Genetic Regulation of CD5⁺ B Cells in Autoimmune Disease and in Chronic Lymphocytic Leukemia

Abstract

CD5+ B cells have attracted much attention, because of their involvement in both autoimmunity and B cell-type chronic lymphocytic leukemia (B-CLL). B-CLL is a type of leukemia most often occurring among close relatives and is partly associated with the major histocompatibility complex (MHC), a finding relevant to autoimmune disease. We established MHC (H-2)-congenic NZB x NZW (NZB/W) F1 mice (H-2d/z, H-2z/z, and H-2d/d), in that only H-2d/z heterozygotes developed severe SLE, associated with IgG anti-DNA antibodies, as the animals aged. Such age-associated changes occurred in parallel with the decrease in the splenic, but not peritoneal, CD5+ B cells. By contrast, H-2z/z homozygotes did not develop SLE but, in turn, a marked clonal proliferation of CD5+ B cells resembling B-CLL did occur. H-2d/d homozygotes also did not develop the typical SLE, and a moderate CD5+ B frequency persisted. Despite the finding that all the three H-2-congenic NZB/W F1 strains produced IgM anti-DNA antibodies, only the H-2d/z heterozygotes produced IgG antibodies. Whereas the surface phenotype of major IgM producers was CD5+ sIgM+, that of IgG producers was CD5-sIgM-. Genetic and cellular analyses supported our thesis that in the heterozygotes IgM to IgG isotype switching probably emerges in CD5+ B cells and that this event is associated with the loss of CD5 molecules. Because of the lack of genetic elements required for differentiation, only signals for proliferation would be functioning in CD5+ B cells in the H-2z/z homozygotes. These observations infer that certain different, but related, MHC haplotypes may predispose either to B-CLL or to autoimmune disease in close relatives.

Transgenic Overexpression of G5PR That Is Normally Augmented in Centrocytes Impairs the Enrichment of High-Affinity Antigen-Specific B Cells, Increases Peritoneal B-1a Cells, and Induces Autoimmunity in Aged Female Mice

“…5H). Male G5PR Tg mice did not show such autoantibody production, suggesting that generation of B-1a cells in G5PR Tg mice is affected by factors including sex hormone (or hormones) and aging, as has been previously described for B-1 cells from New Zealand Black (NZB) mice (29).…”

Role of CD5+B-1 cells in EAE pathogenesis

“…Passive transfer of the NAA to naive mice was sufficient to induce the clinical and serological manifestations of the autoimmune diseases (reviewed in [8]). Higher frequencies of B-1 cells have been reported in patients with autoimmune diseases, such as Sjögren’s disease [12] and rheumatoid arthritis [13], and animal models of autoimmune disease, i.e. lupus in NZB mice [14].…”

Genome Screening for Susceptibility Loci in Systemic Lupus Erythematosus

“…Early abnormalities found prior to the onset of SLE are mostly confined to abnormal proliferation and terminal differentiation of B1 cells, [85][86][87][88][89] a subpopulation of B cells that mainly participates in immune systems by providing natural immunity and even autoimmunity. [90,91] Frequencies of these self-reactive B1 cells are abnormally high, from young ages onward, in the spleen and peripheral blood of all New Zealand mouse strains, including NZW.…”

“…[17] Involvement of NZW loci is worthy of notice, because B1 cells in the NZW strain frequently give rise to B-CLL in later life in this strain. [5,52,53,89,92] B-CLL is typified by the significance of hereditary factors in its pathogenesis. An association of immunological abnormalities, including autoimmune diseases, is frequently seen in patients and/or their family members.…”