SEVERE COMBINED IMMUNODEFICIENCY

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We recently reported an autosomal-recessive mutation causing severe combined immunodeficiency disease (SCID) in mice. Affected mice are severely deficient in T and B lymphocytes and they have little or no immunity, readily succumbing to infections by pathogenic viruses or bacteria. To ensure their survival, SCID mice are kept in a "clean" environment, free of pathogenic microorganisms. The SCID mouse is important for it enables us to study a genetic locus that controls early lymphoid differentiation and serves as a model for a similar disease syndrome in humans. We have shown that the scid mutation blocks lymphoid differentiation and maturation. One strategy for understanding this defect's nature is to characterize lymphoid cells representative of those arrested in SCID mice. Accordingly, we are analyzing early pre-B cell lines obtained by transforming SCID bone marrow cells with Abelson murine leukemia virus. Five Abelson lines have been analyzed with probes specific for the Cmu and the JH regions of the IgH locus. All five show IgH rearrangements, but in all at least one IgH allele appears to have deleted its Jh region. Such deletions are not seen in Abelson lines derived from normal mice bone marrow. These data suggest IgH rearrangements in SCID mouse early B cells may be more error-prone than in normal mice. Similar analyses are in progress with SCID T-cell lymphomas using analogous probes specific for the Tbeta locus which codes for the beta chain of antigen receptors on T cells. These lymphomas arise spontaneously in SCID mice and appear to derive from immature T cells routinely found in the thymus. A second strategy for understanding scid lesion effects is to characterize lymphoid cells that escape or bypass the maturation block. The existence of such cells is inferred because serum immunoglobulin can be detected in 10 to 15% of SCID mice. Some of these mice produce 3 to 4 times the quantity of Ig found in normal mice. Whether the cells responsible are normal or not is not clear, and we continue to investigate the etiology and nature of such Ig-producing cells. (LB)