title: A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis.
abstract: Deposits of Ig and complement are abundant in affected joints of patients with rheumatoid arthritis (RA) and in animal models of RA in which antibodies are demonstrably pathogenic. To identify molecular targets of the Igs deposited in arthritic joints, which may activate local inflammation, we used a combination of mass spectrometry (MS) and protein microarrays. Immune complexes were affinity-purified from surgically removed joint tissues of 26 RA and osteoarthritis (OA) patients. Proteins complexed with IgG were identified by proteomic analysis using tandem MS. A striking diversity of components of the extracellular matrix, and some intracellular components, copurified specifically with IgG from RA and OA tissues. A smaller set of autoantigens was observed only in RA eluates. In complementary experiments, IgG fractions purified from joint immune complexes were tested on protein microarrays against a range of candidate autoantigens. These Igs bound a diverse subset of proteins and peptides from synovium and cartilage, different from that bound by normal serum Ig. One type of intracellular protein detected specifically in RA joints (histones H2A/B) was validated by immunohistology and found to be deposited on the cartilage surface of RA but not OA joints. Thus, autoantibodies to many determinants (whether deposited as "neoantigens" or normal constituents of the extracellular matrix) have the potential to contribute to arthritic inflammation.
authors.affiliation: Section on Immunology and Immunogenetics, The Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hueber
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.forename: Beren H
authors.initials: BH
authors.lastname: Tomooka
authors.forename: Maya
authors.initials: M
authors.lastname: BenBarak
authors.forename: Barry P
authors.initials: BP
authors.lastname: Simmons
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Thornhill
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000302:isolation & purification / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000302:isolation & purification / Q000378:metabolism; D001324:Autoantigens / Q000302:isolation & purification / Q000378:metabolism; D016022:Case-Control Studies; D005109:Extracellular Matrix / Q000276:immunology; D006657:Histones / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000302:isolation & purification / Q000378:metabolism; D007150:Immunohistochemistry; D007596:Joints / Q000276:immunology; D008856:Microscopy, Fluorescence; D010003:Osteoarthritis / Q000276:immunology; D040081:Protein Array Analysis; D040901:Proteomics; D013583:Synovial Membrane / Q000276:immunology; D053719:Tandem Mass Spectrometry
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D006657:Histones; D007074:Immunoglobulin G