Aberrant pro-inflammatory responses of CD20+ T cells in experimental arthritis.

CD20+ T cells comprise a highly inflammatory subset implicated in autoimmunity, including rheumatoid arthritis (RA). We sought to characterize the CD20+ T cell subset in the murine collagen-induced arthritis (CIA) model of RA and investigate the phenotype and functional relevance of CD3+CD20+ T cells in the lymph nodes and arthritic joints using flow cytometry and immunohistochemistry. We demonstrate that CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are expanded in the draining lymph nodes of CIA mice, produce increased levels of pro-inflammatory cytokines and are less susceptible to regulation by regulatory T cells. Notably, CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are enriched with CXCR5+PD-1+ T follicular helper cells and CXCR5-PD-1+ peripheral T helper cells, subsets of T cells implicated in promoting B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues in RA. Our findings suggest CD20+ T cells are associated with inflammatory responses and may exacerbate pathology by promoting inflammatory B-cell responses.

COVID-19 pandemic and Fourth Industrial Revolution (4IR): Reflection on the challenges and opportunities in South Africa.

Coronavirus disease 2019 (COVID-19) has changed people's interactions dramatically, be it with the government, the outside world, or one another. It has compelled society to change the standards for decision-making in areas such as health and education, and how people live, work, play, and do business. As a result of the new behavioral patterns imposed by governments around the world, including the South African government, there has been technological advancement through the Fourth Industrial Revolution (4IR). In South Africa, key economic sectors such as healthcare, education, and finance have served as digital change engines. Without a doubt, technology has been able to halt the spread of the virus. The main objective of this paper is to raise awareness of 4IR and to identify opportunities presented by 4IR for South Africa and the challenges presented by 4IR in resolving COVID-19 issues. It examines the relationship between evolving technological advances brought about by 4IR and COVID-19. Following a review of the relevant literature, the study's findings revealed that prior to the pandemic, several sectors were wary of, and slow to accept, 4IR. Despite the benefits of 4IR, many African countries face difficulties across various sectors. Almost all African countries are unprepared for 4IR, with the exception of South Africa, which is considered partially ready and ranks 22nd on the automation readiness index. African countries that have embraced digital transformation have cited South Africa as a case study due to its adoption of 4IR. Despite the benefits, several barriers to the adoption and use of 4IR technologies have been identified in developing countries, including South Africa, which has the opportunity to adopt consistent 4IR.

Synovial Fibroblast Sialylation Regulates Cell Migration and Activation of Inflammatory Pathways in Arthritogenesis.

Synovial fibroblasts have emerged as critical underlying factors to perpetuate chronic joint inflammation in Rheumatoid Arthritis. Like any other cell, synovial fibroblasts are covered with a complex layer of glycans that can change in response to extracellular signals, such as inflammation. We have previously shown that inflammatory synovial fibroblasts show decreased levels of sialic acid, but our understanding of sialic acid-dependent pathophysiological pathways in these stromal cells is still very limited. In this report, we used in vivo and in vitro studies with exogenous sialidases and RNA sequencing to investigate the responses of murine synovial fibroblasts upon desialylation. Our results show that hyposialylated fibroblasts present a dysregulated migratory ability and an activated phenotype characterized by the expression of inflammatory mediators, such as cytokines and chemokines, and anti-viral related mechanisms. Removal of surface sialic acid also affected the expression of sialyltransferases, revealing the existence of a positive feedback to sustain reduced sialylation. Moreover, we demonstrate that synovial fibroblasts subsets have distinct sialyltransferase expression profiles, both in healthy and arthritic mice. These findings underline the ability of sialic acid to modulate homeostatic and inflammatory responses in non-immune synovial fibroblasts, suggesting that sialylation plays a key role in perpetuating local inflammation in the arthritic joint.

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis.

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.

The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis.

The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

Investigating the Association Between Diabetes Distress and Self-Management Behaviors.

BACKGROUND: Diabetes distress has been linked with suboptimal glycemic control in patients with type 1 diabetes. We evaluated the effect of diabetes distress on self-management behaviors in patients using insulin pumps. METHODS: We analyzed the impact of diabetes distress on self-management behaviors using pump downloads from 129 adults treated with continuous subcutaneous insulin infusion (CSII) at a single hospital clinic. Exclusion criteria were CSII treatment <6 months, pregnancy, hemoglobinopathy, and continuous glucose monitoring/sensor use. People were categorized into three groups based on the Diabetes Distress Scale-2 (DDS-2) score: < 2.5, 2.5-3.9, > 4. RESULTS: Participants had a mean age of 45.2 ± 19.0 years; duration of diabetes 26.6 ± 16.2 years; duration of CSII 6.0 ± 3.5 years; HbA1c 8.0 ± 1.2%; and DDS-2 score 2.7 ± 1.3. Self-monitoring blood glucose (SMBG) frequency and bolus wizard usage was similar between groups. Patients with higher distress had higher HbA1c (7.7 ± 0.9 vs. 8.0 ± 0.9 vs. 8.7 ± 1.8; P = 0.004), lower frequency of set changes (4.7 ± 1.3vs. 4.8 ± 1.9 vs. 3.8 ± 1.1; P = .025), a greater number of appointments booked (5.8 ± 4.4 vs. 8.6 ± 4.8 vs. 8.1 ± 6.9; P = .021), and a greater number of appointments missed (1.9 ± 1.3 vs. 2.5 ± 1.5 vs. 3.8 ± 4.1; P = .004). CONCLUSIONS: Although in some patients, high distress may be caused by reduced self-management, in our highly trained, pump-using patients, high distress was associated with suboptimal biomedical outcomes despite appropriate self-management behaviors. Future work should further explore the relationships between diabetes distress, self-management, and glycemic control.

Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis.

The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62's immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation in vitro. Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA.