Altered CD45 expression and disease

Tchilian, Elma; Beverley, Peter C. L.

doi:10.1016/j.it.2006.01.001

Cited by 99 publications

(106 citation statements)

References 71 publications

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“…In addition to the disease associations of CD45 alleles described in earlier cohort studies [3], there have been several reports of C77G detected in small numbers of patients with a variety of diseases, for example, four patients with systemic lupus erythematosus (SLE) [16], one with myasthenia gravis [30], and two families with haemophagocytic lymphohistiocytosis or erythrocytic haemophagocytosis [31,32]. So far no living G77G homozygous sample has been reported.…”

Section: Discussionmentioning

confidence: 99%

“…CD45 is highly polymorphic in many species [3]. The most extensively studied human CD45 polymorphism is the C77G point mutation in a splice silencer region of exon 4, which prevents excision of the exon.…”

Section: Introductionmentioning

confidence: 99%

“…1a, b, right hand panels), both ex vivo and after mitogen stimulation. C77G heterozygous individuals are relatively rare, with an allele frequency of 0-3·5% in Europe and North America [3,4]. The allele is absent in samples from Africa (Uganda) or in far eastern Orientals [5].…”

Section: Introductionmentioning

confidence: 99%

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Unusual case presentations associated with the CD45 C77G polymorphism

Tchilian

Gil

Navarro

et al. 2006

Clinical and Experimental Immunology

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SummaryCD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unusual case presentations associated with the CD45 C77G polymorphism

Tchilian

Gil

Navarro

et al. 2006

Clinical and Experimental Immunology

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“…Comparison of human T cells with CD45RO, RA or other isoforms has suggested a profound difference in TCR signaling, although other differences in the T cells may contribute to their different responses (11,12). Inherited human PTPRC single-nucleotide variants that alter the splicing of protein tyrosine phosphatase, receptor type C exons 4 or 6 have been associated with differences in TCR signaling, activated T cell numbers, and susceptibility to autoimmune or infectious disease (3). Collectively, these results favor the view that TCR signal strength and quality are modulated by developmentally regulated CD45 splicing.…”

mentioning

confidence: 99%

Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

Yates

Hoyne

et al. 2010

The Journal of Immunology

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“…Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initially hypothesized that CD45, similar to receptor protein tyrosine kinases, would be positively regulated by ligand-mediated dimerization (9).…”

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confidence: 99%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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Altered CD45 expression and disease

Cited by 99 publications

References 71 publications

Unusual case presentations associated with the CD45 C77G polymorphism

Unusual case presentations associated with the CD45 C77G polymorphism

Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

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