Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)includes Crohn’s disease and ulcerative colitis.The exact etiology and pathology of IBD remain unknown.Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals.Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD,involving a wide range of molecules including cytokines.On the other hand,besides T helper(Th)1 and Th2 cell immune responses,other subsets of T cells,namely Th17 and regulatory T cells,are likely associated with disease progression.Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.     

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases(IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis.These idiopathic diseases have environmental, genetic,immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type(Th) 1 and Th2 immune responses,other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin,microRNAs, and serum proinflammatory cytokines.An efficient strategy for IBD therapy is represented by the combination of IL-17 A and IL-17 F in acute IL-17 A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17 F knockout, DSS-induced colitis have been observed.Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused reviewin order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.     

CD28:CTLA4/B7及CD40/CD40L在炎症性肠病发病机制中的作用

炎症性肠病(IBD)是一组病因未明的累及肠道的免疫反应异常性疾病,T细胞功能失调与IBD发病密切相关。CD28：CTLA4/B7及CD40/CD40L是重要共刺激分子,对调节免疫具有非常重要的作用,可能在IBD发生和发展中起着关键作用。     

Dynamics of proinflammatory cytokine in biological therapy of inflammatory bowel disease

Chronic inflammation in IBD is accompanied by an imbalance in the production of TX1 and Th2 cytokines. Imbalance of cytokine profile is important pathogenetic value at chronic inflammatory process, since the formation of a defective immune response to pathogenic agent promotes recurrence of the disease. Analysis of the dynamics of proinflammatory cytokines allows to estimate the activity of the inflammatory process, and effectiveness of the therapy. Increased levels of proinflammatory cytokines: TNF-alpha, IFN-gamma, IL-2, IL-5, IL-8, IL-12, IL-15 in serum of patients with IBD, indicating their possible involvement in the mechanisms of development of CD and UC. The increase in the content of these cytokines was accompanied by increased activity of disease that can be used to diagnose IBD activity.     

Immunopathology of inflammatory bowel disease

Inflammatory bowel disease(IBD)results from a complex series of interactions between susceptibility genes,the environment,and the immune system.The host microbiome,as well as viruses and fungi,play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system.New technologies have allowed researchers to be able to quantify the various components of the microbiome,which will allow for future developments in the etiology of IBD.Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells,innate lymphoid cells,cells of the innate(macrophages/monocytes,neutrophils,and dendritic cells)and adaptive(T-cells and B-cells)immune system,and their secreted mediators(cytokines and chemokines).Either a mucosal susceptibility or defect in sampling of gut luminal antigen,possibly through the process of autophagy,leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity.The antigen presenting cells then mediate the differentiation of na?ve T-cells into effector T helper(Th)cells,including Th1,Th2,and Th17,which alter gut homeostasis and lead to IBD.In this review,the effects of these components in the immunopathogenesis of IBD will be discussed.     

The Interleukin-23 / Interleukin-17 axis in intestinal inflammation

Although the precise aetiology of inflammatory bowel disease (IBD) remains unclear, recent discoveries have led to an improved understanding of disease pathogenesis. Whilst these findings have underscored the central role of innate and adaptive immune responses in intestinal inflammation, they have also precipitated a paradigm shift in the key cytokine pathways that drive disease. The prevailing dogma that IBD was mediated by interleukin (IL)-12-driven T-helper (Th)1 CD4 T cell responses towards the bacterial flora has been largely dispelled by findings that the closely related cytokine IL-23 appears to be the key mediator of intestinal inflammation. IL-23 is associated with a novel subset of IL-17-secreting CD4 T cells termed Th17 cells and rodent studies have implicated the IL-23/IL-17 axis in autoimmune inflammation. Genome-wide association studies in IBD patients have confirmed the predominant role of the IL-23 pathway, indicating that this could represent an important future therapeutic target.     

Old and New Lymphocyte Players in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.     

The immunology of pregnancy.

Pregnancy is an immunological balancing act in which the mother's immune system has to remain tolerant of paternal major histocompatibility (MHC) antigens and yet maintain normal immune competence for defense against microorganisms. The placenta separates fetal and maternal blood and lymphatic systems and it is fetal trophoblast that plays the major role in evading recognition by the maternal immune system. Trophoblast cells fail to express MHC class I or class II molecules and the extravillous cytotrophoblast cells strongly express the nonclassic MHC gene encoding HLA-G, which may downregulate natural killer (NK) cell function. In addition, the trophoblast expresses Fas ligand, thereby conferring immune privilege: maternal immune cells expressing Fas will undergo apoptosis at the placenta/decidua interface. A third protective mechanism exploited by the trophoblast is the expression of the complement regulatory proteins CD46, CD55, and CD59. Uterine decidual and placental cells produce a huge array of cytokines which, in part, contribute to the deviation of the immune response from Th1 to Th2. This may leave the mother more open to infection whose control is Th1-dependent, but increased production of Th1 cytokines has been linked to spontaneous abortion and small-for-dates babies. This bias in cytokines and hormonally mediated effects on the thymus and on B cells may also contribute to the suppression of autoimmune responses and changes in circulating and local T-cell subsets in pregnancy.     

CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity

Natural killer (NK) cells are innate lymphocytes that provide cytokines critical for early host defense against pathogens. One subset of human NK cells (CD56(bright)) constitutively expresses the high-affinity interleukin 2 (IL-2) receptor and produces immunoregulatory cytokines. Here, we demonstrate that CD56(bright) NK cells are present in human lymph nodes and that endogenous T cell-derived IL-2, acting through the NK high-affinity IL-2 receptor, costimulates CD56(bright) NK cells to secrete IFN-gamma. Thus, adaptive immunoregulators influence innate cytokine production, which in turn may influence the developing antigen-specific immune response. These data show a dynamic interaction between innate and adaptive human lymphocytes and emphasize the importance of studying interactions between immune components to understand the immune response as a whole.     

New players in the cytokine orchestra of inflammatory bowel disease

In both Crohn's disease (CD) and ulcerative colitis, the pathologic process is almost certainly driven by an aberrant local immune response directed against normal components of the bacterial microflora. Mucosal immune cells interact with nonimmune cells such as epithelial cells and fibroblasts to promote tissue damage; cytokines are essential mediators of this cross talk. Accumulating evidence now suggests that interleukin-21 (IL-21), the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade. IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with CD, where it contributes to sustaining the ongoing Th1 inflammation. IL-21 also increases the secretion of extracellular matrix-degrading enzymes by fibroblasts and of MIP-3alpha by epithelial cells. Two other cytokines, IL-27 and IL-32, may also be important in the inflammatory pathways that operate in IBD.     

Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease （IBD）, which includes Crohn’s disease （CD） and ulcerative colitis （UC）, rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.     

Suppression of colon inflammation by CD80 blockade: evaluation in two murine models of inflammatory bowel disease

BACKGROUND: Human inflammatory bowel disease (IBD) is a chronic condition mediated by aberrant immune responses to the luminal antigens by activated CD4+ T cells. The CD80/CD86:CD28/CD152 costimulatory pathways transmit signals critical for T cell activation and suppression. Macrophages and epithelial cells are the chief antigen-presenting cells in the gut. Macrophages from the IBD colon express significantly elevated levels of CD80 and CD86 costimulatory molecules. The CD28-CD80 interaction primarily participates in breaking the tolerance and inducing the immune response in murine models of colitis. Blockade of CD80-costimulatory axis is an attractive strategy in the treatment of IBD. METHODS: Incorporating the structural information of the CD80:CD152 complex together with the preferences of interface residues to form polyproline type II helix, we designed novel peptide agents that selectively blocked CD80 receptor interactions. RESULTS: Administration of CD80 blocking agent at the time of adoptive transfer prevented the SCID mice from CD4+CD45Rb(high) T-cell mediated colitis. Significantly, CD80-CAP (competitive antagonist peptide) treatment suppressed established inflammation in TNBS-induced colitis, a model for Th1-mediated Crohn's disease. The colons of the mice receiving the CD80 blocking agent appeared unaffected macroscopically and exhibited negligible microscopic inflammation. The CD80-CAP treatment was associated with significantly reduced Th1 cytokines in the colon. CONCLUSIONS: The CD80 blocking peptide appeared to mediate protection against colitis by inducing Th2 skewing of the cytokine response.     

Prostaglandin E2-dependent IL-23 production in aged murine dendritic cells

CD4+ T cells of the Th17 subtype are over-represented in the aged immune system. Dendritic cells (DC) play a critical role in naïve CD4+ T cell differentiation. However, expression of cytokines by aged DC that promote differentiation or survival of Th17 cells has not been extensively investigated. Using bone marrow-derived DC from C57BL/6 mice of different ages we compared cytokine production after DC activation by Toll-like receptor agonists for TLR4 and/or TLR7/8. DC-derived TNF-α and IL-12p70 production and expression of DC co-stimulatory molecules did not vary significantly by age indicating that TLR expression, function and signal transduction were intact in aged DC. There were relatively minor age-related changes in TGF-β and IL-6 which promote Th17 differentiation, but IL-23, a Th17-suvival cytokine, increased more than 40-fold across the lifespan. DC-derived prostaglandin E2 (PGE2) also increased with age and the up-regulation of IL-23 expression by aged DC was blocked by indomethacin that prevents PGE2 production, and by antagonists of PGE2 receptors. Exogenous PGE2 added to DC cultures further enhanced IL-23 production from aged but not young DCs. These data indicate that age-related changes in DC PGE2 production are necessary, but not sufficient to induce DC IL-23 production. Such changes may play a role in the expansion of Th17 cells in the aged immune system.     

