Allergy and autoimmune diseases are characterised by a multifactorial pathogenic background. Several genes involved in the control of innate and adaptive immunity have been associated with diseases and variably combine with each other as well as with environmental factors and epigenetic processes to shape the characteristics of individual manifestations. Systemic or local perturbations in salt/water balance and in ion exchanges between the intra- and extracellular spaces or among tissues play a role. In this field, usually referred to as elementary immunology, novel evidence has been recently acquired on the role of members of the transient potential receptor (TRP) channel family in several cellular mechanisms of potential significance for the pathophysiology of the immune response. TRP canonical channel 6 (TRPC6) is emerging as a functional element for the control of calcium currents in immune-committed cells and target tissues. In fact, TRPC6 influences leukocytes’ tasks such as transendothelial migration, chemotaxis, phagocytosis and cytokine release. TRPC6 also modulates the sensitivity of immune cells to apoptosis and influences tissue susceptibility to ischemia-reperfusion injury and excitotoxicity. Here, we provide a view of the interactions between ion exchanges and inflammation with a focus on the pathogenesis of immune-mediated diseases and potential future therapeutic implications.

Spondyloarthritis (SpA) contemplates the inflammatory involvement of the musculoskeletal system, gut, skin, and eyes, delineating heterogeneous diseases with a common pathogenetic background. In the framework of innate and adaptive immune disruption in SpA, neutrophils are arising, across different clinical domains, as pivotal cells crucial in orchestrating the pro-inflammatory response, both at systemic and tissue levels. It has been suggested they act as key players along multiple stages of disease trajectory fueling type 3 immunity, with a significant impact in the initiation and amplification of inflammation as well as in structural damage occurrence, typical of long-standing disease. The aim of our review is to focus on neutrophils’ role within the spectrum of SpA, dissecting their functions and abnormalities in each of the relevant disease domains to understand their rising appeal as potential biomarkers and therapeutic targets.

Objective It is still a matter of debate whether low-dose acetylsalicylic acid (LDASA) should be prescribed to all patients with SLE during pregnancy. This study aimed at investigating the impact of LDASA on pregnancy outcomes in patients with SLE without history of renal involvement and without antiphospholipid antibodies (aPL). Methods This is a retrospective analysis of prospectively monitored pregnancies at seven rheumatology centres. Previous/current renal involvement and aPL positivity were the exclusion criteria. Adverse pregnancy outcome (APO) is the composite outcome of the study and included proteinuric pre-eclampsia, preterm delivery <37 weeks, small-for-gestational age infant, low birth weight <2500 g, intrauterine growth restriction and intrauterine fetal death after 12 weeks of gestation of a morphologically normal fetus. Results 216 pregnancies in 187 patients were included; 82 pregnancies (38.0%) were exposed to LDASA treatment. No differences in terms of age at conception, disease duration, clinical manifestations, comorbidities and disease flare during pregnancy were observed between patients taking LDASA and those who did not take LDASA during pregnancy. APO was observed in 65 cases (30.1%), including 13 cases (6.1%) of pre-eclampsia. The incidence of all complications was similar in the two groups. However, it is interesting to note that pre-eclampsia had lower frequency in patients taking LDASA versus those not taking LDASA (2.4% vs 8.3%, p=0.14). Conclusions In pregnant patients with SLE without renal involvement and were aPL-negative, there is a low risk of severe obstetric complications, such as early pre-eclampsia. LDASA treatment does not provide a statistically significant advantage over these complications. However, a careful individual risk–benefit balance is warranted.

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules′ interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.

Tenosynovial inflammation is a hallmark of rheumatoid arthritis (RA), even in the preclinical phase. However, tenosynovium retrieval and characterisation is beyond the current state-of-the-art. We aimed to (1) assess the rate of magnetic resonance imaging (MRI)-detected tenosynovitis in the wrists of patients with preclinical and clinical RA; (2) develop a technique for tenosynovium retrieval; and (3) characterise its cellular composition across disease phases, including the comparison to adjacent synovium. In total, 834 MRI wrist scans were analysed to assess extensor/flexor tendon tenosynovitis rate (168 autoantibody-positive clinical suspect arthralgia (CSA), 473 naïve to treatment RA, and 193 healthy controls). An ultrasound-guided minimally invasive technique was developed to collect tenosynovium from the wrist extensor tendons in an independent cohort: 16 autoantibody-positive CSA patients, 41 RA patients (14 of whom with adjacent synovium with comparable ultrasound-detected inflammation), and 8 osteoarthritis (OA) patients. Tissue representativity, lining hyperplasia, and inflammatory infiltrate degree were assessed by haematoxylin and eosin staining and immunohistochemistry (CD55, CD68, CD3, CD20, CD138, and CD21). Safety and tolerability were assessed. Tenosynovitis of the wrist extensors/flexor tendons was observed in 34% of CSA and 68% of RA patient compared to 8% in healthy. Tenosynovium was successfully retrieved in 89.7% of cases without severe adverse events. Tenosynovial lining hyperplasia and inflammatory infiltrate were significantly higher in active RA than CSA patients without ultrasound-detected subclinical inflammation and RA remission, and comparable to inflamed adjacent synovium. CSA patients with subclinical inflammation showed early CD3^pos and CD55^pos cells enrichment compared to OA controls. Tenosynovium is frequently inflamed and readily accessible in CSA and RA. Future molecular studies of tenosynovial biopsies will advance understanding of the transition from pre-RA to RA.