Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus.
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.
Li
Na
N
Second Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Nakamura
Kazuhiro
K
Jiang
Yi
Y
Tsurui
Hiromichi
H
Matsuoka
Shuji
S
Abe
Masaaki
M
Ohtsuji
Mareki
M
Nishimura
Hiroyuki
H
Kato
Kiyoshi
K
Kawai
Takako
T
Atsumi
Tatsuya
T
Koike
Takao
T
Shirai
Toshikazu
T
Ueno
Hiroo
H
Hirose
Sachiko
S
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
D018956:CD5 Antigens; D019869:Phosphatidylinositol 3-Kinases; C489300:LTK protein, human; C064626:Ltk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases