Syphilis testing algorithms:A review

The methods and strategies used to screen for syp-hilis and to confirm initially reactive results can vary significantly across clinical laboratories. While the performance characteristics of these different appro-aches have been evaluated by multiple studies, there is not, as of yet, a single, universally recommendedalgorithm for syphilis testing. To clarify the currently available options for syphilis testing, this update will summarize the clinical challenges to diagnosis, review the specific performance characteristics of treponemal and non-treponemal tests, and fnally, summarize select studies published over the past decade which have evaluated these approaches. Specifcally, this review will discuss the traditional and reverse sequence syphilis screening algorithms commonly used in the United States, alongside a discussion of the European Centre for Disease Prevention and Control syphilis algorithm. Ultimately, in the United States, the decision of which algorithm to use is largely dependent on laboratory resources, the local incidence of syphilis and patient demographics. Key words： Syphilis; Treponemal infection; Immuno-assay; Reverse sequence screening; Rapid plasma regain; Treponema pallidum particle agglutination test; Automation; Algorithm; Primary infection; Late latent infection

Lessons from Sj?gren's syndrome etiopathogenesis:Novel cellular and molecular targets

Sjogren’s syndrome （SS） is a systemic autoimmune disease that affects primarily the lacrimal and salivary glands. In addition to a systemic autoimmune response directed against ubiquitous antigens （such as Ro and La antigens）, patients with SS mount a localized response that affects the epithelial component of exocrine glands leading to the establishment of a destructive inflammatory infiltrate comprised of activated T and B cells. Local chemokine and cytokine production drive the recruitment and local activation of immune cells that cause injury to acinar cells. CD4 T cells with different functional differentiation programs including Th1 （IFN-γ）, Th2 （IL-13, IL-4） and Th17 （IL-17, IL-21, IL-22） as well as diverse cytokine signaling pathways, are involved at the initiation, perpetuation, and progression of the disease. Which factors initiate this response and allow it to become chronic are unknown. Proposed mecha-nisms include viral infections and acinar cell apoptosis. Moreover risk-conferring genetic variants, probably through the facilitation of innate and adaptive immune activation, most certainly contribute to the creation of an underlying environment that fosters tolerance loss and facilitates perpetuation of the autoimmune response. In this review, we describe the mechanisms through which the immune response causes SS and emphasize the pathways that are amenable of being targeted with therapeutic purposes.

Stem and immune cells in colorectal primary tumour:Number and function of subsets may diagnose metastasis

An important percentage of colorectal cancer （CRC） patients will develop metastasis, mainly in the liver, even after a successful curative resection. This leads to a very high mortality rate if metastasis is not detected early on. Disseminated cancer cells develop from metastatic stem cells （MetSCs）. Recent knowledge has accumulated about these cells particularly in CRC, so they may now be tracked from the removed primary tumour. This approach could be especially important in prognosis of metastasis because it is becoming clear that metastasis does not particularly rely on testable driver mutations. Among the many traits supporting an epigenetic amplifcation of cell survival and self-renewal mechanisms of MetSCs, the role of many immune cell populations present in tumour tissues is becoming clear. The amount of tumour-infiltrating lymphocytes （T, B and natural killer cells）, dendritic cells and some regulatory populations have already shown prognostic value or to be correlated with disease-free survival time, mainly in immunohistochemistry studies of unique cell populations. Parallel analyses of these immune cell populations together with MetSCs in the primary tumour of patients, with later follow-up data of the patients, will define the usefulness of specific combinations of both immune and MetSCs cell populations. It is expected that these combinations, together to different biomarkers in the form of an immune score, may predict future tumour recurrences, metastases and/or mortality in CRC. It will also support the future design of improved immunotherapeutic approaches against metastasis.

Role of IL28B genotype in older hepatitis C virus-infected patients

The average age of hepatitis C virus(HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes available, peginterferon plus ribavirin will play a critical role in the treatment. The perception that older HCVinfected patients may be at higher risk than younger patients for adverse events from peginterferon plus ribavirin treatment but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials. A recent genomewide association study revealed that interleukin-28B(IL28B) genotype closely correlates with the treatment response against HCV. The relationship of IL28 B genotype with the treatment response in older HCV-infected patients is also unknown. In this review, we focused on the treatment response in older patients infected with HCV and the effects of IL28 B genotype. IL28 B major genotype is a useful predictor of sustained virological response in the interferon-including treatment of older patients infected with HCV. It also seems useful for avoiding adverse events, although the mechanisms ofthe effects of IL28 B genotype on the treatment outcome are still poorly understood and are currently under investigation. Further studies will be needed.

