The Th1/Th2 paradigm

The Th1/Th2 paradigm provides a useful model for understanding the pathogenesis of several diseases, as well as for developing novel immunotherapeutic strategies. Here, Sergio Romagnani examines Th1/Th2 polarization in the context of associated pathophysiological conditions.     

Th1/Th2 balance in infection

Cytokines produced by T helper (Th) cells are of critical importance for the outcome of many infectious diseases. Producing the right set of Cyokines in response to an infectious agent can be a matter of life or death. The Th1/Th2 dichotomy, although an oversimplification has proven useful in the analysis of immune responses to infections. In some infectious diseases, most notably leishmaniasis or infections with gastrointestinal helminths, one Th subset is indispensable for clearing the infection, whereas the opposite Th subset is detrimental. More frequently, both Th1 and Th2 responses are required at different time points to effectively eradicate an infectious agent. The granuloma responses to eitherMycobacterium tuberculosis orSchistosoma mansoni provide illustrative examples and are discussed in this review. There is accumulating evidence for frequent coexpression of Th1 and Th2 Cyokines during the in vivo immune response to infections. The mechanisms by which infectious agents modulate Th1/Th2 phenotype development are summarized here. Finally, we review here the current evidence for cytokine imbalances induced by infections as pathogenic or protective factors in autoimmunity and allergy.     

Th1, Th2, and Th3 cytokine alterations in major depression

BACKGROUND: Many studies have shown that the balance between Th1 cytokines and Th2 cytokines plays a role in modulation of cellular responses in the brain during psychological stress and psychiatric disorders. The Th3 cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to regulate the balance between Th-1 and Th-2 cytokines. However, the role of TGF-beta1 in the psychoimmunology of depression has never been explored. METHODS: A total of 40 depressed patients and 80 normal controls were recruited. The plasma levels of IFN-gamma, IL-4, and TGF-beta1 were studied at the time of admission and 8 weeks after antidepressant treatment. RESULTS: The proportion of patients who showed immunoreactivity to IFN-gamma and IL-4 in the plasma, and the plasma IFN-gamma/IL-4 ratio, were significantly higher in depressed patients than in controls. The IFN-gamma/TGF-beta1 ratio was also higher in depressed patients, and TGF-beta1 levels showed a significant negative correlation with the HDRS depression scale. After treatment, TGF-beta1 level increased significantly, and the IFN-gamma/IL-4 ratio decreased significantly, in the patient group. However, Th1 changes in male and female showed different trend such as Th1 arm was decreased after the treatment in all male, whereas it was increased in premenopausal age women. LIMITATIONS: Replication and extension using a larger sample size are required. CONCLUSIONS: The Th1 and Th2 cytokine imbalance was observed in subpopulation of depressed patients. TGF-beta1 seemed to play a role in the pathophysiology of depression in this population. Moreover, antidepressant treatment was found to affect the Th1/Th2 balance through the action of TGF-beta1.     

Th1、Th2、Th17型细胞因子与糖尿病肾病相关性的研究

糖尿病肾病(diabetic Nephropathy,DN)是导致终末期肾脏病(end-stage renal disease,ESRD)的最主要病因,因此,早期诊断和治疗是糖尿病肾病的诊治要点。但目前糖尿病肾病的确切发病机制尚未完全明确,糖尿病肾病的发生发展与血流动力学改变和代谢的紊乱、氧化应激和炎症等多种因素有关,而细胞因子在2型糖尿病及其相关肾脏并发症的病因、发病机制中也起着重要的作用,各种细胞因子的识别将为糖尿病肾病的诊治提供新的潜在治疗靶点。文章就Th1、Th2、Th17型细胞因子与DN相关性的研究作了综述。     

Stability of Th1 and Th2 populations

Using an in vitro model for the development of IFN-y-producIng(Th1) and IL-4-produclng (Th1) cells from CD4 T lymphocytesexpressing a transgenlc TCR, we show that IL-12 and IL-4 arethe most potent stimuli for the differentiation of naive T cellsto effector populations. When combinations of cytokines arepresent during T cell priming, the effect of IL-4 Is dominant.Furthermore, differentiated Th1 cells can be converted intoIL-4 producers by exposure to IL-4, but the Th2 phenotype Isnot reversible. The stability of Th2 populations may limit theability to regulate Th2-domlnant responses In pathologic situations.     

Th1/Th2 balance in infection

Cytokines produced by T helper (Th) cells are of critical importance for the outcome of many infectious diseases. Producing the “right” set of Cyokines in response to an infectious agent can be a matter of life or death. The Th1/Th2 dichotomy, although an oversimplification has proven useful in the analysis of immune responses to infections. In some infectious diseases, most notably leishmaniasis or infections with gastrointestinal helminths, one Th subset is indispensable for clearing the infection, whereas the opposite Th subset is detrimental. More frequently, both Th1 and Th2 responses are required at different time points to effectively eradicate an infectious agent. The granuloma responses to eitherMycobacterium tuberculosis orSchistosoma mansoni provide illustrative examples and are discussed in this review. There is accumulating evidence for frequent coexpression of Th1 and Th2 Cyokines during the in vivo immune response to infections. The mechanisms by which infectious agents modulate Th1/Th2 phenotype development are summarized here. Finally, we review here the current evidence for cytokine imbalances induced by infections as pathogenic or protective factors in autoimmunity and allergy.     

