Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

Aberrant follicular regulatory T cells associate with immunoglobulin hyperproduction in nasal polyps with ectopic lymphoid tissues.

BACKGROUND: Ectopic lymphoid tissues (eLTs) and associated follicular helper T (TFH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (TFR) cells in secondary lymphoid organs counteract TFH cells and suppress immunoglobulin production; however, the presence and function of TFR cells in eLTs in peripheral diseased tissues remain poorly understood. OBJECTIVE: We sought to investigate the presence, phenotype, and function of TFR cells in NPs. METHODS: The presence, abundance, and phenotype of TFR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. RESULTS: TFR cells were primarily localized within eLTs in NPs. TFR cell frequency and TFR cell/TFH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. TFR cells displayed an overlapping phenotype with TFH cells and FOXP3+ regulatory T cells in NPs. Polyp TFR cells had reduced CTLA-4 expression and decreased capacity to inhibit TFH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of TFR cells. Lower vitamin D receptor expression was observed on polyp TFR cells compared with TFR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp TFR cells and restored their suppressive function in vitro. CONCLUSIONS: Polyp TFR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress TFH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

A comparative study on the clinical and magnetic resonance imaging features between seronegative and seropositive rheumatoid arthritis.

OBJECTIVES: Seronegative rheumatoid arthritis (SNRA) is less common and less known compared with seropositive rheumatoid arthritis (SPRA). The aim of this study was to characterise the clinical and magnetic resonance imaging (MRI) features of SNRA and investigate the associated factors of structural damage. METHODS: We retrospectively collected newly diagnosed RA patients who had MRI data of the hands at baseline. The clinical and MRI features and treatment responses during the 12-month follow-up were compared between SNRA and SPRA. The associated factors of the erosion rate were analysed. RESULTS: A total of 310 RA patients were included in this study. Compared with SPRA, SNRA had a higher level of inflammation (p-values were all <0.001), a higher incidence of low bone mineral density (p=0.009), but a lower erosion score (p<0.001) and a lower probability of interstitial lung disease (ILD) (p=0.019). The main eroded bones were different between SNRA (the scaphoid and the lunate) and SPRA (the capitate and the hamate). In the multivariate analysis, synovitis score, the levels of IL-6 and TNF-α, and hyperglobulinaemia were positively associated with the erosion rate of SNRA (p-values were all <0.05). During the 12-month follow-up, the treatment response between the two groups was comparable (p-values were all >0.05). CONCLUSIONS: SNRA had more severe inflammation but milder erosion compared with SPRA. SNRA with severe inflammation or hyperglobulinaemia needs the same powerful therapy of SPRA to prevent erosion progression.

The IL-33/ST2 Axis Promotes Primary Sjögren's Syndrome by Enhancing Salivary Epithelial Cell Activation and Type 1 Immune Response.

The molecular mechanisms of primary Sjögren's syndrome (pSS) are poorly understood. In this study, we explored the role of the IL-33/ST2 axis in the development of pSS. In the mouse model of experimental Sjögren's syndrome, we found that the saliva flow rate at weeks 4 and 30 was preserved in IL-33-/- and ST2-/- mice, compared with that of wild-type mice. At week 30 of experimental Sjögren's syndrome induction, the histological score, anti-nuclear Ab levels, and numbers of Th1 and B cells in draining lymph nodes of the salivary gland were lower in the IL-33-/- and ST2-/- mice, whereas Th17 cells and regulatory T cells were not changed. Primary salivary gland epithelial cells expressed the IL-33 receptor ST2. After stimulation with rIL-33, salivary gland epithelial cells increased the transcriptional levels of CD86 and CCL2, accompanied by the activation of the NF-κB inflammatory pathway. There was a synergistic effect between rIL-33 and rIL-12 in augmenting the production of IFN-γ in CD4+ T cells. In the pSS patients, the expression of IL-33 was elevated in the labial salivary gland, with the number of IL-33+ cells positively correlated with the score of the EULAR (European Alliance of Associations for Rheumatology) Sjögren's syndrome disease activity index (ESSDAI). ST2 was highly expressed in the cytoplasm of ductal epithelial cells, with low levels of expression in lymphatic infiltration sites. Our data suggest that the IL-33/ST2 axis may promote the development of pSS by enhancing salivary epithelial cell activation and the type 1 immune response.

