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Background: Healthcare workers (HCWs),particularly from lower-middle income countries (LMIC), are at high risk of acquiring COVID-19. Limited data exist on the effectiveness of hydroxychloroquine as prophylaxis. Our trial evaluated the effectiveness of a 12-week regimen of hydroxychloroquine among HCWs on the risk of laboratory-confirmed COVID-19 in the 6 months after randomization Methods: We conducted a multicentre parallel-group open-label randomized controlled trial in 9 centres across India. HCWs serving in an environment with exposure to COVID-19 were eligible and randomized in a 1:1 ratio to hydroxychloroquine plus standard practice or to standard practice alone (role-appropriate personal protective equipment). In the intervention arm, participants received 2 doses of 400mg hydroxychloroquine at randomization followed by a weekly dose for 12 weeks. The primary outcome was the proportion of laboratory-confirmed COVID-19 in the 6 months after randomization using an intention-to-treat analysis. The trial was registered on Clinical Trials Registry of India(CTRI/2020/05/025067). Findings: From 29th June 2020 to 4th February 2021, 886 participants were screened and 416 were randomized (203-standard practice and 213- hydroxychloroquine plus standard practice). In the 6 months after randomization (primary analysis population=413), 11 participants assigned to the hydroxychloroquine group and 12 participants assigned to the standard practice group met the primary end point[ 5.1% vs 5.9%; OR 0.85, [95% CI 0.35-2.06] p=0.71]. There was no heterogeneity of treatment effect on the primary outcome in any of the pre-specified subgroups. There were no significant differences in any of the secondary outcomes. The adverse event rates were 9.9% and 6.9% in the hydroxychloroquine and standard practice arms respectively. There were no serious adverse events in either group. Interpretation: Hydroxychloroquine along with standard practice was not superior to standard practice alone on the proportion of lab-confirmed COVID-19. However, conclusions are limited by the premature trial cessation. Trial Registration: Clinical Trials Registry of India (CTRI/2020/05/025067). Funding: Wesley Medical Research, Australia Declaration of Interest: OJ reports being a member of the WHO R&D Blueprint Safety Monitoring Team, ACT Acclerator-R&D Digital Health working group and COVID-19 Clinical Research Coalition data sharing working group. Remaining authors have nothing to declare. Ethical Approval: Written informed consent was obtained from all participants. The trial was approved by the Ethics Committee at all participating sites (coordinating centre EC approval number: The George Institute Ethics Committee:08-2020)

Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed a paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.

Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2 group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol’s ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50 = 6 μM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50 = 5 μM) and COX-2 (IC50 = 20 μM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2 in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.

Phosphatidylinositol 3-kinase p110δ isoform (PI3K p110δ) activity is essential for mast cell activation, suggesting that inhibition of PI3K p110δ might be useful in treating allergic diseases.We sought to determine the effect of the PI3K p110δ-selective inhibitor idelalisib on allergic responses.This phase 1 randomized, double-blind, placebo-controlled, 2-period crossover study was conducted with the Vienna Challenge Chamber. Grass pollen-induced allergic symptoms were documented during screening. Eligible subjects received idelalisib (100 mg twice daily) or placebo for 7 days, with allergen challenge on day 7. After a 2-week washout period, subjects received the alternate treatment and repeated allergen challenge. Study measures included safety, nasal and nonnasal symptoms, nasal airflow, nasal secretions, basophil activation, and plasma cytokine levels.Forty-one patients with allergic rhinitis received idelalisib/placebo (n = 21) or placebo/idelalisib (n = 20). Idelalisib treatment was well tolerated. Mean total nasal symptom scores were lower during the combined idelalisib treatment periods compared with placebo (treatment difference [idelalisib - placebo], -1.78; 95% CI, -2.53 to -1.03; P .001). Statistically significant differences were also observed for the combined treatment periods for total symptom scores, nasal airflow, nasal secretion weight, and nasal congestion scores. The percentage of ex vivo-activated basophils (CD63(+)/CCR3(+) cells; after stimulation with grass pollen) was substantially lower for idelalisib-treated compared with placebo-treated subjects. Plasma CCL17 and CCL22 levels were reduced after idelalisib treatment.Idelalisib treatment was well tolerated in patients with allergic rhinitis and appears to reduce allergic responses clinically and immunologically after an environmental allergen challenge.

