Association of human leukocyte antigen class II alleles with epithelial cell apoptosis and extracellular matrix production in acute COVID-19

Ieva Vanaga; Oksana Kolesova; Aleksandrs Kolesovs; Gunta Sture; Elvira Hagina; Jelena Storozenko; Liene Nikitina-Zake; Ludmila Viksna

doi:10.5114/ceji.2023.133684

Association of human leukocyte antigen class II alleles with epithelial cell apoptosis and extracellular matrix production in acute COVID-19

Cent Eur J Immunol. 2023;48(4):322-329. doi: 10.5114/ceji.2023.133684. Epub 2023 Dec 12.

Authors

Ieva Vanaga^{1

2}, Oksana Kolesova¹, Aleksandrs Kolesovs^{1

3}, Gunta Sture^{1

2}, Elvira Hagina¹, Jelena Storozenko¹, Liene Nikitina-Zake¹, Ludmila Viksna^{1

2}

Affiliations

¹ Riga Stradins University, Riga, Latvia.
² Riga East Clinical University Hospital, Riga, Latvia.
³ University of Latvia, Riga, Latvia.

Abstract

Introduction: Pathogenic mechanisms and long-term consequences of COVID-19 require attention in studies on SARS-CoV-2. The association of the severity of COVID-19 with genetic factors, such as human leukocyte antigen (HLA) genes, remains underexplored. Our study assessed the relationships between HLA class II alleles and COVID-19 severity and blood-based indicators of systemic inflammation and organ damage, serum markers of epithelial cell apoptosis such as caspase-cleaved CK18 fragment M30 (CK18-M30) and the extracellular matrix product hyaluronic acid (HA).

Material and methods: The study included 101 hospitalized COVID-19 patients (mean age 60 ±14 years). Clinical tests were performed at admission to the hospital. The levels of CK18-M30 and HA were detected in serum by enzyme-linked immunosorbent assay (ELISA). HLA typing was performed in HLA-DRB1, -DQA1, and -DQB1 loci by the polymerase chain reaction with low-resolution sequence-specific primers.

Results: Sixty-one patients had a non-severe and 40 had a severe or critical disease course (following the WHO definition). The severity was associated with older age, male gender, higher HA, CK18-M30, and some indicators of inflammation. Despite the lack of direct association between HLA alleles and the severity of COVID-19, the presence of HLA-DRB1*04 and 12 alleles in the genotype was associated with lowered or elevated HA, respectively. The HLA-DQB1*03:01 allele was associated with lowered CK18-M30, aspartate aminotransferase, and ferritin. In addition, HLA-DQB1*06:01 was associated with elevated alanine aminotransferase.

Conclusions: Associations of HLA class II alleles with markers of epithelial cell apoptosis and extracellular matrix production indirectly support the influence of HLA genes on acute COVID-19 severity.

Keywords: COVID-19; HLA class II; apoptosis; cytokeratin 18; hyaluronic acid; liver.