Current research in immunology最新文献

Visceral leishmaniasis (VL) is a serious and neglected disease present worldwide. Chemotherapy using pentavalent antimony (Sb^V) is the most practical and inexpensive strategy available for the VL treatment today, however, it has high toxicity. Alternatively, other drugs are used as viable leishmanicidal therapeutic options. Miltefosine is the only anti-leishmanial agent administered orally, however, it has been reducing its effectiveness. In this sense, there is no ideal therapy for VL since the drugs currently used trigger severe side effects causing discontinuation of treatment, which carries an imminent risk for the emergence of parasite resistance. With that, other therapeutic strategies are gaining prominence. Among them, immunotherapy and/or immunochemotherapy, which the activation/modulation of the immune system can redirect the host's immune response to an effective therapeutic result. Therefore, this work was designed to assess an immunochemotherapy protocol composed of half course of Miltefosine associated with LBSap vaccine (Milt+LBSap) using the hamster Mesocricetus auratus as an experimental model for VL treatment. When evaluating the main hematobiochemical, immunological and therapeutic efficacy parameters, it was demonstrated that the treatment with Milt+LBSap showed restoration of hematobiochemical condition and reduced serum levels of IgG-anti-Leishmania compared to animals infected non treated (INT). Beyond that, an increase in the number of CD4⁺ lymphocytes producers of IFN-γ in relation to INT or to animals treated with miltefosine during 28 days, and TNF-α increased compared to INT were observed. Also, it was found a reduction of IL-10-production in relation to INT, or animals that received LBSap vaccine only, or miltefosine, following by a reduction in the splenic parasitic burden. These results demonstrate that the immunochemotherapy protocol used can stimulate the immune response, inducing an expressive cellular response sufficient to control spleen parasitism, standing out as a promising proposal for the VL treatment.

Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically β-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.

B-cell acute lymphocytic leukemia (B-ALL) is the main neoplasia affecting children worldwide, in which cytotoxic chemotherapy remains the main treatment modality. In this study, we analyzed the profile of inflammatory markers concerning oxidative stress and cytokines in 17 B-ALL patients. Peripheral blood (PB) and bone marrow (BM) samples were collected and evaluated for the pro-oxidative status (nitric oxide products-NOx and hydroperoxides), antioxidants (sulfhydryl groups-SH and total radical-trapping antioxidant parameter-TRAP), and cytokines (TNF-α, IFN-γ), at diagnosis (D0) to and the end of the induction phase (D28). At D28, hydroperoxides were higher in PB, concomitant to TNF-α levels. INF-γ was increased in the BM at D28. Hydroperoxides were higher in patients presenting malignant cells in BM and/or PB after treatment, a condition named minimal residual disease (MRD) when compared to those without MRD at D28. These findings suggest that oxidative stress and cytokines vary across the B-ALL induction phase, and lipid peroxidation is a potential marker associated with MRD status.

Due to potential severity of disease caused by SARS-CoV-2 infection, it is critical to understand both mechanisms of viral pathogenesis as well as diversity of host responses to infection. Reduced A-to-I editing of endogenous double-stranded RNAs (dsRNAs), as a result of inactivating mutations in ADAR, produces one form of Aicardi-Goutières Syndrome, with an immune response similar to an anti-viral response. By analyzing whole genome RNA sequencing data, we find reduced levels of A-to-I editing of endogenous Alu RNAs in normal human lung cells after infection by SARS-CoV-2 as well as in lung biopsies from patients with SARS-CoV-2 infections. Unedited Alu RNAs, as seen after infection, induce IRF and NF-kB transcriptional responses and downstream target genes, while edited Alu RNAs as seen in the absence of infection, fail to activate these transcriptional responses. Thus, decreased A-to-I editing may represent an important host response to SARS-CoV-2 infection.

Various pathological conditions are accompanied by release of adenosine triphosphate (ATP) from the intracellular to the extracellular compartment, where it degrades into adenosine and modulates immune responses. Previous studies concluded that both ATP and its degradation product adenosine are important immune-regulatory molecules; ATP acted as a danger signal that promotes immune responses, but adenosine's effect was inhibitory. We show that adenosine receptor ligation plays an important role in balancing Th1 and Th17 pathogenic T cell responses in experimental autoimmune uveitis (EAU). While its effect on Th1 responses is inhibitory, its effect on Th17 responses is enhancing, thereby impacting the balance between Th1 and Th17 responses. Mechanistic studies showed that this effect is mediated via several immune cells, among which γδ T cell activation and dendritic cell differentiation are prominent; adenosine- and γδ-mediated immunoregulation synergistically impact each other's effect. Adenosine receptor ligation augments the activation of γδ T cells, which is an important promoter for Th17 responses and has a strong effect on dendritic cell (DC) differentiation, tipping the balance from generation of DCs that stimulate Th1 responses to those that stimulate Th17 responses. The knowledge acquired in this study should improve our understanding of the immune-regulatory effect of extracellular ATP-adenosine metabolism and improve treatment for autoimmune diseases caused by both Th1- and Th17-type pathogenic T cells.

