Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus
In: Human Molecular Genetics, Jg. 13 (2003-11-25), S. 171-179
Online
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Zugriff:
Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.
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Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus
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Autor/in / Beteiligte Person: | Jiang, Yi ; Matsuoka, Shuji ; Kawai, Takako ; Li, Na ; Atsumi, Tatsuya ; Kato, Kiyoshi ; Nishimura, Hiroyuki ; Shirai, Toshikazu ; Nakamura, Kazuhiro ; Ueno, Hiroo ; Tsurui, Hiromichi ; Ohtsuji, Mareki ; Hirose, Sachiko ; Koike, Takao ; Abe, Masaaki |
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Zeitschrift: | Human Molecular Genetics, Jg. 13 (2003-11-25), S. 171-179 |
Veröffentlichung: | Oxford University Press (OUP), 2003 |
Medientyp: | unknown |
ISSN: | 1460-2083 (print) |
DOI: | 10.1093/hmg/ddh020 |
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