Perturbated glucose metabolism augments epithelial cell proinflammatory function in chronic rhinosinusitis.

BACKGROUND: Glucose concentrations are increased in nasal secretions in chronic rhinosinusitis (CRS). However, the glucose metabolism and its contribution to disease pathogenesis in CRS remain unexplored. OBJECTIVES: We sought to explore the glucose metabolism and its effect on the function of nasal epithelial cells in CRS with and without nasal polyps (CRSwNP and CRSsNP). METHODS: Glucose metabolites were detected with mass spectrometry. The mRNA levels of glucose transporters (GLUTs), metabolic enzymes, and inflammatory mediators were detected by quantitative RT-PCR. The protein expression of GLUTs was studied by immunofluorescence staining, Western blotting, and flow cytometry. Glucose uptake was measured by using fluorescent glucose analog. Human nasal epithelial cells (HNECs) were cultured. Bioenergetic analysis was performed with Seahorse XF analyzer. Gene expression in HNECs was profiled by RNA sequencing. RESULTS: Increased glucose concentrations in nasal secretions was confirmed in both CRSsNP and CRSwNP. GLUT4, GLUT10, and GLUT11 were abundantly expressed in HNECs, whose expression was upregulated by inflammatory cytokines and D-glucose and was increased in CRS. Glucose uptake, glycolysis and tricarboxylic acid cycle metabolites, metabolic enzymes, and extracellular acidification rate and oxygen consumption rates were increased in HNECs in CRSsNP and CRSwNP, with a predominant shift to glycolysis. HNECs treated with high-level apical D-glucose showed enhanced glucose uptake, predominant glycolysis, and upregulated production of IL-1α, IL-1ß, TNF-α, CCL20, and CXCL8, which was suppressed by 2-deoxy-D-glucose, an inhibitor of glycolysis. CONCLUSIONS: Increased glucose in nasal secretions promotes glucose uptake and predominant glycolysis in epithelial cells, augmenting the proinflammatory function of epithelial cells in CRS.

Regulatory T cells: a new therapeutic link for Sjögren syndrome?

Great advancements have been made in understanding the pathogenesis of SS, but there remain unmet needs for effective and targeted treatments. Glandular and extraglandular dysfunction in SS is associated with autoimmune lymphocytic infiltration that invades the epithelial structures of affected organs. Regulatory T (Treg) cells are a subset of CD4+ T lymphocytes that maintain self-tolerance during physiological conditions. Besides inhibiting excessive inflammation and autoimmune response by targeting various immune cell subsets and tissues, Treg cells have also been shown to promote tissue repair and regeneration in pathogenic milieus. The changes of quantity and function of Treg cells in various autoimmune and chronic inflammatory disorders have been reported, owing to their effects on immune regulation. Here we summarize the recent findings from murine models and clinical data about the dysfunction of Treg cells in SS pathogenesis and discuss the therapeutic strategies of direct or indirect targeting of Treg cells in SS. Understanding the current knowledge of Treg cells in the development of SS will be important to elucidate disease pathogenesis and may guide research for successful therapeutic intervention in this disease.

Prevalence and risk factors of monoclonal gammopathy in patients with autoimmune inflammatory rheumatic disease: A systematic review and meta-analysis.

OBJECTIVE: To systemically investigate the prevalence and risk factors of monoclonal gammopathy (MG) in patients with autoimmune inflammatory rheumatic disease (AIIRD). METHODS: A literature search was conducted using databases of PubMed, EMBASE, and Web of Science for relevant studies from inception to 31 July 2021. The pooled prevalence, odds ratio (OR), weighted mean difference (WMD), and 95% confidence interval (CI) were calculated with Stata 16.0 using a random or fixed effects model. RESULTS: In 17 included studies involving 6667 AIIRD patients, the pooled prevalence of MG in AIIRD patients was 7% (95%CI: 0.06-0.09). Compared to general populations, patients with Sjögren's syndrome (SS) possessed the highest risk for MG (OR 4.51; 95%CI: 3.39-5.74), followed by systemic lupus erythematosus (OR 3.99; 95%CI: 2.84-5.14), ankylosing spondylitis (OR 2.04; 95%CI: 1.11-2.97), and rheumatoid arthritis (OR 2.00; 95%CI: 1.79-2.22). Older age (WMD = 5.17 years; 95%CI: 0.68-9.66), higher erythrocyte sedimentation rate (WMD = 14.04 mm/H; 95%CI: 7.77-20.30), higher serum gammaglobulins level (WMD = 1.92 mg/dl, 95%CI: 0.51-3.32) were associated with a greater risk of MG in AIIRD patients. CONCLUSIONS: MG prevalence was higher in AIIRD patients, especially in SS patients. Older age, higher erythrocyte sedimentation rate, and hypergammaglobulins were risk factors for MG in AIIRD patients.

