title: Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus.
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 (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.
authors.affiliation: Second Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tsurui
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Mareki
authors.initials: M
authors.lastname: Ohtsuji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kato
authors.forename: Takako
authors.initials: T
authors.lastname: Kawai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shirai
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ueno
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018956:CD5 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008875:Middle Aged; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: D018956:CD5 Antigens; D019869:Phosphatidylinositol 3-Kinases; C489300:LTK protein, human; C064626:Ltk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases