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Background The origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-differentiation and production of pro-fibrotic collagen. Methods Primary human alveolar epithelial cells type II were extracted from donor tissues and stimulated with TGFβ and a TGFβ-inhibitor. Transcriptome and pathway analyses as well as validation of results on protein level were conducted. Results A TGFβ-responsive fingerprint was found and investigated for mutual interactions. Interaction modules exhibited enrichment of genes that favor actin cytoskeleton remodeling, differentiation processes and collagen metabolism. Cross-validation of the TGFβ-responsive fingerprint in an independent IPF dataset revealed overlap of genes and supported the direction of regulated genes and TGFβ-specificity. Conclusions Primary human alveolar epithelial cells type II seem undergo a TGFβ-dependent phenotypic change, exhibit differential expression of EMT markers in vitro and acquire the potential to produce collagen.

The present study aimed to assess the therapeutic efficacy of neutralizing monoclonal antibodies targeting a prominent proinflammatory cytokine in a PBMC transfer-induced humanized mouse model of systemic inflammation. Inflammatory cytokines were measured in human and murine sera using the LEGENDplex™ cytokine panel. Humanized mice were treated with neutralizing antibodies against human IL-6 (Siltuximab) or the human IL-6 receptor (Tocilizumab), along with matched IgG isotype controls. Cytokine responses in the humanized mouse model were predominantly of human, not murine, origin. Elevated levels of human IL-6 were observed in both SSc patients and their corresponding mouse models. Preventive administration of Tocilizumab reduced anti-nuclear antibody production and mitigated disease severity in the PBMCs-transfer-induced humanized mouse model. In contrast, treatment with Siltuximab, an antibody targeting human IL-6, did not prevent disease development in the humanized mouse model. The lack of efficacy of Siltuximab was associated with the accumulation of human IL-6/anti-human IL-6 monoclonal antibody immune complexes. These findings highlight the pivotal role of IL-6 signaling in the SSc related systemic inflammation within the humanized mouse model and underscore the therapeutic potential of IL-6 receptor blockade. Furthermore, the PBMCs-based humanized mouse model offers a valuable preclinical platform for evaluating human-specific therapeutic interventions in systemic inflammation.

Background Tuberculosis (TB) remains a major global health challenge, with 10.6 million new cases and 1.3 million deaths annually. HIV coinfection is a well-known risk factor in high-burden regions, but emerging evidence suggests that other viral infections, including cytomegalovirus (CMV), may also impact TB pathogenesis. CMV is a ubiquitous herpesvirus capable of lifelong persistence, and its potential role in modulating TB progression remains unclear. Methods In this study, we established a murine coinfection model in C57BL/6 mice to investigate the effects of latent murine CMV (MCMV) on Mycobacterium tuberculosis (Mtb) infection. Mice were infected with either Mtb alone or with both Mtb and MCMV. Disease progression, mortality, bacterial load, viral clearance, and immune responses were assessed. Results Contrary to our hypothesis, latent MCMV infection improved disease outcomes and reduced mortality following Mtb infection. This effect was independent of bacterial control or viral clearance. Instead, coinfected mice exhibited a distinct immunological environment in the lungs, with elevated levels of inflammatory mediators (IL-1α, IL-1β, TNF, IFN-γ, CXCL9, CXCL10, CCL2) and altered immune cell composition. Lesions in the lungs of coinfected mice were organized differently compared to those infected with Mtb alone. Notably, introducing MCMV during an established Mtb infection led to enhanced disease progression, highlighting the importance of the timing and sequence of infections. Conclusion Our findings demonstrate for the first time that latent MCMV infection can improve disease outcomes in Mtb-infected mice, suggesting that viral latency may modulate the immune response in a way that enhances host defense against tuberculosis.

Due to the historical dogma that host defense against intracellular pathogens is primarily mediated by cell-mediated immunity, B cells have long been considered unimportant in providing protection against (Mtb) and remained understudied for decades. However, emerging evidence highlights the multifaceted role of B cells in tuberculosis (TB) immunity. B cells accumulate at the site of infection in both animal models and human TB patients, suggesting a potential link to protective immunity. Still, the diverse roles of B cells in TB immunity are still being unraveled. In addition to producing antibodies, B cells secrete a wide range of cytokines that can influence the local immune response. In this study, we focused on the relevance of interleukin 10 (IL-10)-secreting B cells in the long-term control of the Beijing strain HN878. B cell-specific IL-10 expression was assessed in IL-10 transcriptional reporter (Vert-X) mice following infection. To investigate the role of B cell-derived IL-10 in TB immunity, both male and female mice with a targeted knockout of IL-10 in B cells (IL-10 /CD19 ) were infected with HN878. Disease progression, control of bacterial replication, and immunological changes were monitored throughout the course of infection. B cells contribute to IL-10 production in the -infected lung in both sexes, with CD138 plasma cells serving as the primary source of B cell-derived IL-10. Mice lacking B cell-derived IL-10 exhibited increased resistance to aerosol infection, demonstrated by a delayed onset of clinical symptoms and prolonged survival. Notably, this effect was significantly more pronounced in males compared to females, and was associated with male-specific immune alterations. Our research highlights a previously unrecognized sex-specific regulatory role of B cell-derived IL-10 during infection.

