Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.

Accumulating evidence links the microbial communities inhabiting the gut to the pathophysiological processes underlying multiple sclerosis (MS). However, most studies on the microbiome in MS are correlative in nature, thus being at risk of confounding and reverse causality. Mendelian randomization (MR) analyses allow the estimation of the causal relationship between a risk factor and an outcome of interest using genetic variants as proxies for environmental exposures. Here, we performed a two-sample MR to assess the causality between the gut microbiome and MS. We extracted genetic instruments from summary statistics from three large genome-wide association studies (GWASs) on the gut microbiome (18,340, 8959, and 7738 subjects). The exposure data were derived from the latest GWAS on MS susceptibility (47,429 patients and 68,374 controls). We pinpointed several microbial strains whose abundance is linked with enhanced MS risk (Actinobacteria class, Bifidobacteriaceae family, Lactobacillus genus) or protection (Prevotella spp., Lachnospiranaceae genus, Negativibacillus genus). The largest risk effect was seen for Ruminococcus Torques (OR, 2.89, 95% C.I. 1.67–5, p = 1.51 × 10⁻⁴), while Akkermansia municiphila emerged as strongly protective (OR, 0.43, 95% C.I. 0.32–0.57, p = 1.37 × 10⁻⁸). Our findings support a causal relationship between the gut microbiome and MS susceptibility, reinforcing the relevance of the microbiome–gut–brain axis in disease etiology, opening wider perspectives on host–environmental interactions for MS prevention.

Actinic keratosis (AK) is a preneoplastic skin disorder which can rapidly progress to cutaneous squamous cell carcinomas (SCCs). In light of our previous findings, indicating a possible oncogenic role of the mesenchymal isoform of FGFR2 (FGFR2c) aberrantly expressed in AK keratinocytes, we analyzed the possible tumor-promoting role of this receptor in the stromal AK counterpart in this work. Molecular analysis showed that, particularly in early AK lesions, FGFR2c dermal upregulation is accompanied by the downregulation of the cancer-associated fibroblasts (CAF) transcription repressor CSL, the upregulation of the CAF activator ULK3, and the consequent CAF gene induction. Immunofluorescence and molecular analysis, coupled with silencing approaches by siRNA, applied on primary cultures of KIN I-derived fibroblasts, indicated that FGFR2c upregulation contribute to CAF signature and the increased autophagy in response to FGF2. Magnetic bead-based multiplex assay, combined with FGFR2 signaling shut-off approaches, indicated that, especially in response to FGF2, IL-6 secretion could depend on FGFR2c high expression and signaling, suggesting the possible establishment of FGFR2c-dependent secretory autophagy, contributing to tumor-promoting factor release. Overall, our results identified FGFR2c as a signaling molecule involved in controlling precancerous/stromal cell oncogenic crosstalk, pointing to this receptor as a possible early molecular marker predictive for AK’s rapid malignant progression.