Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

Abstract

A significant body of work implicates the adaptive immune response in atherosclerosis, the main underlying cause of coronary artery disease (CAD), yet specific antigens involved remain to be fully identified. The pathobiology of CAD is influenced by sex with many factors that may be involved in the underlying mechanisms. Given the reported sexual dimorphic nature of immune-inflammatory responses, we investigated the influence of sex on potential CAD self-antigens from acute coronary syndrome (ACS) patients using immune-precipitation of soluble HLA Class-I/peptide complexes and mass spectrometry. Relevance of identified self-antigens to atherosclerosis, the major underlying cause of CAD, was tested in the apoE-/-atherosclerotic mouse model. Soluble HLA Class-I complexes from ACS patients and self-reported controls were immune-precipitated and subjected to elution, denaturation and size-exclusion to obtain HLA-bound peptides. Peptides were then subjected to mass spectrometry and patient-unique self-peptides were grouped as common to both female and male, or unique to either sex. Three peptides common to both female and male patients (COL6A1, CDSN, and SAA2), and 2 peptides each unique to female (COL1A1 and COL5A2) or male (SAA1 and KRT 9) patients were selected and mouse homologs of the peptides were screened for self-reactive immune responses in apoE-/-mice. The screening step revealed potential sex-influenced immune responses which was associated with differential immune profiles. Based on the frequency in patient plasma, COL6A1, COL5A2, and KRT 9 peptides were then tested in immunization studies. Neither COL5A2 nor KRT 9 peptide immunization resulted in significant effects on atherosclerosis compared to controls. On the other hand, female mice immunized with COL6A1 peptide had significantly reduced atherosclerosis whereas male mice had significantly increased atherosclerosis, associated with differential immune profiles. Our study identified potential self-antigens involved in atherosclerosis using the immune peptidome of CAD patients. Altering self-reactive immune responses to COL6A1 in apoE-/-mice resulted in differential effects on atherosclerosis burden with sex as a determinant of outcome.

Cross-reactivity and sequence similarity between microbial transglutaminase and human tissue antigens

“…When blood vessels are damaged and start to bleed, fibrinogen is converted into fibrin, a key component in the formation of a blood clot. Fibrin forms a network of fibers that trap red blood cells and platelets at the site of injury, forming a temporary barrier that stops the bleeding AIAS AS PA RA SLE 52 – 57 Histone H1.2 (UniProt:P16403) Component of chromatin that plays a role in regulating gene expression and cellular processes Antibodies against histones have been associated with various ADs AIT SS SLE PBC 58 , 59 Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial (DLST, UniProt:P10515) An enzyme that is involved in the regulation of energy metabolism in cells Autoantibodies against DLST have been found in some individuals with ADs PBC patients have been characterized to have autoreactive T-cell and B-cell responses directed at self-PDC-E2. The diagnosis of PBC is readily reached by the detection of specific AMA directed against PDH-E2 PBC SS T1DM SLE RA 60 – 62 Creatine kinase S-type, mitochondrial (mtCK, UniProt:P17540) An enzyme that plays a role in the production of energy within the mitochondria RA, T1DM 63 , 64 Dimethyladenosine transferase 2, mitochondrial (TRMT10C, UniProt:Q9H5Q4) Is involved in the transfer of methyl groups to specific adenosine residues in mitochondrial tRNAs.…”

Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

“…Interestingly, several potential self-antigens were described in context with CAD [131] and in line with this, keratin 8 was recently shown as a self-antigen to elicit effector CD4 + and CD8 + T cell responses in CAD patients [132]. As expected, the stimulation of CAD PBMCs with keratin 8 did not tend to elevate the PD-1 transcripts, signifying an aberrant peripheral tolerance in CAD patients due to massive inflammatory responses against the self-antigen which could be the cause for impaired PD-1 expression, while keratin 8 increased the PD-1 mRNA on PBMCs obtained from control subjects [132].…”

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

“…In addition, clonality of plaque and thrombus T cells (4) suggest specificity to disease-relevant antigens. While generalized profiles of T cell responses in ACS patients have been informative (2,5), specific activation markers in response to antigen stimulation (6)(7)(8)(9) are now under investigation and may provide more clarity on their relevance to the clinical sequelae.…”