Objectives Spleen tyrosine kinase (SYK) is a cytoplasmic protein tyrosine kinase which plays a role in signalling via B cell and Fc receptors. Fc receptor engagement and signalling via SYK is thought to be important in anti-neutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. In this study we investigate the role for SYK in ANCA induced myeloid cell activation and vasculitis pathogenesis. Methods Phosphorylation of SYK in myeloid cells from healthy controls and AAV patients was analysed using flow cytometry. The effect of SYK inhibition on MPO-ANCA IgG activation of cells was investigated using functional assays (IL-8 and ROS production) and targeted gene analysis using Nanostring. Total and phosphorylated SYK at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridisation. Results We identify increased phosphorylated SYK at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to remission patients or healthy controls. SYK is phosphorylated in vitro following MPO-ANCA IgG stimulation and SYK inhibition can prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identify up-regulation of FcR and SYK-dependent signalling pathways following MPO-ANCA IgG stimulation. Finally, we show SYK is expressed and phosphorylated in tissue leucocytes at sites of organ inflammation in AAV. Conclusions These findings indicate that SYK plays a critical role in MPO-ANCA IgG-induced myeloid cell responses that SYK is activated in circulating and tissue immune cells in AAV, and SYK inhibition may therefore be a potential therapeutic option.

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive pigmentary retinopathy, and vestibular dysfunction. The degree and onset of hearing loss vary among subtypes I, II, and III, while blindness often occurs in the second to fourth decades of life. Usher type III (USH3), characterized by postlingual progressive sensorineural hearing loss, varying levels of vestibular dysfunction, and varying degrees of visual impairment, typically manifests in the first to second decades of life. While USH3 is rare, it is highly prevalent in certain populations. RP61, USH3, and USH3A symbolize the same disorder, with the latter symbol used more frequently in recent literature. This review focuses on the clinical features, epidemiology, molecular genetics, treatment, and research advances for sensory deficits in USH3A.

SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 post-mortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID post-mortem controls. SARS-CoV-2 anti-NP staining in the post-mortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained post-mortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms to the organ tropism of SARS-CoV-2 in contemporary cases as well as providing insights into potential long-term complications of COVID-19. This article is protected by