International Reviews of Immunology最新文献

Epigenetic regulators are pivotal factors that influence and control T cell development. Recent findings continue to reveal additional elements of epigenetic modifications that play significant and crucial roles at different stages of T cell development. Through gaining a better understanding of the various epigenetic factors that influence the formation and survival of maturing T cells, new therapies can potentially be developed to combat diseases caused by dysregulated epigenetic chromatin modifications. In this review, we summarize the recent studies which shed light on the epigenetic regulation of T cell development especially at the critical stage of β-selection.

Celiac disease (CD) is an autoimmune disease that occurs in genetically predisposed individuals following the ingestion of gluten. Its prevalence is rising worldwide. A gluten-free (GF) diet is mandatory for the management of CD. However, several issues persist regarding the nutritional quality of GF products. Importantly, deep knowledge about the pathogenic mechanisms in CD highlights the central role of CD4⁺ T cell-mediated immunity in CD. Furthermore, intestinal T regulatory cells are functional in CD, but cytokines such as IL-15, produced under inflammatory conditions, hamper their activity. This paves the way for the development of immunomodulatory strategies to the GF diet. From this perspective, microbiological approaches were considered able to modulate the gluten-specific immune response. Interestingly, gliadin peptide-based immunotherapy to abolish the inflammatory CD4⁺T cell-mediated response has been explored in CD patients. Furthermore, different biotechnological approaches based on the use of chemically/enzymatically modified gluten molecules have been proved effective in different models of CD. However, the choice of the right age in infants to introduce the antigen and thus induce tolerance still remains an important issue to solve. Addressing all these points should help to design an effective intervention strategy for preventing CD.

Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4⁺ Foxp3⁺ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity.

Primary immunodeficiency (PID) or Inborn errors of immunity (IEI) refers to a heterogeneous group of disorders characterized by immune system impairment. Although patients with IEI manifest highly variable symptoms, the most common clinical manifestations are recurrent infections, autoimmunity and malignancies. Some patients present hematological abnormality including thrombocytopenia due to different pathogenic mechanisms. This review focuses on primary and secondary thrombocytopenia as a complication, which can occur in IEI. Based on the International Union of Immunological Societies phenotypic classification for IEI, the several innate and adaptive immunodeficiency disorders can lead to thrombocytopenia. This review, for the first time, describes manifestation, mechanism and therapeutic modalities for thrombocytopenia in different classes of IEI.

Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.

The Coronavirus Disease-2019 (COVID-19) imposed public health emergency and affected millions of people around the globe. As of January 2021, 100 million confirmed cases of COVID-19 along with more than 2 million deaths were reported worldwide. SARS-CoV-2 infection causes excessive production of pro-inflammatory cytokines thereby leading to the development of "Cytokine Storm Syndrome." This condition results in uncontrollable inflammation that further imposes multiple-organ-failure eventually leading to death. SARS-CoV-2 induces unrestrained innate immune response and impairs adaptive immune responses thereby causing tissue damage. Thus, understanding the foremost features and evolution of innate and adaptive immunity to SARS-CoV-2 is crucial in anticipating COVID-19 outcomes and in developing effective strategies to control the viral spread. In the present review, we exhaustively discuss the sequential key immunological events that occur during SARS-CoV-2 infection and are involved in the immunopathogenesis of COVID-19. In addition to this, we also highlight various therapeutic options already in use such as immunosuppressive drugs, plasma therapy and intravenous immunoglobulins along with various novel potent therapeutic options that should be considered in managing COVID-19 infection such as traditional medicines and probiotics.

Despite numerous studies on multiple sclerosis (MS) and understanding many aspects of this disease, researchers still struggle to find proper biomarkers that facilitate diagnosis; prognosis and monitoring of treatment efficacy in MS. MicroRNAs (miRNAs) are considered as endogenous, comparatively stable and small non-coding RNAs involved in various biological and pathological signaling pathways. Interestingly, miRNAs have been emerged as a potential biomarker for monitoring novel therapies in MS patients. In this review, we described the miRNAs alteration in the MS patients as well as their altered expression in patients under common MS therapies.

Insights into T cell form, function, and dysfunction are rapidly evolving. T cells have remarkably varied effector functions including protecting the host from infection, activating cells of the innate immune system, releasing cytokines and chemokines, and heavily contributing to immunological memory. Under healthy conditions, T cells orchestrate a finely tuned attack on invading pathogens while minimizing damage to the host. The dark side of T cells is that they also exhibit autoreactivity and inflict harm to host cells, creating autoimmunity. The mechanisms of T cell autoreactivity are complex and dynamic. Emerging research is elucidating the mechanisms leading T cells to become autoreactive and how such responses cause or contribute to diverse disease states, both peripherally and within the central nervous system. This review provides foundational information on T cell development, differentiation, and functions. Key T cell subtypes, cytokines that create their effector roles, and sex differences are highlighted. Pathological T cell contributions to diverse peripheral and central disease states, arising from errors in reactivity, are highlighted, with a focus on multiple sclerosis, rheumatoid arthritis, osteoarthritis, neuropathic pain, and type 1 diabetes.