Review of immunological responses to porcine coronaviruses and implications on population based control strategies in epidemic and endemic infections

Five major porcine coronaviruses （COVs） have been identifed which cause severe gastrointestinal （GI） and respiratory disease in pigs. They include transmissiblegastroenteritis （TGEV）, porcine epidemic diarrhea virus （PEDV）, porcine deltacoronavirus, porcine respiratory coronavirus, and porcine hemagglutinating encephalo-myelitis. These diseases, especially TGEV and PEDV, have caused epidemics in Europe, Asia, and the Ameri-cas over the past 50 years, causing signifcant economic losses to swine producers. As pigs are a major protein source worldwide there is great interest in understanding, controlling, and preventing these diseases. These disea-ses have no cure, and current vaccines are not fully protective. On-farm prevention and biosecurity are difficult to enforce and have not stopped the spread of these diseases between herds. Recent advances in the immunology of porcine COVs has revealed that the immune response to porcine COVs shares many similarities with the response to human COVs, leading to increased interest in pigs as models for human disease. Highlights of these advances include the key role of local antigen presenting cells in the gastrointestinal tract in stimulating a protective immune response. This understanding has lead to new proposed vaccines. Advances in the understanding of the ways the viruses evade and degrade the host immune system have also lead to novel proposed therapies. Many of these therapies are in the early development stages, as resear-chers attempt to create effcacious, cost-effective, and practical therapies for these diseases.

Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1(PD-1), cytotoxic T lymphocyte associated antigen-4(CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor(GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.

Probiotic treatment of inflammatory bowel disease:Its extent and intensity

Free radicals(reactive oxygen species,superoxides and hydroxyl radicals)lead to the development of oxidative stress because of imbalance in the amount of antioxidants.Continued development of oxidative stress leads to chronic diseases in humans.The instability in the antioxidant activities and accumulation of oxidative stress due to free radicals may occur in diseases like inflammatory bowel disease(IBD).Antioxidants are substances that inhibit or delay the mechanism of oxidation of molecules mediated by free radicals and also transform into lesseractive derivatives.Probiotics are defined as live microorganisms that show beneficial effects on inflamed intestine and balance the inflammatory immune responses in the gut.Probiotic strains have been reported to scavenge hydroxyl radicals and superoxide anions that are abundantly produced during oxidative stress.The most widely studied probiotic strains are Streptococcus,Bifidobacterium and Lactobacillus.Probiotics cultured in broth have shown some amount of antioxidant activities.Fermented milk and soy milk,which possess starter microorganisms(probiotics),tends to increase the antioxidant activities manyfold.This review aims to discuss the in vivo and in vitro antioxidant activities of specific probiotics with various assays with respect to IBD.

Aberrant expression of CD56 by circulating Sézary syndrome malignant T lymphocytes

Sézary syndrome(SS) is an aggressive variant of cutaneous T cell lymphoma characterized by the presence of malignant T cells in the skin, peripheral blood and lymph nodes. The tumoral population typically displays a CD3+ CD4+ CD45RO+ memory T cell phenotype. We report a case of SS with an aberrant CD56+ immunophenotype. This patient presented with a generalized erythroderma and palpable small axillary lymph nodes.SS(stage IVA) was diagnosed on histological criteria and by the detection of a major T cell clone in skin and blood, an elevated CD4/CD8 T cell ratio and Sézary cells count > 1000/mm3. Beside the Sézary cell marker KIR3DL2, immunostainings revealed that two third of the malignant cells expressed CD56 but no other natural killer(NK) cell marker such as CD16, CD160 or NKp46. This atypical expression was not linked to an activation-dependent process and remained stable during the time course of the disease. No loss of the panT-cell markers CD2, CD3 or CD4 was detected while a complete down-modulation of CD26 was observed. Despite several lines of treatment, no durable amelioration was observed and patient died after 10 mo of follow-up. Because this CD4+ CD56+ SS case is the only one reported so far, the functional significance of CD56 expression remained difficult to assess in terms of aggressiveness and prognosis.

Role of tumor associated macrophages in regulating pancreatic cancer progression

Pancreatic cancer has an overall 5-year survival rate of less than 5%. Unfortunately, patient survival has not substantially improved in the last couple of decades despite advances in treatment modalities that have been successful in other cancer types. The poorresponse of pancreatic cancer to therapy is a major obstacle faced by clinicians. Increasing attention is being paid to how tumor cells and non-tumor cells influence each other in the pancreatic tumor microenvironment. Tumor-associated macrophages （TAMs） are a highlight in this field because of their vast presence in the tumor microenvironment. TAMs promote angiogenesis, metastasis, and suppress the anti-tumor immune response. Here we review the current understanding of the role of TAMs in regulating the progression of pancreatic cancer.

