Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation

The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4(+) T lymphocyte subpopulation in peripheral blood, phenotypically CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4(+) responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high) Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo.     

Evaluation of CD40, its ligand CD40L and Bcl-2 in psoriatic patients

Psoriasis is a chronic, recurrent, inflammatory disease. Recent investigations indicate an autoimmune pathogenesis of the disease. Apoptosis plays an important role in the regulation of immune mechanisms in many autoimmune diseases. Although CD40, CD40L, and Bcl-2 have already been studied in psoriatic skin lesions, little is known about their circulating forms. The aim of the present study was to evaluate the serum concentrations of Bcl-2, soluble CD40 and CD40L in psoriatic patients. The study was performed using ELISA kits in 39 psoriatic patients before treatment and after two weeks of topical ointment. Data was analyzed with respect to severity of psoriasis, duration of the disease, and coexisting psoriatic arthritis. Our results revealed that serum concentrations of soluble CD40 and CD40L before and after treatment were significantly higher (p < 0.01 and p < 0.001) in patients with psoriasis compared to the control group. Topical treatment of psoriatic lesions with dithranol ointment failed to decrease serum of CD40 and CD40L, which has not been described until now. There was no significant difference in serum Bcl-2 concentration between the compared groups. We did not find significant differences in serum concentrations of Bcl-2, CD40 or CD40L between patients with mild or severe psoriasis, nor any correlation between disease duration and the presence of psoriatic arthritis symptoms. Our data indicates upregulation of the CD40/CD40L system in psoriatic patients despite topical treatment and suggests their possible role in the pathogenesis of psoriasis.     

In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin

Keratinocytes contribute to cutaneous immune responses through the expression of cytokines. We investigated whether human keratinocytes can express IL-23, a newly defined IFN-gamma-inducing cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12. Cultured keratinocytes from normal and lesional psoriatic skin were found to express constitutively mRNA for both subunits of IL-23. Low but significant levels of the heterodimeric IL-23 protein could be detected in cell lysates and supernatants from stimulated keratinocytes by immunoblotting and ELISA. Functional analysis showed that these low levels of keratinocyte-derived IL-23 were sufficient to enhance the IFN-gamma production by memory T cells. Immunostaining of skin sections confirmed expression of both subunits of IL-23 by keratinocytes in situ and also revealed expression of this cytokine in the dermal compartment. IL-23 expression was significantly higher in psoriatic lesional skin, compared with normal and psoriatic nonlesional skin. The immunostained preparations of cultured cells and IL-23 levels in culture supernatants did not show any difference between normal and psoriatic keratinocytes indicating no intrinsic aberration of IL-23 expression in keratinocytes from psoriatic skin. Double staining of cytospin preparations demonstrated that IL-23 p19 is also expressed by epidermal Langerhans cells, dermal dendritic cells, and macrophages. Psoriasis is a chronic inflammatory skin disease mediated by IFN-gamma-expressing type 1 memory T cells. As IL-23 is important to activate memory T cells to produce IFN-gamma, its augmented expression of IL-23 by keratinocytes and cutaneous APC may contribute to the perpetuation of the inflammation process in this disease.     

Epigenetic Control of Immunity

Immunity relies on the heterogeneity of immune cells and their ability to respond to pathogen challenges. In the adaptive immune system, lymphocytes display a highly diverse antigen receptor repertoire that matches the vast diversity of pathogens. In the innate immune system, the cell''s heterogeneity and phenotypic plasticity enable flexible responses to changes in tissue homeostasis caused by infection or damage. The immune responses are calibrated by the graded activity of immune cells that can vary from yeast-like proliferation to lifetime dormancy. This article describes key epigenetic processes that contribute to the function of immune cells during health and disease.     

Heat Shock Protein-Derived T-Cell Epitopes Contribute to Autoimmune Inflammation in Pediatric Crohn's Disease

Pediatric Crohn''s disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn''s disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF〈 and IFN© induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.     

