Y chromosome-linked B and NK cell deficiency in mice.

There are no primary immunodeficiency diseases linked to the Y chromosome, because the Y chromosome does not contain any vital genes. We have established a novel mouse strain in which all males lack B and NK cells and have Peyer's patch defects. By 10 wk of age, 100% of the males had evident immunodeficiencies. Mating these immunodeficient males with wild-type females on two different genetic backgrounds for several generations demonstrated that the immunodeficiency is linked to the Y chromosome and is inherited in a Mendelian fashion. Although multicolor fluorescence in situ hybridization analysis showed that the Y chromosome in the mutant male mice was one third shorter than that in wild-type males, exome sequencing did not identify any significant gene mutations. The precise molecular mechanisms are still unknown. Bone marrow chimeric analyses demonstrated that an intrinsic abnormality in bone marrow hematopoietic cells causes the B and NK cell defects. Interestingly, fetal liver cells transplanted from the mutant male mice reconstituted B and NK cells in lymphocyte-deficient Il2rg(-/-) recipient mice, whereas adult bone marrow transplants did not. Transducing the EBF gene, a master transcription factor for B cell development, into mutant hematopoietic progenitor cells rescued B cell but not NK cell development both in vitro and in vivo. These Y chromosome-linked immunodeficient mice, which have preferential B and NK cell defects, may be a useful model of lymphocyte development.

Glatiramer acetate treatment does not modify the clinical course of (NZB x BXSB)F1 lupus murine model.

Glatiramer acetate (GA, copolymer-1, Copaxone), a therapy approved for treatment of multiple sclerosis (MS), prevents and reverses experimental autoimmune encephalomyelitis, the animal model of MS. In central nervous system autoimmune disease, GA is thought to act through modulation of antigen-presenting cells, such as monocytes, mediating an antigen-independent T(h)2 shift and development of FoxP3+ regulatory T cells. Recent reports indicate that GA may also be effective in models of other autoimmune diseases such as uveoretinitis, inflammatory bowel disease and graft rejection. To date, the potential effect of GA in lupus animal models has not been described. (NZB x BXSB)F1, male mice bearing Y-linked autoimmune acceleration , is a lupus-prone mouse model which is associated with a monocytosis accelerating disease progression. These mice were treated with GA before disease onset until death and both mortality rate and biological parameters were assessed to investigate whether GA may be beneficial in this spontaneous model of systemic lupus erythematosus. GA exerted no beneficial effect on the median survival after up to 7 months of treatment. Humoral and cellular parameters used as markers for lupus progression, such as anti-chromatin, anti-double-stranded DNA and anti-erythrocytes antibodies, hematocrit and monocytosis, were similarly unchanged. Our study demonstrates that GA has no significant effect on the progression of the (NZB x BXSB)F1 lupus-prone animal model. These results reinforce the hypothesis that GA may exert its beneficial effect in some specific autoimmune diseases only.

FoxP3: a genetic link between immunodeficiency and autoimmune diseases.

It has long been observed that patients with autoimmune diseases also have immune deficiency. How these two opposite extremes of immunity can be found in the same individual is largely unclear. Here we review the evidence that a FoxP3 defect may provide a critical link between autoimmunity and immune deficiency. Disruption of FoxP3 results in severe autoimmune syndromes in both human and mice. Bone marrow chimera experiments indicate that FoxP3 defects in both hematopoietic and non-hematopoietic cells are required for the development of severe autoimmune disease. FoxP3 mutation in the hematopoietic cells impairs the development of regulatory T cells (Treg). Our data demonstrate that the mutation in non-hematopoietic cells results in deficient thymopoiesis. Defective T cell production may be an underlying cause of T cell hyperproliferation, which together with Treg defects, may lead to fatal autoimmune disease in mouse and man.