Probiotics in inflammatory bowel disease: Pathophysiological background and clinical applications

Ulcerative colitis and Crohn's disease, collectively termed the inflammatory bowel diseases(IBD), are chronic inflammatory disorders of the gastrointestinal tract. A "dysbiotic" relationship between the commensal gut flora and the intestinal mucosa-associated immune system has been at the core of the pathogenesis of these conditions. Probiotics are "good bacteria" with the ability to benefit the health of the host and their therapeutic application has been studied in IBD. The theoretical basis for such utilization relies upon the ability of probiotic microorganisms to interfere with the dysregulated homeostasis that takes place in IBD and restore the immune-bacterial interaction at the intestinal mucosa. Proposed mechanisms of action include the reconstitution of altered flora composition, enhancement of the integrity of the epithelial barrier, promotion of tolerogenic action by dendritic cells, strengthening of the defensive mechanisms of the innate immunity, and the suppression of pro-inflammatory adaptive immune responses. Despite this abundance of supporting experimental evidence, clinical application of probiotics in IBD has been disappointing. Possible explanations for such discrepancy include the great diversity of microorganisms that fall under the definition of probiotics, the lack of standardization of dosages and administration schemes, the heterogeneity between clinical trials, and the inclusion in the treatment arms of patients with a large variety of clinical phenotypes. Addressing these important issues will be critical for the optimal usage of probiotic-based therapies for patients with IBD.

Autoimmune hepatitis in a patient infected by HIV-1 and under highly active antiretroviral treatment:Case report and literature review

Liver disease has recently been described as an im-portant cause of morbidity and mortality in patientsinfected with human immunodeficiency virus （HIV）.Liver test changes are useful surrogates of the burdenof liver disease. Previous studies have shown that trans-aminase elevations are frequent among these patients.The cause of those changes is harder to establish inHIV-patients. We present a 61-year-old caucasian male,diagnosed with HIV type 1 infection since 1998, underhighly active antiretroviral treatment （HAART）, withvirological suppression and immunological recovery.He presented in a follow-up laboratory workup highvalues of transaminases, arthralgia at the hip joints and hepatomegaly. Liver function tests were normal. Theantibodies to hepatitis viruses were negative. However,autoimmune study and liver biopsy were compatible with autoimmune hepatitis （AIH）. The AIH is a rare di-agnosis in HIV-infected patients perhaps because the elevation of transaminases and changes in liver function tests are often associated to HAART or to other possible liver diseases, namely viral hepatitis and non-alcoholic steatohepatitis. The diagnosis may be underestimated. There are no specifc recommendations available for the treatment of HIV-associated AIH although the immuno-supression with slower tapering seems the most reason-able approach.

RNA polymerases in plasma cells trav-ELL2 the beat of a different drum

There is a major transformation in gene expression between mature B cells （including follicular, marginal zone, and germinal center cells） and antibody secreting cells （ASCs）, i.e. , ASCs, （including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells）. This signifcant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors Prdm1 （B-lymphocyte-induced maturation protein 1）, interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of Pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA proce-ssing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specifc. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA Polymerase Ⅱ in ASCs to acquire different properties, leading to differences in RNA processing and histone modifcations.

Immunological aspects of drug-induced liver injury

Drug induced liver injury(DILI) is a common condition of increasing incidence. Many environmental and genetic factors are involved in its pathogenesis,and immunological mechanisms are also thought to contribute to the development and severity of DILI. This review summarizes current understanding of the immunological pathogenesis of DILI and discusses the perspective for clinical applications.

Gut immune response in the presence of hepatitis C virus infection

Hepatitis C virus （HCV） is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocel-lular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive im-mune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are ca-pable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its as-sociation with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver infammation. Additionally, we investigated the relation-ship between Gut immune responses to HCV and IL28B genotypes, which were identifed as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.

