Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the ...two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis
. However, both the exact origin and the role of macrophages in inflammatory joint disease ...remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX
CR1
tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX
CR1
mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX
CR1
lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory ...disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
Innate lymphoid cells (ILC) have a high potency for cytokine production independent of specific Ag stimulation. Imbalance of ILC subsets may influence cytokine production in humans and hence be ...associated with the development of inflammatory disease. Evidence for an imbalance of ILC homeostasis in human disease, however, is very limited to date. In this study we show that psoriatic arthritis (PsA), a severe disease of the joints depending on the activation of the IL-23/IL-17 pathway, is characterized by a skewed ILC homeostasis. Circulating ILC3s as potent source of IL-17/IL-22 were elevated in active PsA, whereas ILC2s, which produce proresolving cytokines, were decreased. The ILC2/ILC3 ratio was significantly correlated with clinical disease activity scores and the presence of imaging signs of joint inflammation and bone damage. Multivariable analysis showed that a high ILC2/ILC3 ratio is associated with remission in PsA, suggesting that specific alterations of ILC homeostasis control disease activity in PsA.
Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. ...In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis.
To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. ...IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients.
Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24 weeks.
51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ± SD SPARCC index at baseline was 4.8 ± 2.6 in the UST group and 3.5 ± 2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95).
These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.
Arthritis patients develop hand bone loss, which leads to destruction and functional impairment of the affected joints. High resolution peripheral quantitative computed tomography (HR-pQCT) allows ...the quantification of volumetric bone mineral density (vBMD) and bone microstructure in vivo with an isotropic voxel size of 82 micrometres. However, image-processing to obtain bone characteristics is a time-consuming process as it requires semi-automatic segmentation of the bone. In this work, a fully automatic vBMD measurement pipeline for the metacarpal (MC) bone using deep learning methods is introduced. Based on a dataset of HR-pQCT volumes with MC measurements for 541 patients with arthritis, a segmentation network is trained. The best network achieves an intersection over union as high as 0.94 and a Dice similarity coefficient of 0.97 while taking only 33 s to process a whole patient yielding a speedup between 2.5 and 4.0 for the whole workflow. Strong correlation between the vBMD measurements of the expert and of the automatic pipeline are achieved for the average bone density with 0.999 (Pearson) and 0.996 (Spearman's rank) with Formula: see text for all correlations. A qualitative assessment of the network predictions and the manual annotations yields a 65.9% probability that the expert favors the network predictions. Further, the steps to integrate the pipeline into the clinical workflow are shown. In order to make these workflow improvements available to others, we openly share the code of this work.
A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis ...(PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes.
Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks.
Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks.
These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals.
Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus ...disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.
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