Exploring the reciprocal relationship between immunity and inflammation in chronic inflammatory arthritis

Experimental models seeking to explore how susceptible individuals develop rheumatoid arthritis (RA) propose that genetic and environmental factors shape a complex series of molecular and cellular interactions leading to a chronic inflammatory response. T lymphocytes and MHC class II genes have featured prominently in these models. More recent studies have suggested that perpetuation of inflammation in a disease-susceptible host might occur through failure to down-regulate the inflammatory process. One prediction from this model is that effective mechanisms of immunoregulation might be most easily investigated in non-susceptible individuals. However, this has been difficult to study in man. Based on the observation that extended MHC haplotypes are strongly associated with RA in different ethnic groups, I have explored the function of human MHC-encoded genes in transgenic mice using two different experimental approaches. First, by comparing the molecular interactions between disease-associated or non-associated HLA-DR4 molecules and CD4+ T lymphocytes, it has been possible to gain insight into how immune responses in non-susceptible individuals might differ from T-cell responses observed in a susceptible host. This has been achieved using transgenic mice expressing RA disease-associated and non-associated human HLA class II molecules. Secondly, the effects of prolonged exposure of T cells to the proinflammatory cytokine tumour necrosis factor alpha (TNF) have been studied in vitro and in vivo, focusing on T-cell receptor (TCR) signalling and effector responses. In studies of HLA class II transgenic mice, the major differences between disease-associated and non-associated alleles in terms of T-cell responses occur at the level of presentation of antigenic peptides, and the sustained expression of inflammatory cytokines such as TNF. Chronic exposure of T cells to inflammatory cytokines such as TNF induces a phenotype which resembles RA synovial T cells, including the induction of non-deletional and reversible hyporesponsiveness to TCR ligation and uncoupling of proximal TCR signal transduction pathways. The experimental findings are consistent with a model in which HLA class II-driven inflammatory cytokine expression uncouples TCR signalling pathways in the susceptible host in such a way as to profoundly suppress proliferative and immunoregulatory cytokine responses, while at the same time promoting cell survival and effector responses.     

Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases

Inflammatory bowel disease(IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effec...     

CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis

CD4(+)CD25(+) regulatory T cells (Treg) play a crucial role in the regulation of immune responses. Although many mechanisms of Treg suppression in vitro have been described, the mechanisms by which Treg modulate CD8(+) T cell differentiation and effector function in vivo are more poorly defined. It has been proposed, in many instances, that modulation of cytokine homeostasis could be an important mechanism by which Treg regulate adaptive immunity; however, direct experimental evidence is sparse. Here we demonstrate that CD4(+)CD25(+) Treg, by critically regulating IL-2 homeostasis, modulate CD8(+) T-cell effector differentiation. Expansion and effector differentiation of CD8(+) T cells is promoted by autocrine IL-2 but, by competing for IL-2, Treg limit CD8(+) effector differentiation. Furthermore, a regulatory loop exists between Treg and CD8(+) effector T cells, where IL-2 produced during CD8(+) T-cell effector differentiation promotes Treg expansion.     

TCRzetadim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues

The T-cell receptor zeta (TCRzeta) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRzeta expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRzeta expression and effector function in T cells. We report here that TCRzeta(dim) lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRzeta(bright) counterparts, TCRzeta(dim) cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRzeta(dim) T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRzeta(dim) T cells make them promising cellular targets for the treatment of chronic inflammatory disease.     

Treg/Th17平衡与血吸虫感染免疫

血吸虫感染可诱导调节性T细胞（Treg）和Th17型免疫反应。研究表明,Treg和Th17细胞及其平衡在血吸虫感染中具有非常重要的作用。Treg细胞抑制宿主体内过度病理反应,并有助于血吸虫逃避宿主的免疫攻击;而Th17细胞促进血吸虫感染过程中的免疫病理发展。本文就Treg/Th17平衡与血吸虫感染免疫关系的研究进展作一综述。     

Histamine in chronic allergic responses.

In addition to its well-characterized effects in the acute inflammatory and allergic responses, histamine has been shown to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to chronic inflammation. On the other hand histamine acting through its receptor (HR) type 2 positively interferes with the peripheral antigen tolerance induced by T regulatory (Treg) cells in several pathways. Histamine also regulates antigen-specific TH1 and TH2 cells, as well as related antibody isotype responses. These findings provide suitable explanation for the observations in the experimental model of asthma showing that allergic inflammatory responses and bronchial hyperresponsiveness may be susceptible to HR1 blockade. Apparently, the various effects of histamine on immune regulation are due to differential expression and regulation of 4 histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors is highly decisive on the biological effects of histamine and drugs that target histamine receptors. This article highlights novel discoveries in histamine immunobiology and discusses their relevance to the allergic inflammatory responses.     

Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease

The recent discovery and characterization of T helper 17 cells (Th17) and their signature cytokines (IL-17) represents a hallmark in T-cell immunobiology by providing a new distinctive pathway for the communication between adaptive and innate immunity. From the six members of the IL-17 cytokine family presently known, at least two have evident proinflammatory qualities and are involved in several chronic inflammatory disorders, including inflammatory bowel disease (IBD). IL-17A and IL-17F are abundantly found in inflamed IBD mucosa, suggesting their pivotal role in IBD. However, the precise implication of IL-17 cytokine family members in IBD pathogenesis and the mechanisms regulating their secretion are incompletely understood. Importantly, recent findings suggest that beyond IL-17 production-Th17 cells may secret a plethora of other effector cytokines such as IL-21, IL-22, and IL-9- which is in part induced by its own IL-9 production. However, the use of anti-IL-17 therapeutic strategies in experimental models of chronic inflammation results in disease-ameliorating effects suggesting their potential use in IBD patients. In this review article we discuss the latest findings on the role of Th17 cells and IL-17 family members in IBD immunopathology, as well as research perspectives.     

Effektor-Memory-T‑Zellen in der Pathogenese von ANCA-assoziierten Vaskulitiden

Patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) have an expansion of effector memory T?cells in peripheral blood. The enlarged effector memory cell population contains distinct cell subsets, including T?helper type 1 (Th1) CD4+ T?cells lacking co-stimulatory CD28 expression and Th17 cells in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and Th2 type and Th17 cells in eosinophilic granulomatosis with polyangiitis (EGPA). The cytokine response of autoreactive proteinase 3 (PR3)-specific effector memory T?cells is skewed towards an increase of Th2 type, Th17 and Th22 cell fractions in GPA. Anomalous effector memory CD4+ T?cell co-stimulation is suggested by the aberrant expression of P?selectin glycoprotein ligand?1, beta?2 integrin, chemokine receptors, natural-killer group 2 member D (NKG2D) and other activating receptors. The increased expression of these receptors is accompanied by T?cell activation and migration to inflamed tissues. The T?cells are abundant and secrete proinflammatory cytokines in inflammatory lesions in AAV. The T?cell mediated tissue damage correlates with renal outcome, whereas B-cell infiltration does not. Activation of lesional CD4+NKG2D+ effector memory T?cells is independent of the antigen; moreover, CD4+NKG2D+ effector memory T?cells display NK-cell-like cytotoxicity towards microvascular endothelial cells in vitro. Thus, effector memory T?cells play an important role in tissue damage and disease progression in AAV. Sequentially administered or combined with B-cell depleting therapy, T?cell-directed therapies, especially those directed against effector memory CD4+ T?cells, may further improve the outcome and help to achieve long-term remission in AAV.     

Th17 Cells in Immunopathogenesis and treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the sequestration of various leukocyte subpopulations within both the developing pannus and synovial space. The chronic nature of this disease results in inflammation of multiple joints, with subsequent destruction of the joint cartilage and erosion of bone. Identification of T helper (Th)17 cells led to breaking the dichotomy of the Th1/Th2 axis in immunopathogenesis of autoimmune diseases such as RA, and its experimental model, collagen‐induced arthritis (CIA). Th17 cells produce cytokines, including interleukin (IL)‐17, IL‐6, IL‐21, IL‐22 and tumor necrosis factor (TNF)‐α, with pro‐inflammatory effects, which appear to have a role in immunopathogenesis of RA. Regarding the wide ranging production of pro‐inflammatory cytokines and chemokines by Th17 cells, it is expected that Th17 cell could be a potent pathogenic factor in disease immunopathophysiology. Thus the identification of effector mechanisms used by Th17 cells in induction of disease lesions may open new prospects for designing a new therapeutic strategy for treatment of RA.     

