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Iga and Igg Antineutrophil Cytoplasmic Antibody Engagement of Fc Receptor Genetic Variants Influences Granulomatosis with Polyan

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Iga and Igg Antineutrophil Cytoplasmic Antibody Engagement of Fc Receptor Genetic Variants Influences Granulomatosis with Polyan IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis James M. Kelleya,b,c, Paul A. Monachd, Chuanyi Jia, Yebin Zhoua, Jianming Wua, Sumiaki Tanakaa,e, Alfred D. Mahrd,f, Sharleen Johnsond, Carol McAleard, David Cuthbertsong, Simon Caretteh, John C. Davis, Jr.i, Paul F. Dellaripaj,k,l, Gary S. Hoffmanm, Nader Khalidin, Carol A. Langfordm, Phillip Seoo, E. William St. Clairp, Ulrich Specksq,JohnH.Stonel,o,r, Robert F. Spieras,t, Steven R. Ytterbergq, Peter A. Merkeld, Jeffrey C. Edberga,1, and Robert P. Kimberlya,1 aDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Departments of bPathology and kMedicine, Brigham and Women’s Hospital, Boston, MA 02115; Departments of cPathology and lMedicine, Harvard Medical School, Boston, MA 02115; eDepartment of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0373, Japan; dDepartment of Medicine, Boston University, Boston, MA 02118; fDepartment of Medicine, Hospital Saint-Louis, 75010 Paris, France; gDepartment of Pediatrics, University of South Florida, Tampa, FL 33620; hDepartment of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A1; iDepartment of Medicine, University of California, San Francisco, CA, 94143; jDepartment of Rheumatology, Lahey Clinic, Burlington, MA 01805; mDepartment of Rheumatic and Immunologic Diseases, The Cleveland Clinic Foundation, Cleveland, OH 44195; nDepartment of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8; oDepartment of Medicine, Johns Hopkins University, Baltimore, MD 21287; pDepartment of Medicine, Duke University, Durham, NC 27713; qDepartment of Medicine, Mayo Clinic, Rochester, MN 55905; rDepartment of Medicine, Massachusetts General Hospital, Boston, MA 02114; sDepartment of Medicine, Beth Israel Medical Center, New York City, NY 10003; and tDepartment of Medicine, Hospital for Special Surgery, New York City, NY 10021 Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved November 11, 2011 (received for review June 14, 2011) Granulomatosis with polyangiitis (Wegener’s) is a rare autoimmune 3 (PR3), a serine protease expressed in azurophilic granules of neutrophil-mediated vasculitis that can cause renal disease and mu- neutrophils. Serum anti-PR3 antibodies produce a cytoplasmic cosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) staining pattern on immunofluorescence assays, explaining the are present in many patients, vary in level over time, and induce designation cANCA. These antibodies occur in over 90% of neutrophil activation through engagement with Fc receptors (FcRs). patients with active systemic disease and 40% of patients in re- MEDICAL SCIENCES Given roles for FcRs in ANCA-mediated neutrophil activation and IgA mission (6), and may influence disease pathogenesis. When acti- antibodies in mucosal immunity, we hypothesized that FcR genetics vated, neutrophils display the majority of granular PR3 on their and previously unappreciated IgA ANCA affect clinical presentation. cell-surface membranes (7); anti-PR3 antibodies then bind to the We assembled a total of 673 patients and 413 controls from two surface of primed neutrophils, resulting in initiation of subsequent multicenter cohorts, performed ELISA and immunofluorescence neutrophil-effector programs, such as an oxidative burst (8). assays to determine IgA and IgG ANCA positivity, and used Illumina, Such ANCA-induced effector mechanisms involve engagement TaqMan, or Pyrosequencing to genotype eight haplotype-tagging of activating IgG Fc receptors (FcRs) (9), namely FCGR2A SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of (CD32A) and FCGR3B (CD16B) by anti-PR3 antibodies. Anti- FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neu- PR3 antibodies preferentially engage FCGR3B because of its trophil activation by measuring degranulation marker CD11b with numeric predominance on the neutrophil cell surface (10). flow cytometry or neutrophil extracellcular trap formation with con- FCGR3B copy number variation (CNV) has been associated with focal microscopy. Functional polymorphisms in FCGR3B and FCAR development of systemic autoimmune conditions, including GPA differed between patient groups stratified by renal involvement. (11). Within FCGR3B, two common genetic variants (named NA1 IgAANCAwerefoundin∼30% of patients and were less common and NA2) influence the ANCA-effector response, with the NA1 in patients with severe renal disease. Neutrophil stimulation by IgA allele producing stronger phagocytosis, respiratory burst, and or IgG ANCA led to degranulation and neutrophil extracellcular trap neutrophil degranulation compared with the NA2 allele (12), formation in a FcR allele-specific manner (IgA:FCAR P =0.008;IgG: suggesting these alleles influence the strength of ANCA-induced FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA to- neutrophil activation and, subsequently, disease severity. gether, IgG ANCA induced neutrophil activation was reduced (P = Ig isotypes of ANCA other than IgG have yet to be observed in 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prog- patients with GPA. Given the mucosal manifestations of GPA, nostic and therapeutic targets for understanding the pathogenesis IgA is an isotype of interest; however, IgA ANCA have not been and presentation of granulomatosis with polyangiitis (Wegener’s). previously reported in GPA (13, 14). IgA can induce a wide range of immune mechanisms, including phagocytosis, respiratory burst, genetic association | functional genomics | Fc receptor alleles cytokine release, and antibody-dependent cell-mediated cytotox- icity (15), as well as mediate an anti-inflammatory response (16, ranulomatosis with polyangiitis (Wegener’s) (GPA), formerly 17); therefore, IgA ANCA are plausible mediators of disease ac- Gknown as Wegener’s granulomatosis (1), is a rare autoim- tivity and severity in GPA. Serum IgA ANCA have been associated mune vasculitis marked by neutrophil-related tissue damage to with erythema elevatum diutinum (a neutrophil-associated vascu- small- and medium-sized vessels. Patients with GPA can experi- ence a broad range of clinical manifestations, predominately af- fecting the mucosal upper airways and kidneys (2). Over half of Author contributions: J.M.K., P.A. Monach, P.A. Merkel, J.C.E., and R.P.K. designed re- these patients develop some form of renal involvement, ranging in search; J.M.K., C.J., Y.Z., S.T., S.J., J.C.E., and R.P.K. performed research; P.A. Monach, J.W., fi C.M., S.C., J.C.D., P.F.D., G.S.H., N.K., C.A.L., P.S., E.W.S.C., U.S., J.H.S., R.F.S., S.R.Y., P.A. severity from mild renal insuf ciency to rapidly progressing glo- Merkel, J.C.E., and R.P.K. contributed new reagents/analytic tools; J.M.K., A.D.M., D.C., merulonephritis, culminating in end-stage renal disease (3, 4). The P.A. Merkel, J.C.E., and R.P.K. analyzed data; and J.M.K. and R.P.K. wrote the paper. basis for the varied clinical manifestations and disease severity is The authors declare no conflict of interest. not well understood but may result from both genetic and envi- This article is a PNAS Direct Submission. ronmental factors (5). 1To whom correspondence may be addressed. E-mail: [email protected] or [email protected]. Antineutrophil cytoplasmic antibodies (ANCA) are frequently This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. observed in patients with GPA. ANCA primarily target proteinase 1073/pnas.1109227109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1109227109 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 Table 1. IgA and IgG isotypes of anti-PR3 antibodies are present ANCA were present in patients with GPA. We showed that in patients with GPA stimulation with IgA or IgG ANCA affected neutrophil activation Controls WGGER VCRC measures, such as degranulation and neutrophil extracellular trap (NET) formation, in FcR-genotype–dependent fashion, suggest- IgA positive only 1 (1%) 12 (3.6%) 45 (17.1%) ing that the pathogenesis of GPA is influenced by multiple ANCA IgG positive only 1 (1%) 151 (45.1%) 80 (30.4%) isotypes and FcR genotypes. IgA and IgG positive 0 (0%) 49 (14.6%) 56 (21.3%) Negative 97 (98%) 123 (36.7%) 82 (31.2%) Results Total 99 335 263 Patient Samples and Clinical Data. We assembled samples and data from a total of 673 patients with GPA and 413 healthy controls Data were obtained by ELISA. Of the 463 Caucasian patients with GPA in from WGGER and VCRC. Chart review confirmed disease WGGER, 335 had single samples available. Patients from the VCRC cohort fi typically contributed multiple samples (263 participants, 1,470 samples), and presence using the modi ed American College of Rheumatology a patient was counted as positive if any sample tested positive. Healthy diagnostic criteria and the Chapel Hill Consensus definitions of controls were assayed to determine a threshold for positivity, as described disease for vasculitis (2, 23). in Methods. WGGER is a cross-sectional collection of 477 patients and 413 healthy controls enrolled at the Beth Israel Medical Center (New York, NY), Boston University (Boston, MA), the Cleveland Clinic litis of the skin) (18), cutaneous vasculitis (19), ulcerative colitis Foundation (Cleveland, OH), Duke University Medical Center (20), and Henoch-Schönlein purpura (21). Some of these IgA (Durham, NC), John Hopkins University (Baltimore, MD), the ANCA-associated diseases have clinical presentations
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