Mechanism of granuloma formation in sarcoidosis.

PURPOSE OF REVIEW: The formation of noncaseating granuloma is a hallmark of pulmonary sarcoidosis. This review summarizes recent progress made to explain the cellular dynamics within the granuloma structure that may considerably differ between the two clinically distinct variants, that is, acute and chronic sarcoidosis. RECENT FINDINGS: Compelling evidence exists that in acute but not chronic sarcoidosis CD4 T lymphocytes specifically recognizing the auto-antigen vimentin on human leukocyte antigen-DR3 molecules accumulate in sarcoid granuloma. These so-called TH17.1 cells produce high amounts of the TH17-related cytokines interleukin-17 (IL-17) and IL-22 in addition to interferon-γ. Moreover, regulatory T cells from patients with acute sarcoidosis are ICOS, providing a mechanistic link to the comparably high concentration of IL-10 exclusively found in the airways of these patients. Next to obvious differences in T effector cell and Treg subsets, alveolar macrophages harbor a functional mitochondrial system in acute sarcoidosis patients, while this system is impaired in patients with chronic disease. SUMMARY: We provide a comprehensive update on the cellular components and their functional implications in sarcoid granuloma formation, with special emphasis on the specific characteristics of granuloma in acute versus chronic sarcoidosis. Moreover, the specific antigens thought to be involved in both forms of the disease are discussed.

Soluble CD200 Correlates With Interleukin-6 Levels in Sera of COPD Patients: Potential Implication of the CD200/CD200R Axis in the Disease Course.

BACKGROUND: COPD represents a multifactorial lung disorder with high morbidity and mortality. Despite intensive research concerning the underlying disease mechanisms, the involvement of the CD200/CD200R axis in supporting or preventing the onset of COPD has not yet been addressed. Since the CD200/CD200R axis is crucially implicated in the maintenance of pulmonary immune homeostasis, we hypothesized that it might be involved in controlling the onset of COPD. METHODS: To address this, we analyzed the serum samples from COPD patients and normal controls for soluble (s) CD200 and correlated the data to COPD-relevant clinical parameters. In addition, basic studies were conducted in CD200-deficient and wild-type mice in which COPD-like inflammation was induced with elastase/LPS followed by lung and serum component analysis. RESULTS: We observed a positive correlation between serum sCD200 and IL-6 levels as well as a trend toward a negative correlation of sCD200 with vitamin D3 in COPD patients. Further investigations in mice revealed that despite elevated serum concentration of MMP-9 in CD200KO mice, the early onset of COPD-like lung inflammation was similar in CD200-deficient and wild-type animals in terms of immune cell infiltration, emphysematous changes, and mucus overproduction. CONCLUSIONS: While our murine studies suggest that the co-inhibitory molecule CD200 does not appear to play a prominent role in the early onset of COPD-like features, correlation of sCD200 serum levels with COPD-related parameters in humans with established disease revealed that the CD200/CD200R axis may be mechanistically linked to the disease course in COPD patients.

Abscisic Acid: A Phytohormone and Mammalian Cytokine as Novel Pharmacon with Potential for Future Development into Clinical Applications.

The isoprenoid stress-associated phytohormone abscisic acid (ABA) has recently been recognized to possess multifaceted biological functions in mammals and to exert potent curative effects in a number of clinically relevant human diseases. Studies with human specimens have unequivocally shown that ABA retains its stress-related functional attributes, previously identified in plants, which contribute to enhanced inflammatory defense mechanisms in mammals. Besides, studies performed in animal models revealed prominent anti-inflammatory properties of ABA as indicated by a marked reduction of immune cell infiltrates at the sites of inflammation. Thus, ABA treatment ultimately leads to the profound improvement of both non-communicable and communicable diseases which are associated with an overall alleviated course of inflammation. In addition to its action on the mammalian immune system, ABA was also shown to exert diverse physiological functions on non-immune components. One of the most remarkable features of ABA is to stimulate and expand mesenchymal stem cells, which may open a new avenue for its potential use in the field of regenerative medicine. Furthermore, ABA has been reported to play an important role in the maintenance of glycemic control. In this review, we summarize current understanding of the significance of ABA in the mammalian system, its prophylactic and therapeutic effects in various disease settings and the future directions for the development of ABA as novel drug candidate for the improved treatment of inflammatory and infectious human diseases.

Attenuation of immune-mediated influenza pneumonia by targeting the inducible co-stimulator (ICOS) molecule on T cells.

