期刊
JOURNAL OF IMMUNOLOGY
卷 179, 期 4, 页码 2318-2329出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.4.2318
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- NIDCR NIH HHS [R01 DE014344, T32 DE07200, DE014344, R21 DE015152, DE015152, R01 DE014344-04, T32 DE007200, DE013769, R01 DE013769] Funding Source: Medline
The role of complement in the etiology of Sjogren's syndrome (SjS), a human autoimmune disease manifested primarily by salivary and lacrimal gland dysfunction resulting in dry mouth/dry eye syndrome, remains ill-defined. In the present study, we examined the role of complement component-3 (C3) using a newly constructed C3-gene knockout mouse, C57BL/6.NOD-Aec/Aec2.C3(-/-). Inactivation of C3 in the parental C57BL/6.NOD.Aec1Aec2 strain, a model of primary SjS, resulted in a diminished or total absence of both preclinical and clinical manifestations during development and onset of disease, including reduced acinar cell apoptosis, reduced levels of caspase-3, lack of leukocyte infiltration of submandibular glands, reduced synthesis of disease-associated autoantibodies, maintenance of normal glandular architecture, and retention of normal saliva secretion. In addition, C57BL/6-NOD.Aec1Aec2.C3(-/-) mice did not exhibit increased numbers of marginal zone B cells, a feature of SjS-prone C57BL/6-NOD.Aec1Aec2 mice. Interestingly, C57BL/6-NOD.Aec1Aec2.C3(-/-) mice retained some early pathological manifestations, including activation of serine kinases with proteolytic activity for parotid secretory protein. This improvement in the clinical manifestations of SjS-like disease in C57BL/6.NOD.Aec1Aec2.C3(-/-) mice, apparently a direct consequence of C3 deficiency, supports a much more important role for complement in the adaptive autoimmune response than previously recognized, possibly implicating an essential role for innate immunity.
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