Autoimmune diseases such as rheumatoid arthritis (RA) cause significant morbidity and loss of productivity. Many potent conventionally used drugs are available for these diseases, but their prolonged use is accompanied by severe adverse effects besides a high cost. Therefore, there is an unmet need for effective but less expensive medications for RA and other autoimmune diseases. Natural plant products belonging to the traditional systems of medicine, such as the traditional Chinese medicine and Indian Ayurvedic medicine, offer a vast and promising resource in this regard. However, herbal medicinal products are often poorly characterized for their composition as well as mechanisms of action. We review here the results of our systematically performed studies aimed at defining the anti-arthritic activity of three herbal extracts, namely, modified Huo-luo-xiao-ling dan (HLXL), Celastrus aculeatus Merr., and polyphenolic fraction of green tea (Camellia sinensis), as well as a purified compound Celastrol, a bioactive component of Celastrus. Specifically, we examined the effects of these herbal products on the immunological, biochemical and molecular biological effector pathways in autoimmune arthritis. We have also reviewed here related studies on these herbal products by other investigators. Taken together, we suggest further testing of these herbal products in RA patients.

Using phage peptide library screening, we identified peptide-encoding phages that selectively home to the inflamed central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). A phage peptide display library encoding cyclic 9-amino-acid random peptides was first screened ex-vivo for binding to the CNS tissue of EAE mice, followed by in vivo screening in the diseased mice. Phage insert sequences that were present at a higher frequency in the CNS of EAE mice than in the normal (control) mice were identified by DNA sequencing. One of the phages selected in this manner, denoted as MS-1, was shown to selectively recognize CNS tissue in EAE mice. Individually cloned phages with this insert preferentially homed to EAE CNS after an intravenous injection. Similarly, systemically-administered fluorescence-labeled synthetic MS-1 peptide showed selective accumulation in the spinal cord of EAE mice. We suggest that peptide MS-1 might be useful for targeted drug delivery to CNS in EAE/MS.

Until recently, autoimmune disease research has primarily been focused on elucidating the role of the adaptive immune system. In the past decade or so, the role of the innate immune system in the pathogenesis of autoimmunity has increasingly been realized. Recent findings have elucidated paradigm-shifting concepts, for example, the implications of “trained immunity” and a dysbiotic microbiome in the susceptibility of predisposed individuals to clinical autoimmunity. In addition, the application of modern technologies such as the quantum dot (Qdot) system and ‘Omics’ (e.g., genomics, proteomics, and metabolomics) data-processing tools has proven fruitful in revisiting mechanisms underlying autoimmune pathogenesis and in identifying novel therapeutic targets. This review highlights recent findings discussed at the American Autoimmune Related Disease Association (AARDA) 2019 colloquium. The findings covering autoimmune diseases and autoinflammatory diseases illustrate how new developments in common innate immune pathways can contribute to the better understanding and management of these immune-mediated disorders.

Both genetic and environmental factors contribute to the pathogenesis of inflammatory and autoimmune diseases. The association of specific major histocompatibility complex (MHC) alleles with susceptibility to particular autoimmune diseases is well known, although the mechanistic aspects of this link are not fully unraveled yet. Furthermore, the prevalence of many autoimmune diseases is much higher in females than in males. Intensive efforts are currently being directed to defining the role of sex hormones, the hypothalamic–pituitary–adrenal (HPA) axis, and other modifying factors in this sexual dimorphism. Among the environmental factors, emerging understanding of the interplay between the gut microbiota and the immune system has opened up a new frontier of biomedical research with a renewed perspective of host-environment interactions. In addition, besides specific T helper subsets and their cytokine products, the roles of the scavenger receptors, the inflammasome, the newer cytokines of the IL-1 (e.g., IL-33, IL-37) and IL-12 (e.g., IL-27, IL-35) families, and the soluble mediators produced by adipocytes (adipokines) (e.g., leptin, adiponectin) in the pathogenesis of inflammation, autoimmunity, and metabolic disorders are increasingly being realized. In this special issue, "Cytokines in Immune Pathology and Therapy," second volume, leading experts have shared their research work and perspectives on the above-mentioned cytokines and other modulators of inflammation and autoimmunity. An outline of 15 articles in volume 2 is presented here. Volume 1 of this special issue containing 14 articles was published recently.

