| Autor: |
Li N; Second Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan., Nakamura K, Jiang Y, Tsurui H, Matsuoka S, Abe M, Ohtsuji M, Nishimura H, Kato K, Kawai T, Atsumi T, Koike T, Shirai T, Ueno H, Hirose S |
| Jazyk: |
angličtina |
| Zdroj: |
Human molecular genetics [Hum Mol Genet] 2004 Jan 15; Vol. 13 (2), pp. 171-9. |
| DOI: |
10.1093/hmg/ddh020 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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