De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease

Published on Sep 1, 2014in The Journal of Allergy and Clinical Immunology10.228
· DOI :10.1016/J.JACI.2014.03.034
Hamid Mattoo21
Estimated H-index: 21
(Harvard University),
Vinay S. Mahajan23
Estimated H-index: 23
(Harvard University)
+ 6 AuthorsShiv Pillai50
Estimated H-index: 50
(Harvard University)
Background IgG 4 -related disease (IgG 4 -RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG 4 -expressing plasma cells at disease sites. Objective The role of B cells and IgG 4 antibodies in IgG 4 -RD pathogenesis is not well defined. We evaluated patients with IgG 4 -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 IgG 4 -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 IgG 4 -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 IgG 4 antibodies are self-reactive. Conclusions Clonally expanded CD19 + CD27 + CD20 − CD38 hi plasmablasts are a hallmark of active IgG 4 -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.
📖 Papers frequently viewed together
325 Citations
544 Citations
257 Citations
#1Mai Takeuchi (Okayama University)H-Index: 11
#2Yasuharu Sato (Okayama University)H-Index: 31
Last. Tadashi Yoshino (Okayama University)H-Index: 60
view all 10 authors...
T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease
55 CitationsSource
: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesi...
213 CitationsSource
#1Emanuel Della-Torre (UniSR: Vita-Salute San Raffaele University)H-Index: 25
#2Gabriella Passerini (UniSR: Vita-Salute San Raffaele University)H-Index: 12
Last. Diego FranciottaH-Index: 44
view all 10 authors...
To the Editor: Immunoglobulin G4-related disease (IgG4-RD) is characterized by fibrous swelling of affected organs, elevations in serum IgG4 concentrations, and responsiveness to glucocorticoid treatment1. Affected tissues display similar histological features: diffuse lymphoplasmacytic infiltration by numerous IgG4-positive plasma cells, occasional eosinophils, storiform fibrosis, and obliterative phlebitis2. IgG4-related hypertrophic pachymeningitis (IgG4-HP) has been identified as a character...
30 CitationsSource
#1Elena G. Kamburova (Radboud University Nijmegen)H-Index: 10
#2Hans J. P. M. Koenen (Radboud University Nijmegen)H-Index: 34
Last. Luuk B. Hilbrands (Radboud University Nijmegen)H-Index: 32
view all 6 authors...
A single dose of the anti-CD20 monoclonal antibody rituximab induces a nearly complete B cell depletion in peripheral blood, but not in secondary lymphoid organs. Modulation of this remaining B cell population due to rituximab treatment may contribute to the therapeutic effects of rituximab. To assess the in vivo effects of rituximab we used lymph nodes (LNs) collected during renal transplant surgery in patients who had received rituximab 4 weeks earlier in preparation for an ABO-incompatible tr...
71 CitationsSource
#2Marieke E. Doorenspleet (UvA: University of Amsterdam)H-Index: 15
Last. Ulrich BeuersH-Index: 66
view all 9 authors...
Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is a manifestation of the recently discovered idiopathic IgG4-related disease. The majority of patients have elevated serum IgG4 levels and/or IgG4-positive B-cell and plasma cell infiltrates in the affected tissue. We hypothesized that clonally expanded, class-switched IgG4-positive B cells and plasma cells could be causal to these poorly understood phenomena. In a prospective cohort of six consecutive IAC patients, six healthy controls, and...
97 CitationsSource
#1Maria J. Leandro (UCL: University College London)H-Index: 31
In humans, different B-cell subpopulations can be distinguished in peripheral bloodand other tissues on the basis of differential expression of various surface markers.These different subsets correspond to different stages of maturation, activation anddifferentiation. B-cell depletion therapy based on rituximab, an anti-CD20 mAb, iswidely used in the treatment of various malignant and autoimmune diseases. Rituximabinduces a very significant depletion of B-cell subpopulations in the peripheral bl...
99 CitationsSource
#1John H. Stone (Harvard University)H-Index: 76
#2John K.C. ChanH-Index: 45
Last. Yoh ZenH-Index: 69
view all 6 authors...
IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by an elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4-RD encompasses a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), hypophysitis, Riedel thyroiditis, tubulointerstitial nephritis, prostatitis, retroperitoneal fibrosis, inflammatory aortic aneurysm and inflammatory pseudotumor. However, like a crow f...
365 CitationsSource
IgG4-related disease (IgG4-RD) is a chronic and relapsing disease. The diagnosis of IgG4-RD is based on a combination of features that include clinical, imaging, serologic, histology, and immunohistochemistry. Nonetheless, histopathology has emerged as the gold standard for the diagnosis of IgG4-RD. Guidelines for the pathologic diagnosis of this condition have been published by an international group of experts: a triumvirate of histologic features allows for a confident diagnosis of IgG4-RD to...
65 CitationsSource
#1Kevin Larimore (UW: University of Washington)H-Index: 6
Last. Philip D. Greenberg (UW: University of Washington)H-Index: 72
view all 4 authors...
