Immunological Medicine最新文献

Helicobacter pylori (HP) is the primary etiologic factor that induces events in the immune system that lead to peptic ulcers. Toll-like receptors (TLRs) are an important part of the innate immune system, as they play pivotal roles in pathogen-associated molecular pattern (PAMP) recognition of HP as well host-associated damage-associated molecular patterns (DAMPs). Recent advancements such as COX-2 production, LPS recognition through TLR2, CagL, and CagY protein of HP activating TLR5, TLR9 activation via type IV secretion system (T4SS) using DNA transfer, TLR polymorphisms, their adaptor molecules, cytokines, and other factors play a significant role in PUD. Thus, some novel PUD treatments including Chuyou Yuyang granules, function by TLR4/NF-κB signaling pathway suppression and TNF-α and IL-18 inhibition also rely on TLR signaling. Similarly glycyrrhetinic acid (GA) treatment activates TLR-4 in Ana-1 cells not via TRIF, but via MYD88 expression, which is significantly upregulated to cure PUD. Therefore, understanding TLR signaling complexity and its resultant immune modulation after host-pathogen interactions is pivotal to drug and vaccine development for other diseases as well including cancer and recent pandemic COVID-19. In this review, we summarize the TLRs and HP interaction; its pathophysiology-related signaling pathways, polymorphisms, and pharmaceutical approaches toward PUD.

Not all T cells are effector cells of the anti-tumor immune system. One of the subpopulations of CD4⁺ T cells that express CD25⁺ and the transcription factor FOXP3, known as Regulator T cells (T_Reg), plays an essential role in maintaining tolerance and immune homeostasis preventing autoimmune diseases, minimalize chronic inflammatory diseases by enlisting various immunoregulatory mechanisms. The balance between effector T cells (T_eff) and regulator T cells is crucial in determining the outcome of an immune response. Regarding tumors, activation or expansion of T_Reg cells reduces anti-tumor immunity. T_Reg cells inhibit the activation of CD4⁺ and CD8⁺ T cells and suppress anti-tumor activity in the tumor microenvironment. In addition, T_Reg cells also promote tumor angiogenesis both directly and indirectly to ensure oxygen and nutrient transport to the tumor. There is accumulating evidence showing a positive result that removing or suppressing T_Reg cells increases anti-tumor immune response. However, depletion of T_Reg cells will cause autoimmunity. One strategy to improve or restore tumor immunity is targeted therapy on the dominant effector T_Reg cells in tumor tissue. Various molecules such as CTLA-4, CD4, CD25, GITR, PD-1, OX40, ICOS are in clinical trials to assess their role in attenuating T_Reg cells' function.

Despite the considerable success of cancer immunotherapy with immune checkpoint inhibitors, their nonspecific release of the immunosuppressive mechanism is often associated with immune-related adverse events (irAEs). irAEs significantly disturb patients' quality of life and can even be life-threatening. Therefore, the appropriate management of irAEs is crucial for the development of further reliable cancer immunotherapies. irAEs have the appearance of ordinary autoimmune diseases in one aspect but often have distinct features. Although the detailed pathogenesis of irAEs remains unclear, increasing numbers of studies have provided numerous clues. Here, we review the current knowledge on irAEs, particularly from an immunopathological basis.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by clinical manifestations such as thrombosis and obstetric complications with documented persistence of antiphospholipid antibodies (aPLs). Recent studies have revealed that the cause of aPL-related obstetric complications is dysfunction of placental trophoblasts and inflammation of the maternal-fetal interface induced by aPLs, not thrombosis. Although aPLs are associated with recurrence of serious complications during pregnancy, appropriate combination therapy with heparin and low-dose aspirin can improve the course of 70-80% of subsequent pregnancies. Preconception counseling and patient-tailored treatment are fundamental to improving maternal and fetal outcomes. Non-anticoagulant treatments such as hydroxychloroquine and statins are being developed for cases refractory to conventional treatment. Risk factors for thrombosis after pregnancy complications were identified based on the analysis of large databases of obstetric APS.

Th17 cells are implicated in the pathogenesis of several autoimmune diseases. During the inflammation, Th17 cells exposed to IL-12 can shift towards the Th1 phenotype. These shifted cells are defined as 'non-classic Th1 cells'. Th17-derived non-classic Th1 cells play a critical role in late-onset chronic inflammatory diseases and are more pathogenic than the unshifted Th17 cells. Eomes is a transcription factor highly expressed in non-classic Th1 cells. To study the functional role of Eomes without genetic alteration, novel recombinant protein, ntEomes-TMD, was generated by fusing TMD of Eomes and Hph-1-PTD that facilitate intracellular delivery of its cargo molecule. ntEomes-TMD was delivered into the nucleus of the cells without influencing the T cell activation and cytotoxicity. ntEomes-TMD specifically inhibited the Eomes- and ROR-γt-mediated transcription and suppressed the Th1 and Th17 differentiation. Interestingly, ntEomes-TMD blocked the generation of non-classic Th1 cells from Th17 cells, leading to the inhibition of IFN-γ and GM-CSF secretion. In EAE, ntEomes-TMD alleviated the symptoms of EAE, and the combination treatment using ntEomes-TMD and anti-IL-17 mAb together showed better therapeutic efficacy than anti-IL-17 mAb treatment. The results suggest that ntEomes-TMD can be a new therapeutic reagent for treating chronic inflammatory diseases associated with non-classic Th1 cells.

Antibiotics are widely prescribed for mothers in the peripartum period today. Approximately 40% of pregnant women at term are exposed to antibiotics. Antibiotics are useful against infectious conditions such as chorioamnionitis; however, they alter the maternal microbiome. The maternal microbiome, particularly the gut microbiome, is transmitted to their neonates and is one of the major sources that shape the child's gut microbiome. The gut microbiome early in life plays a crucial role in the development of the gut microbiome itself as well as the host health over the entire life. Microbes structure the commensal ecosystem in the host. Simultaneously, microbial components and metabolites influence the host organ functions including the immune system, and vice versa, the various factors of the host impact the microbiome. The alterations of the gut microbiome induced by antibiotics in mothers can lead to gut dysbiosis in children eventually resulting in chronic disease conditions including immune disorders. Knowledge of the lasting impacts of maternal peripartum exposure to antibiotics on the gut microbiome and health in offspring and reconsideration of the adequate use of antibiotics in clinical practice are needed. Avoiding and restoring neonatal dysbiosis following maternal antibiotics-induced dysbiosis could be a new preventive strategy for various diseases.