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Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.
Jarrell, Justin A; Baker, Matthew C; Perugino, Cory A; Liu, Hang; Bloom, Michelle S; Maehara, Takashi; Wong, Heidi H; Lanz, Tobias V; Adamska, Julia Z; Kongpachith, Sarah; Sokolove, Jeremy; Stone, John H; Pillai, Shiv S; Robinson, William H.
Affiliation
  • Jarrell JA; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Baker MC; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif.
  • Perugino CA; Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • Liu H; Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • Bloom MS; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Maehara T; Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • Wong HH; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Lanz TV; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif; Department of Neurology, Medical Faculty Mannheim, Univers
  • Adamska JZ; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Kongpachith S; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Sokolove J; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
  • Stone JH; Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • Pillai SS; Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • Robinson WH; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif. Electronic address: w.robinson@stanford.edu.
J Allergy Clin Immunol ; 149(1): 358-368, 2022 01.
Article in En | MEDLINE | ID: mdl-33974929
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoantibodies / Fibrosis / Immunoglobulin G / Receptors, Interleukin-1 / Antibodies, Neutralizing Type of study: Prognostic_studies Limits: Adolescent / Adult / Aged / Aged80 / Child / Child, preschool / Female / Humans / Male / Middle aged Language: En Journal: J Allergy Clin Immunol Year: 2022 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoantibodies / Fibrosis / Immunoglobulin G / Receptors, Interleukin-1 / Antibodies, Neutralizing Type of study: Prognostic_studies Limits: Adolescent / Adult / Aged / Aged80 / Child / Child, preschool / Female / Humans / Male / Middle aged Language: En Journal: J Allergy Clin Immunol Year: 2022 Document type: Article Country of publication: