Critical Reviews in Immunology最新文献

Programmed cell death-1 (PD-1) immunoinhibitory receptor expression is found on T cells, B cells, natural killer (NK) cells, and myeloid cells. Upon activation of T cells through peptide-major histocompatibility complex (MHC) engagement of the T cell receptor and costimulatory signaling, checkpoints including PD-1 are activated to regulate T cells. Since decreased expression of PD-1 in mice model was found to be associated with breakdown of peripheral tolerance, and demonstrated autoimmune disease characteristic, this receptor may be important therapeutic target for autoimmunity. In addition, decreased NK cell numbers and cytotoxicity in peripheral blood and altered expression of activating receptors and cytokine secretion of NK cells was seen in autoimmune disease patients. Therefore, in this review we discuss the relevance of PD-1 function in NK and T cells in autoimmunity, and demonstrate similarities and differences of its function in autoimmune diseases and cancer. Thus, PD-1 can be targeted to treat each disease entity accordingly. In cancer, the function of PD-1 can be blocked in order to enhance immune activation, whereas in autoimmune diseases it can be enhanced to block heightened immune function. However, we are far from understanding the exact functioning of this receptor in a complex tissue microenvironment, and further studies are required to establish its function at different stages of the disease, and at different stages of the maturation of immune effectors.

The recognition of self-antigens by the T-cell immune system can results in autoimmunity. Current treatments of autoimmunity include non-steroid anti-inflammatory drugs and treatments aimed to control the immune system directly. Additionally, inhibiting signaling pathways that encourage T cell activation are promising strategies to help increase self-tolerance and control the inflammatory immune response. Despite the many treatments available, there are still great risks that accompanies each therapy; therefore, the shift towards immune checkpoint therapy is promising as it specifically targets the activated autoimmune T cells. In contrast to cancer, immune check point inhibitors (ICIs) for autoimmune treatment are attractive targets for the amplification of inhibitory functions of autoimmune T cells. A particular protein of interest for autoimmune therapy is the immune checkpoint protein V-type immunoglobin domain-containing suppressor of T cell activation (VISTA) or programmed dealth-1 homolog (PD-1H) of the B7 family. VISTA acts as both a ligand [on antigen presenting cells (APCs) and other cells] and as a receptor (on T cells). It functions as an immuno-suppressor by decreasing T cell proliferation, balancing the T cell/T regulatory cells (Tregs) ratio, and inhibiting cytokine production and inflammation. For the treatment of autoimmunity, an agonist anti-VISTA mAb is needed to interact and activate the inhibitory intracellular signaling pathways that result in the inactivation of the autoimmune T cells. New developments such as VISTA.cartilage oligomeric matrix protein (VISTA.COMP) and anti-human VISTA (anti-hVISTA) mAbs 7E12 and 7GF are potential drug candidates to help downregulate autoimmune responses and reduce the inflammatory states of patients with autoimmunity.

Immune system escape is one of the major strategies required for cancer growths. In this scenario, the advent of immune checkpoint inhibitors (ICIs) revolutionized the landscape of treatment options for tumors. Despite their wide use, these agents are associated with a unique spectrum of toxicities known as immune-related adverse events (irAEs). IrAEs are cause of treatment suspension (up to 60% of all causes of treatment interruption) and potentially impact on patients' quality of life. These toxicities are the main limitations on the use of these innovative drugs. IrAEs are peculiar, due to the mechanism of actions of ICIs, and any body organs may be involved (skin, thyroid, colon, lungs, in particular). Thus, the management often requires a multidisciplinary approach. The aim of this manuscript is to review current literature on autoimmune skin diseases described in association with ICIs (i.e., vitiligo, lupus erythematosus, vasculitis, morphea/scleroderma, alopecia areata, bullous pemphigoid, dermatomyositis), in order to provide a comprehensive overview for the physician.

Upon engaging cognate peptide MHC-II complexes (pMHC-IIs), naive CD4+ T cells differentiate and acquire several T helper (Th) fates, guided by a dynamic cytokine milieu following antigenic challenge. This physiological Th fate choice process is often erroneously conflated with a maladaptive pathological process historically termed Th polarization. Here we propose why these two processes are distinct and separable. We posit that, though innate signaling alone is sufficient for Th fate choice in naive CD4+ T cells, Th polarization instead strictly originates from pre-existing cross-reactive memory CD4+ T cells. We further posit that Th polarization is normally prevented by thymus-derived cross-reactive antigen-specific regulatory T cells (Tregs) and inevitably manifests as immunopathology when the Treg repertoire and the microbiota that maintains it are selectively depleted. Bifurcating Th fate choice and polarization delineate Th effector pathways more accurately and tangibly improve the scope of targeted therapies for allergies, autoimmune diseases, and effective vaccines.

Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).

Immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly advanced the treatment of cancer and other conditions. However, these therapies can also cause immune-related adverse events (irAEs), which are unintended side effects due to their effects on the immune system of the treated patient. These effects can be classified as organ-specific or systemic, with the latter being of particular interest due to their potential overlap with systemic autoimmune diseases (SADs). Autoantibodies, which are proteins produced by the immune system that react with self components, are often used to diagnose and classify SAD. However, the diagnostic value of autoantibodies in the context of systemic irAEs (sirAEs) triggered by ICIs is not well understood. This review aims to evaluate the diagnostic value of conventional autoantibodies in the identification and classification of sirAEs. A comprehensive search of the literature was conducted using the PubMed database, with a focus on articles published in the past 10 years. The results of the review suggest that, although autoantibodies can be useful in the diagnosis and classification of some SAD triggered by ICIs, there is a clear predominance of seronegative irAEs. The lack of traditional autoantibodies may suggest a unique mechanism for sirAEs and increases the already complex diagnostic approach of these manifestations, requiring evaluation by multidisciplinary teams with extensive experience in immunomediated diseases. Further research is needed to fully understand the diagnostic value of autoantibodies in this context and to determine the optimal approach for their detection and interpretation.

Microbial plaque that builds up in the gingival crevice area causes inflammation and leads to periodontal disease. Previous research has shown an association between interleukins with periodontitis. The association between interleukin-18 (IL-18) gene polymorphism and periodontitis risk was studied extensively, but the results are contradictory. The aim of this study is to find the association of two IL-18 promoter variants namely -607 C > A (rs1946518) and -137 G > C (rs187238), and the risk of chronic and aggressive periodontal disease by meta-analysis. The databases of PubMed, Medline, Web of Science, and Google Scholar were all explored to find the appropriate studies. The MetaGenyo software was used to calculate each analysis. Outcomes of the pooled analyses revealed significantly elevated risk for periodontitis for both polymorphisms. There is no significant heterogeneity between studies. No significant publication bias was observed. This meta-analysis provided the evidence of a link between IL-18 gene polymorphism in periodontitis.

The large amount of data collection coupled with the time-consuming nature of traditional methods of data analysis hinder the advancement of disease diagnosis and treatment. Precision medicine and personalized patient care approaches have positively impacted treatment. The utilization of artificial intelligence (AI), which ranges from deep learning to machine learning, may assist in accomplishing the purpose set out by precision medicine. AI creates greater efficiency in terms of the analysis and organization of "big data," while also facilitating the improvement of ultrasound techniques such as enhancing image processing. We have selected hepatocellular carcinoma (HCC) as an example to illustrate the role of AI and precision medicine. The use of AI can play a prominent role in biomarker exploration as it aids in the recognition of HCC, helps to reconstruct electronic health records, and can determine the outcome of therapy such as immunotherapy for HCC. The evolving role of AI within precision medicine and other facets of the treatment of HCC are reviewed in this report.