Cells In Human Autoimmune Diseases Research Articles

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity.

CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.

Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ−IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases.

Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System.

It is being increasingly recognized that a dysregulation of the immune system plays a vital role in neurological disorders and shapes the treatment of the disease. Aberrant T cell responses, in particular, are key in driving autoimmunity and have been traditionally associated with multiple sclerosis. Yet, it is evident that there are other neurological diseases in which autoreactive T cells have an active role in pathogenesis. In this review, we report on the recent progress in profiling and assessing the functionality of autoreactive T cells in central nervous system (CNS) autoimmune disorders that are currently postulated to be primarily T cell driven. We also explore the autoreactive T cell response in a recently emerging group of syndromes characterized by autoantibodies against neuronal cell-surface proteins. Common methodology implemented in T cell biology is further considered as it is an important determinant in their detection and characterization. An improved understanding of the contribution of autoreactive T cells expands our knowledge of the autoimmune response in CNS disorders and can offer novel methods of therapeutic intervention.

Regulatory B cells in human autoimmune diseases

B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in clinical research using human samples.

Interleukin-17 in human inflammatory diseases.

Human Th17 pro-inflammatory cells are currently defined as cells that produce IL-17A and F, tumor necrosis factor (TNF)-α, IL-6, IL-21, IL-22 and IL-23. Recently discovered related molecules are forming a family of cytokines, the IL-17 family, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The associated receptors for the IL-17 family identified are IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. This review introduces the roles of IL-17 and Th17 cells in human autoimmune diseases. Studies have shown that T cells with inflammatory effects on epithelial, endothelial and fibroblast cells express IL-17. Th17 cells are supposed to be involved in various autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases. Base on the biologic functions and regulation, IL-17 has regulatory roles in host defense and chronic inflammation which result in tissue damage and autoimmunity. So the IL-17 links links innate and adaptive immunity and has both beneficial and pathological effects on the immune system. This paper will focus on the possible roles of IL-17 in autoimmune diseases, a fundamental player in immune regulation.

Regulatory B cells in autoimmune diseases.

B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4(+) T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B cells are defined as regulatory B (Breg) cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.

Identification of T helper type 1–like, Foxp3+ regulatory T cells in human autoimmune disease

CD4(+)CD25(high)CD127(low/-) forkhead box p3 (Foxp3)(+) regulatory T cells (T(reg) cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (T(H)1)-like, interferon-γ (IFN-γ)-secreting Foxp3(+) T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-β, the frequency of IFN-γ(+)Foxp3(+) T cells is similar to that in healthy control subjects. In vitro, human T(reg) cells from healthy subjects acquire a T(H)1-like phenotype when cultured in the presence of interleukin-12 (IL-12). T(H)1-like T(reg) cells show reduced suppressive activity in vitro, which can partially be reversed by IFN-γ-specific antibodies or by removal of IL-12.

Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.

A lack of regulatory T (T(Reg)) cells that express CD4, CD25 and forkhead box P3 (FOXP3) results in severe autoimmunity in both mice and humans. Since the discovery of T(Reg) cells, there has been intense investigation aimed at determining how they protect an organism from autoimmunity and whether defects in their number or function contribute to the development of autoimmunity in model systems. The next phase of investigation - that is, to define the role that defects in T(Reg) cells have in human autoimmunity - is now underway. This Review summarizes our progress so far towards understanding the role of CD4(+)CD25(+)FOXP3(+) T(Reg) cells in human autoimmune diseases and the impact that this knowledge might have on the diagnosis and treatment of these diseases.