Initiation of lung immunity: the afferent limb and the role of dendritic cells

The lung is the largest epithelial surface in the body and constitutes a major portal of entry for microorganisms. Dendritic cells (DCs) are bone marrow-derived cells that populate the respiratory tract from the nasal mucosa to the lung pleura. DCs are dexterous cells playing a role in both the innate and the adaptive immune responses. DCs can respond to dangers in the lung by immediately generating protective cytokines that stimulate natural killer (NK) cells to produce cytokines and kill targets. Direct (by pathogen recognition receptors) and indirect (by inflammatory cytokines) recognition of the infectious agent can also trigger signaling pathways in the DCs that activate an integrated developmental program called maturation, which transforms DCs into efficient antigen-presenting cells (APCs) for naive T cell stimulation. Furthermore, DCs play a role in generating effector B cells in the lymph nodes draining the lung. This review focuses on how DCs sense the health of the lung and translate messages regarding the lung microenvironment to cells of the innate and adaptive immune response to initiate effector functions to clear an invading microorganism [T helper 1 (Th1) or Th2 response] or generate tolerance [T regulatory (Tr), anergy, or deletion] to inhaled antigen when no danger is sensed.     

Les aéroallergènes chez le sujet non allergique : quels mécanismes ?

Non-allergic individuals are in contact with the same allergens as allergic individuals but their immune response to these allergens is one of tolerance, the mechanisms of which must be understood in oder to develop effective immunotherapy. Recent experimental reports have described several subpopulations of regulatory T cells (Tr1, Th3, Treg) that play an important role in peripheral tolerance. The mechanism of this tolerance depends on the effects of IL-10 and TGF-β, as well as on the inhibitory effect of membrane molecules such as ICOS and CTLA4. It has been demonstrated in non-allergic individuals that CD4+CD25+ T regulatory cells can inhibit both T cell proliferation and IL-5 production, whereas this T cell subpopulation is deficient in allergic individuals.     

Regulatory T cells: peace keepers in the gut

The mucosa-associated lymphoid tissue (MALT) has the task of protecting the host from pathogens while maintaining the integrity of the gut. Immune responses are tightly regulated such that there is tolerance of nonpathogenic bacteria as well as dietary antigens present in the intestinal lumen. The failure to control these responses leads to a disruption in tolerance, which has been proposed as one mechanism involved in the development of inflammatory bowel disease (IBD). Different mechanisms are involved in the control of immune responses in the intestinal tract, including active suppression by regulatory T cells. Distinct subsets of regulatory T cells coexist in the intestinal mucosa, which is a fertile environment for their growth. Most of these are defined by their phenotype and/or their ability to produce regulatory cytokines such as interleukin-10 and transforming growth factor-beta A lack of activation and/or expansion of regulatory cells could play a role in the uncontrolled inflammation seen in IBD. Regulatory T cells may be activated by cytokines, and their inductive phase may be antigen-driven. There are limited data relating to the true surface interactions regulating the activation of these cells. Most of the CD4 regulatory T cells (Tr1, Th3, and CD4 CD25+) are thought to interact with dendritic cells. Subsets of regulatory T cells (such as CD8 TrE cells) may recognize antigens presented by intestinal epithelial cells. A better understanding of the mechanisms by which these regulatory T cells are expanded and/or activated in the intestinal mucosa may provide clues as how to use them as a novel therapeutic tool in the treatment of patients with IBD.     

Foxp3~+调节性T细胞及其与鼻部炎性疾病的关系

CD4+CD25+调节性T细胞(Tregulatory cells,Treg)能抑制病理性免疫反应,维持自身免疫耐受和免疫平衡。CD4+CD25+Treg主要由两类细胞亚群组成,一类是胸腺来源的自然Treg,另一类是在外周由幼稚T细胞分化而来的诱导性Treg。叉头状转录因子p3是CD4+CD25+Treg的特异性标志,在其发生及功能发挥中起关键作用。同时,CD4+CD25+Treg的扩增和激活也受到细胞因子、共刺激分子等多种分子和信号通路的控制。目前研究认为,变应性鼻炎、慢性鼻窦炎和鼻息肉等鼻部炎性疾病与CD4+CD25+Treg功能障碍密切相关。