IL-23 Induces Atopic Dermatitis-Like Inflammation Instead of Psoriasis-Like Inflammation in CCR2-Deficient Mice

Psoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. IL-23 is expressed in psoriatic skin, and IL-23 injected into the skin of mice produces IL-22-dependent dermal inflammation and acanthosis. The chemokine receptor CCR2 has been implicated in the pathogenesis of several inflammatory diseases, including psoriasis. CCR2-positive cells and the CCR2 ligand, CCL2 are abundant in psoriatic lesions. To examine the requirement of CCR2 in the development of IL-23-induced cutaneous inflammation, we injected the ears of wild-type (WT) and CCR2-deficient (CCR2^−/−) mice with IL-23. CCR2^−/− mice had increased ear swelling and epidermal thickening, which was correlated with increased cutaneous IL-4 levels and increased numbers of eosinophils within the skin. In addition, TSLP, a cytokine known to promote and amplify T helper cell type 2 (Th2) immune responses, was also increased within the inflamed skin of CCR2^−/− mice. Our data suggest that increased levels of TSLP in CCR2^−/− mice may contribute to the propensity of these mice to develop increased Th2-type immune responses.     

Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system

Understanding of the innate immune response to viral infections is rapidly progressing, especially with regards to the detection of DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a large dsDNA virus that is responsible for three human diseases: Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. The major target cells of KSHV (B cells and endothelial cells) express a wide range of pattern recognition receptors (PRRs) and play a central role in mobilizing inflammatory responses. On the other hand, KSHV encodes an array of immune evasion genes, including several pirated host genes, which interfere with multiple aspects of the immune response. This review summarizes current understanding of innate immune recognition of KSHV and the role of immune evasion genes that shape the antiviral and inflammatory responses.     

甲状腺激素对适应性免疫细胞的作用

摘要：甲状腺激素（Thyroid hormones,THs）参与免疫功能的调节,在固有免疫和适应性免疫中发挥着重要作用。THs异常分泌所致的免疫功能失调被认为参与了格雷夫斯病和桥本甲状腺炎等自身免疫性疾病的发生发展。目前,THs在固有免疫细胞（中性粒细胞、巨噬细胞、树突状细胞、自然杀伤细胞、肥大细胞）中的作用已得到了较好的阐明,但THs对适应性免疫细胞（T淋巴细胞与B淋巴细胞）的影响等方面的研究仍未引起足够的重视。因此,本研究从适应性免疫细胞的角度出发,重点讨论了THs对这些细胞的发育、分化及功能等方面的影响,为进一步理解THs调节免疫功能的作用提供新视角。     

Insights into T‐cell dysfunction in Alzheimer's disease

T cells, the critical immune cells of the adaptive immune system, are often dysfunctional in Alzheimer''s disease (AD) and are involved in AD pathology. Reports highlight neuroinflammation as a crucial modulator of AD pathogenesis, and aberrant T cells indirectly contribute to neuroinflammation by secreting proinflammatory mediators via direct crosstalk with glial cells infiltrating the brain. However, the mechanisms underlying T‐cell abnormalities in AD appear multifactorial. Risk factors for AD and pathological hallmarks of AD have been tightly linked with immune responses, implying the potential regulatory effects of these factors on T cells. In this review, we discuss how the risk factors for AD, particularly Apolipoprotein E (ApoE), Aβ, α‐secretase, β‐secretase, γ‐secretase, Tau, and neuroinflammation, modulate T‐cell activation and the association between T cells and pathological AD hallmarks. Understanding these associations is critical to provide a comprehensive view of appropriate therapeutic strategies for AD.     

Neurotrophins in bronchial asthma

Allergic bronchial asthma (BA) is characterized by chronic airway inflammation, development of airway hyperreactivity and recurrent reversible airway obstruction. T-helper 2 cells and their products have been shown to play an important role in this process. In contrast, the mechanisms by which immune cells interact with the cells residing in lung and airways, such as neurons, epithelial or smooth muscle cells, still remains uncertain. Sensory and motor neurons innervating the lung exhibit a great degree of functional plasticity in BA defined as 'neuronal plasticity'. These neurons control development of airway hyperresponsiveness and acute inflammatory responses, resulting in the concept of 'neurogenic inflammation'. Such quantitative and/or qualitative changes in neuronal functions are mediated to a great extent by a family of cytokines, the neurotrophins, which in turn are produced by activated immune cells, among others in BA. We have therefore developed the concept that neurotrophins such as nerve growth factor and brain-derived neurotrophic factor link pathogenic events in BA to dysfunctions of the immune and nervous system.     