Natural killer cells in human autoimmune diseases

Natural killer (NK) cells have been implicated in tumour surveillance and in the early control of several microbial infections. In autoimmune disease their involvement in these processes has been evaluated in animal models, with conflicting results. Both a disease-controlling and a disease-promoting role have been suggested. In human autoimmune disease only a few studies, mainly descriptive, have demonstrated qualitative and quantitative modification of NK cells. These changes were observed on blood- or tissue-infiltrating NK cells. Taken together with our expanding knowledge of the genetical variability of NK cell receptors and NK cell physiology, these findings pave the way for the dissection of the role of NK cells in human autoimmune diseases. NK cells may be directly involved in these diseases through their potential autoreactivity or through their interaction with dendritic cells, macrophages or T lymphocytes, thereby inducing excessive inflammation or favouring the adaptive autoimmune response. Thus, NK cells may be implicated in the onset, the maintenance or the progression of autoimmune diseases. Some reports also suggest the involvement of NK cells in the treatment of human autoimmune disease by biotherapies. All these observations suggest that NK cells are involved in the complex processes of autoimmune diseases. Nevertheless, further careful analysis of NK cells at different steps of these diseases, in different tissues and through combined genetical and functional studies will contribute to a better understanding of their role in autoimmune diseases. This knowledge might allow the development of new therapeutic strategies based on NK cells for the treatment of some autoimmune diseases.

Th17 cells in autoimmune arthritis

The role of Th17 cells in the pathogenesis of human autoimmune diseases is elusive. To gain insights into the role of Th17 cells in human autoimmune diseases, the authors analysed...

Mixed results with modulation of TH-17 cells in human autoimmune diseases

The outcomes of clinical trials provide the most convincing data to clarify the role of particular cytokines in the pathogenesis of human diseases. The immunology community, for a variety of practical reasons, spends most of its research time and funds on studies in model systems, mainly mice. In this perspective I discuss results of clinical trials assessing the effect of blocking the differentiation and/or function of interleukin-17-producing CD4(+) T cells on human autoimmune disease, and devote more limited attention to corroborating preclinical studies from animal models. Thus far, these outcomes in human trials have been mixed, with notable success in psoriasis and Crohn's disease but a negative result in relapsing-remitting multiple sclerosis.

Increased Th17 cell activity in patients with early rheumatoid and psoriatic arthritis (137.30)

Abstract To gain insights into the role of Th17 cells in human autoimmune diseases, we analyzed Th17 cell biology in patients with ongoing inflammatory autoimmune arthritis (e.g., rheumatoid (RA) and psoriatic arthritis (PsA)), and for control in patients with osteoarthritis and healthy individuals. Frequencies of Th17 cells were significantly elevated in the blood of patients with early, treatment-naive RA and PsA. Moreover, upon activation in vitro, CD4 T cells from the patients yielded enhanced Th17 frequencies and elevated levels of IL-17. In contrast, Th1 frequencies and IFNγ production were not different between patients and controls. As the frequencies of Th17 cells and IL-17 production, but not of Th1 cells or IFNγ production correlated with disease activity, early inflammation in RA and PsA is characterized by both, selectively enhanced Th17 cell generation and increased Th17 cell activity. Of interest for the pathogenesis of autoimmune arthritis, CD4 T cells from early RA and PsA patients were partially resistant to the inhibitory capacity of IL-4 and IFNγ on Th17 generation, suggesting a potential mechanism underlying the breakdown of peripheral tolerance at disease onset. However, as effective immunosuppressive treatment was associated with normalization of Th17 cell activity in the patients, the data further suggest that Th17 cells might also contribute to sustained autoimmune inflammation in RA and PsA.

How to cope with pathogenic long-lived plasma cells in autoimmune diseases

Recently, it has been shown that plasma cells secreting antibodies can be long lived and as such constitute an independent component of immunological memory. They are generated in the context...

Decreased CD4+CD25+bright T cells in peripheral blood of patients with primary Sjögren's syndrome

