Innate lymphoid cells: a potential innate functional equivalent of adaptive cells in infertility and inflammatory arthropathies

Background. Studies over the past few years have indicated that adaptive immunity is most commonly associated with several autoimmune conditions such as unexplained infertility and inflammatory arthropathies. However, the identification of innate subsets that mimic T response has greatly advanced our understanding of how innate immune responses may orchestrate and shape the pathomechanisms involved in autoimmune diseases. Aim. Aim of the research was to evaluate the role of innate lymphoid cells (ILCs) in unexplained infertility and inflammatory arthropathies in order to explore whether ILCs control or induce autoimmune processes, i.e., whether an innate functional equivalent of T cells is in place. Methods. In an observational setting, women with unexplained infertility were evaluated for their peripheral blood natural killer (NK) cell levels: the associations between NK and clinical features as well as the effects of the prolactin (PRL) and the thyroid function (in terms of both autoimmune and non-autoimmune diseases) on NK cells were analyzed. In a prospective cohort study, patients with enteropathic spondyloarthritis (EspA) were enrolled in order to characterize peripheral blood T and non-T cells, and ILCs subsets. EspA patients were compared with healthy subjects and patients with inflammatory bowel disease (IBD) as controls. Interferon (IFN)-ɣ and interleukin IL)-17 expressing cells and their associations with the SpA disease activity were analyzed. Results. A higher percentage of peripheral blood NK cells were registered in infertile women compared with fertile controls. In multiple regression analyses, PRL was confirmed to be the only factor to have a significant effect on NK cell levels in infertile women. The most commonly associated thyroid dysfunction in infertile women was the non-autoimmune thyroid disorder while women with higher mean NK cells levels were mainly euthyroid. A higher proportion of women with abnormal NK cells (≥15%) was detected in women with non-autoimmune thyroid disorder. ESpA patients showed higher levels of IL-17 producing non T-cells with the respect to the controls. In this context, IL-17 producing nonT cells correlated with SpA disease activity. Levels of IL-17 expressing ILCs resulted significantly higher in ESpA patients compared with both healty controls and patients with IBD and positively correlated with IFN-ɣ expressing ILCs. Discussion. The higher levels of NK cells in patients with infertility and their correlation with PRL suggest a role of both nervous and endocrine systems in the regulation of the immune response. However, thyroid dysfunctions in infertility seem to be related with non-autoimmune thyroid disorders as well as with elevated peripheral blood NK cells as possible alloimmune mechanisms in reproductive failure. Peripheral blood of ESpA patients is enriched for IL-17 expressing ILCs with the respect to the controls. That evidence might support the role of IL-17 producing ILCs in SpA pathogenesis as well as their potential role as a biomarker for a SpA condition in IBD. Conclusion. Infertile women and ESpA patients represent two human models of well accepted conditions due to an inappropriate T cell response and where the inappropriate inflammatory response may not occur primarily or exclusively due to T cell dysfunction, but is probably promoted by a disturbed placental barrier or synovial tissues. Elucidating whether innate immune cells detectable in peripheral blood can be related with immunological outcomes and clinical features can be crucial. In the long term, a better understanding of the very first events that take place early on during the initiation of an immune response may be key in designing better strategies of diagnostic and therapeutic intervention.