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An interview with functional medicine healthcare provider Dr. Datis Kharrazian is presented. Topics of the interview include the start of Kharrazian's interest in being a chiropractor and a nutritionist, his stand on the move of some reviewers in medical journals to reject research paper without any useful commentary, and his clinical research fellowship at Harvard University.

The inflammation theory of depression, proposed over 20 years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced ‘omics’ technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account. [ABSTRACT FROM AUTHOR]

Aim To evaluate CD4+ CD28+ and CD8+ T-cell genes and the gene expression of IFN-γ, TNF-α, IL-1-β, IL-17A, IL-10, CCL-2/ MCP-1, CCL-4, CCL-5 ( RANTES), CXCR4, CCR5 and RANKL from cells in the periapical interstitial fluid from root canal infections in healthy patients ( HIV−) and HIV-positive individuals ( HIV+). Methodology Subjects included 20 HIV− and 23 HIV+ patients referred to the School of Dentistry at the Universidade Federal de Minas Gerais (Belo Horizonte, MG, Brazil). Almost all HIV+ patients were undergoing highly active antiretroviral therapy ( HAART). Clinical samples were taken from teeth with pulp necrosis, and no patients had acute periapical symptoms at the time of the appointments. After cleaning and drying, 3 paper points were introduced into the root canal, passing passively through the root apex (2 mm) into the periapical tissues for 1 min. The samples were collected immediately after root canal cleaning and 7 days later (restrained root canal bacterial load) to characterize those gene expressions using real-time PCR. Results Significantly higher levels of CD4+ CD28+ and CD8+ T cells in teeth with restrained bacterial loads (second collection) compared with the first collection were observed in both HIV− and HIV+ samples. In HIV− patients, an increase in IL-10 and CXCR4 expression was demonstrated as well as a decrease in pro-inflammatory cytokines such as RANKL, IFN-γ, IL1-β and CCL5. However, in HIV+ patients an increase in cytokines IFN-γ, IL-1-β, TNF-α and IL-17A, and chemokines CCL-2, CXCR4 and CCR5 were observed. The chemokine CCL-5 was not detected in HIV+ individuals. Conclusions These findings suggest that after reducing the root canal bacterial load in HIV− individuals an anti-inflammatory response is generated whilst in HIV+ patients a pro-inflammatory response is sustained in the periapical area. [ABSTRACT FROM AUTHOR]

Human Th17 pro-inflammatory cells are currently defined as cells that produce IL-17A and F, tumor necrosis factor (TNF)-a, 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. [ABSTRACT FROM AUTHOR]

Tanshinone IIA (Tan II A) is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti-inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Context: Benign prostatic hyperplasia (BPH) is one of the most common diseases associated with the aging process in men, particularly men aged >50 yr, yet only a few predictive factors have been identified. In recent years, attention has focused on the role of prostatic inflammation in the pathogenesis and progression of BPH. Objective: This article reviews recent findings related to the potential link between local and systemic inflammation and BPH. Evidence acquisition: In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled “Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,” was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. A structured PubMed literature search was performed, and emphasis was placed on results from the past 10 yr. Evidence synthesis: BPH is characterized by progressive hyperplasia of stromal and glandular cells, and clinically it is defined by lower urinary tract symptoms. In recent years, there has been accumulating evidence linking prostatic inflammation with BPH. The inflammatory infiltrates observed in patients with BPH are composed primarily of chronically activated T-lymphocytes. Cytokines and growth factors released from inflammatory cells create a proinflammatory environment that may support the fibromuscular growth seen in BPH and may also be responsible for inducing a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells. A number of clinical studies have confirmed the presence of inflammatory infiltrate in men with BPH, and this infiltrate has been shown to be involved in the pathogenesis, clinical appearance, and progression of this disorder. There is evidence emerging that systemic inflammation may also play a role in BPH, since in men with metabolic syndrome there was a significant correlation between prostate diameter/volume and the number of metabolic syndrome components. Conclusions: It is clear that a number of different mechanisms are involved in the development and progression of BPH. Prostatic inflammation is an important feature, since it appears to be involved in the pathogenesis, symptomatology, and progression of the disease. [Copyright &y& Elsevier]

