Development of Sjogren's syndrome in nonobese diabetic-derived autoimmune-prone C57BL/6.NOD-Aec1Aec2 mice is dependent on complement component-3.
The role of complement in the etiology of Sjögren'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-Aec1Aec2.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.
Nguyen
Cuong Q
CQ
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA. Nguyen@pathology.ufl.edu
Kim
Hyuna
H
Cornelius
Janet G
JG
Peck
Ammon B
AB
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012463:Saliva / Q000276:immunology / Q000378:metabolism; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012471:Salivary Proteins and Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
C511597:Bpifa2 protein, mouse; D003176:Complement C3; D012471:Salivary Proteins and Peptides; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3