Macrophages in the synovial lining niche initiate neutrophil recruitment and articular inflammation

The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins with the activation of lining macrophages. We show that lining, but not sublining macrophages phagocytose immune complexes containing the model antigen. Using the antigen-induced arthritis (AIA) model, we demonstrate that on recognition of antigen-antibody complexes, lining macrophages undergo significant activation, which is dependent on interferon regulatory factor 5 (IRF5), and produce chemokines, most notably CXCL1. Consequently, at the onset of inflammation, neutrophils are preferentially recruited in the vicinity of antigen-laden macrophages in the synovial lining niche. As inflammation progresses, neutrophils disperse across the whole synovium and form swarms in synovial sublining during resolution. Our study alters the paradigm of lining macrophages as immunosuppressive cells to important instigators of synovial inflammation

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

Decoding heterogeneity and specialisation of interstitial synovial macrophages: what, where and how

Synovial macrophages are a highly heterogeneous population of tissue-resident cells, and they have distinct functions at steady-state and during synovial inflammation. We have identified that their heterogeneity reflects distinct ontogeny, localisation, and function at least in two subsets of murine synovial macrophages. AQP1-positive macrophages are localised in a specific niche in the interior of the murine knee joint, near the structural elements including the patella, menisci, and cruciate ligaments. They can self-maintain by proliferation and only a minority of them is replenished by monocytes at steady-state. Furthermore, these cells appear to function as tissue-resident precursors of lining macrophages and their functions may be shaped by biophysical forces including mechanical and osmotic pressure. Conversely, RELM⍺-positive macrophages are localised in the vicinity of blood vessels in the interstitium, they are largely replenished by monocytes, and they secrete the monocyte chemoattractant CCL2 to recruit monocytes to the interstitium at the onset of synovial inflammation. Overall, we have identified that macrophage localisation in the synovium significantly impacts their function and that biophysical forces may be important contributors to their phenotype, particularly in mechano-sensitive organs such as the knee