The most potent cell wall-derived inflammatory toxins (\"pathogenicity factors\") of Gram-negative and -positive bacteria are lipopolysaccharides (LPS) (endotoxins) and lipoproteins (LP), respectively. Despite the fact that the former signals toll-like receptor 4 (TLR4) and the latter TLR2, the physico-chemistry of these compounds exhibits considerable similarity, an amphiphilic molecule with a polar and charged backbone and a lipid moiety. While the exterior portion of the LPS (i.e., the O-chain) represents the serologically relevant structure, the inner part, the lipid A, is responsible for one of the strongest inflammatory activities known. In the last years, we have demonstrated that antimicrobial peptides from the Pep19-2.5 family, which were designed to bind to LPS and LP, act as anti-inflammatory agents against sepsis and endotoxic shock caused by severe bacterial infections. We also showed that this anti-inflammatory activity requires specific interactions of the peptides with LPS and LP leading to exothermic reactions with saturation characteristics in calorimetry assays. Parallel to this, peptide-mediated neutralization of LPS and LP involves changes in various physical parameters, including both the gel to liquid crystalline phase transition of the acyl chains and the three-dimensional aggregate structures of the toxins. Furthermore, the effectivity of neutralization of pathogenicity factors by peptides was demonstrated in several models together with the finding that a peptide-based therapy sensitizes bacteria (also antimicrobial resistant) to antibiotics. Finally, a significant step in the understanding of the broad anti-inflammatory function of Pep19-2.5 was the demonstration that this compound is able to block the intracellular endotoxin signaling cascade.

Autoantibody-mediated complement activation plays an essential role in a variety of autoimmune disorders. However, the role of complement in systemic sclerosis (SSc) remains largely unknown. In this study, we aimed to determine the role of complement C3 in the development of a recently described SSc mouse model based on autoimmunity to angiotensin II receptor type 1 (AT1R). Mice were immunized with cell membrane extract isolated from Chinese hamster ovary (CHO) cells overexpressing AT1R or non-transfected CHO cells as a control. Peripheral blood, dorsal skin and the lung were then collected to evlauate disease characteristics. Apoptotic cells in the lung of mice were detected using the DeadEnd™ Fluorometric TUNEL System. Our results showed that experimental SSc in this model was featured by the deposition of IgG, but not of complement C3, in the lung. After immunization with AT1R, C3-deficient mice developed more severe pulmonary inflammations than wild type controls, whereas skin inflammation and fibrosis were not different as well as the anti-AT1R ab levels. Further, C3-deficient mice showed an increased rate of pulmonary cell apoptosis as compared to controls. The apoptosis rate correlated with the corresponding degree of lung inflammation. Taken together, our findings suggest an anti-apoptotic and anti-inflammatory role of complement C3 in pulmonary autoimmune inflammation.

Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas “multifocal” granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40–60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68 , CD14 , ITGAM , ITGAX , and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA–IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.

In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden \"foamy\" macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetylCoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.

Targeting checkpoint inhibitors using monoclonal antibodies results in significantly better outcome of cancer patients compared to conventional chemotherapy. However, the current companion diagnostics to predict response is so far suboptimal, since they base on more or less reliable immunohistochemical approaches. In order to overcome these limitations, we analyzed epigenetic modifications of PDCD1 (PD1), CD274 (PD-L1), and CTLA4 in NSCLC tissues from 39 patients. Results were correlated with transcriptome data. Significant differences in the CpG-methylation patterns between tumor tissues and matched controls were observed for CTLA4 and PDCD1 (PD1) showing a decreased methylation of these genes compared to matched tumor-free tissues from the same patients. Results were confirmed by bisulfide sequencing in an independent validation cohort. Hypomethylation also resulted in increased expression of these genes as shown by transcriptome data. These epigenetic pathways as a hallmark of NSCLC might be useful to generate more precise diagnostic approaches in the future.