CD4+CD25+bright T cells played a crucial role in the suppression of immune response. Recently, decreased levels of CD4+CD25+bright T cells in the peripheral blood of patients with systemic lupus erythematosus were reported, suggesting the potential role of CD4+CD25+bright T cells in human autoimmune diseases. Primary Sjögren's syndrome (pSS) is another common human systemic autoimmune disease. The present study aimed to investigate the levels of CD4+CD25+bright T cells in pSS and to correlate their levels with some biomarkers of inflammation and immune activation. Thirty-three patients with pSS and 35 age- and sex-matched normal individuals were enrolled in the study. The flowcytometric method was applied in the measurement of CD4+CD25+bright T cells. The results showed that patients with pSS had statistically lower levels of CD4+CD25+bright T cells than normal controls, expressed either as absolute cell numbers (mean+/-SD: 47.07+/-25.53 cells/mm3 versus 79.55+/-34.56 cells/mm3, P<0.001) or as percentages of peripheral blood mononuclear cells (mean+/-SD: 2.79+/-1.06% versus 3.84+/-1.42%, P<0.001) or as percentages of CD4+ T cells (mean+/-SD: 7.85+/-2.62% versus 11.68+/-3.78%, P<0.005). Moreover, there were statistically significant inverse correlations between the levels of CD4+CD25+bright T cells and some parameters of inflammation or immune activation including erythrocyte sedimentation rate, C-reactive protein, IgG and rheumatoid factors. The result suggested that CD4+CD25+bright T cells were likely to play anti-inflammatory and immunosuppressive roles in the pathogenesis of pSS. However, the exact functions of decreased circulating CD4+CD25+bright T cells in pSS need further elucidated.

Regulatory T cells in human autoimmune diseases

In the most simplistic terms, immune tolerance can be envisioned as a balance with autoreactive cells that arise naturally in all individuals on one side and regulatory mechanisms designed to counter those autoreactive processes on the other. A tilt of the balance toward the autoreactive side, either by increasing the number or function of autoreactive cells or by diminishing regulatory mechanisms, is manifested as autoimmunity. In contrast, tilting of the balance toward increased regulation could conceivably cause immunodeficiency. Regulatory T cells (T(REG)), and particularly the naturally arising CD4(+)CD25(+) subset of T(REG) cells, provide a substantial component of the autoimmune counterbalance. The identification of forkhead box P3 (FOXP3) as a critical determinant of CD4(+)CD25(+) T(REG) development and function has provided new opportunities and generated expanded interest in studying the delicate balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. Identification of both human and mouse syndromes in which FOXP3 is mutated, and consequently CD4(+)CD25(+) T(REG) cells are absent, has led to a rapid accumulation of knowledge regarding T(REG) development and function over the past 5 years. The recent development of antibody reagents to specifically identify CD4(+)CD25(+) T(REG) cells by their FOXP3 expression has provided new tools to identify these elusive cells and investigate their role in human disease. This review will focus on the current state of knowledge regarding the role of T(REG) in human autoimmune diseases and on specific human immunodeficiencies that provide interesting models of autoimmunity.

Imbalance of regulatory T cells in human autoimmune diseases

The breakdown of mechanisms assuring the recognition of self and non-self is a hallmark feature of autoimmune diseases. In the past 10 years, there has been a steadily increasing interest in a subpopulation of regulatory T cells, which exert their suppressive function in vitro in a contact-dependent manner and preferentially express high levels of CD25 and forkhead and winged-helix family transcription factor forkhead box P3 (FOXP3) (TREGs). Recent findings of changed prevalences and functional efficiencies indicate that these TREGs play a unique role in autoimmune diseases. Clinical findings in patients with mutated FOXP3 genes and a specific polymorphism in the promotor region of FOXP3 also support the role of FOXP3 as a 'master control gene' in the development and functioning of TREGs. Both altered generation of TREGs and insufficient suppression of inflammation in autoimmune diseases are considered to be crucial for the initiation and perpetuation of disease. TREG-related somatic cell therapy is considered as an intriguing new intervention to approach autoimmune diseases.

Aberrant gene expression by CD25+CD4+ immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene

Transgenic rats expressing the env-pX gene of human T cell leukemia virus type-I under the control of the viral long terminal repeat promoter (env-pX rats) developed systemic autoimmune diseases. Prior to disease manifestation, the immunosuppressive function of CD25(+)CD4(+) T (T-reg) cells was impaired in these rats. Since T cell differentiation appeared to be disordered in env-pX rats, we assumed that the impairment of T-reg cells might be caused by an abortive differentiation in the thymus. However, reciprocal bone marrow transfers between env-pX and wild-type rats revealed that direct effects of the transgene unrelated to the thymus framework induced the abnormality of T-reg cells. To identify molecular changes, comparative analyses were done between env-pX and wild-type T-reg cells. Expression of the Foxp3 gene and cell-surface markers supported a naive phenotype for env-pX T-reg cells. Array analyses of gene expression showed some interesting profiles, e.g. up-regulation of genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in env-pX T-reg cells. Additionally, expression of the suppressor of cytokine signaling (SOCS) family genes, which inhibit the JAK/STAT signals, was extremely low in env-pX T-reg cells. These findings suggest that the transgene may mediate the down-regulation of the SOCS family genes and that subsequent excess signals through the JAK/STAT pathways may result in the loss of function of env-pX T-reg cells. We suggest that investigation of the pathology of T-reg cells in our autoimmune-prone rat model may aid in understanding the roles of T-reg cells in human autoimmune diseases.

