Do MHCII-Presented Neoantigens Drive Type 1 Diabetes and Other Autoimmune Diseases?

Marrack, Philippa; Kappler, John W.

doi:10.1101/cshperspect.a007765

Cited by 45 publications

(56 citation statements)

References 93 publications

(93 reference statements)

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“…There is increasing appreciation that, in contrast to those of most pathogen-specific T cells, T-cell receptors recognizing autoantigens may often bind unconventional ligands in which the peptides either adopt unfavorable binding registers and/or only partially occupy the peptide binding groove (30,41). Both mechanisms may be relevant to T1DM, and the R3:RE and R3: RGE mimotopes were designed to mimic the truncated peptides B:9-21 and B:9-20, as previous observations have suggested that these two variants can stimulate distinct subsets of pathogenic B:9-23 T cells (29,30).…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

Zhang

Crawford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The primary autoantigen triggering spontaneous type 1 diabetes mellitus in nonobese diabetic (NOD) mice is insulin. The major T-cell insulin epitope lies within the amino acid 9-23 peptide of the β-chain (B:9-23). This peptide can bind within the peptide binding groove of the NOD MHC class II molecule (MHCII), IA g7 , in multiple positions or "registers." However, the majority of pathogenic CD4 T cells recognize this complex only when the insulin peptide is bound in register 3 (R3). We hypothesized that antibodies reacting specifically with R3 insulin-IA g7 complexes would inhibit autoimmune diabetes specifically without interfering with recognition of other IA g7 -presented antigens. To test this hypothesis, we generated a monoclonal antibody (mAb287), which selectively binds to B:9-23 and related variants when presented by IA g7 in R3, but not other registers. The monoclonal antibody blocks binding of IA g7 -B:10-23 R3 tetramers to cognate T cells and inhibits T-cell responses to soluble B:9-23 peptides and NOD islets. However, mAb287 has no effect on recognition of other peptides bound to IA g7 or other MHCII molecules. Intervention with mAb287, but not irrelevant isotype matched antibody, at either early or late stages of disease development, significantly delayed diabetes onset by inhibiting infiltration by not only insulin-specific CD4 T cells, but also by CD4 and CD8 T cells of other specificities. We propose that peptide-MHC-specific monoclonal antibodies can modulate autoimmune disease without the pleiotropic effects of nonselective reagents and, thus, could be applicable to the treatment of multiple T-cell mediated autoimmune disorders.immunotherapy | antigen processing I n the nonobese diabetic (NOD) mouse, a spontaneous mouse model of type 1 diabetes mellitus (T1DM), autoimmune targeting of (pro)insulin appears essential for development of disease (1-7). For example, 90 percent of CD4 + insulin-reactive T-cell clones isolated from the islets of prediabetic NOD mice target the insulin β-chain 9-23 peptide (B:9-23) (8, 9), and this peptide is likely the primary epitope recognized by T cells that either induce (6, 7, 9) or prevent T1DM (8)(9)(10)(11)(12)(13)(14). Similarly, autoimmunity to insulin is essential for the loss of tolerance to the β-cell antigen islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) (11,15), but the converse is not true. The NOD mouse expresses a single MHC class II (MHCII) molecule, IA g7 , whose presence is essential for the development of T1DM (16-18). We previously suggested that a particular version of IA g7 -insulin B:9-23 complex is crucial for the initiation of islet autoimmunity in the NOD mouse (19)(20)(21)(22) and that a homologous complex involving the structurally related MHCII molecules human leukocyte antigen DQ8 (HLA-DQ8) and HLA-DQ2 may play a similar role in humans (23-25).As with other MHCII molecules, the selective binding of peptides to the IA g7 peptide binding groove is governed by interactions between the side chains at particul...