The T helper (Th) cell subsets are characterized by the type of cytokines produced and the master transcription factor expressed. Th1 cells participate in cell-mediated immunity, whereas Th2 cells promote humoral immunity. Furthermore, the two subsets can control each other. Thereby, Th1-Th2 balance offered a key paradigm in understanding the induction and regulation of immune pathology in autoimmune and other diseases. However, over the past decade, Th17 cells producing interleukin-17 (IL-17) have emerged as the major pathogenic T cell subset in many pathological conditions that were previously attributed to Th1 cells. In addition, the role of CD4+CD25+ T regulatory cells (Treg) in controlling the activity of Th17 and other T cell subsets has increasingly been realized. Thereby, examination of the Th17/Treg balance in the course of autoimmune diseases has significantly advanced our understanding of the pathogenesis of these disorders. The differentiation of Th17 and Treg cells from naïve T cells is inter-related and controlled in part by the cytokine milieu. For example, transforming growth factor β (TGFβ) is required for Treg induction, whereas the same cytokine in the presence of IL-6 (or IL-1) promotes the differentiation of Th17. Furthermore, IL-23 plays a role in the maintenance of Th17. Accordingly, novel therapeutic approaches are being developed to target IL-23/IL-17 as well as to modulate the Th17/Treg balance in favor of immune regulation to control autoimmunity.

Cytokines serve as key mediators of inflammation and tissue damage in a variety of immune-mediated disorders. The induction, progression, and resolution of inflammation in such disorders are characterized by a dynamic balance between both the pro-inflammatory and anti-inflammatory cytokines as well as the pathogenic and protective T cell subsets. Over the past two decades, the roles of the interleukin-17 (IL-17) /IL-23 axis and the T helper 17 (Th17)/ T regulatory (Treg) cell balance in the pathogenesis of autoimmunity and other inflammatory diseases have extensively been analyzed, and their significance validated. However, these studies, coupled with others devoted to well-established Th1/Th2 cytokines, have unraveled some challenging issues including the dual action of cytokines and the plasticity of T cell subsets. Nevertheless, major positive advances have also been made regarding cytokines and T cell subsets as therapeutic targets/agents. In this special issue, "Cytokines in Immune Pathology and Therapy," leading experts have shared their research work and perspectives on the roles of cytokines in the development and control of immune-mediated diseases. An outline of 14 articles in the first volume is presented here. The second volume will follow soon.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting the synovial joints. The currently available drugs for RA are effective only in a proportion of patients and their prolonged use is associated with severe adverse effects. Thus, new anti-arthritic agents are being sought. We tested Pristimerin, a naturally occurring triterpenoid, for its therapeutic activity against rat adjuvant arthritis. Pristimerin effectively inhibited both arthritic inflammation and cartilage and bone damage in the joints. Pristimerin-treated rats exhibited a reduction in the pro-inflammatory cytokines (IL-6, IL-17, IL-18, and IL-23) and the IL-6/IL-17-associated transcription factors (pSTAT3 and ROR-γt), coupled with an increase in the immunomodulatory cytokine IL-10. Also increased was IFN-γ, which can inhibit IL-17 response. In addition, the Th17/Treg ratio was altered in favor of immune suppression and the RANKL/OPG ratio was skewed towards anti-osteoclastogenesis. This is the first report on testing Pristimerin in arthritis. We suggest further evaluation of Pristimerin in RA patients.