The aberrant levels of decorin induce damages of human salivary gland epithelial cells and polarization of macrophages.

OBJECTIVES: This study aimed to preliminarily address the levels of decorin (DCN, a critical component of extracellular matrix) and its potential roles in primary Sjögren's syndrome (pSS). METHODS: DCN levels were determined in the salivary glands of experimental SS (ESS) mice and pSS patients by RNA sequencing, bioinformatics analysis, or immunohistochemical staining. Its correlation with interested genes and co-localization with a putative receptor was studied in pSS patients. In addition, its potential roles on salivary gland epithelium and macrophages were tested by exogenous administration to corresponding cell lines, followed by the evaluation of apoptosis using flow cytometry or cytokine expression using quantitative real-time polymerase chain reaction. RESULTS: Our data revealed a significant elevation of DCN in the salivary glands of the ESS mice model and pSS patients. In addition, the bioinformatics analysis of DCN in the GSE40611 (RNA-seq, parotid glands) dataset displayed an elevation of the DCN level in the parotid glands of pSS patients that positively correlated with several chemokines (CXCL13, CXCL9, and CCL20), Interleukin -1 ß (IL1 -ß), and caspase3 but negatively correlated with the proliferation relative gene MKI67. The stimulatory effects of DCN on the salivary gland epithelial cells (A253 cell line) and macrophages have been determined as they are considered active participants in the progression of SS. The data showed that DCN induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype, characterized by the expression of pro-inflammatory cytokines. CONCLUSIONS: Our study provided preliminary evidence to understand the clinical significance of DCN in pSS and broadened our horizons in understanding the mechanism of pSS.

The landscape of T and B lymphocytes interaction and synergistic effects of Th1 and Th2 type response in the involved tissue of IgG4-RD revealed by single cell transcriptome analysis.

OBJECTIVES: To investigate the landscape of T-B cell interaction, immune receptor profiles and effects of different types of immune responses in the involved tissues of IgG4-RD. METHODS: Single cell RNA sequencing, bulk sample RNA sequencing, immune receptor repertoire analysis (both BCR and TCR), multi-color flow cytometry, and in-vitro assays with model cells (e.g. EBV-immortalized B cells from IgG4-RD patient) and histologic methods were applied to investigate the immunopathological features of IgG4-RD from multiple aspects. RESULTS: Ectopic germinal center formation was observed in IgG4-RD patients at advanced disease stage, and a large part of B cells in involved tissue were germinal center B cell-like. Germinal center reaction in IgG4-RD led to the irregularities of both TCR and BCR clones in the involved tissues, and limited clonal overlaps among different samples. Enhanced Th1- and Th2-type responses were observed in involved tissues of IgG4-RD and patients with both increased Th1- and Th2-type response related cell subsets possessed more severe inflammatory indices. Analyses to the origin of IGHG4 transcripts in IgG4-RD indicated that IgG4 could be switched from IgM directly, or from other IgG subclasses. In vitro assays with EBV-immortalized B cells, fibroblasts and epithelial cells revealed the effects of Th1-type and Th2-type responses on germinal center reaction, ectopic expression of MHC-II molecules, and formation of tertiary lymphoid structures. CONCLUSIONS: Synergistic effects of Th1- and Th2-type responses were involved in the pathogenesis of IgG4-RD via their influences on both acute inflammatory processes and the chronicity and complexity of IgG4-RD.

Characterization and associated risk factors of Pneumocystis jirovecii pneumonia in patients with AIRD: a retrospective study.

OBJECTIVES: To explore clinical features of autoimmune inflammatory rheumatic disease (AIRD) patients with Pneumocystis jirovecii pneumonia (PJP) and identify potential risk factors and prognostic factors. METHODS: AIRD patients who had respiratory symptoms and underwent P. jirovecii detection were identified from the database in our department from November 2018 to October 2020. These patients were categorized into PJP and non-PJP groups according to the diagnostic criteria of PJP. Univariate and multivariate analyses were conducted. RESULTS: A total of 173 patients were enrolled and 46 of them had laboratory-confirmed PJP. Glucocorticoid increased the risk of PJP in a dose-dependent manner. In addition, shorter duration of immunosuppressive therapy (IST), combination therapy with CSA and chronic pulmonary comorbidities were also strongly associated with a higher risk of PJP. Combination of IgM and IgA could well identify AIRD patients with PJP from other AIRD patients with respiratory symptoms, with the optimal cut-off value of -0.96 g/l. Seven of 46 AIRD patients with PJP died (15.2%). A higher level of serum LDH, dyspnoea and ARDS, and the presence of extensive ground glass opacity (GGO) in radiologic examinations were more common in deceased patients. CONCLUSIONS: AIRD patients with high-dose glucocorticoid treatment, recent initiation of IST, combination therapy with CSA and history of chronic pulmonary diseases had a greater risk of PJP infection. PJP patients with a higher level of serum LDH, dyspnoea, moderate and severe ARDS, and the presence of extensive GGO in radiologic examinations had poorer prognosis. TRIAL REGISTRATION: Chinese Clinical Trial Register; https://www.chictr.org.cn/; ChiCTR2100044095.

Role of eosinophilia in IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous immune-mediated condition that can affect almost any organ and is now being recognised with increasing frequency. Laboratory abnormalities including peripheral eosinophilia, hypergammaglobulinaemia, elevated serum IgE level, and hypocomplementaemia often provide initial clues to the diagnosis of IgG4-RD. The distinctive histopathological hallmarks of IgG4-RD are a dense lymphoplasmacytic infiltration with a high percentage of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia. Around 20-40% of patients with IgG4-RD presented with peripheral eosinophilia and 51-86% are manifested as tissue eosinophilia. These data indicate an extensive involvement of eosinophil in IgG4-RD. Here, we review the biology of eosinophil, the discovery of eosinophilia in IgG4-RD, and its association with disease activity and relapse. We also discuss the possible functions and therapeutic potential of eosinophil in IgG4-RD.

Laboratory Predictors of COVID-19 Mortality: A Retrospective Analysis from Tongji Hospital in Wuhan.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. OBJECTIVE: To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. METHODS: Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. RESULTS: We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70; p < 0.001) and hypoalbuminemia (OR: 5.68, 95% CI: 3.97-8.32; p < 0.001) between deceased and recovered patients. The percentages of hyperuricemia in deceased patients and recovered patients were 23.6% and 8.9%, respectively, which were higher than the reported age-standardized prevalence of 6.2% in Chinese population. Of note, the percentages of both IL-6 and uric acid levels in survived COVID-19 patients were above 90%, suggesting that they might be good specificity for indicators of mortality in COVID-19 patients. The serum level of uric acid (UA) was positively associated with ferritin, TNF-α, and IL-6 but not with anti-inflammatory cytokine IL-10. In addition, the levels of these proinflammatory cytokines in COVID-19 patients showed a trend of reduction after uric acid lowering therapy. CONCLUSIONS: Our results suggest that uric acid, the end product of purine metabolism, was increased in deceased patients with COVID-19. In addition, the serum level of uric acid was positively associated with inflammatory markers. Uric acid lowering therapy in COVID-19 patients with hyperuricemia may be beneficial.

Effect of GLP-1/GLP-1R on the Polarization of Macrophages in the Occurrence and Development of Atherosclerosis.