Inducible Co-stimulator (ICOS) plays a critical role in mediating T cell differentiation and function and is considered a key player in balancing T effector and T regulatory (Treg) cell responses. Here we show that activation of the ICOS signalling pathway during acute influenza A virus (IAV) infection by application of an agonistic ICOS antibody reduced the frequency of CD8+ T cells in the respiratory tract of IAV infected animals and delayed pathogen elimination. In line with this, immune-mediated influenza pneumonia was significantly ameliorated in mice that received ICOS agonist as indicated by significantly reduced alveolar infiltrations and bronchointerstitial pneumonia, while at the same time virus-related pathology remained unaffected. Importantly, ICOS agonist treatment resulted in expansion of CD4+Foxp3+ Tregs in IAV infected mice, which was associated with elevated levels of the immunosuppressive cytokine IL-10 in the alveolar space. Together, our findings suggest a prominent role of ICOS signaling during acute IAV infection by increasing the Treg/CD8+ T cell ratio with beneficial outcome on immune-mediated pneumonia and underline the suitability of ICOS as potential therapeutic target for immune intervention in those infectious conditions characterized by strong immunopathology rather than virus-mediated cytopathic effects.

Intranasal formulations: promising strategy to deliver vaccines.

INTRODUCTION: The emergence of new diseases and the lack of efficient vaccines against numerous non-treatable pathogens require the development of novel vaccination strategies. To date, only a few mucosal vaccines have been approved for humans. This was in part due to i) the use of live attenuated vaccines, which are not suitable for certain groups of individuals, ii) safety concerns derived from implementation in humans of some mucosal vaccines, iii) the poor stability, absorption and immunogenicity of antigens delivered by the mucosal route and iv) the limited number of available technologies to overcome the bottlenecks associated with mucosal antigen delivery. Recent advances make feasible the development of efficacious mucosal vaccines with adequate safety profile. Thus, currently intranasal vaccines represent an attractive and valid alternative to conventional vaccines. AREAS COVERED: The present review is focused on the potentials and limitations of market-approved intranasal vaccines and promising candidates undergoing clinical investigations. Furthermore, emerging strategies to overcome main bottlenecks including efficient breaching of the mucosal barrier and safety concerns by implementation of new adjuvants and delivery systems are discussed. EXPERT OPINION: The rational design of intranasal vaccines requires an in-depth understanding of the anatomic, physicochemical and barrier properties of the nasal mucosa, as well as the molecular mechanisms governing the activation of the local innate and adaptive immune system. This would provide the critical knowledge to establish effective approaches to deliver vaccine antigens across the mucosal barrier, supporting the stimulation of a long-lasting protective response at both mucosal and systemic levels. Current developments in the area of adjuvants, nanotechnologies and mucosal immunology, together with the identification of surface receptors that can be exploited for cell targeting and manipulating their physiological properties, will become instrumental for developing a new generation of more effective intranasal vaccines.

Therapeutic intervention in cancer and chronic viral infections: antibody mediated manipulation of PD-1/PD-L1 interaction.

Programmed Death-1 (PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2. The well-established immunosuppressive properties of PD-1/PD-L1 interaction resulting in the re-establishment of peripheral tolerance makes PD-1 an interesting target for therapeutic intervention in cancer patients. In addition to its relevance in tumor-specific immunity, recent studies demonstrate that PD-1 expression on T cells correlates with viral load in HIV and HCV infected patients and further identified PD-1 expression as a marker for exhausted virus-specific CD8+ T cells. In particular, PD-1+CD8+ T cells show impaired effector functions and PD-1 associated T cell exhaustion could be restored by blocking the PD-1/PD-L1 interaction. This results in recovery of virus-specific CD8+ T cell mediated immunity, suggesting that interrupting PD-1 signaling using an antagonistic antibody restores T-cell effector functions. Thus, immunotherapy based on the blockade of PD-1/PD-L1 interaction does not only result in breakdown of effector T-cell tolerance to tumor antigens, but in addition also represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections. In this review, we give a comprehensive overview about the immunological functions of PD-1 mediated signaling in T cells with special emphasis on its immune regulatory functions in the context of cancer and chronic viral infections. Moreover, we will summarize recent data obtained in animal models, in-vitro preclinical approaches in patients and their implementation in clinical trials for treating patients with cancer and chronic viral infections.

Circulating soluble CTLA-4 is related to inflammatory markers in the 70 year old population.

OBJECTIVE: Measurement of inflammatory mediators is an important tool to assess inflammation. We have, therefore, conducted a survey within the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study to evaluate the inter-relationship between soluble CTLA-4 (sCTLA-4) and other inflammatory markers. MATERIALS AND METHODS: This is a population-based study, designed to quantify the circulating serum levels of sCTLA-4 and other inflammatory markers such as CRP and pro-inflammatory cytokines and chemokines by in-house ELISA, Immuno-turbidimetry and multiplex ELISA, respectively. A total of 1016 Swedish Caucasians aged 70 years old were recruited. The statistical analysis was performed by ANOVA. RESULTS: The levels of sCTLA-4 were directly related to the levels of pro-inflammatory cytokines such as IL-6, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma and chemokines such as IL-8. However, the levels of sCTLA-4 were inversely related to the levels of MCP-1. Also, we could not demonstrate any relation between the levels of sCTLA-4 and CRP or soluble adhesion molecules. CONCLUSIONS: Circulating sCTLA-4 could be used as a biomarker for inflammation, potentially reflecting dysregulated T lymphocytes.

