Research Article: Keratin 8 is a potential self-antigen in the coronary artery disease immunopeptidome: A translational approach

Date Published: February 27, 2019

Publisher: Public Library of Science

Author(s): Peter M. Mihailovic, Wai Man Lio, Romana Herscovici, Kuang-Yuh Chyu, Juliana Yano, Xiaoning Zhao, Jianchang Zhou, Bo Zhou, Michael R. Freeman, Wei Yang, Prediman K. Shah, Bojan Cercek, Paul C. Dimayuga, Gualtiero I. Colombo.


Inflammation 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.

Soluble 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).

The 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.

An 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.

Partial Text

Inflammation plays an important role in atherosclerosis, the underlying cause of coronary artery disease (CAD) [1]. It is a significant risk factor for a cardiovascular event underscored by the outcome of the CANTOS trial [2], where residual inflammatory risk [3,4] was targeted for therapy. Clinical biomarkers of inflammation in CAD do not completely disclose the fundamental characteristics of the process nor do they reveal the pathways involved.

We report on novel self-antigens potentially involved in atherosclerosis using IP of soluble MHC-I/peptide complexes from CAD patient plasma and MS/MS to identify specific peptides. Several generalizations can be made based on our results: 1) Soluble MHC-I/peptide complexes from CAD patients can be used to generate immunopeptidomic profiles of the underlying disease, evidenced by the novel self-antigens described; 2) Feeding of mice with high fat diet increased the propensity for memory T cells to respond to the self-peptides tested; 3) The peptides identified appear to be of more relevance to a response to atherosclerosis rather than a response to MI; and 4) CAD patients have T cells reactive to Keratin 8 peptide.




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