期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 183, 期 2, 页码 352-368出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.04.027
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资金
- German Federal Ministry of Education and Research Nationales Genomforschungsnetz-Plus [01GS0850, 01GS0851, 01GS0852, 01GS0868]
- Infrafrontier grant [01KX1012]
- OSTE-OPATH grant [01EC1006B]
- German Center for Diabetes Research
- EU ANABONOS [LSH-2002-2.1.4-3]
Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these Lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of Liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus Like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development.
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