Twenty-four-hour rhythms in immune parameters and functions are robustly observed phenomena in biomedicine. Here, we summarize the important role of sleep and associated parameters on the neuroendocrine regulation of rhythmic immune cell traffic to different compartments, with a focus on human leukocyte subsets. Blood counts of “stress leukocytes” such as neutrophils, natural killer cells, and highly differentiated cytotoxic T cells present a rhythm with a daytime peak. It is mediated by morning increases in epinephrine, leading to a mobilization of these cells out of the marginal pool into the circulation following a fast, beta2-adrenoceptor-dependent inhibition of adhesive integrin signaling. In contrast, other subsets such as eosinophils and less differentiated T cells are redirected out of the circulation during daytime. This is mediated by stimulation of the glucocorticoid receptor following morning increases in cortisol, which promotes CXCR4-driven leukocyte traffic, presumably to the bone marrow. Hence, these cells show highest numbers in blood at night when cortisol levels are lowest. Sleep adds to these rhythms by actively suppressing epinephrine and cortisol levels. In addition, sleep increases levels of immunosupportive mediators, such as aldosterone and growth hormone, which are assumed to promote T-cell homing to lymph nodes, thus facilitating the initiation of adaptive immune responses during sleep. Taken together, sleep–wake behavior with its unique neuroendocrine changes regulates human leukocyte traffic with overall immunosupportive effects during nocturnal sleep. In contrast, integrin de-activation and redistribution of certain leukocytes to the bone marrow during daytime activity presumably serves immune regulation and homeostasis.

Background: Systemic sclerosis (SSc) primary heart involvement (SSc‐pHI) is one of the leading causes of mortality in SSc. We aimed to evaluate risk factors for SSc‐pHI and its progression and the outcomes in the EUSTAR (European Scleroderma Trials and Research) cohort. Methods: SSc‐pHI was defined according to the World Scleroderma Foundation/Heart Failure Association definition. Data from 5741 patients with SSc in the EUSTAR cohort were analyzed. Additional cardiovascular data were collected from a subcohort of 838 patients with SSc. Lasso regression was used for risk factor analyses. Kaplan–Meier estimator was used for survival analyses. Progression of SSc‐pHI was evaluated by a study definition developed by rheumatology and cardiology experts. Results: Risk factors for the presence of SSc‐pHI comprised skeletal muscle atrophy (odds ratio [OR], 2.00 [95% CI, 1.00–2.68]), age (OR, 1.91 [95% CI, 1.73–2.03]), male sex (OR, 1.77 [95% CI, 1.42–2.05]), swollen joints (OR, 1.70 [95% CI, 1.47–1.98]), skeletal muscle weakness (OR, 1.38 [95% CI, 1.00–1.85]), and tendon friction rubs (OR, 1.46 [95% CI, 1.00–1.77]) (n=3276). Telangiectasia (OR, 2.10 [95% CI, 1.38–2.72]), intestinal symptoms (OR, 1.70 [95% CI, 1.04–2.42]), age (OR, 1.47 [95% CI, 1.21–1.62]), and antitopoisomerase I antibodies (OR, 1.37 [95% CI, 1.00–1.77]) were associated with an increased risk for new onset of SSc‐pHI (n=1000). Survival rate was significantly lower in patients with SSc‐pHI than in those without ( P value <0.0001, n=3768). Patients with SSc‐pHI had a lower survival rate than patients with interstitial lung disease (n=3365). Swollen joints were associated with an increased risk of progressive SSc‐pHI (OR, 2.49 [95% CI, 1.79–3.52]) (n=595). Tendon friction rubs (OR, 1.21 [95% CI, 0.94–1.90]) increased the risk of heart failure with preserved ejection fraction in patients with SSc‐pHI. Conclusions: We defined progressive SSc‐pHI and identified risk factors for new onset and progression of SSc‐pHI and for SSc‐pHI‐associated heart failure with preserved ejection fraction in the largest cohort with SSc. These findings may guide patient stratification for diagnostic workup and therapy.

Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE^(−/−) mice for preclinical validation. The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima–media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine–cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE^(−/−) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis. The schematic overview over the present study including description of the analysis sample, cross-sectional analyses, and data on clinical outcome, expressed by hazard ratios derived from Cox regression analysis with corresponding 95% confidence intervals and P-values, as well as experimental data on anti-CXCR3 autoantibodies and murine atherosclerosis. aAbs, autoantibodies; ApoE, apolipoprotein E; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; CXCR3, CXC-motif-chemokine receptor 3; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MACE, major adverse cardiac events (comprising coronary artery disease, myocardial infarction, and cardiac death); ME, membrane extract; NT-proBNP, N-terminal pro-B-type natriuretic peptide; pct, percentile; SD, standard deviation; WTD, western-type diet.

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies. In this review, we present mechanisms of the innate immune system leading to the generation of autoantibodies, alterations of the B-cell compartment in SSc, autoantibodies as biomarkers and autoantibody-mediated pathologies in SSc as well as potential therapeutic approaches to target these.

Objective: Cellular mechanisms driving transition from psoriasis to psoriatic arthritis have remained largely elusive. Thus, we investigated changes within the peripheral blood T cell compartment associated with the transition phase. Methods: In an observational study, 116 patients were examined and categorized into subgroups including psoriasis with at least one risk factor for transition to psoriatic arthritis, subclinical psoriatic arthritis according to EULAR taskforce recommendations from 2023, and definitive psoriatic arthritis meeting the Classification Criteria for Psoriatic Arthritis. Demographic and clinical characteristics of patient subgroups were analyzed. Deep T cell phenotyping using multicolor flow cytometry and machine‐learning techniques were applied. Results: Overlapping T cell endotypes were found among patients with subclinical psoriatic arthritis exhibiting the most notable divergence from the others. Frequencies of effector memory CD4 ⁺ T cells, Th17, and Tc17 cells differed among patients with psoriasis with at least one risk factor for transition, subclinical psoriatic arthritis, and psoriatic arthritis. Transition‐associated changes of Tc17 cell frequencies were confirmed by machine‐learning–assisted unsupervised clustering analysis. Moreover, patients with enthesitis could be distinguished from those without, with Tc17 cells being the main distinctive feature. Conclusion: Transition from psoriasis to psoriatic arthritis was associated with distinct alterations of the peripheral blood T cell compartment, with Tc17 cells exhibiting the greatest discriminatory power. These findings provide insight into pathomechanisms driving disease progression during transition from psoriasis to psoriatic arthritis and identify Tc17 cells as the foremost novel potential therapeutic target for the prevention of transition.

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.