CXCL12 (SDF-1α) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell–derived factor 1α), redirects the polarization of effector Th1 cells into CD4+CD25−Foxp3−interleukin (IL) 10high antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10–deficient mice. Anti–IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4+CD25−Foxp3−IL-10high, which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig–induced tolerance is IL-10 dependent, IL-10–independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases

Stigmatic attitudes towards mentally ill patients in Hungary between 2001 and 2015: results of a time-trend analysis

Background: Stigmatic attitudes towards people with the diagnosis of mental illness are widespread in the general public [1] and are the major obstacle for successful treatment, rehabilitation and reintegration of patients into the society [2]. Given the magnitude of this issue, and in the effort to develop effective anti stigma intervention programs, trend analysis studies were conducted, examining the changes in attitudes over the years [3]. The construct of social distance, which involves the desire to avoid contact with a particular group of people was commonly used to assess stigma. These studies have consistently reported that despite the improvement in mental health literacy of the public, social distance preferences concerning mentally ill patients have not changed over the last 20 years, and in some cases have even increased [3]. However, the number of studies using trend analysis is scarce and mainly limited to wealthier countries because such studies are both costly and time intensive. Consequently, most studies to date have been carried out in North Western Europe whereas data from Central and Eastern European countries, especially from former communist countries, is lacking [4,5]. Objective: In the face of underfinanced mental health system and the lack of any national anti-stigma programs or research, the aim of this study is to shed light into mental illness stigma in Hungary. More specifically, this study aimed to explore for the first time, potential changes concerning attitudes of the Hungarian population towards mentally ill patients. Method: National representative surveys (N=7605) of adults aged 18-53 years were carried out in Hungary in 2001, 2003, 2007 and 2015. An interview was conducted, asking for socio-demographic information and participants' desire for social distance from mentally ill patients, measured by Bogardus social distance scale. In order to put into context the stigmatic attitudes towards mentally ill patients, participants were also asked to report on their social distance preferences towards other minorities in the Hungarian society. Trend analysis was performed to examine the trends of social distance. Results: Time-trend analysis indicated a significant (positive) trend in public preferences for social distance towards more accepting attitudes during the years of 2001-2015. However, closer examination reveals that the effect size is very small (0.05) and the 2015 rejection level is still high (57%) compared to over 60% in both 2001 and 2003. Moreover, during a period of 15 years, mentally ill patients are among the three most rejected groups in the society (with only alcoholics and drug users being more rejected). Conclusions: As was found in other countries around the world, in Hungary as well, stigmatic attitudes towards mentally ill patients are highly prevalent, and have not changed over the last decade. While stressing a worrisome reality in Hungary, where no efforts to tackle mental illness stigma were done, this study also verifies the enormity of the stigma phenomenon. It is evident, maybe more than anything, that much effort is needed in Hungary, but also worldwide, in order to understand and defeat mental illness stigma

The paradoxical role of insight in mental illness: the experience of stigma and shame in schizophrenia, mood disorders, and anxiety disorders

This study examined the factor structure of the Hungarian version of the Birchwood Insight Scale (BIS) and analyzed its association with socio-demographics, diagnosis, internalized stigma, and shame using confirmatory factor analysis (CFA) with covariates. Mentally ill patients (N = 200) completed self-report questionnaires. CFA supported a two-factor structure. While previous hospitalizations and diagnosis were associated with insight, insight predicted higher internalized stigma and shame. Efforts to increase insight should be matter of importance in the wider spectrum of mental diagnoses. However, such efforts should be conducted with special care as further research is needed to understand the impact of insight on wellbeing

CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis

A single G protein–coupled receptor (GPCR) can activate multiple signaling cascades based on the binding of different ligands. The biological relevance of this feature in immune regulation has not been evaluated. The chemokine-binding GPCR CXCR3 is preferentially expressed on CD4+ T cells, and canonically binds 3 structurally related chemokines: CXCL9, CXCL10, and CXCL11. Here we have shown that CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, while CXCL11/CXCR3 binding induces an immunotolerizing state that is characterized by IL-10hi (Tr1) and IL-4hi (Th2) cells, mediated via p70 kinase/mTOR in STAT3- and STAT6-dependent pathways. CXCL11 binds CXCR3 with a higher affinity than CXCL10, suggesting that CXCL11 has the potential to restrain inflammatory autoimmunity. We generated a CXCL11-Ig fusion molecule and evaluated its use in the EAE model of inflammatory autoimmune disease. Administration of CXCL11-Ig during the first episode of relapsing EAE in SJL/J mice not only led to rapid remission, but also prevented subsequent relapse. Using GFP- expressing effector CD4+ T cells, we observed that successful therapy was associated with reduced accumulation of these cells at the autoimmune site. Finally, we showed that very low doses of CXCL11 rapidly suppress signs of EAE in C57BL/6 mice lacking functional CXCL11

Social rejection towards mentally ill people in Hungary between 2001 and 2015: Has there been any change?