The expanding realm of heterologous immunity: friend or foe?

Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co-infecting pathogens has been referred to as 'heterologous immunity' and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross-reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross-react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a host's history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses.     

Psoriatic arthritis: from pathogenesis to therapy

Psoriatic arthritis is a multigenic autoimmune disease that involves synovial tissue, entheseal sites and skin, and that may result in significant joint damage. Although there are no diagnostic tests for psoriatic arthritis, research has identified consistent features that help to distinguish the condition from other common rheumatic diseases. Comparison of HLA-B and HLA-C regions in psoriatic arthritis with those in psoriasis without joint involvement demonstrates significant differences, such that psoriatic arthritis cannot be viewed simply as a subset of genetically homogeneous psoriasis. T-cell receptor phenotypic studies have failed to identify antigen-driven clones, and an alternative hypothesis for CD8 stimulation involving innate immune signals is proposed. Finally, imaging studies have highlighted entheseal involvement in psoriatic arthritis, and it is possible that entheseal-derived antigens may trigger an immune response that is critically involved in disease pathogenesis.     

A Novel Method for the Culture and Polarized Stimulation of Human Intestinal Mucosa Explants

Few models currently exist to realistically simulate the complex human intestine''s micro-environment, where a variety of interactions take place. Proper homeostasis directly depends on these interactions, as they shape an entire immunological response inducing tolerance against food antigens while at the same time mounting effective immune responses against pathogenic microbes accidentally ingested with food.Intestinal homeostasis is preserved also through various complex interactions between the microbiota (including food-associated beneficial bacterial strains) and the host, that regulate the attachment/degradation of mucus, the production of antimicrobial peptides by the epithelial barrier, and the "education" of epithelial cells'' that controls the tolerogenic or immunogenic phenotype of unique, gut-resident lymphoid cells'' populations. These interactions have been so far very difficult to reproduce with in vitro assays using either cultured cell lines or peripheral blood mononuclear cells. In addition, mouse models differ substantially in components of the intestinal mucosa (mucus layer organization, commensal bacteria community) with respect to the human gut. Thus, studies of a variety of treatments to be brought in the clinics for important stress-related or pathological conditions such as irritable bowel syndrome, inflammatory bowel disease or colorectal cancer have been difficult to carry out.To address these issues, we developed a novel system that enables us to stimulate explants of human intestinal mucosa that retain their in situ conditioning by the host microbiota and immune response, in a polarized fashion. Polarized apical stimulation is of great importance for the outcome of the elicited immune response. It has been repeatedly shown that the same stimuli can produce completely different responses when they bypass the apical face of the intestinal epithelium, stimulating epithelial cells basolaterally or coming into direct contact with lamina propria components, switching the phenotype from tolerogenic to immunogenic and causing unnecessary and excessive inflammation in the area.We achieved polarized stimulation by gluing a cave cylinder which delimited the area of stimulation on the apical face of the mucosa as will be described in the protocol. We used this model to examine, among others, differential effects of three different Lactobacilli strains. We show that this model system is very powerful to assess the immunomodulatory properties of probiotics in healthy and disease conditions.     

