A novel TH17-type cell is rapidly increased in the liver in response to acetaminophen-induced liver injury: TH17 cells and the innate immune response

Helper T (T_H) cells are an important part of the adaptive immune system. It is hypothesized that one type of helper T-cell, T_H17 cells, play an important role in idiosyncratic drug-induced liver failure, and it was found that interleukin (IL)-17, the signature cytokine of T_H17 cells, was elevated in most patients with idiosyncratic drug-induced liver failure. However, it was also found that IL-17 was elevated in some patients with acetaminophen (APAP)-induced liver failure. It is unlikely that APAP-induced liver failure is mediated by the adaptive immune system, but there are other cells such as macrophages and natural killer (NK) cells that also produce IL-17. Therefore, the phenotype of cells that produce IL-17 was studied in a mouse model of APAP-induced liver toxicity. To the authors’ surprise, it was found that most of the IL-17 producing cells in the liver were T_H17 cells, and they were increased within hours of APAP treatment. This is too fast for a response of the adaptive immune system. These data suggest that T_H17 cells can be part of the innate immune response; however, it is unclear what role they play in the pathogenesis of APAP-induced hepatotoxicity.     

TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection

Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation, chronic infections, and pregnancy is in an exciting developmental phase that might lead to a variety of targeted therapeutic approaches. Recent progress in the interaction between immune/inflammatory cell subsets through cytokines, particularly the extension of the knowledge on reciprocal regulation and counterbalance between subsets of T(H)1, T(H)2, T(H)9, T(H)17, T(H)22, T follicular helper cells and different subsets of regulatory T cells, as well as corresponding and co-orchestrating B-cell, natural killer cell, dendritic cell, and innate lymphoid cell subsets, offers new possibilities for immune intervention. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. T(H)17 and T(H)22 cells are 2 emerging T(H) cell subsets that link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both cytokines play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. This review focuses on current knowledge on T(H)17 and T(H)22 cells and their role in inflammation, with special focus on the mechanisms of their generation and driving and effector cytokines, as well as their role in host defense, autoimmunity, and allergic diseases.     

TH17 deficiency in human disease

The differentiation of naive T cells into distinct subsets of effector T cells is critical for effective immunity against a wide variety of infectious agents in the environment. Activation of innate immune responses by Candida species through pattern-recognition receptors directs the subsequent development of naive T cells into T(H)17 cells, which are essential for effective mucosal immunity against fungi. Thorough analyses of cohorts of patients with unusual susceptibility to chronic mucocutaneous candidiasis resulting from T(H)17 deficiency have confirmed the role of T(H)17 cells and T(H)17 cytokines in human host defense against Candida species and have provided valuable insights into the complex process of T(H)17 cell development.     

Biology of human TH1 and TH2 cells

Evidence is accumulating to suggest the existence of polarized human T-cell responses, reminiscent of T_H1 and T_H2 subsets described for mouse T cells. Human T_H1 cells preferentially develop during infections by intracellular bacteria and trigger phagocyte-mediated host defense, whereas T_H2 cells, which predominate during helminthic infestations and in response to common environmental allergens, are responsible for phagocyte-independent host response. Human T_H1 and T_H2 cells exhibit not only different functional properties but probably also distinct surface markers; T_H2, but not T_H1, clones express membrane CD30 and release the soluble form of CD30, a member of the TNF receptor superfamily. The cytokine profile of natural immunity evoked by different offending agents in the context of different host genetic backgrounds appears to be the most critical factor in determining the phenotype of the subsequent specific response. IL-12 and IFN- and produced by macrophages and NK cells favor the development of T_H1 cells, whereas the early production of IL-4 by a stillunidentified cell type favors the development of T_H2 cells. Clearly, polarized human T_H1 and T_H2 responses not only play different roles in protection, they can also promote different immunopathological reactions. Strong and persistent T_H1 responses seen to be involved in organ-specific autoimmunity, contact dermatitis, and some chronic inflammatory disorders of unknown etiology. In contrast, polarized T_H2 responses favor a reduced protection against the majority of infectious agents (including HIV) and, in genetically predisposed hosts, are responsible for triggering of allergic atopic disorders.     

MBL对树突状细胞体外分化成熟的影响

目的: 探讨甘露聚糖结合凝集素 (MBL)对人外周血单核细胞来源的树突状细胞 (MoDC)分化成熟的影响。方法: 以天然人MBL刺激MoDC, 在倒置显微镜下观察DC的形态; 用FACS分析DC的表型; 用 3H- TdR掺入法测定DC刺激同种异体T细胞增殖的能力; 以酵母多糖颗粒吞噬试验评估DC的抗原摄取能力; 用ELISA检测DC培养上清中IL- 12和TNF- α的含量。结果: MBL刺激的DC表面分子CD1a、CD83、CD40、CD80、CD86和MHC DR的表达均上调,摄取酵母多糖颗粒的能力降低, 激发初始T细胞增殖的能力加强, 分泌的IL- 12增多但几乎不分泌TNF- α。结论: MBL能诱导DC分化成熟, 提示其可能通过调节DC的功能而参与获得性免疫应答。     

Barrier immunity and IL-17

CD4⁺ T_H17 cells display a featured role in barrier immunity. This effector population of T cells is important for clearance of microorganisms but can also promote autoimmunity at barrier sites. Recent work has indicated that these effector cells share a pathway with CD4⁺ regulatory T cells (T_R cells) that also have a critical function in barrier protection and immune regulation. The development and function of T_H17 cells, and their relationship with T_R cells are discussed.     

Regulation of B lymphocytes and plasma cells by innate immune mechanisms and stromal cells in rheumatoid arthritis

B cells mediate multiple functions that influence immune and inflammatory responses in rheumatoid arthritis. Production of a diverse array of autoantibodies can happen at different stages of the disease, and are important markers of disease outcome. In turn, the magnitude and quality of acquired humoral immune responses is strongly dependent on signals delivered by innate immune cells. Additionally, the milieu of cells and chemokines that constitute a niche for plasma cells rely strongly on signals provided by stromal cells at different anatomical locations and times. The chronic inflammatory state therefore importantly impacts the developing humoral immune response and its intensity and specificity. We focus this review on B cell biology and the role of the innate immune system in the development of autoimmunity in patients with rheumatoid arthritis.     

Plasmacytoid dendritic cells act as the most competent cell type in linking antiviral innate and adaptive immune responses

Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.     

Accelerated in vitro differentiation of blood monocytes into dendritic cells in human sepsis

Summary Sepsis-induced immune depression is characterized by infection susceptibility and monocyte early deactivation. Because monocytes are precursors for dendritic cells (DC), alterations in their differentiation into DC may contribute to defective immune responses in septic patients. We therefore investigated the ability of monocytes to differentiate into functional DC in vitro in patients undergoing surgery for peritonitis. Monocytes from 20 patients collected immediately after surgery (D0), at week 1 and at weeks 3-4 and from 11 control donors were differentiated into immature DC. We determined the phenotype of monocytes and derived DC, and analysed the ability of DC to respond to microbial products and to elicit T cell responses in a mixed leucocyte reaction (MLR). We show that, although monocytes from septic patients were deactivated with decreased responses to lipopolysaccharide (LPS) and peptidoglycan and low human leucocyte antigen D-related (HLA-DR) expression, they expressed the co-stimulatory molecule CD80, CD40 and CCR7. Monocytes collected from patients at D0 and week 1 differentiated faster into DC with early loss of CD14 expression. Expression of HLA-DR increased dramatically in culture to reach control levels, as did responses of DC to LPS and peptidoglycan. However, although patient and control immature DC had similar abilities to induce T cell proliferation in MLR, maturation of DC derived from patients did not increase T cell responses. These results show that circulating monocytes from septic patients express markers of activation and/or differentiation despite functional deactivation, and differentiate rapidly into phenotypically normal DC. These DC fail, however, to increase their T cell activation abilities upon maturation.     

Targeting IL-17 in psoriasis: From cutaneous immunobiology to clinical application

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility. Although the hallmark of psoriasis is characterized by cutaneous inflammation and keratinocyte hyperproliferation, recent studies show that the pathologic features observed in psoriasis arises as a result of innate and adaptive immune activation in genetically prone individuals. Studies focused on the microenvironment in the skin of psoriasis lesions have revealed novel cellular and cytokine abnormalities of the immune system. One pathway important is the role of the T_H17/IL-17 dysregulation. The recent development of biologics that target the IL-17 cytokine pathway has confirmed the importance of T_H17 and IL-17 homeostasis in the skin and yielded potent therapies in the treatment of psoriasis, and potentially other autoimmune diseases.