Role of interleukin-1-family cytokines on effector CD4 T cell differentiation

The ability of CD4 T cells to differentiate into various effector or regulatory T cell subsets explains the successful adaptation of immune responses to different types of infectious pathogens. Immune responses in the context of cancer are also shaped by CD4 T cells, which can directly affect cancer prognosis in patients. While the proinflammatory mediator interleukin(IL)-1β was initially shown to enhance Th2 cell responses, recent findings support a predominant role of two other members of the IL-1 family, IL-18 and IL-33, on the production of Th1 and Th2-derived cytokines. In addition, IL-1β was found to profoundly affect the biology of two recently identified CD4 T cell subsets, Th17 and Th9 cells. IL-1β is critical for Th17 cell differentiation and it enhances the production of IL-9 and IL-21 by Th9 cells, thus increasing their anticancer properties. We will here review the mechanisms accounting for the ability of IL-1 cytokines to affect the differentiation of CD4 effector T cells with a focus on Th17 and Th9 cells. The physiopathological relevance of IL-1-driven effects on CD4 T cells will also be discussed.

CD28/CTLA-4/B7 and CD40/CD40L costimulation and activation of regulatory T cells

Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen(CTLA)-4/B7 interaction(using CTLA-4Ig) and the CD40/CD40 L interaction(using anti-CD40 L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis(abatacept) and to prevent rejection of renal transplants(belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells(Teff) and regulatory T cells(Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding ofthe costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40 L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.

Dendritic cells and the extracellular matrix:A challenge for maintaining tolerance/homeostasis

The importance of the extracellular matrix （ECM） in contributing to structural, mechanical, functional and tissue-specific features in the body is well appreciated. While the ECM was previously considered to be a passive bystander, it is now evident that it plays active, dynamic and fexible roles in shaping cell survival, differentiation, migration and death to varying extents depending on the specific site in the body. Dendritic cells （DCs） are recognized as potent antigen presenting cells present in many tissues and in blood, continuously scrutinizing the microenvironment for antigens and mounting local and systemic host responses against harmful agents. DCs also play pivotal roles in maintaining homeostasis to harmless self-antigens, critical for preventing autoimmunity. What is less understood are the complex interactions between DCs and the ECM in maintaining this balance between steady-state tissue residence and DC activation during inflammation. DCs are finely tuned to inflammation-induced variations in fragment length, accessible epitopes and post-translational modifications of individual ECM components and correspondingly interpret these changes appropriately by adjusting their profiles of cognate binding receptors and downstream immune activation. The successful design and composition of novel ECM-based mimetics in regenerative medicine and other applications rely on our improved understanding of DC-ECM interplay in homeostasis and the challenges involved in maintaining it.

Modulation of monocyte subsets in infectious diseases

Monocytes are effector immune cells but a precise anal-ysis of their role in immune response has been preclud-ed by their heterogeneity. Indeed, human monocytesare composed of at least three different subsets withdifferent phenotypic characteristics and functional prop-erties, the so-called classical, intermediate and non-classical monocytes. A review of the literature showsthat these monocyte subsets are differently affectedduring viral, bacterial, parasitic and fungal infections.The expansion of the CD16＋ compartment （intermedi-ate and non-classical monocytes） is typically observedin the majority of infectious diseases and the increasedproportion of CD16＋ monocytes is likely related totheir activation through their direct interaction with thepathogen or the infammatory context. In contrast, thenumber of non-classical and intermediate monocytesis decreased in Q fever endocarditis, suggesting thatcomplex mechanisms govern the equilibrium among monocyte subsets. The measurement of monocyte sub-sets would be useful in better understanding of the role of monocyte activation in the pathophysiology of infec-tious diseases.

Historical evolution,overview,and therapeutic manipulation of costimulatory molecules

Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families,structure,and functions has improved in recent decades.Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions.Currently,modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.

Biologic response modifiers in retinal vasculitis

Intraocular inflammation is an important cause of blindness both in the developing and developed world. Corticosteroids play a pivotal role in the treatment of intraocular inflammation. Lately, therapy by immuno-suppression has taken the center stage for patients with severe intraocular infammation. However, the side effects of immunosuppressive drugs are oncogenic, in-fectious, and hematological. Recently, biologic response modifiers specifically targeting suppression of the im-mune effector responses have revolutionized the treat-ment of intraocular infammation. Anti-tumour necrosis factor agents are etanercept, infiximab, and adalimum-ab. Newer drugs include certolizumab and golimumab. Infiximab has been found to be superior to corticoste-roids in treating retinal vasculitis. Anti-interlenkin thera-pies include rituximab, daclizumab, anakinra, tocilizum-ab and secukinumab. Rituximab has been proven to be quite effective. Other biologics used are interferons and abatacept. However, there are several limitations and side effects associated with their use.