To understand better how selection processes balance the benefits of Ig repertoire diversity with the risks of autoreactivity and nonfunctionality of highly variable IgH CDR3s, we collected millions of rearranged germline IgH CDR3 sequences by deep sequencing of DNA from mature human naive B cells purified from four individuals and analyzed the data with computational methods. Long HCDR3 regions, often components of HIV-neutralizing Abs, appear to derive not only from incorporation of long D gen...
154 CitationsSource
#1Mollie N. Carruthers (Harvard University)H-Index: 15
#2John H. Stone (Partners HealthCare)H-Index: 76
Last. Arezou KhosroshahiH-Index: 30
view all 4 authors...
IgG4-related disease (IgG4-RD) is a multiorgan inflammatory disease in which diverse organ manifestations are linked by common histopathological and immunohistochemical features. Prospective studies of IgG4-RD patients are required to clarify the natural history, long-term prognosis, and treatment approaches in this recently recognized condition. Patients with IgG4-RD have different organ manifestations and are followed by multiple specialties. Divergent approaches to the assessment of patients ...
147 CitationsSource
Cited By205
#1Krishna Pattabathula (Royal Brisbane and Women's Hospital)
#2Peadar S. Waters (Royal Brisbane and Women's Hospital)
Last. Nicholas O'Rourke (UQ: University of Queensland)H-Index: 24
view all 8 authors...
BACKGROUND Autoimmune processes are now an increasingly recognized cause of acute and chronic pancreatitis. Autoimmune pancreatitis is a rare, benign pathology with two distinct clinicopathologic subtypes. The aim of this study was to compare the presentation, diagnostic considerations and outcomes of patients with biopsy-proven type 1 and 2 autoimmune pancreatitis (AIP). METHODS A retrospective review of the Queensland Health pathology database of histologically proven AIP was conducted. Parame...
#2A. Pérez GómezH-Index: 2
Last. M. Álvarez-Mon SotoH-Index: 3
view all 4 authors...
#1Marco Lanzillotta (UniSR: Vita-Salute San Raffaele University)H-Index: 14
#2Andreu Fernández-Codina (UWO: University of Western Ontario)H-Index: 9
Last. Emanuel Della-Torre (UniSR: Vita-Salute San Raffaele University)H-Index: 25
view all 7 authors...
INTRODUCTION Awareness of IgG4-related disease (IgG4-RD) is increasing worldwide and specialists are now familiar with most of its clinical manifestations and mimickers. IgG4-RD promptly responds to glucocorticoids and repeated courses are typically used to induce and maintain remission because the disease relapses in most patients. If left untreated it can lead to organ dysfunction, organ failure and death. Advancement in our understanding of IgG4-RD pathogenesis is leading to the identificatio...
Objectives: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder affecting virtually any organ. Type 1 autoimmune (type 1 AIP) is its pancreatic manifestation. To date, steroids are considered the first-line pancreatitis treatment. The CD20-binding antibody rituximab (RTX) appears a promising steroid-sparing therapy, although long-term data are lacking. We aimed to bridge this gap with a cohort of IgG4-RD patients treated with RTX and to assess the potential value of the Respo...
#1Han Joo Kim (UOU: University of Ulsan)
#2Eunkyoung You (Inje University)H-Index: 1
Last. Chan-Jeoung Park (UOU: University of Ulsan)H-Index: 19
view all 4 authors...
Resumen La enfermedad relacionada con IgG4 (ER-IgG4) es una enfermedad sistemica reconocida. Se describio tras observarse que pacientes diagnosticados de pancreatitis autoinmune mostraban signos de enfermedad extrapancreatica. La clinica de estos pacientes es subaguda y se manifiesta por aparicion de lesiones seudotumorales, o tumores inflamatorios o fibrosos. En ocasiones, puede ser grave, como en el caso de pacientes con colangitis o vasculitis de gran vaso. Los criterios diagnosticos incluyen...
Resumen La enfermedad relacionada con IgG4 (ER-IgG4) es una enfermedad sistemica reconocida. Se describio tras observarse que pacientes diagnosticados de pancreatitis autoinmune mostraban signos de enfermedad extrapancreatica. La clinica de estos pacientes es subaguda y se manifiesta por aparicion de lesiones seudotumorales, o tumores inflamatorios o fibrosos. En ocasiones, puede ser grave, como en el caso de pacientes con colangitis o vasculitis de gran vaso. Los criterios diagnosticos incluyen...
#2Faisal AlsufyaniH-Index: 2
Last. Shiv PillaiH-Index: 50
view all 10 authors...
Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be s...
1 CitationsSource
BACKGROUND Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis with slow progression over the years that is particularly difficult to diagnose. CASES Here we report three cases of ECD without BRAF mutation presenting with a renal mass, hairy kidney appearance, and a rather benign course, for which the diagnosis of ECD was delayed, characterized by multiple investigations and unsuccessful treatments attempts. In two cases the distinction from IgG4-related disease required multipl...