There is currently a global epidemic of obesity as a result of recent changes in lifestyle. Excess body fat deposition is caused by an imbalance between energy intake and energy expenditure due to interactions between genetic and environmental factors. The signals and biological mechanisms that trigger fat accumulation by disrupting energy homeostasis are not well understood. There is considerable evidence now supporting a possible role of protein kinase C beta (PKCβ) in energy homeostasis. This review highlights recent findings on the role of PKCβ activation in the genesis and progression of obesity, and of PKCβ repression in mediating the beneficial effects of physical exercise. Available data support a model in which adipose PKCβ activation is among the initiating events that disrupt mitochondrial function through interaction with p66shc and amplify fat accumulation and adipose dysfunction, with systemic consequences. Manipulation of PKCβ levels, activity, or signaling could provide a therapeutic approach to combat obesity and associated metabolic disorders.

Phosphatidylinositol 3-kinases (PI3K) participate in numerous signaling pathways, and control distinct biological functions. Studies using pan-PI3K inhibitors suggest roles for PI3K in osteoclasts, but little is known about specific PI3K isoforms in these cells. Our objective was to determine effects of isoform-selective PI3K inhibitors on osteoclasts. The following inhibitors were investigated (targets in parentheses): wortmannin and LY294002 (pan-p110), PIK75 (α), GDC0941 (α, δ), TGX221 (β), AS252424 (γ), and IC87114 (δ). In addition, we characterized a new potent and selective PI3Kδ inhibitor, GS-9820, and explored roles of PI3K isoforms in regulating osteoclast function. Osteoclasts were isolated from long bones of neonatal rats and rabbits. Wortmannin, LY294002, GDC0941, IC87114, and GS-9820 induced a dramatic retraction of osteoclasts within 15–20 min to 65–75% of the initial area. In contrast, there was no significant retraction in response to vehicle, PIK75, TGX221, or AS252424. Moreover, wortmannin and GS-9820, but not PIK75 or TGX221, disrupted actin belts. We examined effects of PI3K inhibitors on osteoclast survival. Whereas PIK75, TGX221, and GS-9820 had no significant effect on basal survival, all blocked RANKL-stimulated survival. When studied on resorbable substrates, osteoclastic resorption was suppressed by wortmannin and inhibitors of PI3Kβ and PI3Kδ, but not other isoforms. These data are consistent with a critical role for PI3Kδ in regulating osteoclast cytoskeleton and resorptive activity. In contrast, multiple PI3K isoforms contribute to the control of osteoclast survival. Thus, the PI3Kδ isoform, which is predominantly expressed in cells of hematopoietic origin, is an attractive target for anti-resorptive therapeutics.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints, deformities, and disability. The prolonged use of conventional anti-inflammatory drugs is associated with severe adverse effects. Therefore, there is an urgent need for safer and less expensive therapeutic products. Celastrol is a bioactive component of Celastrus, a traditional Chinese medicine, and it possesses anti-arthritic activity. However, the mechanism of action of Celastrol remains to be fully defined. In this study based on the rat adjuvant-induced arthritis (AA) model of RA, we examined the effect of Celastrol on two of the key mediators of arthritic inflammation, namely chemokines and their receptors, and related pro-inflammatory cytokines. We treated arthritic Lewis rats with Celastrol (200 μg/rat) or its vehicle by daily intraperitoneal (i.p.) injection beginning at the onset of AA. At the peak phase of AA, the sera, the draining lymph node cells, spleen adherent cells, and synovial-infiltrating cells of these rats were harvested and tested. Celastrol-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC) as well as cytokines (TNF-α and IL-1β) that induce them, compared to the vehicle-treated rats. However, Celastrol did not have much effect on cellular expression of chemokine receptors except for an increase in CCR1. Further, Celastrol inhibited the migration of spleen adherent cells in vitro. Thus, Celastrol-induced suppression of various chemokines that mediate cellular infiltration into the joints might contribute to its anti-arthritic activity. Our results suggest that Celastrol might offer a promising alternative/adjunct treatment for RA

