Primary Sjogren Syndrome (pSS) is a complex, multifactorial rheumatic disease that mainly targets salivary and lacrimal glands, inducing epithelitis. The cause behind the autoimmunity outbreak in pSS is still elusive; however, it seems related to an aberrant reaction to exogenous triggers such as viruses, combined with individual genetic pre-disposition. For a long time, autoantibodies were considered as the hallmarks of this disease; however, more recently the complex interplay between innate and adaptive immunity as well as the consequent inflammatory process have emerged as the main mechanisms of pSS pathogenesis. The present review will focus on innate cells and on the principal mechanisms of inflammation connected. In the first part, an overview of innate cells involved in pSS pathogenesis is provided, stressing in particular the role of Innate Lymphoid Cells (ILCs). Subsequently we have highlighted the main inflammatory pathways, including intra- and extra-cellular players. A better knowledge of such processes could determine the detection of new therapeutic targets that are a major need for pSS.

The microbial community acts as an active player in maintaining homeostasis and immune functions through a continuous and changeable cross-talk with the host immune system. Emerging evidence suggests that altered microbial composition, known as dysbiosis, might perturb the delicate balance between the microbiota and the immune system, triggering inflammation and potentially contributing to the pathogenesis and development of chronic inflammatory diseases. This review will summarize the current evidence about the microbiome-immunity cross-talk, especially focusing on the microbiota alterations described in patients with rheumatic diseases and on the recent findings concerning the interaction between microbiota, metabolic function, and the immune system.

Modern “omics” sciences, including metabolomics and microbiomics, are currently being applied to inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), to investigate the interplay between microbiota, metabolic function, and the immune system. In recent decades, robust evidence has suggested that disruption of the normal composition of the microbiome, known as dysbiosis, in the gut and mouth of RA patients contributes to immune dysregulation and alterations in the metabolic pathways, shaping the pathogenesis of the disease and playing a central role in the risk and progression of RA. Metabolic pathways can be influenced by various agents such as the surrounding environment, lifestyle, and exposure to microbiota imbalance. In turn, the body’s metabolic homeostasis influences the immune response, making metabolomics helpful not only to understand pathogenesis pathways, but also to improve early disease detection and therapeutic chances. Combined gut microbiome and metabolome studies set out to unravel the interactions between these two entities, providing insights to discover new treatment targets and potential biomarkers to prevent joint damage. The purpose of this review is to summarize the main recent findings that suggest promising new research directions for the pathogenesis of RA.