Autoimmune skin diseases are complex and are thought to arise from a combination of genetics and environmental exposures, which trigger an ongoing immune response against self-antigens. Companion animals including cats and dogs are known to develop inflammatory skin conditions similar to humans and share the same environment, providing opportunities to study spontaneous disease that encompasses genetic and environmental factors with a One Health approach. A strength of comparative immunology approaches is that immune profiles may be assessed across different species to better identify shared or conserved pathways that might drive inflammation. Here, we performed a comparative study of skin from canine discoid lupus erythematosus (DLE) using NanoString nCounter technology. We compared these gene expression patterns to those of human DLE and a mouse model of cutaneous lupus. We found strong interferon signatures, with CXCL10, ISG15, and an S100 gene family member among the highest, most significant DEGs upregulated across species. Cell type analysis revealed marked T-cell and B-cell infiltration. Interestingly, canine DLE samples also recapitulated downregulated skin homeostatic genes observed in human DLE. We conclude that spontaneous DLE in dogs captures many features that are present in human disease and may serve as a more complete model for conducting further genomic and/or transcriptomic studies.

The isolation of single monoclonal antibodies (mAbs) against a given antigen was only possible with the introduction of the hybridoma technology, which is based on the fusion of specific B lymphocytes with myeloma cells. Since then, several mAbs were described for therapeutic, diagnostic, and research purposes. Despite being an old technique with low complexity, hybridoma-based strategies have limitations that include the low efficiency on B lymphocyte-myeloma cell fusion step, and the need to use experimental animals. In face of that, several methods have been developed to improve mAb generation, ranging from changes in hybridoma technique to the advent of completely new technologies, such as the antibody phage display and the single B cell antibody ones. In this review, we discuss the hybridoma technology along with emerging mAb isolation approaches, taking into account their advantages and limitations. Finally, we explore the usefulness of the hybridoma technology nowadays.

The innate immune system is a complex collection of physical barriers and physiological defense responses to internal and external environmental assaults. Recent studies in the model organism Caenorhabditis elegans have highlighted how the nervous system interacts with the innate immune system to generate coordinated protective responses. Indeed, studies on neuro-immune interaction pathways have provided mechanistic insights into the roles of neuro-immune communication in modulating both immune and behavioral responses to pathogen attacks. The nervous system releases a variety of neurotransmitters, peptides, and hormones that regulate the innate immune response, while the innate immune system also relays information to the nervous system to affect learning and behavioral responses. Although these interactions still need further investigation, the knowledge that we have gained thus far has improved our understanding of how separate biological systems can act collectively for the survival and well-being of an organism. Here, we review recent studies on neuro-immune communication related to the survival and defense of C. elegans against pathogens.

The content of tumor-derived extracellular vesicles (EVs) can regulate the tumor microenvironment and functionally acts in favor of cancer aggressiveness. To better elucidate the role of EVs in the interplay between immune system and tumor microenvironment, the purpose of this study was to analyze the effect of head and neck squamous cells carcinoma (HNSCC)-derived EVs on the modulation of inflammasomes - mediators of pyroptosis and secretion of inflammatory factors by macrophages. Our results showed that macrophages treated with the Vesicular Secretome Fraction (VSF) isolated from patient-derived HNSCC presented a reduction in the secretion of mature IL-1β and caspase-1 without affecting cell viability. An analysis of the protein content of HNSCC-derived VSF by antibody array revealed that some of the most expressed proteins share a correlation with Transforming Growth Factor-beta (TGF-β) activity. Since TGF-β is related to the inhibition of the NF-kB-related pathways, including those required for the priming phase of the inflammasomes, we sought to evalute the interference of the VSF in the induction of inflammasome components. In fact, HNSCC-derived VSF inhibited the induction of pro-IL-1β and pro-caspase-1 proteins and NLRP3 gene expression during the priming phase of inflammasome activation. Thus, our findings contribute to a better understanding of how tumor-derived EVs modulate inflammatory response by demonstrating their role in inhibiting NLRP3 inflammasomes.

Conventional dendritic cells (cDCs) are antigen-presenting cells specialized in naïve T cell priming. Mice splenic cDCs are classified as cDC1s and cDC2s, and their main functions have been elucidated in the last decade. While cDC1s are specialized in priming type 1 helper T cells (T_H1) and in cross presentation, cDC2s prime T follicular helper (T_FH) cells that stimulate germinal center (GC) formation, plasma cell differentiation and antibody production. However, less is known about the molecular mechanisms used by cDCs to prime those responses. Here, using WT and STAT6-deficient mice (STAT6 KO), we targeted a model antigen to cDC1s and cDC2s via DEC205 and DCIR2 receptors, respectively, in an attempt to study whether the STAT6 signaling pathway would modulate cDCs’ ability to prime helper T cells. We show that the differentiation and maturation of cDCs, after stimulation with an adjuvant, were comparable between WT and STAT6 KO mice. Besides, our results indicate that, in STAT6 KO mice, antigen targeting to cDC2s induced reduced T_FH and GC responses, but did not alter plasma cells numbers and antibody titers. Thus, we conclude that the STAT6 signaling pathway modulates the immune response after antigen targeting to cDC2s via the DCIR2 receptor: while STAT6 stimulates the development of T_FH cells and GC formation, plasma cell differentiation occurs in a STAT6 independent manner.