title: De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.
abstract: BACKGROUND
  IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites.
  
  
  OBJECTIVE
  The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis.
  
  
  METHODS
  B-cell populations from the peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy.
  
  
  RESULTS
  Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+), are increased in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive.
  
  
  CONCLUSIONS
  Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process.
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Vinay S
authors.initials: VS
authors.lastname: Mahajan
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Della-Torre
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Sekigami
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Mollie
authors.initials: M
authors.lastname: Carruthers
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Wallace
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass. Electronic address: jhstone@partners.org.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Mass. Electronic address: pillai@helix.mgh.harvard.edu.
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000916:Antibody Diversity / Q000235:genetics; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D002999:Clone Cells; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology* / Q000628:therapy; D007074:Immunoglobulin G / Q000378:metabolism*; D008213:Lymphocyte Activation; D008218:Lymphocytosis / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D000069283:Rituximab; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D001324:Autoantigens; D007074:Immunoglobulin G; D000069283:Rituximab
keywords: CDR3; IgG(4)-related disease; autoreactivity; immunoglobulin heavy chain variable region repertoire; next-generation sequencing; plasmablasts; rituximab; somatic hypermutation