Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway.

Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.

Clinical significance of interleukin-6, total bilirubin, CD3 + CD4 + T cells counts in the acute exacerbation of connective tissue disease-associated interstitial lung disease: a cross-sectional study.

OBJECTIVE: Interstitial lung disease (ILD) is a severe complication of connective tissue disease (CTD) that can significantly impact patients' prognosis and quality of life. However, the current diagnostic arena lacks reliable biomarkers for detecting and monitoring the progression and exacerbation of CTD-ILD. This study aimed to investigate the clinical value of 12 serum cytokines in the diagnosis of CTD-ILD and prediction of the risk of acute exacerbation (AE) in this disease. METHODS: This study was a cross-sectional investigation. Ninety-one hospitalized CTD patients were allocated into two groups: CTD-ILD group (n = 61) and CTD-non-ILD group (n = 30), and 30 sex-age matched healthy volunteers were enrolled as controls. The serum concentrations of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, and IL-1ß were measured by Luminex suspension arrays. Logistic regression was employed to determine the significance of variables in the occurrence of AE-CTD-ILD. A nomogram was constructed to visualize the independent variables. RESULTS: Elevated levels of IL-6, IL-8, and TNF-α were observed and compared in the CTD-ILD group with CTD-non-ILD (all P < 0.05). Similarly, the levels of IL-6, IL-8 and TNF-α were higher in the acute exacerbation (AE-CTD-ILD) group compared with stable CTD-ILD (S-CTD-ILD) (P < 0.001, P < 0.001, and P = 0.022). Significant correlations between serum IL-6 and PaO2/FiO2 ratio (r = - 0.463, P < 0.001), percent predicted forced vital capacity (FVC%; r = - 0.362, P < 0.05), and total ground-glass opacity (GGO) score (r = 0.439, P < 0.001) were observed in CTD-ILD patients. Multivariate logistic regression analysis revealed that elevated IL-6 levels, total bilirubin (TBil), and decreased CD3 + CD4 + T cells counts were independent risk factors for the occurrence of AE-CTD-ILD (OR = 1.121, P = 0.024; OR = 1.865, P = 0.047; OR = 0.983, P = 0.037, respectively). Furthermore, by employing these three variables in combination for the prediction of AE status, their collective impact surpasses the independent effects of any single biomarker. CONCLUSIONS: Elevated levels of serum IL-6, IL-8, and TNF-α were associated with the complication of ILD in CTD patients and the occurrence of AE in CTD-ILD patients. IL-6 could be a promising serum biomarker of severity and the occurrence of AE in CTD-ILD patients. The combination of the three variables (IL-6 level, TBil and CD3 + CD4 + T cells) predicted the AE-CTD-ILD better.

Serum amyloid A/anti-CCL20 induced the rebalance of Th17/regulatory T cells in SodA-induced sarcoidosis.

Sarcoidosis is a multisystemic granulomatous inflammation associated with Th17/regulatory T cell (Treg) polarization. As a marker of inflammation, serum amyloid A (SAA) could upregulate the expression of chemokine ligand 20 (CCL20), which induces the migration of Treg cells and Th17 cells by binding and activating thechemokine C-C receptor (CCR) 6. Our goal was to determine whether SAA/anti-CCL20 induces Th17/Treg rebalance in pulmonary sarcoidosis. The deposition of SAA- and Th17/Treg-related proteins in SodA-induced granulomas was tested using immunohistochemistry. Mice with SodA-induced sarcoidosis were treated with SAA or SAA + anti-CCL20, and then Th1/Th2 and Th17/Treg cells were detected by fluorescence-activated cell sorting (FACS) analysis. The expression of SAA/CCL20 and IL-23/IL-17A was detected by enzyme-linked immunosorbent assay (ELISA) and multiplex. Key proteins in the TGF-ß/Smad signaling pathway were tested by western blot. SAA mainly plays a pro-inflammatory role by promoting the expression of CCL20 and IL-17A in bronchoalveolar lavage fluid (BALF) and serum, exacerbating this elevation of CD4+/CD8+ T cells in both mediastinal lymph nodes (LNs) and BALF, as well as proliferating Th1 in LNs in SodA-induced pulmonary sarcoidosis. In addition, SAA could also promote the proliferation of Tregs in LNs. Intriguingly, blocking of CCL20 could partially reverse the expression of Th17-related cytokine, ameliorate Th1/Th2 and Treg/Th17 bias in mice with SodA-induced pulmonary sarcoidosis, and rescue the overactivation of the TGF-ß/Smad2/Smad3 signaling pathway. Anti-CCL20 may have the potential for therapeutic translation, targeting on the immunopathogenesis of pulmonary sarcoidosis.