Melanoma cancer vaccines and anti-tumor T cell responses

Melanoma is a disease which has been shown to be responsive to immune intervention. This has been suggested by reports of spontaneous responses of metastatic disease with strong immune infiltrates, and supported by recent data correlating clinical response after IFNalpha treatment with development of generalized autoimmunity. Since the identification of melanoma-associated tumor antigens, many groups have performed clinical trials to take advantage of this discovery with melanoma-specific cancer vaccines. These trials, in which multiple antigen delivery strategies have been tested in hundreds of patients, have demonstrated that these vaccines are safe, immunogenic, and yield a low frequency of objective clinical responses. The ability to perform careful immunological monitoring has allowed important insights into the nature of the anti-tumor immunity generated by these vaccinations. While many trials have found that the absolute frequency of T cells specific for a vaccine-encoded antigen are a marker of immunization, it does not correlate with objective clinical response. Induction of broad immunity to multiple tumor antigens, taking advantage of cross-reactive T cells and activation of persistent T cells may be more important. Harnessing additional modes of amplifying immune responses (lymphodepletion, cytokine support, inhibition of negative immune self-regulation) are now being tested and should improve clinical responses from 5% to 10% complete response seen currently.     

Antitumor activity and action mechanisms of Lactobacillus casei through the regulation of immune responses

Lactobacillus casei strain Shirota (LcS) has been demonstrated to have beneficial effects in numerous disease models, especially murine autoimmune disease and carcinogenesis models, via host immune modulation. It has also been reported that LcS induced recovery of the host immune responses that were decreased by treatment with carcinogens, and that augmented the natural killer activity and T cell functions of host immune cells. After LcS is ingested by the host, it is incorporated into M cells in Peyer's patches (PP) and digested to form active components. In PP, macrophages or dendritic cells that phagocytosed LcS gained ability to produce tumor necrosis factor-alpha. The components of LcS digested in PP were then recognized through toll-like receptor 2 in macrophages, resulting in the production of several cytokines which elicit varied responses in host immune cells. Also, it was observed by 2D-PAGE analyses that the expression level and/or the phosphorylation of some proteins in PP and mesenteric lymph nodes were definitely altered after the ingestion of LcS, providing more evidence of cellular responses.     

Isolation of Functional Cardiac Immune Cells

Cardiac immune cells are gaining interest for the roles they play in the pathological remodeling in many cardiac diseases.^1-5 These immune cells, which include mast cells, T-cells and macrophages; store and release a variety of biologically active mediators including cytokines and proteases such as tryptase.^6-8 These mediators have been shown to be key players in extracellular matrix metabolism by activating matrix metalloproteinases or causing collagen accumulation by modulating the cardiac fibroblasts'' function.^9-11 However, available techniques for isolating cardiac immune cells have been problematic because they use bacterial collagenase to digest the myocardial tissue. This technique causes activation of the immune cells and thus a loss of function. For example, cardiac mast cells become significantly less responsive to compounds that cause degranulation.¹² Therefore, we developed a technique that allows for the isolation of functional cardiac immune cells which would lead to a better understanding of the role of these cells in cardiac disease.^{13, 14}This method requires a familiarity with the anatomical location of the rat''s xiphoid process, axilla and falciform ligament, and pericardium of the heart. These landmarks are important to increase success of the procedure and to ensure a higher yield of cardiac immune cells. These isolated cardiac immune cells can then be used for characterization of functionality, phenotype, maturity, and co-culture experiments with other cardiac cells to gain a better understanding of their interactions.     

Selenium and Psoriasis

Psoriasis is a chronic, immune-mediated skin disease characterized by production of reactive oxygen species due to the activation of tumor necrosis factor alpha (TNF-??), which is thought to be an important factor in inducing and maintaining psoriatic lesions. As an external factor, ultraviolet B (UVB) radiation stimulates TNF-?? production and secretion by human keratinocytes in vitro and can also reach the upper dermis and suppress endothelial cells in vitro. The selenium level in psoriatic patients has been found to be lower than expected, but studies on its role in the pathogenesis of the disease are scarce. Selenium can influence immune response by changing the expression of cytokines and their receptors or by making immune cells more resistant to oxidative stress. It was reported that selenium supplementation had inhibitory effects on TNF-?? levels in patients with psoriasis, but the details are not completely elucidated. Selenium compounds are also known to prevent the in vitro release of UVB-induced proinflammatory cytokines by inhibition of mRNA in human keratinocytes. In the present review, the protective role of selenium in oxidative stress, lesions, and immune system regulation in patients with psoriasis is summarized.