Induction of pulmonary HLA-G expression by SARS-CoV-2 infection.

The non-classical human leukocyte antigen (HLA)-G exerts immune-suppressive properties modulating both NK and T cell responses. While it is physiologically expressed at the maternal-fetal interface and in immune-privileged organs, HLA-G expression is found in tumors and in virus-infected cells. So far, there exists little information about the role of HLA-G and its interplay with immune cells in biopsies, surgical specimen or autopsy tissues of lung, kidney and/or heart muscle from SARS-CoV-2-infected patients compared to control tissues. Heterogeneous, but higher HLA-G protein expression levels were detected in lung alveolar epithelial cells of SARS-CoV-2-infected patients compared to lung epithelial cells from influenza-infected patients, but not in other organs or lung epithelia from non-viral-infected patients, which was not accompanied by high levels of SARS-CoV-2 nucleocapsid antigen and spike protein, but inversely correlated to the HLA-G-specific miRNA expression. High HLA-G expression levels not only in SARS-CoV-2-, but also in influenza-infected lung tissues were associated with a high frequency of tissue-infiltrating immune cells, but low numbers of CD8+ cells and an altered expression of hyperactivation and exhaustion markers in the lung epithelia combined with changes in the spatial distribution of macrophages and T cells. Thus, our data provide evidence for an involvement of HLA-G and HLA-G-specific miRNAs in immune escape and as suitable therapeutic targets for the treatment of SARS-CoV-2 infections.

HLA-G 14-bp insertion/deletion polymorphism and risk of coronavirus disease 2019 (COVID-19) among Iraqi patients.

Human leukocyte antigen (HLA)-G molecules are proposed to influence susceptibility to coronavirus disease 2019 (COVID-19). A case-control study was conducted on 209 patients with COVID-19 and198 controls to assess soluble HLA-G (sHLA-G) levels and HLA-G 14-bp insertion [Ins]/deletion [Del] polymorphism. Results revealed that median levels of sHLA-G were significantly higher in serum of COVID-19 patients than in controls (17.92 [interquartile range: 14.86-21.15] vs. 13.42 [9.95-17.38] ng/mL; probability <0.001). sHLA-G levels showed no significant differences between patients with moderate, severe or critical disease. Del allele was significantly associated with the risk of COVID-19 (odds ratio = 1.89; 95% confidence interval = 1.44-2.48; corrected probability = 0.001), while a higher risk was associated with Del/Del genotype (odds ratio = 2.39; 95% confidence interval = 1.25-4.58; corrected probability = 0.048). Allele and genotype frequencies of HLA-G 14-bp Ins/Del polymorphism stratified by gender or disease severity showed no significant differences in each stratum. Further, there was no significant impact of genotypes on sHLA-G levels. In conclusion, sHLA-G levels were up-regulated in COVID-19 patients regardless of disease severity. Further, it is suggested that HLA-G 14-bp Ins/Del polymorphism is associated with COVID-19 risk.

Soluble HLA-G is upregulated in serum of patients with severe COVID-19.

Soluble HLA-G (sHLA-G) molecules are considered potent immunomodulators, and their dysregulated expression has been implicated in several pathological conditions, including coronavirus disease 19 (COVID-19). Therefore, a case-control study (103 COVID-19 patients and 105 controls) was performed to determine sHLA-G role in severity of COVID-19. Results revealed that median levels of sHLA-G were significantly increased in serum of patients compared to controls (19.3 vs. 12.7 ng/mL; p <0.001). When patients and controls were stratified by age group, gender, body mass index, chronic disease, or ABO and Rh blood groups, the sHLA-G level did not show a significant difference in each stratum. Logistic regression analysis demonstrated that the up-regulated expression of sHLA-G was associated with an elevated risk of developing COVID-19. Receiver operating characteristic curve analysis showed that sHLA-G was a very good predictor of COVID-19, and at a cut-off value of 15.4 ng/mL, the sensitivity and specificity of sHLA-G were 79.6 and 79.0%, respectively. Spearman rank correlation analysis revealed that sHLA-G was positively correlated with age, erythrocyte sedimentation rate, white blood cell count, and random blood glucose, while a negative correlation was recorded with vitamin D. In conclusion, up-regulated expression of sHLA-G was indicated in patients with severe COVID-19.