title: Reversal of Arthritis by Human Monomeric IgA Through the Receptor-Mediated SH2 Domain-Containing Phosphatase 1 Inhibitory Pathway.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA), one of the most frequent chronic inflammatory rheumatic disorders, is characterized by the presence of autoantibodies and joint infiltration by activated immune cells, leading to cartilage and bone destruction. IgA occurs predominantly as monomers (mIgA) in plasma and regulates many cell responses through interaction with the Fcα receptor type I (FcαRI). FcαRI targeting by anti-FcαRI Fab inhibits activating receptors by inducing an inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) configuration through SH2 domain-containing phosphatase 1 (SHP-1) recruitment. The aim of this study was to investigate the potential utility of mIgA for the treatment of arthritis by acting as an inducer of ITAMi signaling.
  
  
  METHODS
  The effect of plasma-derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcαRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcαRI-transgenic mice and wild-type mice treated with mIgA were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The mice were assessed for development of arthritis using an arthritis score, and joint tissue samples were evaluated for the extent of leukocyte infiltration and expression of phosphatase.
  
  
  RESULTS
  Treatment with mIgA impaired cell activation in an FcαRI-FcRγ-dependent manner, involving ITAMi signaling. Human mIgA or anti-FcαRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcαRI-transgenic mice. Administration of mIgA markedly inhibited the recruitment of leukocytes to the inflamed joints of mice, which was associated with induction of SHP-1 phosphorylation in joint tissue cells. Moreover, mIgA reversed the state of inflammation in the synovial fluid of RA patients by inducing an ITAMi configuration.
  
  
  CONCLUSIONS
  These results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA.
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, CNRS ERL8252, Université Paris Diderot, Sorbonne Paris Cité, Site Xavier Bichat, Laboratoire d'Excellence Inflamex, and Service d'Immunologie, DHU FIRE, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rossato
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, CNRS ERL8252, Université Paris Diderot, Sorbonne Paris Cité, Site Xavier Bichat, Laboratoire d'Excellence Inflamex, and Service d'Immunologie, DHU FIRE, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
authors.forename: Sanae
authors.initials: S
authors.lastname: Ben Mkaddem
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, CNRS ERL8252, and Université Paris Diderot, Sorbonne Paris Cité, Site Xavier Bichat, Paris, France.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanamaru
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, CNRS ERL8252, Université Paris Diderot, Sorbonne Paris Cité, Site Xavier Bichat, Laboratoire d'Excellence Inflamex, and Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
authors.forename: Margarita
authors.initials: M
authors.lastname: Hurtado-Nedelec
authors.affiliation: Service de Rhumatologie, Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Hayem
authors.affiliation: Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Descatoire
authors.affiliation: CSL Behring, Bern, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Vonarburg
authors.affiliation: CSL Behring, Bern, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Miescher
authors.affiliation: CSL Behring, Bern, Switzerland.
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Zuercher
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, CNRS ERL8252, Université Paris Diderot, Sorbonne Paris Cité, Site Xavier Bichat, Laboratoire d'Excellence Inflamex, and Service d'Immunologie, DHU FIRE, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010586:Phagocytes / Q000187:drug effects / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000187:drug effects / Q000502:physiology*; D011961:Receptors, Fc / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology
chemical_list: D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6