Chapter Five - The Beta Cell Immunopeptidome
Introduction
The cellular immune response depends upon recognition of peptides presented on the cell surface by human leukocyte antigen (HLA) molecules encoded by the major histocompatibility complex (MHC). These peptides are derived from the degradation of intracellular or extracellular proteins with hundreds of thousands of different HLA-bound peptides (the immunopeptidome) displayed simultaneously on the cell surface for scrutiny by passing T cells. Because of pathogen-driven genetic diversification of the MHC region, HLA alleles and their gene products are frequently associated with resistance to disease. However, the very polymorphism that drives antigen specificity is also linked to selective presentation of self-peptides, leading to autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis, and multiple sclerosis. Over 40 susceptibility loci have been identified in genetic studies of T1D (Pociot et al., 2010). However, of the genes that predispose to this disease in humans, the strongest contributing factor is the genotype of an individual's MHC molecules. Between 50% and 60% of the familial clustering seen in T1D can be attributed to allelic variation in the HLA genes encoding classical class I and II MHC proteins (Concannon et al., 2005, Noble and Erlich, 2012). In Caucasian populations, the most commonly associated HLA class II haplotypes are HLA-DR3/DQ2 and HLA-DR4/DQ8, with approximately 30–50% of patients carrying both haplotypes. Indeed, heterozygosity for both haplotypes confers the greatest risk for developing T1D, potentially through the formation of an additional trans-encoded HLA-DQ molecule (Kooy-Winkelaar et al., 2011, van Lummel et al., 2012). In the nonobese diabetic (NOD) mouse, a widely used murine model of spontaneous diabetes, genetic susceptibility is linked to the MHC class II allele IAg7. IAg7 is highly homologous to the human HLA-DQ8 molecule and shares a common peptide-binding specificity during selection of natural ligands (Suri, Walters, Gross, & Unanue, 2005). Although not as striking as class II associations, a number of class I alleles are also linked to the development of T1D. The most commonly associated alleles include HLA-A2, HLA-A24, HLA-B39, and HLA-A11 (Nejentsev et al., 2007). These HLA associations, taken together with findings in murine models that the interaction of autoreactive lymphocytes with both class I and II molecules is required for the initiation and progression of T1D (Eisenbarth, 2007), have led to the hypothesis that islet-derived peptides are presented differentially by disease-associated and nonassociated alleles. Although this is a simple postulate, the complexity of the immunopeptidome and the multitude of other environmental and genetic influences involved in rendering an individual susceptible to developing T1D have made this difficult to assess.
Section snippets
Autoantigens in T1D
T1D results from the immune-mediated destruction of insulin-secreting beta cells, leading to insulin deficiency and hyperglycemia. This damage occurs slowly over months to years, eventually resulting in the near complete loss of insulin-secreting cells. Both humoral and cellular immune responses can be detected prior to and at diagnosis of disease (Roep and Peakman, 2011, Vehik et al., 2011). Serological screening for serum autoantibodies against (pro)insulin, glutamic acid decarboxylase
Class I presentation
A large number of factors influence the processing and presentation of peptides by MHC molecules. These include protein turnover, protein accessibility, protease specificity, and the ability to bind to specific MHC molecules. Cytokine-induced expression of proteasome subunits and the action of signal peptidases together with cytoplasmic and endoplasmic reticulum (ER)-associated aminopeptidases all contribute to the complexity and plasticity of peptide generation. Tissue-specific differences in
Identifying T Cell Epitopes in T1D
The inaccessibility of the target tissue in humans and the limited amount of islet material in NOD mice makes identifying the peptides presented by beta cells or antigen-presenting cells in the surrounding tissues difficult. In NOD mice, it has often been the case that a diabetogenic T cell clone has been used for many years to study the mechanisms of disease without knowing the precise specificity of the clone. This is true for two of the best-studied T cell clones in NOD mice, the CD8+ NY8.3
Peptide-Based Intervention and the Role of Small Molecules
One of the aims of mapping T cell responses in T1D is to provide avenues for immunotherapeutic intervention, prior to the initiation of disease in at-risk individuals, during the long progression to clinical diabetes, or after diagnosis. In some patients, residual beta cell function remains, giving impetus to studies aimed at beta cell regeneration or replacement. Strategies aimed at replacement also require immunomodulation to prevent recurrent autoimmunity. While this may be achieved by broad
Advances in Mass Spectrometry for the Identification of PTMs
The identification of peptide ligands of disease relevance in T1D presents some major technical hurdles, given the complexity of the immunopeptidome and the compounding factors of register shifting, noncanonical acquisition of peptides, posttranslational modification, and low ligand abundance. While one strategy alone will not be sufficient to identify and assess the importance of candidate peptides, several advances in mass spectrometry make identifying relevant peptides from primary beta
Conclusions
Identifying the peptides presented by pancreatic beta cells and by the antigen-presenting cells within and around the target tissue remains an important goal in T1D research. Many factors impact on the generation of peptide ligands during antigen processing. Protein turnover, protein accessibility, protease specificity, and the affinity for MHC molecules all come into play before a peptide can be presented at the cell surface. The site of presentation, the type of cell type displaying the
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Complimentary electrostatics dominate T-cell receptor binding to a psoriasis-associated peptide antigen presented by human leukocyte antigen C∗06:02
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2017, Journal of Biological ChemistryCitation Excerpt :Autoimmune disorders are typically multifactorial; as such the identification of specific autoantigens has been difficult. Nonetheless, progress has been made identifying insulin epitopes in diabetes (11, 12) and in the setting of CD4+ T-cell recognition of specific autoantigenic epitopes presented by HLA-II molecules. For example, the presentation of citrullinated self-epitopes by HLA-DRB1*04:01/04 in rheumatoid arthritis (13, 14) and the presentation of deamidated peptides derived from dietary gluten by HLA-DQ8 and HLA-DQ2 in celiac disease (15–17).
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