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.
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA. Nguyen@pathology.ufl.edu
Cuong Q
CQ
Nguyen
Hyuna
H
Kim
Janet G
JG
Cornelius
Ammon B
AB
Peck
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