The regulators of Gprotein signaling (RGS) protein superfamily negatively controls Gprotein-coupled receptor signal transduction pathways. RGS16 is enriched in activated/effector T lymphocytes. In this paper, we show that RGS16 constrains pulmonary inflammation by regulating chemokine-induced T cell trafficking in response to challenge with Schistosoma mansoni. Naive Rgsl6-/- mice were "primed" for inflammation by accumulation of CCR10+ T cells in the lung. Upon pathogen exposure, these mice developed more robust granulomatous lung fibrosis than wild-type counterparts. Distinct Th2 or putative Thl7 subsets expressing CCR4 or CCR10 accumulated more rapidly in Rgsl6-/- lungs following challenge and produced proinflammatory cytokines IL-13 and IL-17B. CCRA+Rgsl6-/- Th2 cells migrated excessively to CCL17 and localized aberrantly in challenged lungs. T lymphocytes were partially excluded from lung granulomas in Rgsl6-/- mice, instead forming peribronchial/perivascular aggregates. Thus, RGS16-mediated confinement of T cells to Schistosome granulomas mitigates widespread cytokine-mediated pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Abstract: This paper reports the cloning and sequencing of interleukin (IL)-23 p19 subunit for the first time within a non-mammalian species, the zebrafish (Danio rerio), which was discovered using a synteny approach. In addition, amino acid sequences were for IL-23 p19 subunits were also predicted from the stickleback, Fugu and Tetraodon genomes and included in this investigation. The zebrafish IL-23 p19 cDNA consisted of a 66bp 5′ UTR, a 249bp 3′ UTR and a single open reading frame of 567bp giving a predicted 188 aa IL-23 p19 molecule. Multiple alignment of zebrafish IL-23 p19, with other known IL-23 p19 and IL-12 p35 amino acid sequences revealed areas of amino acid conservation, such as the presence of four predicted α-helixes, cysteines important for disulphide bond formation and the conservation of a tryptophan known to interact with the receptor. Amino acid homologies and phylogenetic analysis confirmed the relationship of the fish IL-23 p19 subunits with their mammalian homologues. All the teleost fish IL-23 p19 subunits were found to have 4 exons and 3 introns similar to that of human and mouse IL-23 p19 and a limited degree of synteny was found between the organisms for the regions containing the IL-23 p19 genes with only PAB-dependent poly(A)-specific ribonuclease subunit 2 (PAN2) and IL-23 p19 found in the same order on human chromosome 12 and all the fish genomes looked at. Lastly using real-time PCR, constitutive expression of IL-12 p40 and IL-23 p19 was observed in the kidney, liver, gut and muscle with IL-12 p40 expression higher than IL-23 p19. As soon as an hour after stimulation with LPS, there was an increase of IL-23 p19 in zebrafish leukocytes and an increase of IL-1β, IL-12 p40 and IL-23 p19 expression was found after infection of zebrafish for 1 or 6 days with Mycobaterium marinum strain E11. [Copyright &y& Elsevier]

Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1β. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10-inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI. [ABSTRACT FROM AUTHOR]

Please cite this paper as: In vitro and in vivo analysis of pro- and anti-inflammatory effects of weak and strong contact allergens. Experimental Dermatology 2010; : 1007-1013. Inflammation is a crucial step in the development of allergic contact dermatitis. The primary contact with chemical allergens, called sensitization, and the secondary contact, called elicitation, result in an inflammatory response in the skin. The ability of contact allergens to induce allergic contact dermatitis correlates to a great extent with their inflammatory potential. Therefore, the analysis of the sensitizing potential of a putative contact allergen should include the examination of its ability and potency to cause an inflammation. In this study, we examined the inflammatory potential of different weak contact allergens and of the strong sensitizer 2,4,6-trinitrochlorobenzene (TNCB) in vitro and in vivo using the contact hypersensitivity model, the mouse model for allergic contact dermatitis. Cytokine induction was analysed by PCR and ELISA to determine mRNA and protein levels, respectively. Inflammation-dependent recruitment of skin-homing effector T cells was measured in correlation with the other methods. We show that the sensitizing potential of a contact allergen correlates with the strength of the inflammatory response. The different methods used gave similar results. Quantitative cytokine profiling may be used to determine the sensitizing potential of chemicals for hazard identification and risk assessment. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04041.x Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (Treg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and receptor-related orphan receptor (ROR)α and RORγt for Th17 cells. Tregs and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-β or TGF-β plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-β and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. Tregs are generated from naive precursors both in the thymus (natural, nTregs) and in the periphery (induced, iTregs). The highly suppressive function of Tregs enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the Treg phenotype is therefore of paramount importance in this context. Recent descriptions of Treg biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of Tregs in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of Tregs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review Treg to Th17 conversion and propose some potential mechanisms for this phenomenon. [ABSTRACT FROM AUTHOR]

The inflammatory bowel diseases (Crohn's disease; ulcerative colitis) are idiopathic chronic inflammatory disorders of the intestine and/or colon. A major advancement in our understanding of the pathogenesis of these diseases has been the development of mouse models of chronic gut inflammation. One model that has been instrumental in delineating the immunological mechanisms responsible for the induction as well as regulation of intestinal inflammation is the T cell transfer model of chronic colitis. This paper presents a detailed protocol describing the methods used to induce chronic colitis in mice. Special attention is given to the immunological concepts that explain disease pathogenesis in this model, considerations and potential pitfalls in using this model, and finally different "tricks" that we have learned over the past 12 years that have allowed us to develop a more simplified version of this model of experimental IBD. [ABSTRACT FROM AUTHOR]