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Abstract
BackgroundUnderstanding how sexual dimorphism affects the physiological and pathological responses of the immune system is of considerable clinical importance and could lead to new approaches in therapy. Sexual dimorphism has already been noted as an important factor in autoimmune diseases: the aim of this study was to establish whether sexual dimorphism in autoimmune diseases is the result of differing pathways being involved in the regulation of T-helper (Th) cell network homeostasis.MethodsWe focused on sexually dimorphic changes in the immune response in multiple sclerosis (MS) patients in order to ascertain how these alterations relate to the pathway regulation of the cytokine homeostasis and the Th cell networks. We studied antigen presenting cell (APC)-dependent T cell activation in groups of healthy subjects, in patients under interferon (IFN) β-therapy and untreated. Cytokines, soluble (s) CD30 and the expanded disability status scale (EDSS) were used as biomarkers for T cell differentiation and neurological deficit.ResultsThe data confirm our belief that sexual dimorphism in autoimmune diseases is the result of differing pathways that regulate Th cell network homeostasis: interleukin (IL) 6 pathways in women and IFNγ pathways in men. Given the increased susceptibility of women to MS and the significance of IL6 in the autoimmune process compared to IFNγ, it is logical to assume that IL6 pathways are in some way implicated in the prevalence of autoimmune diseases in women. Indeed, our data indicate that IL6 pathways are also involved in T regulatory (Treg) cell imbalance and an increase in neurological deficit in both men and women groups of MS patients, underlining the autoimmune etiology of multiple sclerosis. In further support of differing cytokine pathways in men and women, we noted that the efficacy of IFNβ-treatment in the re-establishment of Th-network balance and in the delaying of the neurological disability progression is linked to the IL6 pathway in women, but to the IFNγ pathway in men. Lastly, we also identified specific gender biomarkers for the use in therapy.ConclusionsThe identification of gender-specific drugs is of considerable importance in translational medicine and will undoubtedly lead to more appropriate therapeutic strategies and more successful treatment.
Highlights
Understanding how sexual dimorphism affects the physiological and pathological responses of the immune system is of considerable clinical importance and could lead to new approaches in therapy
Our results show that antigen presenting cell (APC) regulate Th cell differentiation and Th cell network homeostasis under resting and activated conditions of the immune system in both men and women: relationships were found between APC cytokines (L-cytokines: IFNγ, L6, IL10) and Th cell cytokines under resting (b-cytokines: IL2, IL4, IFNγ, L6, IL10) and activated (p-cytokines: IL2, IL4, IFNγ L6, IL10) conditions (Figure 1)
IL6 pathways are involved in Th cell network imbalance and an increase in neurological deficit in both men and women suffering from multiple sclerosis (MS) we found that the susceptibility of the female sex to abnormal autoimmune function can be attributed to the dominant role of ΙL6 in T regulatory (Treg) imbalance
Summary
Understanding how sexual dimorphism affects the physiological and pathological responses of the immune system is of considerable clinical importance and could lead to new approaches in therapy. In the early 1980s, the Th1-Th2 hypothesis was put forward [6,7]: Th1 lymphocytes secrete pro-inflammatory cytokines (e.g. IL-2, IFNγ IL-12, and lymphotoxin) and they are specific against viruses and intracellular pathogens; whereas, Th2 cells secrete anti-inflammatory cytokines (e.g. IL-4, IL6, IL-5, IL-10) and act against extracellular pathogens, mediating humoral immune responses [7,8] Subsequent research made it clear that the cytokine environment at the time of CD4+ T cell activation was the determining key in generating these effector subsets, due to the ability of cytokines to activate tailored transcription factors required for the differentiation of the specific Th subsets: Th1 requires the expression of T bet transcription factor; whereas, Th2 cells are controlled by expression of GATA-3 [9,10,11]. This concept led to the identification of other Th subsets with distinct functions in the immune response, namely Treg cells, Th17 cells and Th9 cells
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