AIMS: To investigate the effect of GLP-1/GLP-1R on the polarization of macrophages in the occurrence and development of atherosclerosis. METHODS: Totally, 49 patients with coronary heart disease (CHD) and 52 cases of health control (HC) were recruited, all subjects accept coronary angiography gold standard inspection. One or more major coronary arteries (LM, LAD, LCx, and RCA) stenosis degree in 50% of patients as CHD group; the rest of the stenosis less than 50% or not seen obvious stenosis are assigned to the HC group. Flow cytometry were used to detect the percentage of (CD14+) M macrophages, (CD14+CD80+) M1 macrophages, (CD14+CD206+) M2 macrophages, and their surface GLP-1R expression differences in the two groups, using BD cytokine kit to detect the levels of IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70. RESULTS: GLP-1R expression on the surface of total macrophages and M2 macrophages was different between the CHD group and the HC group (P < 0.05). There was no difference in the percentage of total, M1 or M2 macrophages (P > 0.05). Concentration of IL-8 in the HC group was higher than that in the CHD group (P < 0.05). There is no significant difference in the cytokine IL-1ß, IL-6, IL-10, TNF, and IL-12p70 in the two groups (P > 0.05). After controlling for potential confounders including age, gender, smoking status (S.S.), drinking status (D.S.), HR, SBP, DBP, PP, TC, TG, HDL-C, LDL-C, GHbA1c, M, M1, M2, GLP-1R_M, GLP-1R_M1, GLP-1R_M2, IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70 by multiple linear regression, decreasing Gensini Score was significantly associated with increased percentage of M1 macrophage. CONCLUSION: GLP-1R agonist is independent of the hypoglycemic effect of T2DM and has protective effect on cardiovascular system. GLP-1R may regulate the polarization of macrophages toward M2, thus playing a protective role in the progression of coronary atherosclerosis.

Clinical features of rheumatic patients infected with COVID-19 in Wuhan, China.

OBJECTIVE: The clinical features of rheumatic patients with coronavirus disease 2019 (COVID-19) have not been reported. This study aimed to describe the clinical features of COVID-19 in rheumatic patients and provide information for handling this situation in clinical practice. METHODS: This is a retrospective case series study. Deidentified data, including gender, age, laboratory and radiological results, symptoms, signs, and medication history, were collected from 2326 patients diagnosed with COVID-19, including 21 cases in combination with rheumatic disease, in Tongji Hospital between 13 January and 15 March 2020. RESULTS: Length of hospital stay and mortality rate were similar between rheumatic and non-rheumatic groups, while the presence of respiratory failure was more common in rheumatic cases (38% vs 10%, p<0.001). Symptoms of fever, fatigue and diarrhoea were seen in 76%, 43% and 23% of patients, respectively. There were four rheumatic patients who experienced a flare of rheumatic disease during hospital stay, with symptoms of muscle aches, back pain, joint pain or rash. While lymphocytopaenia was seen in 57% of rheumatic patients, only one patient (5%) presented with leucopenia in rheumatic cases. Rheumatic patients presented with similar radiological features of ground-glass opacity and consolidation. Patients with pre-existing interstitial lung disease showed massive fibrous stripes and crazy-paving signs at an early stage. Five rheumatic cases used hydroxychloroquine before the diagnosis of COVID-19 and none progressed to critically ill stage. CONCLUSIONS: Respiratory failure was more common in rheumatic patients infected with COVID-19. Differential diagnosis between COVID-19 and a flare of rheumatic disease should be considered. TRIAL REGISTRATION NUMBER: ChiCTR2000030795.

MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance.

OBJECTIVE: Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance. SUBJECTS AND RESULTS: Wild-type (WT) and Mrp14-/- mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14-/- mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14-/- macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14-/- macrophages. CONCLUSION: Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome.

Middle East respiratory syndrome coronavirus (MERS-CoV) is an important emerging pathogen that was first described in 2012. While the cell surface receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4), the mouse DPP4 homologue does not allow virus entry into cells. Therefore, development of mouse models of MERS-CoV has been hampered by the fact that MERS-CoV does not replicate in commonly available mouse strains. We have previously described a mouse model in which mDPP4 was replaced with hDPP4 such that hDPP4 is expressed under the endogenous mDPP4 promoter. In this study, we used this mouse model to analyze the host response to MERS-CoV infection using immunological assays and transcriptome analysis. Depletion of CD4+ T cells, CD8+ T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8+ T cells protects and depletion of macrophages exacerbates MERS-CoV-induced pathology and clinical symptoms of disease. Overall, we demonstrate an important role for the inflammatory response in regulating MERS-CoV pathogenesis in vivo IMPORTANCE: The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged from zoonotic sources in 2012. Human infections are still occurring throughout Saudi Arabia at a 38% case fatality rate, with the potential for worldwide spread via air travel. In this work, we identify the host response to the virus and identify inflammatory pathways and cell populations that are critical for protection from severe lung disease. By understanding the immune response to MERS-CoV we can develop targeted therapies to inhibit pathogenesis in the future.