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by bone erosion and cartilage destruction in the joints. Many of the conventional antiarthritic drugs are effective in suppressing inflammation, but they do not offer protection against bone damage. Furthermore, the prolonged use of these drugs is associated with severe adverse reactions. Thus, new therapeutic agents that can control both inflammation and bone damage but with minimal side effects are sought. Celastrus is a Chinese herb that has been used for centuries in folk medicine for the treatment of various inflammatory diseases. However, its utility for protection against inflammation-induced bone damage in arthritis and the mechanisms involved therein have not been examined. We tested celastrus and its bioactive component celastrol for this attribute in the adjuvant-induced arthritis model of RA. The treatment of arthritic rats with celastrus/celastrol suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints as demonstrated by histology and bone histomorphometry. The protective effects against bone damage are mediated primarily via the inhibition of defined mediators of osteoclastic bone remodeling (e.g. receptor activator of nuclear factor-κB ligand (RANKL)), the deviation of RANKL/osteoprotegerin ratio in favor of antiosteoclastic activity, and the reduction in osteoclast numbers. Furthermore, both the upstream inducers (proinflammatory cytokines) and the downstream effectors (MMP-9) of the osteoclastogenic mediators were altered. Thus, celastrus and celastrol controlled inflammation-induced bone damage by modulating the osteoimmune cross-talk. These natural products deserve further consideration and evaluation as adjuncts to conventional therapy for RA.

Rheumatoid arthritis (RA) is a chronic debilitating disease characterized by synovial inflammation, damage to cartilage and bone, and deformities of the joints. Several drugs possessing anti-inflammatory and immunomodulatory properties are being used in the conventional (allopathic) system of medicine to treat RA. However, the long-term use of these drugs is associated with harmful side effects. Therefore, newer drugs with low or no toxicity for the treatment of RA are actively being sought. Interestingly, several herbs demonstrate anti-inflammatory and anti-arthritic activity. In this review, we describe the role of the major biochemical and molecular mediators in the pathogenesis of RA, and highlight the sites of action of herbal medicinal products that have anti-arthritic activity. With the rapidly increasing use of CAM products by patients with RA and other inflammation-related disorders, our review presents timely information validating the scientific rationale for the use of natural therapeutic products.

Heat-shock proteins (Hsps) are among the most highly conserved and immunogenic proteins shared by microbial agents and mammals. Under physiological conditions, the ubiquitously distributed Hsps maintain the integrity and function of other cellular proteins when cells are exposed to stressful stimuli. However, owing to their conserved nature and stress inducibility, Hsps may become targets of immune response. The T cells and/or antibodies induced by a microbial Hsp may crossreact with the corresponding mammalian Hsp (molecular mimicry) and trigger an autoimmune response, which if unchecked can lead to immune pathology and clinical manifestations. Furthermore, enhanced expression of Hsp under stress can unveil previously hidden antigenic determinants that can initiate and perpetuate autoimmune reactivity. Also, the innate immune mechanisms activated by an Hsp can reinforce and even direct the type of adaptive immune response to that protein. Hsps have been implicated in the induction and propagation of autoimmunity in several diseases, including rheumatoid arthritis, atherosclerosis and type 1 diabetes. However, Hsps possess immunoregulatory attributes as well and therefore, are being exploited for immunomodulation of various immune-mediated disorders.