Bench to bedside of CTLA-4: a novel immuno-therapeutic agent for inflammatory disorders.

Co-stimulatory molecules are antigen-independent generators of secondary signals which aid in maintaining the homeostasis of the immune system. CTLA-4 is one among extensively studied co-stimulatory molecules which down-regulate immune response. The attributes of immunosuppressive qualities and capacity to induce tolerance have made its recognition as a potential immuno-therapeutic agent for autoimmune mediated inflammatory disorders. In 2007, European Medical Drug Agency (EMEA) has approved administration of CTLA-4Ig (commercial name: Orencia; generic name: Abatacept), as a mean for co-stimulation blockade, for treating patients with rheumatoid arthritis. This review is focused on working mechanism of CTLA-4 from its recognition (bench) to its usage as a potential therapeutic agent (bedside) for several inflammatory diseases. The efficacious aspects of chimeric CTLA-4 in phase I, II and III clinical trials for rheumatoid arthritis, psoriasis, multiple sclerosis are concisely described. This article highlights recent patents and the future usage of co-stimulatory molecules as a therapeutic agent providing a promising immuno-modulatory approach in regulating inflammation.

Polymorphisms in PDCD1 gene are not associated with Wegener's granulomatosis.

Genetic association of programmed cell death-1 (PDCD1) has been implicated in several autoimmune inflammatory disorders. Hence, in this study, our main objective is to evaluate the association of PDCD1 gene to Wegener's granulomatosis (WG). We, thus, analyzed three single nucleotide polymorphisms (SNPs) in PDCD1 gene among WG patients and controls. Further, we quantified circulating serum levels of soluble (s) PD-1 in patients and controls. The methodologies used were ABI Taqman allelic discrimination and restriction fragment length polymorphism for genotyping and in-house ELISA for quantifying sPD-1. Statistical relevance was analyzed by Fischer's exact test. As a result, reduced AA homozygote for SNP in intron-1 was observed, among the patients. However, no association was demonstrated after Bonferroni correction. Also, no differences in genotype and allele frequency were elucidated for SNPs in intron-4 and exon-5. Moreover, we could not demonstrate circulating sPD-1. In conclusion, we show no association of selected SNPs in PDCD1 gene with WG.

Programmed Death-1: from gene to protein in autoimmune human myasthenia gravis.

The key role of an inhibitory receptor, Programmed Death-1, has been evaluated in 273 patients with autoimmune myasthenia gravis. At the genetic level, SNP's genotyping showed no significant association to the disease. Gene expressions in patients were not different from that in controls. Interestingly, at the cell-surface protein level, there were significant elevated levels of PD-1 on T cells and its ligand PD-L1 on monocytes in the patients compared to controls. However, we could not demonstrate any secreted soluble forms of PD-1 among the patients and controls. Thus, our study shows PD-1 might have a natural regulatory property behind MG.

Autoantibodies against neuropeptides are associated with psychological traits in eating disorders.

Previously, we identified that a majority of patients with anorexia nervosa (AN) and bulimia nervosa (BN) as well as some control subjects display autoantibodies (autoAbs) reacting with alpha-melanocyte-stimulating hormone (alpha-MSH) or adrenocorticotropic hormone, melanocortin peptides involved in appetite control and the stress response. In this work, we studied the relevance of such autoAbs to AN and BN. In addition to previously identified neuropeptide autoAbs, the current study revealed the presence of autoAbs reacting with oxytocin (OT) or vasopressin (VP) in both patients and controls. Analysis of serum levels of identified autoAbs showed an increase of IgM autoAbs against alpha-MSH, OT, and VP as well as of IgG autoAbs against VP in AN patients when compared with BN patients and controls. Further, we investigated whether levels of these autoAbs correlated with psychological traits characteristic for eating disorders. We found significantly altered correlations between alpha-MSH autoAb levels and the total Eating Disorder Inventory-2 score, as well as most of its subscale dimensions in AN and BN patients vs. controls. Remarkably, these correlations were opposite in AN vs. BN patients. In contrast, levels of autoAbs reacting with adrenocorticotropic hormone, OT, or VP had only few altered correlations with the Eating Disorder Inventory-2 subscale dimensions in AN and BN patients. Thus, our data reveal that core psychobehavioral abnormalities characteristic for eating disorders correlate with the levels of autoAbs against alpha-MSH, suggesting that AN and BN may be associated with autoAb-mediated dysfunctions of primarily the melanocortin system.