gene expression, as a result of exposure to environmental antigens. Obviously, the peripheral B-cell pool characterized by stochastic VH gene expression is selectively replenished by newly generated B cells in bone marrow that preferentially expresses 3'VH genes. The V kappa genes are, however, expressed in a non-random manner in the neonatal and adult B-lymphocyte repertoire that is probably related to VH and V kappa association dynamics and/or positive or negative selection. Interestingly, these characteristics of neonatal and adult primary repertoire are noted in both B1 and B2 lymphocytes. No remarkable age-related differences are evident for VH and V kappa gene expression. In healthy mice, both the mitogen responsive (available) and unstimulated (expressed) B-cell repertoire show similar VH gene expression. Interestingly, VH gene expression varies in different organs which may reflect, or occur as a result of, the specialized function of each organ. For example, J558 gene expression is higher in the peripheral LN where B cells continuously encounter exogenous antigens. The skewed VH and V kappa gene expression noted in immunodeficient and autoimmune lupus-prone mice reflects the impairment of the primary antibody repertoire associated with immunodeficiency and autoimmune disorders.
