Wegener's granulomatosis (WG) is a multisystem disease of unknown etiology which is characterized by small to medium vessel vasculitis, pauci-immune glomerulonephritis, necrosis/granuloma formation of the respiratory tracts and autoantibodies to neutrophilic components. Although the underlying pathophysiology of this disorder remains an enigma, several lines of evidence strongly support c-ANCA, particularly anti-PR3, has a role in disease pathogenesis. Unfortunately, the specific mechanisms that initiate and perpetuate this anti-PR3 response remain to be elucidated. One approach to delineate a potential etiology for these autoantibodies, and/or to understand their role in the pathogenesis of vasculitis would be to fully characterize the antigenic determinants of the PR3 autoantigen. By defining the common autoantigenic targets of PR3 we could arrive at molecular mimicry triggers for this autoimmune response. An animal model of WG autoimmunity could show to what tissues particular epitopes are targeted. Over the past decade our lab has conducted extensive work on the immunochemistry of lupus autoantigens (1-7). These previous studies provide the technical background for this proposal. Epitope mapping experiments of the spliceosomal autoantigens have led to our peptide induced model of lupus autoimmunity (8,9). We will now apply these well-honed techniques, as well as a similar scientific strategy, to analyze the humoral fine specificity of the WG reponse to PR3. Early work in the lab of Ralph Williams suggests that sequential eptiopes are common targets of PR3. Exciting new results from our co-PI's lab uncover a potential mechanism of anti-PR3 vascular damage. He has observed that PR3 can bind to endothelial protein C receptor (EPCR), a regulatory protein in the protein C anticoagulant pathway and that this binding is inhibited by c-ANCA. He has also observed that EPCR can inhibit tight neutrophil to activated endothelium and the subsequent spreading/activation. These observations lead to the hypothesis that EPCR plays a role in regulating leukocyte adhesion and activation, in part through interactions with PR3, and that antibodies to PR3 disrupt this physiological regulation contributing to the vascular damage in WG. This RFA response seeks to integrate the strengths of two labs to build on these early observations and to identify the common humoral epitopes of PR3, to track the development of the humoral autoimmune response of WG patients to PR3 over time, to develop an animal model of vasculitis, to evaluate EPCRs influence on the c-ANCA-PR3 interaction, and to identify the common T cell targets in WG.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047575-04
Application #
6534258
Study Section
Special Emphasis Panel (ZAR1-AAA-B (O2))
Program Officer
Johnson, David R
Project Start
1999-09-30
Project End
2004-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$261,630
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Bruner, B F; Vista, E S; Wynn, D M et al. (2011) Epitope specificity of myeloperoxidase antibodies: identification of candidate human immunodominant epitopes. Clin Exp Immunol 164:330-6
Bruner, B F; Vista, E S; Wynn, D M et al. (2010) Anti-neutrophil cytoplasmic antibodies target sequential functional proteinase 3 epitopes in the sera of patients with Wegener’s granulomatosis. Clin Exp Immunol 162:262-70
Heinlen, Latisha D; Ritterhouse, Lauren L; McClain, Micah T et al. (2010) Ribosomal P autoantibodies are present before SLE onset and are directed against non-C-terminal peptides. J Mol Med (Berl) 88:719-27
McClain, Micah T; Heinlen, Latisha D; Dennis, Gregory J et al. (2005) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11:85-9
Ireland, H; Konstantoulas, C J; Cooper, J A et al. (2005) EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 183:283-92
Kaneko, Toshihiro; Stearns-Kurosawa, D J; Taylor Jr, Fletcher et al. (2003) Reduced neutrophil CD10 expression in nonhuman primates and humans after in vivo challenge with E. coli or lipopolysaccharide. Shock 20:130-7
Boomsma, M M; Stearns-Kurosawa, D J; Stegeman, C A et al. (2002) Plasma levels of soluble endothelial cell protein C receptor in patients with Wegener's granulomatosis. Clin Exp Immunol 128:187-94
Stearns-Kurosawa, Deborah J; Swindle, Kandice; D'Angelo, Armando et al. (2002) Plasma levels of endothelial protein C receptor respond to anticoagulant treatment. Blood 99:526-30