Cytokines and alcohol

Cytokines are multifunctional proteins that play a critical role in cellular communication and activation. Cytokines have been classified as being proinflammatory (T helper 1, Th1) or anti-inflammatory (T helper 2, Th2) depending on their effects on the immune system. However, cytokines impact a variety of tissues in a complex manner that regulates inflammation, cell death, and cell proliferation and migration as well as healing mechanisms. Ethanol (alcohol) is known to alter cytokine levels in a variety of tissues including plasma, lung, liver, and brain. Studies on human monocyte responses to pathogens reveal ethanol disruption of cytokine production depending upon the pathogen and duration of alcohol consumption, with multiple pathogens and chronic ethanol promoting inflammatory cytokine production. In lung, cytokine production is disrupted by ethanol exacerbating respiratory distress syndrome with greatly increased expression of transforming growth factor beta (TGFbeta). Alcoholic liver disease involves an inflammatory hepatitis and an exaggerated Th1 response with increases in tumor necrosis factor alpha (TNFalpha). Recent studies suggest that the transition from Th1 to Th2 cytokines contribute to hepatic fibrosis and cirrhosis. Cytokines affect the brain and likely contribute to changes in the central nervous system that contribute to long-term changes in behavior and neurodegeneration. Together these studies suggest that ethanol disruption of cytokines and inflammation contribute in multiple ways to a diversity of alcoholic pathologies.     

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.     

Host and viral factors contributing to CD8＋ T cell failure in hepatitis C virus infection

Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.     

B7h is required for T cell activation, differentiation, and effector function

T helper (Th) cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a recently identified costimulatory receptor expressed on activated T cells. A ligand for ICOS, B7h, is expressed on B cells and other types of antigen-presenting cells (APC). Although ICOS has been shown to be essential in T cell activation and differentiation, the regulatory roles of B7h at different stages of T cell immune responses have not been examined genetically. In this study, we generated and analyzed B7h-deficient mice. We present evidence that B7h is the only ligand for ICOS, and ICOS, its only corresponding receptor. Th cells, when activated with B7h-deficient APC, exhibited reduced proliferation and IL-2 production. In addition, Th cells produced significantly reduced amounts of IL-4 and -13 after differentiation at the presence of B7h-/- APC. This cytokine defect was associated with a deficiency in c-Maf expression and could be rescued completely by c-Maf overexpression in T cells. Furthermore, we showed that effector T cells, when restimulated in the presence of B7h-deficient APC, exhibited reduced Th2 cytokine production. Therefore, B7h is required for proper Th cell activation, differentiation, and effector cytokine expression.     

Anti-interferon-inducible chemokine, CXCL10, reduces colitis by impairing T helper-1 induction and recruitment in mice

BACKGROUND: Colitis in interleukin (IL)-10 mice is a CD4 T helper 1 (TH1)-mediated disease characterized by intermittent, transmural inflammation reminiscent of human Crohn's disease. In this study, we investigated the hypothesis that production of the CXC chemokine CXCL10 (interferon [IFN]gamma-inducible protein 10) enhances induction of inflammatory responses in draining lymph nodes (LNs) and promotes colonic TH1 cell recruitment. METHODS: Colitis was induced in B6 IL-10 mice. Mice were given anti-CXCL10 mAb in 2-week intervals before and after peak colitis. Colitis severity was graded and cytokine/chemokine levels were analyzed by real-time polymerase chain reaction. Cell yields were quantitated and effector cell recruitment was assessed by recovery of transferred D011.10 TH1 cells shortly (72 h) after transfer. RESULTS: Treatment with anti-CXCL10 during colitis development decreased clinical and histologic disease severity as well as cytokine/chemokine mRNA and accumulation of mononuclear cells in LNs and colon. Treatment of mice with severe colitis reduced colitis scores and cell yields to lesser degrees. Anti-CXCL10 specifically decreased recruitment of transferred TH1 cells into mesenteric LNs (MLNs) and colon of IL-10 mice by 75% (P<0.05). CONCLUSION: These results suggest that CXCL10 plays a dual role in colitis development by enhancing TH1 cell generation in inductive sites and promoting effector cell recruitment to inflamed tissue. Blockade of CXCL10 may be a useful adjunct to remission-inducing therapies in inflammatory bowel disease (IBD) by impairing disease recurrence through selective inhibition of effector cell generation and trafficking in vivo.