The Severity of COVID-19 Affects the Plasma Soluble Levels of the Immune Checkpoint HLA-G Molecule

Abstract

The non-classical histocompatibility antigen G (HLA-G) is an immune checkpoint molecule that has been implicated in viral disorders. We evaluated the plasma soluble HLA-G (sHLA-G) in 239 individuals, arranged in COVID-19 patients (n = 189) followed up at home or in a hospital, and in healthy controls (n = 50). Increased levels of sHLA-G were observed in COVID-19 patients irrespective of the facility care, gender, age, and the presence of comorbidities. Compared with controls, the sHLA-G levels increased as far as disease severity progressed; however, the levels decreased in critically ill patients, suggesting an immune exhaustion phenomenon. Notably, sHLA-G exhibited a positive correlation with other mediators currently observed in the acute phase of the disease, including IL-6, IL-8 and IL-10. Although sHLA-G levels may be associated with an acute biomarker of COVID-19, the increased levels alone were not associated with disease severity or mortality due to COVID-19. Whether the SARS-CoV-2 per se or the innate/adaptive immune response against the virus is responsible for the increased levels of sHLA-G are questions that need to be further addressed.

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

“…Regarding a putative link between HLA-G and COVID-19 infection, it has been suggested that in an early inflammatory stage, the host might produce the anti-inflammatory cytokine IL-10, which could later enhance HLA-G expression to avoid injuries [ 57 ]. These data were further extended by a positive correlation next to IL-10 with IL-6 and IL-8 in the acute phase of the SARS-CoV-2 infection [ 58 ]. Thus, HLA-G expression and/or secretion might reflect a negative feedback response to inflammatory processes during viral infections [ 29 ].…”

An observational study investigating soluble immune checkpoints as indicators of severe COVID-19

“…Another clinical study in Korea reported that increased levels of sCD27, sCD40, sCD152, soluble cytotoxic T-lymphocyte-associated protein 4 (sCTLA-4), and sTIM3 were significantly higher in COVID-19 patients who died than in survivors ( 11 ). Moreover, in independent studies that included COVID-19 patients with severe to critical disease, increased levels of specific sICPs, such as the non-classic histocompatibility antigen G (HLA-G), sCD279, soluble programmed cell death 1 (sPD-1), soluble programmed cell death-ligand 1 (sPDL1), sTIM-3, and soluble CD137 (sCD137) ( 12 – 18 ) were found in peripheral blood. However, to determine whether sICPs can function as potential blood biomarkers and therapeutic targets in COVID-19, more studies are necessary to better understand their immunomodulatory behavior in the pathophysiology of this disease.…”

O desbalanço de CD36 e CD14 está correlacionado com os níveis de acetilcolina, de mediadores lipídicos e com a gravidade em pacientes infectados com SARS-CoV-2

“…A tempestade de citocinas tem sido responsabilizada por esses eventos [263]- [265], no entanto, muito ainda precisa ser compreendido, e vários grupos continuam a descrever outros efeitos adversos e importantes induzidos pelo SARS-CoV-2, no homem. Nesse contexto, nosso grupo de pesquisa tem contribuído substancialmente, tendo já publicado artigos sobre a participação do TREM-1 [72], [74], HLA-G [71], hormônios sexuais [73], e dos eicosanoides e acetilcolina [99]. Nesse último, mostramos que tanto sistemicamente como nos pulmões, além de citocinas, há aumento significativo de eicosanoides e ACh, cujas alterações se relacionam com mudanças da expressão genica de enzimas e de receptores, relacionados à síntese ou ação desses compostos [99].…”

“…Para a análise estatística 71 Esta análise foi realizada utilizando os testes Kruskal-Wallis, Mann-Whitney, Spearman's correlation, ou Chi-square (χ2).…”

“…Esses marcadores preditivos também podem ajudar os médicos a decidir se os pacientes precisam de monitoramento mais agressivo ou não [65], [67]. Além dos marcadores citados anteriormente, nosso grupo de pesquisa identificou outros possíveis biomarcadores, tais como s-TREM1, HLA-G, hormônios sexuais, ACh e metaloproteinases [71]- [74]. Normalmente, mais de 80% das pessoas infectadas apresentam sintomas leves e devem ser monitoradas em casa, mas quase 20% delas evoluem para o estágio 3 da doença e até desenvolvem pneumonia aguda [65], [66], [69].…”