Evidence for Local Expansion of IgA Plasma Cell Precursors in Human Ileum

Yuvaraj, Saravanan; Dijkstra, Gerard; Burgerhof, Johannes G. M.; Dammers, Peter M.; Stoel, Maaike; Visser, Anita; Kroese, Frans G. M.; Bos, Nicolaas A.

doi:10.4049/jimmunol.0901315

Cited by 31 publications

(27 citation statements)

References 34 publications

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“…The IGH, IGK, and IGL chain gene repertoire of intestinal plasmablasts showed no significant differences to systemic B cell populations, including IgG + peripheral blood memory B cells. Our results confirm the high Ig gene mutation load and strong clonal expansion of IgA + plasmablasts in terminal ileum and report similar results for IgG + plasmablasts (27,28). Clonally related antibodies were identified in IgA + and IgG + plasmablasts but were not shared between both compartments, suggesting that they may originate from independent precursor cells.…”

Section: Discussionsupporting

confidence: 78%

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

Benckert¹,

Schmolka²,

Kreschel³

et al. 2011

J. Clin. Invest.

216

224

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Mucosal antibody responses play a major role in mediating homeostasis with the intestinal flora. It has been suggested that imbalance in the IgA + and IgG + intestinal B cell repertoire may be associated with the development of diseases such as inflammatory bowel disease. Despite this, little is known about the antibody specificity of human intestinal plasmablasts. Here, we have determined the reactivity profile of single isolated IgA + and IgG + plasmablasts from human terminal ileum using antibody cloning and in vitro expression. We found that approximately 25% of intestinal IgA and IgG plasmablast antibodies were polyreactive; the majority were antigen-specific. Antigen specificity was not only directed against enteropathogenic microbes but also against commensal microbes and self antigens. Regardless of their reactivity, all intestinal antibodies were somatically mutated and showed signs of antigen-mediated selection, suggesting that they developed from antigen-specific B cell responses. Together, our data indicate that antigen-specific immune responses to intestinal microbes are largely responsible for the maintenance of intestinal homeostasis and thus provide a basis for understanding the deregulated immune responses observed in patients with inflammatory bowel disease.

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Section: Discussionsupporting

confidence: 78%

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

Benckert¹,

Schmolka²,

Kreschel³

et al. 2011

J. Clin. Invest.

216

224

View full text Add to dashboard Cite

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“…Evidence for clonally expanded PCs have been found both in human and mouse intestine (35)(36)(37). In the analysis of single TG2-specific PCs, two pairs of sister cells with identical Ig gene sequences were found among 36 single-sorted cells from one individual (12), suggestive of clonal expansion of gut TG2-specific PCs.…”

Section: Tg2-specific Pcs Have a Low Degree Of Diversity And Are Clonmentioning

confidence: 95%

Analysis of Celiac Disease Autoreactive Gut Plasma Cells and Their Corresponding Memory Compartment in Peripheral Blood Using High-Throughput Sequencing

Snir

Mesin

Gidoni

et al. 2015

The Journal of Immunology

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Autoreactive IgA plasma cells (PCs) specific for the enzyme transglutaminase 2 (TG2) are abundant in the small intestine of patients with active celiac disease (CD), and their number drops in patients treated by dietary gluten elimination. Little is known about their characteristics and their role in the disease. In this study, using high-throughput sequencing of the IgH V region (IGHV) genes, we have studied features of TG2-specific PCs and their related B cell clones in peripheral blood. We found that TG2-specific PCs from both untreated and treated patients have acquired lower number of somatic hypermutation and used focused IGHV repertoire with overrepresentation of the IGHV3-48, IGHV4-59, IGHV5-10-1, and IGHV5-51 gene segments. Furthermore, these PCs were clonally expanded and showed signs of affinity maturation. Lineage trees demonstrated shared clones between gut PCs and blood memory B cells, primarily IgAs. Some trees also involved IgG cells, suggesting that anti-TG2 IgA and IgG responses are related. Similarly to TG2-specific PCs, clonally related memory IgA B cells of blood showed lower mutation rates with biased usage of IGHV3-48 and IGHV5-51. Such memory cells were rare in peripheral blood, yet detectable in most patients assessed by production of anti-TG2 Abs in vitro following stimulation of cells from patients who had been on a long-term gluten-free diet. Thus, the Ab response to TG2 in CD, while maintaining its IGHV gene usage, is dynamically regulated in response to gluten exposure with a low degree of maintenance at both PC and memory B cell levels in patients in remission.

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“…Total RNA was extracted from each batch. These RNA samples were converted to cDNA and amplified by RT-PCR using primers specific for the IGHV3 gene (24) in combination with C region primers specific for the CH1 domains of the Ca (25) or Cg (18) C regions. RT-PCR and cloning were performed as reported previously (18).…”

Section: Cloning Sequencing and Analysis Of Ig Sequencesmentioning

confidence: 99%

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

Hamza

Hershberg

Kallenberg

et al. 2015

The Journal of Immunology

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In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren’s syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36–52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients’ parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.

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Evidence for Local Expansion of IgA Plasma Cell Precursors in Human Ileum

Cited by 31 publications

References 34 publications

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

Analysis of Celiac Disease Autoreactive Gut Plasma Cells and Their Corresponding Memory Compartment in Peripheral Blood Using High-Throughput Sequencing

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

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