Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases.

Sajad Rashidi,Reza Mansouri,Carmen Vieira,Renu Tuteja,Raúl Manzano-Román,Mohammad Ali-Hassanzadeh,Paul Nguewa,Antonio Muro

doi:10.3390/biom12020257

Abstract

Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.

Highlights

Major Histocompatibility Complex (MHC or the synonymous HLA, Human LeucocyteAntigens) has three regions designated as Class I, Class II, and Class III, and genes belonging to each of them encode the synthesis of molecules with different structure and function.The main function of class I gene products is the presentation of endogenous peptide antigens to CD8+ T cells
Human Leukocyte Antigen-G (HLA-G) plays a major role in the down-regulation of the functions of the innate and adaptive immune system cells through interaction with multiple inhibitory receptors such as Leukocyte Immunoglobin-Like Receptors (LILRs) and in the presentation of nonpeptidic antigens to non-classical T cells, leading to unique and fast immune responses upon infections [2]
The molecule has a particular conformation that allows the presentation of a promiscuous repertoire of peptides similar to its functional homologue in mice, promoting a number of immunomodulatory effects as specific non-classical cytotoxic T cell responses rapidly responding to infections [13]

Summary

Introduction

Antigens) has three regions designated as Class I, Class II, and Class III, and genes belonging to each of them encode the synthesis of molecules with different structure and function. HLA-G plays a major role in the down-regulation of the functions of the innate and adaptive immune system cells through interaction with multiple inhibitory receptors such as Leukocyte Immunoglobin-Like Receptors (LILRs) and in the presentation of nonpeptidic antigens to non-classical T cells, leading to unique and fast immune responses upon infections [2]. A number of studies have highlighted the important role of this immune checkpoint molecule in the modulation of the immune system in immune-related diseases, tumors, and infections through the structure and dynamics of the different HLA-G isoforms [8,9,10,11]. The molecule has a particular conformation that allows the presentation of a promiscuous repertoire of peptides similar to its functional homologue in mice, promoting a number of immunomodulatory effects as specific non-classical cytotoxic T cell responses rapidly responding to infections [13]. CD8 CTL/ Suppressing CD4 T cell proliferation in response to allogeneic stimulation

Functions of HLA-G in Diseases

HLA-G Expression in Parasitic Diseases

HLA-G as Target for Potential Immunotherapeutic Strategy

Findings

Conclusions