Despite the improving mental health literacy of the public over recent years, people's attitudes towards people with the diagnosis of mental illness do not appeared to have changed. Long-term studies are scarce and mainly limited to Northwestern Europe. Given that no study has ever been carried out in Hungary, the present study examined attitudinal trends towards mentally ill people in the country, and evaluated its determinants using one item of the Social Distance Scale to assess social rejection towards others. National representative surveys of Hungarian adults were conducted in 2001, 2003, 2007 and 2015 (n = 7605). By means of interview and a self-administered questionnaire, socio-demographic information, preferences for social distance, and familiarity with mental illnesses were assessed. Trend analysis demonstrated that no meaningful change had occurred in the desire for social distance over a period of 15 years. Being a woman, having low education level, and lower familiarity with mental illnesses were all related to higher preferences for social distance. However, the explanatory power of these factors was very small (4.2%). As found in other countries, attitudes towards mentally ill people have not changed in Hungary. More effort is needed to understand better and overcome social rejection concerning mental illness

Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer’s and cat allergy

Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMVTT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMVTT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer’s, β-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficient in vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMVTT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMVTT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations

Apoptosis of Inflammatory Cells in Immune Control of the Nervous System: Role of Glia

Normal individuals have T lymphocytes capable of reacting to central nervous system (CNS) antigens such as myelin basic protein (MBP) (Martin et al., [1990]). In view of recent evidence indicating that T cells are much more cross-reactive than previously thought (Mason, [1998]), it is likely that these autoreactive T cells are often primed by exposure to cross-reacting environmental antigens. Indeed it has been shown that viral and bacterial peptides can activate myelin-reactive human T cells (Wucherpfennig and Strominger, [1995]; Hemmer et al., [1997]). Furthermore, normal healthy subjects experience surges of increased frequencies of circulating myelin-reactive T cells that might be driven by cross-reactive environmental antigens (Pender et al., [2000]). Such activated myelin-reactive T cells would be expected to enter the CNS in healthy individuals, because activated T cells of any specificity, including autoreactive T cells, enter the normal CNS parenchyma (Wekerle et al., [1986]; Hickey et al., [1991]). If CNS-reactive T cells survive in the CNS, they have the potential to attack the CNS, either directly or through the recruitment of other inflammatory cells, and thus lead to CNS damage such as demyelination. Therefore, the physiological control of autoreactive T cells in the CNS is likely to have an important role in preventing the development of autoimmune CNS disorders such as multiple sclerosis (MS) (Pender, [1998]). T-cell apoptosis in the CNS has been proposed to be an important mechanism for controlling autoimmune attacks on the CNS (Pender et al., [1992]; Schmied et al., [1993]). Although other mechanisms, such as immune deviation (Wenkel et al., [2000]), may possibly also contribute to the control of the immune response in the CNS, this review will focus on T-cell apoptosis in the CNS and the role of glia in this process

Dissecting the Autocrine and Paracrine Roles of the CCR2-CCL2 Axis in Tumor Survival and Angiogenesis

The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX3CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2−/−, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX3CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX3CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx3cr1gfp), together with the CD45.1 congene. Using this system we dissected the selective contribution of CX3CR1+CCR2+ cells, which comprise only about 7% of CD11b+ BM cells, to tumor development and angiogenesis. Showing that aside for their direct pro-angiogenic effect they are essential for the recruitment of other CD11b+ cells to the tumor site. We further show that the administration of CCR2-Ig, that selectively and specifically neutralize CCL2, to mice in which CCR2 is expressed only on tumor cells, further suppressed tumor development, implicating for the key role of this chemokine supporting tumor survival in an autocrine manner. This further emphasizes the important role of CCL2 as a target for therapy of cancer diseases

Mechanisms of immunological tolerance in central nervous system inflammatory demyelination.

Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti-inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long-lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance by promoting the generation of regulatory T cells and inducing apoptosis of pathogenic T cells. Safe and effective methods of inducing long-lasting immune tolerance are essential for the treatment of multiple sclerosis. By exploring tolerogenic mechanisms, new strategies can be devised to strengthen the regulatory, anti-inflammatory cell populations thereby weakening the pathogenic, pro-inflammatory cell populations

Immune Responses Elicited in Tertiary Lymphoid Tissues Display Distinctive Features

During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also “stochastic,” since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts