The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huët anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states.
SummaryB cell knockout mice p, MT/p, MT were used to examine the requirement for B cell antigen (Ag) presentation in the establishment of CD4 + T cell tolerance. CD4 + T cells from p, MT mice injected with exogenous protein Ag in adjuvant responded to in vitro challenge by transcription of cytokine mKNA, cytokine secretion, and proliferation. Peripheral tolerance could be established in p~MT mice with a single dose of deaggragated protein. This tolerance was manifested by a loss of T cell proliferation and cytokine production (including both T helper cell type 1 [Thl]-and Th2-related cytokines), indicating that B cells are not required for the induction of peripheral T cell tolerance and suggesting that the dual zone tolerance theory is not applicable to all protein Ags and is not mediated through Ag presentation by B cells.T he role of B cells in Ag presentation to peripheral CD4 + T cell responses is controversial. Although B cells are the most abundant MHC class II-positive cell and have been shown in some studies to be involved in the activation of peripheral T cells, other investigators have argued against the notion that B cells are necessary as APCs for induction of T cell responses. Thus, results from studies have ranged from, first, the B cell as the crucial initiating APC in the lymph node (1), through second, the B cell as a necessary mediator of T cell clonal expansion and secondary proliferation (2-5), to third, normal priming and proliferation of T cells in the absence of B cells (6, 7). These studies all examined Ag-specific T cell activation in mice that had been rendered deficient in B cells, either by continuous injection of anti-p, Ab, by reconstitution of SCID mice with naive T cells, or, most recently, by targeted deletion of either the IgM heavy chain gene (8) or the JH gene segment (5, 9). The role of B cells in the induction of peripheral T cell tolerance is less controversial. B cells can serve as APCs in the induction of Ag-specific tolerance in naive CD4 + and CD8 + T cells (10, 11) and in Ag-specific T cell clones (12). These reports led to speculation by investigators that tolerance induction in virgin T cells is a primary function of the B cell.To reevaluate the role of B cells as APCs for activation and tolerization ofCD4 + T cells, we used the B cell knockout mouse ~MT/p~MT (hereafter p~MT), which was generated by introduction of a nonsense mutation into the transmembrane exon of the IgM heavy chain gene, resulting in a total deletion of B cells (13). The Ag used to investigate CD4 + T cell responses in these mice was human ~/-globulin (HGG), 1 which is a T-dependent Ag able to induce either tolerance or activation ofT cells, depending on the injection procedure. HGG injected subcutaneously in adjuvant induces T cell proliferation and cytokine secretion as well as a significant anti-HGG Ag response, whereas a single injection of deaggregated HGG (DHGG) induces a long-lasting peripheral tolerance that affects both B cells and T cells (reviewed in 14 and 15). In the case ofT cells, ...
We have discussed more than 30 mutant genes known to cause abnormalities in the development and regulation of the immune system. The loci defined by these deleterious alleles have been assigned to 13 different autosomal chromosomes in addition to X and Y. It is important to note that these single genes do not act alone but function in concert with the background genome. Studies of these mutations on different inbred strain backgrounds are contributing important information on the influence of background modifying genes. The development of stocks of mice carrying multiple mutations on an inbred strain background enables the use of a well-characterized mutation to explore a less-well-understood genetic model. Investigators are urged to assure proper conditions for studies with immunological mutants by using the appropriate methods of animal husbandry. A detailed guide for maintaining immunologically compromised rodents has been prepared. These experiments performed by nature provide a valuable resource for investigating the immune system in normal and pathologic states. As the gene products of the loci defined by these mutations become known, the information obtained will provide additional insight into mechanisms underlying normal immune function as well as immunologic disease processes in man.
Treatment of C57BL/6 mice with one transfusion of BALB/c spleen cells and a brief course of anti-CD154(anti-CD40 ligand) antibody permits BALB/c islet grafts to survive indefinitely and BALB/c skin grafts to survive for ~50 days without further intervention. We now report adaptation of this protocol to the transplantation of islet and skin xenografts. We observed prolonged survival of rat islet xenografts in mice treated with donor-specific spleen cell transfusion and anti-CD154 monoclonal antibody (mAb). Challenge islet xenografts placed on these animals indicated that graft acceptance was species-specific but not strain specific. Spleen cells from recipients bearing intact grafts led to rejection of rat islet xenografts in scid mice, suggesting that graft acceptance was not due to complete clonal deletion of xenoreactive cells. We also observed prolonged survival of rat skin xenografts in mice treated with donor-specific transfusion and anti-CD154 mAb. Prolonged survival of skin xenografts was also species specific. We conclude that treatment with appropriately timed donor-specific transfusion and anti-CD154 mAb induces durable survival of both islet and skin xenografts in mice. Because this procedure is targeted directly at CD154, a co-activation molecule expressed predominantly by activated CD4 + T-cells, the results suggest that CD4 + cells have a major role in the cellular immune response to xenografts. Diabetes
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