Characterization of the autoimmune response against the nerve tissue S100β in patients with type 1 diabetes

Abstract

SummaryType 1 diabetes results from destruction of insulin-producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non-beta cell-specific antigens has also been reported, including targeting of the calcium-binding protein S100β. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100β, determined their affinity for the human leucocyte antigen (HLA)-DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100β reactivity, characterized by interferon (IFN)-γ secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100β as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non-beta cell-specific autoantigens may have a role in type 1 diabetes pathogenesis.

Naturally presented HLA class l–restricted epitopes from the neurotrophic factor S100‐β are targets of the autoimmune response in type 1 diabetes

“…1C). Comparison of proteasome-generated peptides with A2.1-eluted peptide MS data (Table 1) indicates that the carboxy-terminal end of peptides S100 [10][11][12][13][14][15][16][17][18] (ALIDVFHQY) and S100 [20][21][22][23][24][25][26][27][28] ΔDa, difference between experimental and theoretical m/z (in Da); Experimental m/z, unique m/z present only in the peptide mix derived from K562/A2.1-S100-b cells; Position, amino acid position in the S100-b protein of the predicted peptide; Sequence, amino acid sequence of the predicted peptide; Theoretical m/z, m/z predicted by Findpept.…”

“…pSC cells express specific antigens, such as glial fibrillary acidic protein (GFAP) and the neurothrophic factor S100-b. Those antigens have been shown to be targeted by autoantibodies (19,20) and T lymphocyte responses (16,(21)(22)(23)(24)(25). Lymphocyte proliferation against GFAP and S100-b antigens has been demonstrated in NOD mice and human T1D patients (16,22).…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…However, the role played by autoantibodies in the development of insulin resistance and diabetes is still controversial and more studies are needed to resolve this. Both S100beta and GFAP also induce T cell responses both in the NOD mice and human T1D patients (Banwell et al 2008;Gomez-Tourino et al 2015;Serre et al 2015;Standifer et al 2006;Tsui et al 2008;Winer et al 2003): for S100beta, several peptide epitopes presented by HLA DR4 molecule were identified and T cell Han et al 2013) PPI pre-proinsulin, GAD 65 glutamic acid decarboxylase 65, IA-2 insulinoma antigen-2, ZnT8 zinc transporter 8, IGRP islet-specific glucose-6-phosphatase catalytic subunit related protein, GFAP glial fibrillary acidic protein, S100β neurotropic factor S100β a Antibodies: autoantibody detection in animal models and/or T1D patients; T cells: detection of either CD4 and/or CD8 T cell responses; Disease transfer: diabetes development after transfer of T cell lines/clones (either CD4 or CD8) into diabetes-free animals or diabetogenic autoantigen-specific TCR transgenic mice; Immunotherapy: disease treatment/clinical trials using whole antigen, peptides or antigen-encoding DNA vaccines b Only in irradiated NOD mice …”

“…Furthermore, pro-inflammatory responses characterized by the secretion of interferon (IFN)-γ were seen more frequently in T1D patients compared to healthy donors (Gomez-Tourino et al 2015). Interestingly, responses seen against some of the epitopes were also found in long-standing T1D patients, indicating that these autoreactive T cells may contribute to the complications arising in these patients.…”

“…In the case of MHC class II, S100b-derived peptide epitopes were discovered by incubating the lymphoblastoid cell line Priess (homozygous for the HLA class II DRB1*04:01 molecule) with the antigen. These epitopes were recognized more frequently by PBMCs from T1D patients compared to healthy donors (Gomez-Tourino et al 2015), and this response was characterized by the secretion of IFN-γ. Interestingly, for some of this new S100b epitopes, significant responses were also detected in long-standing T1D patients suggesting that these S100b-specific cells could participate in the complications seen in these patients.…”