Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

Seay, Howard R.; Yusko, Erik; Rothweiler, Stephanie J.; Zhang, Lin; Posgai, Amanda L.; Campbell‐Thompson, Martha; Vignali, Marissa; Emerson, Ryan; Kaddis, John S.; Ko, Dave; Nakayama, Maki; Smith, Mia J.; Cambier, John C.; Pugliese, Alberto; Atkinson, Mark A.; Robins, Harlan; Brusko, Todd M.

doi:10.1172/jci.insight.88242

Cited by 110 publications

(121 citation statements)

References 68 publications

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“…Similar to our previous work on gut and liver T‐cell clonality in PSC‐IBD, we found that the productive clonality of the gut and liver B‐cell compartment to range from 0.04 to 0.16, values that are higher than those reported in the blood of patients with systemic lupus erythematosus and comparable with those observed in the pancreatic draining lymph nodes of patients with type 1 diabetes . These findings suggest that B cells in the gut and liver of patients with PSC‐IBD are more oligoclonal and expanded compared to those in the periphery and support further study of gut and liver tissue as a means of determining potential antigenic triggers in PSC‐IBD.…”

Section: Discussionsupporting

confidence: 90%

Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis–Inflammatory Bowel Disease

Chung

Henriksen

Jørgensen

et al. 2018

Hepatology Communications

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B cells express an antigen‐specific B‐cell receptor (BCR) and may contribute to liver inflammation by recognizing shared antigens in the gut and liver. Herein, we used high‐throughput BCR sequencing of the immunoglobulin heavy chain, specifically the complementarity‐determining region 3 (CDR3), to characterize the B‐cell repertoire of freshly‐frozen paired gut and liver tissue samples from patients with primary sclerosing cholangitis (PSC) and concurrent inflammatory bowel disease (IBD) (PSC‐IBD, n = 10) and paired formalin‐fixed paraffin‐embedded (FFPE) tumor‐adjacent normal colon and liver tissue from patients with colorectal liver metastases (controls, n = 10). We observed significantly greater numbers of B cells (P < 0.01) and unique B‐cell clonotypes (P < 0.05) in gut samples compared to liver samples of patients with PSC‐IBD, whereas BCR sequences in FFPE normal gut and liver samples were nearly absent (14 ± 5 clonotypes; mean ± SD; n = 20). In PSC‐IBD, an average of 8.3% (range, 1.6%‐18.0%) of B‐cell clonotypes were found to overlap paired gut and liver samples following the exclusion of memory clonotypes reported in the blood of healthy controls. Overlapping gut and liver clonotypes showed stronger evidence of antigen‐driven activation compared to non‐overlapping clonotypes, including shorter CDR3 lengths and higher counts of somatic hypermutation (P < 0.0001). Conclusion: A proportion of gut and liver B cells originate from a common clonal origin (i.e., likely to recognize the same antigen) in patients with PSC which suggests B‐cell antigens are shared across the gut–liver axis. (Hepatology Communications 2018; 00:000‐000)

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Section: Discussionsupporting

confidence: 90%

Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis–Inflammatory Bowel Disease

Chung

Henriksen

Jørgensen

et al. 2018

Hepatology Communications

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“…(181) analyzed islet-infiltrating T cells from nPOD donors, focusing on proinsulin-specific CD4 + T cells. The study included 3 nPOD T1D donors overlapping with those of Babon et al (175) and nPOD donor 6323 examined by Seay et al (182), described below. These donors were 6, 14, and 19 years old, had T1D for 2, 3, and 6 years, respectively, and displayed insulitis in the pancreatic islets.…”

Section: Ex Vivo Studies Of T Cells In T1d-relevant Tissuesmentioning

confidence: 99%

“…Together with the data of Michels et al on the same donor (181), these findings support the existence of public TCRs shared among patients. Additional evidence for public TCRs derives from the observation that TCR sequences of GAD65 autoreactive CD4 + T cells from a patient with T1D recurrence in the transplanted pancreas (109) overlapped with sequences from a large number of the nPOD T1D donors studied by Seay et al (182).…”

Section: Ex Vivo Studies Of T Cells In T1d-relevant Tissuesmentioning

confidence: 99%

Autoreactive T cells in type 1 diabetes

Pugliese¹

2017

Journal of Clinical Investigation

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269

226

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“…Some skewing of TCRVα chains has been seen [49]. The largest effort to profile TCR sequences from donor tissues from individuals with T1D comes from Brusko and colleagues within the nPOD consortium [80••]. Tissue donors with T1D ( n = 18) and non-diabetic controls ( n = 9) had PLN, nonpancreatic lymph nodes, spleen, and peripheral blood FACS sorted into T cell subsets and TCRVβ chains sequenced.…”

Section: Pancreatic Histology and Autoreactive T Cells In T1dmentioning

confidence: 99%

Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

et al. 2017

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Purpose of Review Autoimmune-mediated destruction of insulin-producing β-cells within the pancreas results in type 1 diabetes (T1D), which is not yet preventable or curable. Previously, our understanding of the β-cell specific T cell repertoire was based on studies of autoreactive T cell responses in the peripheral blood of patients at risk for, or with, T1D; more recently, investigations have included immunohistochemical analysis of some T cell specificities in the pancreas from organ donors with T1D. Now, we are able to examine live, islet-infiltrating T cells from donors with T1D. Recent Findings Analysis of the T cell repertoire isolated directly from the pancreatic islets of donors with T1D revealed pro-inflammatory T cells with targets of known autoantigens, including proinsulin and glutamic acid decarboxylase, as well as modified autoantigens. Summary We have assayed the islet-infiltrating T cell repertoire for autoreactivity and function directly from the inflamed islets of T1D organ donors. Design of durable treatments for prevention of or therapy for T1D requires understanding this repertoire.

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Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

Cited by 110 publications

References 68 publications

Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis–Inflammatory Bowel Disease

Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis–Inflammatory Bowel Disease

Autoreactive T cells in type 1 diabetes

Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

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