Th1, Th2, and Th17 cytokines in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the breakdown of immune tolerance leading to excessive inflammation and tissue damage. Imbalance in the levels of cytokines represents one of the multifactorial causes of SLE pathogenesis and it contributes to disease severity. Deregulated levels of T helper type 1 (Th1), type 2 (Th2), and type 17 (Th17) cytokines have been associated with autoimmune inflammation. Growing evidence has shown deregulated levels of Th1, Th2, and Th17 cytokines in SLE patients compared to healthy controls associated with disease activity and severity. In this review, we describe and discuss the levels of Th1, Th2, and Th17 cytokines in SLE patients, and clinical trials involving Th1, Th2, and Th17 cytokines in SLE patients. In particular, with the exception of IL-2, IL-4, and TGF-β1, the levels of Th1, Th2, and Th17 cytokines are increased in SLE patients associated with disease severity. Current phase II or III studies involve therapeutic antibodies targeting IFN-α and type I IFN receptor, while low-dose IL-2 therapy is assessed in phase II clinical trials.     

Revisiting the Th1/Th2 Paradigm

The identification of subsets of CD4⁺ helper cells producing distinct pattern of cytokines has provided a valuable framework for understanding how different effector populations of immune cells can be recruited in vivo during infection. In the view of most investigators, Th1 and Th2 cells produce factors that serve as their own autocrine factors and cytokines exerting suppressive activities on each other's development and activity. This concept intuitively explains the natural tendency of immune responses to become progressively polarized. However, several experimental observations appear difficult to rationalize with a simple, 'symmetrical' Th1/Th2 paradigm including those that Th1 cells do not produce their own growth factor; that both Th1 and Th2 cells can promote inflammatory responses; that interleukin-10 (IL-10) inhibits inflammatory responses in a Th1/Th2-independent fashion; that IL-10 promotes the development of Th1-type effector cells; and that IL-12 can amplify pre-established Th2 responses. The purpose of the present analysis is to provide a revised model for better understanding how cytokines regulate immune responses in vivo .     

Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells

PROBLEM: To examine whether normal pregnancy involves type 2 T-helper (Th2) immune condition or not. METHOD OF STUDY: We measured the percentage of Th0, Th1, and Th2 and the Th1/Th2 cell ratios of human peripheral blood and endometrial T cells using flow cytometry, which can analyze both the surface marker CD3, and intracellular cytokines, interleukin 4 (IL-4) and interferon gamma (IFNgamma). RESULTS: No significant differences were found in the percentages of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in the peripheral blood T cells of nonpregnant women and women in early pregnancy. On the other hand, the percentage of Th1 cells was highest during the proliferative phase of the endometrium, followed by the secretory phase and early pregnancy decidua. The percentage of Th2 cells was highest in early pregnancy decidua and lowest during the proliferative phase of the endometrium. The Th1/Th2 ratio was 147.48+/-96.68 during the proliferative phase of the endometrium, 37.74+/-21.33 during the secretory phase, and 1.31+/-0.48 in the early pregnancy decidua. CONCLUSIONS: These data indicate that Th1 cells predominate in the nonpregnant endometrium, especially during the proliferative phase, while Th2 cells predominate in early pregnancy decidua.     

支气管哮喘与Th1/Th2/Th17的相关性分析

支气管哮喘是一种涉及多种临床症状,例如咳嗽、气喘、呼吸困难等常见的呼吸系统疾病,其发病率之高严重威胁着人类的健康.哮喘的发病与遗传和环境都有着密切的联系,因其发病机制十分复杂至今尚未明了.众多的细胞及其细胞因子均参与了哮喘的发病过程,其中辅助性T细胞(Thelper,Th)及其亚群(Th1、Th2和Th17)已被证实与支气管哮喘的发生有着十分密切的关系.     

Development of Neonatal Th1/Th2 Function

Newborn animals generally mount poor T cell-mediated immune responses in vivo. As a result, neonates fall prey to infectious agents and diseases which have little impact on immunocompetent adult animals. For some time, it was believed that this phenomenon was due to an intrinsic inability of newborns to mount developmentally mature Th1 responses. Recent studies in mice have challenged that view; under certain conditions, adult-level Th1 function has been achieved in newborns. More often, however, neonates develop Th2-dominant responses. A major challenge in the field of developmental immunology is to understand why the ‘default’ response for neonates is Th2 function. Cell intrinsic as well as environmental influences may contribute to Th2 skewing in neonates.     

Toll样受体与Th1和Th2型免疫应答

Toll样受体是广泛表达在哺乳动物细胞表面的跨膜信号传导受体,其通过识别多种类型的病原体相关分子模式及一些内源性配体,激活天然免疫系统,同时通过诱导树突状细胞分化成熟,调控获得性免疫反应的建立。大多数TLRs的配体可诱导机体产生Th1型免疫应答,然而在某些条件下也可导致Th2型免疫应答的发生。弄清TLRs参与调节Th0分化的机制,可为今后在感染免疫、自身免疫、超敏反应等方面进行深入研究及相关疾病的治疗提供新的切入点。     

The Th1/Th2 balance in autoimmunity

The study of autoimmune disease in the context of T-helper type 1 (Th1) and T-helper type 2 (Th2) CD4⁺ T-cell responses demonstrates that the relative contribution of either T-cell type to the development of a particular autoimmune response can influence whether or not this response leads to clinical disease. Moreover, this influence can be quite different depending on whether the particular disease process is cell mediated or antibody mediated. Recent studies have demonstrated that the development of Th1 and Th2 responses may be significantly influenced by the costimulatory molecules recognized by responding CD4 T cells, and by other undefined factors in the genetic background. It has also been demonstrated that autoreactive Th2 CD4⁺ cells can regulate the activity of disease-causing Th1 CD4⁺ T cells in vivo. Control of autoimmune disease may thus be achieved by procedures that regulate the relative contribution of Th1/Th2 CD4 T cells to an autoimmune response.     

The paradigm of Th1 and Th2 cytokines

In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4⁺ T helper (Th)—and the CD8⁺ T cytotoxic (Tc)—cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1 or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologie disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.