CD4 CD25 high regulatory T cells are not impaired in patients with primary Sjögren's syndrome

In animal models of autoimmunity, CD4 CD25 high T cells play a key role in the control of the autoimmune process. Few studies have investigated the role of these cells in human autoimmune diseases. We aimed to investigate CD4 CD25 high T cells in the peripheral blood of patients with primary Sjögren's syndrome (pSS). The proportion of blood CD4 CD25 high T cells was determined by flow cytometry in 21 patients with pSS as determined by the American–European consensus group criteria and two groups of controls (18 patients with lumbar back pain of mechanical origin and 15 healthy blood donors). The suppressive function of CD4 CD25 cells was assessed using co-culture assays. The Vbeta repertoire of CD4 CD25 T cells was examined by flow cytometry. The proportion of CD4 CD25 T cells depended on age in patients and controls. In an age-matched comparison, no significant difference was observed in the proportion of total CD4 CD25 low T cells between patients with pSS and controls ( P=0.36). In contrast, the pool of CD4 CD25 high was significantly increased in patients with pSS (8.5% vs 4.1% in controls, P=0.04). There was a slight but not significant higher proportion of CD4 CD25 high cells in patients with a more active disease. CD4 CD25 T cells in patients with pSS effectively suppressed the proliferation of CD4 CD25 − autologous responder T cells. The Vbeta repertoire of regulatory T cells from patients with pSS was polyclonal and was not significantly restricted as compared with that in controls. Functional CD4 CD25 high regulatory cells are increased in patients with established pSS, through a reactive feedback, despite ongoing autoimmunity. These results suggest that pSS does not occur as a result of reduced level of CD4 CD25 high regulatory T cells, nor as a defect of inhibition of proliferation of responder cells.

Antigen-based immunointervention in human autoimmune diseases

Antigen administration can ameliorate autoimmune disease via various mechanisms, including deletion of autoreactive cells, induction of regulatory T cells, and deviation to non-pathogenic or protective responses. All these mechanisms of immunointervention have been successfully used to prevent and sometimes treat experimental models of autoimmune diseases. Based on these results, expectations have been raised for exploiting similar strategies to inhibit pathogenic autoreactive T cells in human autoimmune diseases. Among them, mucosal administration of autoantigen is an attractive mode of immunointervention still awaiting demonstration of clinical efficacy in human autoimmune diseases. A further step in this direction is now provided by the clear-cut immune deviation observed following oral administration of a disease-related peptide to rheumatoid arthritis patients, leading to inhibition of Th1 while enhancing Th2 and possibly Foxp3-positive regulatory T cells.

Potential of targeting natural killer T cells for the treatment of autoimmune diseases

Natural killer (NK) T cells emerge as unique lymphocytes subsets implicated in the regulation of autoimmunity. Abnormalities in the numbers and functions of NKT cells have been observed in patients with diverse autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for the development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the nonpolymorphic MHC class I-like protein, CD1d. Recently, vigorous activation of NKT cells by synthetic glycolipids such as α-galactosylceramide (α-GC) or its sphingosine truncated derivative OCH have been shown to suppress autoimmune diseases such as experimental auto-immune encephalomyelitis (EAE), diabetes in nonobese diabetic (NOD) mice, and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. In this review, we examine the potential roles of NKT cells in the pathogenesis of autoimmune disease regulation, and the recent advances in glycolipid therapy for autoimmune disease models. In addition, we summarize studies suggesting a role for NKT cells in human autoimmune disease, and discuss the potential of targeting NKT cells for the treatment of autoimmunity.