2003 Fiscal Year Final Research Report Summary
Ltk gene polymorphism and aberrant activation of autoreactive B cells
| Project/Area Number |
14380385
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Laboratory animal science
|
|---|
| Research Institution | JUNTENDO UNIVERSITY |
|---|
Principal Investigator |
HIROSE Sachiko Juntendo Univ. Sch. Med., Dept. Pathol., Associate Prof., 医学部, 助教授 (00127127)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
多田 昇弘 順天堂大学, 医学部, 講師 (50338315)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | Ltk / Systemic lupus erythematosus / Gain-of-function polymorphism / B1 cell / SNP / Linkage study / PI3 kinase / Susceptible gene |
|---|
| Research Abstract |
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 (P13K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared to the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic aspect for susceptibility to abnormal proliferation of self-reactive B cells in SLE.
|
Research Products
(12 results)
-
-
-
-
-
-
-
-
[Publications] Miura-Shimura Y, Nakamura K, Ohtsuji M, Tomita H, Jiang Y, Abe M, Zhang D, Hamano Y, Tsuda H, Hashimoto H, Nishimura H, Taki S, Shirai T, Hirose S: "C1q regulatory region polymorphism down-regulating murine C1q protein levels with linkage to lupus nephritis"J Immunol. 169. 1334-1339 (2002)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Xie Y, Nakamura K, Abe M, Li N, Wen X-S, Jiang Y, Zhang D, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T, Shimokawa T, Ra C, Shirai T, Hirose S: "Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses."J Immunol. 169. 4340-4346 (2002)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Matsuoka S, Tsurui H, Abe M, Terashima K, Nakamura K, Hamano Y, Ohtsuji M, Honma N, Serizawa I, Ishii Y, Takiguchi M. Hirose S, Shirai T.: "A monoclonal antibody to the α2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model."J Exp Med. 198. 497-503 (2003)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Li N, 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: "Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus."Hum Mol Genet. 13. 171-179 (2004)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Wen X, Zhang D, Abe M, hang Y, Nakamura K, Hamano Y, Kikuchi Y, Takatsu K, Shirai T, Hirose S: "Transgene-mediated over-expression of interleukin-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia."J Immunol. (in press).
Description
「研究成果報告書概要(欧文)」より
