Loss of CXCR3 expression on memory B cells in individuals with long-standing type 1 diabetes

Powell, Wendy; Hanna, Stephanie; Hocter, Claire N.; Robinson, Erick; Davies, Joanne; Dunseath, Gareth; Luzio, Stephen Denis; Farewell, Daniel; Li, Wen; Dayan, Colin; Price, David A.; Ladell, Kristin; Wong, F. Susan

doi:10.1007/s00125-018-4651-x

Cited by 13 publications

(14 citation statements)

References 49 publications

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“…Alterations within CD19 + B cell subsets were only found in patients with HT despite that autoantibodies are also present in T1D, GD and AD. Previous studies addressing peripheral B cells in T1D and GD have reported that frequencies were similar compared to HC (32)(33)(34) or that functional responses toward autoantigens were changed (35,36).…”

Section: Discussionmentioning

confidence: 96%

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

et al. 2020

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Although there is evidence that autoimmune diseases share similar immunogenetic mechanisms, studies comparing peripheral CD45 + cells from patients with autoimmune endocrine diseases in parallel are limited. In this study, we applied high-dimensional single-cell mass cytometry to phenotypically characterize PBMC from patients with new-onset (N-T1D) and long-standing type 1 diabetes, Hashimoto's thyroiditis (HT), Graves' disease and autoimmune Addison's disease (AD), as well as healthy controls. The frequency of CD20 lo CD27 hi CD38 hi HLA-DR int plasmablasts, CD86 + CD14 lo CD16 + non-classical monocytes and two subsets of CD56 dim HLA-DR + IFN-γ + NK cells were increased in patients with HT. Subsets of CD56 dim CD69 + HLA-DR − NK cells and CD8 + TEMRA cells, both expressing IFN-γ, were expanded and reduced, respectively, in the N-T1D group. In addition, patients with AD were characterized by an increased percentage of central memory CD8 + T cells that expressed CCR4, GATA3, and IL-2. We demonstrate that patients with N-T1D, HT, and AD had altered frequencies of distinct subsets within antigen-presenting and cytotoxic cell lineages. Previously unreported alterations of specific cell subsets were identified in samples from patients with HT and AD. Our study might contribute to a better understanding of shared and diverging immunological features between autoimmune endocrine diseases.

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Section: Discussionmentioning

confidence: 96%

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

et al. 2020

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“…Spanning-tree progression analysis of density-normalised events Live T cells were identified in serial gates as singlets, lymphocytes, LIVE/DEAD Fixable Aqua − , CD19 − , CD3 + events and gated as CD4 + , CD8 + , CD4/CD8 double-positive, or CD4/CD8 double-negative cells using FlowJo. Compensated flow cytometry files were exported for Spanning-tree Progression Analysis of Density-normalized Events (SPADE) using fixed settings (K-means algorithm, 100 clusters, Arcsinh transformation with cofactor 150) in SPADE software version 3.0 [6,20,21]. Expression of cell surface markers (CD3, CD4, CD8, CD27, CD57, CD95, CD45RA, CD127, CXCR3 and programmed cell-death protein 1 [PD-1]) was assessed.…”

Section: Methodsmentioning

confidence: 99%

“…People with type 1 diabetes display altered frequencies and function of a number of lymphocyte subsets, as well as different expression levels of surface markers; frequency and suppressive ability of Tregs are reduced in type 1 diabetes [3]. Expression of C-X-C motif chemokine receptor 3 (CXCR3) is reduced on CD3 + T cells in individuals with long-standing type 1 diabetes [4][5][6]. Although beta cellautoreactive CD8 + T cells are found in healthy volunteers, these CD8 + T cells from people with type 1 diabetes have a more differentiated phenotype that includes T SCM [7].…”

Section: Introductionmentioning

confidence: 99%

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Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

et al. 2020

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Aims/hypothesis The aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes. Methods Immunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8 + T cells were quantified using peptide-HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs. Results Islet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4 + and CD8 + T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4 + T cells with a central memory phenotype (CD27 int , CD127 + , CD95 int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4 + T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8 + T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06). Conclusions/interpretation In this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications.

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“…Chemokine CXCL10 is functionally classified as an inflammatory chemokine. The role of the CXCL10/CXCR3 axis in the immunopathogenesis of type 1 diabetes has been extensively studied with the blockade of the CXCL10/CXCR3 system considered as a promising therapeutic target [30,31].…”

Section: Discussionmentioning

confidence: 99%

Elevated peripheral blood levels of CXCL10 are associated with the presence of diabetic polyneuropathy in subjects with type 2 diabetes

Ascaso

Palanca

Martínez-Hervás

et al. 2020

Preprint

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Background : Diabetic peripheral neuropathy (DPN) has high morbidity and mortality. Major risk factors of DPN include metabolic changes, duration of diabetes, nerve ischemia, and derangements in regeneration and nerve repair programs. The implication of chemokines in the pathogenesis of various neuropathies and neuropathic pain processes has been studied previously. This pilot study aimed to evaluate the association between plasma levels of chemokines CXCL9, CXCL10, and CXCL11 with the presence of DPN in a cohort of type 2 diabetes (T2D) patients. Methods : We have studied a total of 73 T2D patients (36 patients with DPN, and 37 without DPN). DPN was established through the Semmes-Weinstein test (SW). Plasma levels of circulating chemokines CXCL9, CXCL10, and CXCL11 were determined using Duoset ELISA kits (Abingdon, UK). Results: In T2D patients with similar gender distribution, duration of the disease, peripheral macroangiopathy, and metabolic control, we detected significantly higher serum levels of chemokine CXCL10 among patients with DPN than among patients without DPN (57.6 ± 38.3 vs. 38.1 ± 33.4 pg/mL, respectively; p = 0.034). Serum levels of chemokine CXCL9 were also higher among patients with DPN (188.1 ± 72.7 and 150.4 ± 83.6 pg/mL, respectively, p = 0.06). Conclusions : DPN in T2D patients was associated with a significant increase in CXCL10 circulating levels, suggesting a role for this chemokine in the DPN. Novel inflammatory markers that allow for early detection and therapeutic strategies in order to reverse and prevent the DPN should be investigated.

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Loss of CXCR3 expression on memory B cells in individuals with long-standing type 1 diabetes

Cited by 13 publications

References 49 publications

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

Elevated peripheral blood levels of CXCL10 are associated with the presence of diabetic polyneuropathy in subjects with type 2 diabetes

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