HLA-G as a negative regulator of immune responses and useful marker for sportsmen

Human leukocyte antigens (HLA) are key components of the adaptive part of the human immune system. The “classical” class I HLA glycoproteins (HLA-A/B/C) serve as antigen presentation molecules for T lymphocytes. The non-classical class I molecules (HLA-E/F/G) serve other functions. Namely, HLA-G is a broadly negative regulator of antigen presenting cells as well as T, B and NK lymphocytes. This molecule has been intensively studied, mainly because of its essential roles in reproductive immunology (1). In addition to the cell surface, membrane-anchored form, several soluble variants of HLA-G exist (2) . The inhibitory activity of HLA-G is based mainly on its interaction with the ILT-2/4 inhibitory leukocyte receptors (3). Due to its inhibitory activities, HLA-G belongs to so called immune check point molecules. Overexpression of HLA-G on some tumors contributes to intratumoral tolerogenic environment, making it a potential target of cancer immunotherapy. On the other hand, HLA-G expression on cells of transplanted organs or tissues affected by autoimmune diseases is beneficial as it suppresses the detrimental attack of the immune system.

The importance of HLA-G is documented by the fact that there are more than 2500 papers on HLA-G and Google returns more than 7,5 million entries related to this molecule.

It has been known for a long time that intense physical activity may down-regulate the immune functions and that very intense and prolonged exercise is associated with higher morbidity and mortality, in contrast to healthy modest exercise. Indeed, moderate exercise may lower the risk of respiratory infection, whereas excessive exercise increases the risk. Actually, the greater risk for upper respiratory infection has been observed in over-trained compared with well-trained athletes (4).

A recent study (5) demonstrates that in bodybuilders, especially those with less body fat, the systemic levels of soluble HLA-G are significantly increased, which may contribute to the previously observed mild induced immunodeficiency. This seemingly paradoxical result is probably related to the fact that intense exercise leads more or less to muscle damage, which elicits an inflammatory immune response. The increased expression of soluble HLA-G (and possibly other immunosuppressive molecules) may thus serve to mitigate this potentially damaging inflammatory response. The level of soluble HLA-G thus may be a useful indicator of a too extreme training.
 

Prof. Václav Hořejší, PhD
Inst. of Molecular Genetics AS CR
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REFERENCES:
1. Rouas-Freiss N, Moreau P, LeMaoult J, Papp B, Tronik-Le Roux D, Carosella ED. Role of the HLA-G immune checkpoint molecule in pregnancy. Hum Immunol. 2021 Mar 18:S0198-8859(21)00010-0. doi: 10.1016/j.humimm.2021.01.003.

2. Nardi Fda S, König L, Wagner B, Giebel B, Santos Manvailer LF, Rebmann V. Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker. HLA. 2016 Sep;88(3):77-86.

3. Naji A, Menier C, Morandi F, et al. Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses. J Immunol 192(4): 1536–1546, 2014.

4. Nielsen HG. Exercise and Immunity. In: Hamlin M, Draper N and Kathiravel Yeditors. Current Issues in Sports and Exercise Medicine; 2013. pp.121–140. 2013. 5. Fernandes TM, Puggina EF, Mendes-Junior CT, de Paula MC, Sonon P, Donadi EA, Fernandes APM. High plasma soluble levels of the immune checkpoint HLA-G molecule among bodybuilders. PLoS One. 2020 Sep 30;15(9):e0238044.