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Section: Discussionmentioning

confidence: 99%

Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

Zhang

Crawford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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confidence: 99%

“…WE14 shares the motif with the mimotopes, WSRMD, but it lies at the N terminus of the peptide. Therefore, we have suggested that, to bind similarly to IA g7 as the mimotopes, the N-terminal motif would fill p5 to p9, leaving p1 to p4 empty, resulting in a very unstable complex (3,7,10).In this article, we show that extending the N terminus of WE14 with four amino acids optimal for the p1-to-p4 positions of the IA g7 groove creates a "super agonist" that stimulates a variety of ChgA-specific T cells much better than WE14 itself. The crystal structure of this peptide bound to IA g7 confirmed the validity of the strategy, showing the WSRMD motif in the p5-to-p9 positions of the IA g7 binding groove.…”

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confidence: 99%

N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes

Jin

Wang

Crawford

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chromogranin A (ChgA) is an autoantigen for CD4 + T cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). The natural ChgA-processed peptide, WE14, is a weak agonist for the prototypical T cell, BDC-2.5, and other ChgA-specific T-cell clones. Mimotope peptides with much higher activity share a C-terminal motif, WXRM(D/E), that is predicted to lie in the p5 to p9 position in the mouse MHC class II, IA g7 binding groove. This motif is also present in WE14 (WSRMD), but at its N terminus. Therefore, to place the WE14 motif into the same position as seen in the mimotopes, we added the amino acids RLGL to its N terminus. Like the other mimotopes, RLGL-WE14, is much more potent than WE14 in T-cell stimulation and activates a diverse population of CD4 + T cells, which also respond to WE14 as well as islets from WT, but not ChgA −/− mice. The crystal structure of the IA g7 -RLGL-WE14 complex confirmed the predicted placement of the peptide within the IA g7 groove. Fluorescent IA g7 -RLGL-WE14 tetramers bind to ChgA-specific T-cell clones and easily detect ChgA-specific T cells in the pancreas and pancreatic lymph nodes of NOD mice. The prediction that many different N-terminal amino acid extensions to the WXRM(D/E) motif are sufficient to greatly improve T-cell stimulation leads us to propose that such a posttranslational modification may occur uniquely in the pancreas or pancreatic lymph nodes, perhaps via the mechanism of transpeptidation. This modification could account for the escape of these T cells from thymic negative selection. (T1D) is an autoimmune disease characterized by infiltration of T cells into the pancreatic islets of Langerhans, resulting in destruction of insulin-secreting beta cells (reviewed in ref. 1). Numerous autoantigens, including insulin/ proinsulin itself and chromogranin A (ChgA), have been reported to be T-cell targets in the disease in mice and/or humans (reviewed in refs. 2 and 3). In the nonobese diabetic (NOD) mouse model of T1D, epitopes in the insulin B chain have been shown to be essential for T1D development (4), and CD4 + T-cell clones specific for insulin or ChgA have been shown to be particularly potent in induction of T1D in immune-deficient NOD-scid mice (5). ChgA (gene name CHGA) is a member of the granin family of neuroendocrine secretory proteins. Full-length ChgA is proteolytically processed to yield several functional peptides including a small peptide, WE14 (6). Our group participated in the study that first identified ChgA as the autoantigen and the WE14 peptide as the key epitope for the prototypical BDC-2.5 and other NOD-derived CD4 + T cells (7). WE14 is a weak agonist for these ChgA-specific T cells, but we (7) and others (8, 9) have identified a series of mimotope peptides that are very strong agonists for these T cells. Comparison of the sequence of WE14 with these mimotope peptides reveals the presence of a common amino acid motif, WXRM(D/E), at the C terminus where it is predicted to occupy positions p5 to p9 in the IA g7 binding groove. WE14...

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“…Implicit in this model is that type 1 diabetes is not caused by failure of normal clearance of autoreactive T cells. That neo-epitopes might play a role in the development of type 1 diabetes has also recently been considered by other researchers [13][14][15]. However, here we place the generation of neo-epitopes arising from modified beta cell proteins into a pathogenetic context (Fig.…”

Section: Introductionmentioning

confidence: 95%

Do post-translational beta cell protein modifications trigger type 1 diabetes?

et al. 2013

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Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate.

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Do MHCII-Presented Neoantigens Drive Type 1 Diabetes and Other Autoimmune Diseases?

Cited by 45 publications

References 93 publications

Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes

Do post-translational beta cell protein modifications trigger type 1 diabetes?

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