Abstract
BackgroundInflammation is an important risk factor in atherosclerosis, the underlying cause of coronary artery disease (CAD). Unresolved inflammation may result in maladaptive immune responses and lead to immune reactivity to self-antigens. We hypothesized that inflammation in CAD patients would manifest in immune reactivity to self-antigens detectable in soluble HLA-I/peptide complexes in the plasma.MethodsSoluble HLA-I/peptide complexes were immuno-precipitated from plasma of male acute coronary syndrome (ACS) patients or age-matched controls and eluted peptides were subjected to mass spectrometry to generate the immunopeptidome. Self-peptides were ranked according to frequency and signal intensity, then mouse homologs of selected peptides were used to test immunologic recall in spleens of male apoE-/- mice fed either normal chow or high fat diet. The peptide detected with highest frequency in patient plasma samples and provoked T cell responses in mouse studies was selected for use as a self-antigen to stimulate CAD patient peripheral blood mononuclear cells (PBMCs).ResultsThe immunopeptidome profile identified self-peptides unique to the CAD patients. The mouse homologs tested showed immune responses in apoE-/- mice. Keratin 8 was selected for further study in patient PBMCs which elicited T Effector cell responses in CAD patients compared to controls, associated with reduced PD-1 mRNA expression.ConclusionAn immunopeptidomic strategy to search for self-antigens potentially involved in CAD identified Keratin 8. Self-reactive immune response to Keratin 8 may be an important factor in the inflammatory response in CAD.
Highlights
Inflammation plays an important role in atherosclerosis, the underlying cause of coronary artery disease (CAD) [1]
Keratin 8 was selected for further study in patient peripheral blood mononuclear cells (PBMCs) which elicited T Effector cell responses in CAD patients compared to controls, associated with reduced PD-1 mRNA expression
An immunopeptidomic strategy to search for self-antigens potentially involved in CAD identified Keratin 8
Summary
Inflammation plays an important role in atherosclerosis, the underlying cause of coronary artery disease (CAD) [1]. MHC-I molecules present self-peptides to CD8 + T cells, which normally ignore or are tolerant to these self-antigens This process is considered to be a key element of immune surveillance [15]. Under conditions of persistent inflammation in diseased states, response to self-antigens is altered and is postulated to contribute to the development of autoimmunity [16]. Psoriasis is one such autoimmune condition that is associated with increased risk of cardiovascular events [17] and a T cell-reactive selfantigen in psoriasis has been identified [18]. We hypothesized that inflammation in CAD patients would manifest in immune reactivity to self-antigens detectable in soluble HLA-I/peptide complexes in the plasma
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