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Anti-Inflammatory Action of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Patients with Autoimmune Endocrine Disorders.

ABSTRACT: Our previous studies documented that human fibroblast-limbal stem cells (f-LSCs) possess immunosuppressive capabilities, playing a role in regulating T-cell activity. This study highlights the molecular activities by which human f-LSCs can attenuate the inflammatory responses of self-reactive peripheral blood mononuclear cells (PBMCs) collected from patients with autoimmune endocrine diseases (AEDs). Anti-CD3 activated PBMCs from twenty healthy donors and fifty-two patients with AEDs were cocultured on f-LSC monolayer. 2D-DIGE proteomic experiments, mass spectrometry sequencing and functional in vitro assays were assessed in cocultured PBMCs. We identified the downmodulation of several human heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) isoforms in healthy and AED activated PBMCs upon f-LSC interaction. The reduction of hnRNPA2/B1 protein expression largely affected the cycling ki67+, CD25+, PD-1+ reactive cells and the double marked CD8+/hnRNPA2B1+ T cell subset. Anti-PD1 blocking experiments evoked hnRNPA2/B1 overexpression, attributing putative activation function to the protein. hnRNPA2/B2 transient silencing inverted immunopolarization of the self-reactive PBMCs from AEDs toward a M2/Th2-type background. Pharmacological inhibition and co-immunoprecipitation experiments demonstrated the involvement of NF-?B in hnRNPA2/B activity and turnover. Our data indicate cardinal involvement of hnRNP A2/B1 protein in peripheral mechanisms of tolerance restoration and attenuation of inflammation, identifying a novel immunoplayer potentially targetable in all AEDs.

SUBMITTER: Coppola A

PROVIDER: S-EPMC7019344 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Anti-Inflammatory Action of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Patients with Autoimmune Endocrine Disorders.

Coppola Antonina A Cancemi Patrizia P Tomasello Laura L Guarnotta Valentina V Pitrone Maria M Failla Valentina V Cillino Salvatore S Feo Salvatore S Pizzolanti Giuseppe G Giordano Carla C

Journal of clinical medicine 20191219 1

Our previous studies documented that human fibroblast-limbal stem cells (f-LSCs) possess immunosuppressive capabilities, playing a role in regulating T-cell activity. This study highlights the molecular activities by which human f-LSCs can attenuate the inflammatory responses of self-reactive peripheral blood mononuclear cells (PBMCs) collected from patients with autoimmune endocrine diseases (AEDs). Anti-CD3 activated PBMCs from twenty healthy donors and fifty-two patients with AEDs were cocult ...[more]

PMID: 31861546

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Project description:A hallmark of systemic lupus erythematosus (SLE) is the appearance of autoantibodies to nuclear antigens, including autoantibodies directed to the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2), which occur in 20% to 30% of SLE patients as well as in animal models of this disease. To investigate the underlying cellular reactivity and to gain further insight into the nature and potential pathogenic role of this autoimmune response we characterized the T cell reactivity against hnRNP-A2 in patients with SLE in comparison to healthy controls. Cellular proliferation of peripheral blood T cells to hnRNP-A2 was determined by [3H]thymidine incorporation and T cell clones (TCCs) specific for hnRNP-A2 were grown by limiting dilution cloning; IFNgamma, IL-4 and IL-10 in culture supernatants were measured by ELISA. Bioactivity of culture supernatants was determined by incubation of anti-CD3/anti-CD28 stimulated peripheral blood CD4+ T cells with supernatants of TCCs. Stimulation assays performed with peripheral blood mononuclear cells of 35 SLE patients and 21 healthy controls revealed pronounced proliferative responses in 66% of SLE patients and in 24% of the controls, which were significantly higher in SLE patients (p < 0.00002). Furthermore, hnRNP-A2 specific TCCs generated from SLE patients (n = 22) contained a relatively high proportion of CD8+ clones and mostly lacked CD28 expression, in contrast to TCCs derived from healthy controls (n = 12). All CD4+ TCCs of patients and all control TCCs secreted IFNgamma and no IL-4. In contrast, CD8+ TCCs of patients secreted very little IFNgamma, while production of IL-10 did not significantly differ from other T cell subsets. Interestingly, all CD8+ clones producing IL-10 in large excess over IFNgamma lacked expression of CD28. Functional assays showed a stimulatory effect of the supernatants derived from these CD8+ CD28- hnRNP-A2 specific TCCs that was similar to that of CD4+ CD28+ clones. Taken together, the pronounced peripheral T cell reactivity to hnRNP-A2 observed in the majority of SLE patients and the distinct phenotype of patient-derived CD8+ TCCs suggest a role for these T cells in the pathogenesis of SLE.

Dataset Information

Anti-Inflammatory Action of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Patients with Autoimmune Endocrine Disorders.

Publications

Anti-Inflammatory Action of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Patients with Autoimmune Endocrine Disorders.

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