The herbal formula Huo Luo Xiao Ling Dan (HLXL) and its modifications have been used in traditional Chinese medicine for about one hundred years to alleviate pain and inflammation.To investigate the effects of HLXL on complete Freund's adjuvant (CFA)-induced multiple-joint arthritis in rats.Male Lewis rats, 190-210 g, were immunized subcutaneously at the base of the tail with 200 microl of heat-killed Mycobacterium tuberculosis in mineral oil (5 mg/ml). HLXL (2.30 and 4.60 g/kg) or vehicle control (n=8 per group) was administered orally (i.g.) once a day between days 16 and 25 post-CFA injection. The rats were observed for signs of arthritis with arthritic changes (erythema, edema, induration) being scored on a scale of 0-4 of increasing severity using a standard scoring system. The maximum arthritis score per rat was 16. A plethysmometer was used to measure edema volume in each paw. Adverse effects of HLXL were monitored by closely observing the animals for unusual behavioral changes. Levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) in local tissue were measured by enzyme-linked immunosorbent assay on day 25 post-CFA.HLXL significantly decreased arthritis scores between days 23-25 in the 2.30 g/kg group and 21-25 in the 4.60 g/kg group (p0.05). It reduced paw edema on days 22 and 24 in the 2.30 g/kg group and on days 20, 22 and 24 in the 4.60 g/kg group compared to control (p0.05). Local tissue TNF-alpha and IL-1beta levels on day 25 post-CFA injection were significantly (p0.05) lower in rats treated with HLXL than in control rats. No observable adverse effects were found.The data suggest that HLXL produces significant anti-arthritic effects that may be mediated by suppressing pro-inflammatory cytokines, and it appears to be safe.

Objectives To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action, and limitations. Methods We reviewed the published literature in Medline (PubMed) on the induction of antigen-specific tolerance and its effect on autoimmune arthritis, as well as the recent work on B-cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed. Results Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro expansion of CD4+CD25+ regulatory T-cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens. Conclusion An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.

Green tea, a product of the dried leaves of Camellia sinensis, is the most widely consumed beverage in the world. The polyphenolic compounds from green tea (PGT) possess antiinflammatory properties. We investigated whether PGT can afford protection against autoimmune arthritis and also examined the immunological basis of this effect using the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA). AA can be induced in Lewis rats (RT.1(l)) by immunization with heat-killed Mycobacterium tuberculosis H37Ra (Mtb), and arthritic rats raise a T cell response to the mycobacterial heat-shock protein 65 (Bhsp65). Rats consumed green tea (2-12 g/L) in drinking water for 1-3 wk and then were injected with Mtb to induce disease. Thereafter, they were observed regularly and graded for signs of arthritis. Subgroups of these rats were killed at defined time points and their draining lymph node cells were harvested and tested for T cell proliferative and cytokine responses. Furthermore, the sera collected from these rats were tested for anti-Bhsp65 antibodies. Feeding 8 g/L PGT to Lewis rats for 9 d significantly reduced the severity of arthritis compared with the water-fed controls. Interestingly, PGT-fed rats had a lower concentration of the proinflammatory cytokine interleukin (IL)-17 but a greater concentration of the immunoregulatory cytokine IL-10 than controls. PGT feeding also suppressed the anti-Bhsp65 antibody response. Thus, green tea induced changes in arthritis-related immune responses. We suggest further systematic exploration of dietary supplementation with PGT as an adjunct nutritional strategy for the management of RA.

Metabolic syndrome is common in the general population, but there is little information available on the underlying signaling mechanisms regulating triglyceride (TG) content in the body. In the current study, we have uncovered a role for protein kinase Cbeta (PKCbeta) in TG homeostasis by studying the consequences of a targeted disruption of this kinase. PKCbeta(-/-) mutant mice were considerably leaner and the size of white fat depots was markedly decreased compared with wild-type littermates. TG content in the liver and skeletal muscle of PKCbeta(-/-) mice was also significantly low. Interestingly, mutant animals were hyperphagic and exhibited higher food intake and reduced feed efficiency versus wild type. The protection from obesity involves elevated oxygen consumption/energy expenditure and increased fatty acid oxidation in adipose tissue with concurrent increased mitochondria genesis, up-regulation of PGC-1alpha and UCP-2, and down-regulation of perilipin. The ability of PKCbeta deficiency to promote fat burning in adipocytes may suggest novel therapeutic strategies for obesity and obesity-related disorders.

SummaryClass-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphatidylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3Kδ. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo) of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID.

Background Bronchial asthma is characterized by inflammation of the airways, which is usually accompanied by increased vascular permeability, resulting in plasma exudation. Vascular endothelial growth factor (VEGF) has been implicated in contributing to asthmatic tissue edema through its effect on vascular permeability. Many cellular responses of VEGF are regulated by the lipid products of phosphoinositide 3-kinase (PI3K). However, the effect of PI3K catalytic subunit p110δ on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110δ catalytic activity, has been identified. Objective We have sought to investigate the role of PI3K-δ, more specifically in the increase of vascular permeability. Methods Female BALB/c mice were sensitized and challenged with ovalbumin. We have investigated the effect of IC87114 on airway inflammation, T H 2 cytokines expression, airway hyperresponsiveness, plasma extravasation, hypoxia-inducible factor 1α expression, and VEGF expression in a murine model of asthma. Results Our current study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of T H 2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110δ reduces ovalbumin-induced upregulation of VEGF level. Conclusion These results suggest that PI3K-δ inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice. Clinical implications These findings provide a crucial molecular mechanism for the potential role of PI3K-δ in asthma and other airway inflammatory disorders.

In this opinion, we propose that the hierarchy of antigenic determinants within self-antigens is the major influence in molding the potentially autoreactive T-cell repertoire. The well processed and presented determinants constitute a 'dominant self', whereas the poorly processed and/or presented determinants will be invisible to T cells and comprise a 'cryptic self', which we consider a fundamental cornerstone of a theory of autoimmunity. It accounts for the large repertoire of self-reactive clones because a similar hierarchy is established in the thymus and controls positive and negative selection. Furthermore, this residual T-cell repertoire, largely directed against cryptic determinants, will contain some T cells with sufficient affinity for MHC and antigen that enables them to respond under inflammatory conditions, thus facilitating presentation of previously cryptic determinants.

Here, we demonstrate that the Wistar Kyoto (WKY/NHsd) rat, which bears the same RT1l haplotype as the experimental autoimmune encephalomyelitis (EAE)-susceptible Lewis rat strain, is highly resistant to myelin basic protein (MBP)-induced EAE. No differences between Lewis and WKY strains were found in T cell proliferative specificity or the use of Vβ8.2 T cell receptors in response to MBP. A Th2 cytokine bias correlated with WKY's EAE resistance. MBP challenge of WKY-into-Lewis adoptive transfer recipients produced a novel biepisodic EAE. The WKY strain should be useful in studies of many tissue-specific autoimmune diseases to which the Lewis rat is susceptible.

In this paper, we report that SB202190 alone, a specific inhibitor of p38MAPK, induces low density lipoprotein (LDL) receptor expression (6–8-fold) in a sterol-sensitive manner in HepG2 cells. Consistent with this finding, selective activation of the p38MAPK signaling pathway by expression of MKK6b(E), a constitutive activator of p38MAPK, significantly reduced LDL receptor promoter activity. Expression of the p38MAPK α-isoform had a similar effect, whereas expression of the p38MAPK βII-isoform had no significant effect on LDL receptor promoter activity. SB202190-dependent increase in LDL receptor expression was accompanied by induction of p42/44MAPK, and inhibition of this pathway completely prevented SB202190-induced LDL receptor expression, suggesting that p38MAPK negatively regulates the p42/44MAPK cascade and the responses mediated by this kinase. Cross-talk between these kinases appears to be one-way because modulation of p42/44MAPK activity did not affect p38MAPK activation by a variety of stress inducers. Taken together, these findings reveal a hitherto unrecognized one-way communication that exists between p38MAPK and p42/44MAPK and provide the first evidence that through the p42/44MAPK signaling cascade, the p38MAPKα-isoform negatively regulates LDL receptor expression, thus representing a novel mechanism of fine tuning cellular levels of cholesterol in response to a diverse set of environmental cues.