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Malaria is one of the most infectious disease that affects lives of million people throughout the world. Recently, there are several reports which indicate Plasmodium vivax (P. vivax) causing severe disease in infected patients from different parts of the world. For P. vivax disease severity, the data related to immunological and inflammatory status in human host is very limited. In the present study clinical parameters, cytokine profile and integrin gene were analyzed in P. vivax clinical patients. A total of 169 P. vivax samples were collected and categorized into severe vivax malaria (SVM; n = 106) and non-severe vivax malaria (NSVM; n = 63) according to WHO severity criteria. We measured host biomarker levels of interferon (IFN-γ), superoxide dismutase (SOD-1), interleukins viz. (IL-6, IL-10), and tumor necrosis factor (TNF-α) in patient plasma samples by ELISA for pro- and anti-inflammatory cytokines in severe malaria. Host integrin gene was genotyped using PCR assay. In our study, thrombocytopenia and anemia were major symptoms in severe P. vivax patients. In analyzed SVM and NSVM groups a significant increase in cytokine levels (IL-10, IL-6, and TNF-α) and anti-oxidant enzyme SOD-1 was found. Our study results also showed a higher pro-inflammatory (TNF-α, IL-6 and IFN-γ) to anti-inflammatory (IL-10) cytokine ratio in severe vivax patients. Integrin gene showed no mutation with respect to thrombocytopenic patients among clinically defined groups. It was observed that severe vivax cases had increased cytokine levels irrespective of age and sex of the patients along with thrombocytopenia and other clinical manifestations. The results of current findings could serve as baseline data for evaluating severe malaria parameters during P. vivax infections and will help in developing an effective biomarker for diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Communications between immune cells are essential to ensure appropriate coordination of their activities. Here, we observed the infiltration of activated macrophages into the joint-footpads of chikungunya virus (CHIKV)-infected animals. Large numbers of CD64+MHCII+ and CD64+MHCII- macrophages were present in the joint-footpad, preceded by the recruitment of their CD11b+Ly6C+ inflammatory monocyte precursors. Recruitment and differentiation of these myeloid subsets were dependent on CD4+ T cells and GM-CSF. Transcriptomic and gene ontology analyses of CD64+MHCII+ and CD64+MHCII- macrophages revealed 89 differentially expressed genes, including genes involved in T cell proliferation and differentiation pathways. Depletion of phagocytes, including CD64+MHCII+ macrophages, from CHIKV-infected mice reduced disease pathology, demonstrating that these cells play a pro-inflammatory role in CHIKV infection. Together, these results highlight the synergistic dynamics of immune cell crosstalk in driving CHIKV immunopathogenesis. This study provides new insights in the disease mechanism and offers opportunities for development of novel anti-CHIKV therapeutics.

Scabies is an itchy skin disease caused by the burrowing mite Sarcoptes scabiei. During their lifespan, the female mites invade the stratum corneum and create tunnels, in which they reside, move, feed, deposit fecal pellets, and lay eggs. Recently, scabies was included in the World Health Organization roadmap for neglected tropical diseases 2021–2030. This review attempts to summarize our knowledge about the mite's biology and the disease pathogenesis, pathological changes, and complications. Generally, the host–parasite interaction in scabies is highly complex and involves different mechanisms, some of which are yet largely unknown. Elucidation of the nature of such interaction as well as the underlying mechanisms could allow a better understanding of the mite's biology and the development of novel diagnostic and therapeutic options for scabies control programs. Moreover, identification of the molecular basis of such interaction could unveil novel targets for acaricidal agents and vaccines. [ABSTRACT FROM AUTHOR]

Behçet's syndrome is a recurring inflammatory multiorgan disorder affecting the skin, mucosa, eyes, joints, stomach, and central nervous system. Behçet's syndrome epidemiology varies greatly among populations (0.64–420/100,000), and Behçet's syndrome has gained increasing international acclaim in the recent 50 years due to raising awareness of the syndrome, although it is rare in most population. In addition to the unclear etiology of the syndrome, the diagnosis of Behçet's syndrome is complicated by a vague clinical presentation, phenotypic heterogeneity and/or incomplete representation, and the lack of any specific laboratory, radiographic, or histological findings. There exists a dire need to elucidate factors that contribute to disease pathogenesis and/or are associated with clinical features of Behçet's syndrome and the classification of different forms of the syndrome. The identification of such molecular, cellular, and/or clinical factors are crucial for timely diagnosis and efficacious management of Behçet's syndrome. We discuss recent advances in the clinical diagnosis of Behçet's syndrome and related contributions of genetics, epigenetics, microbiome, inflammasomes, and autoantibodies to the improved diagnosis, management, and understanding of Behçet's syndrome. [ABSTRACT FROM AUTHOR]

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1β (IL-1β) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1β and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs. [ABSTRACT FROM AUTHOR]

Myocarditis is an inflammatory cardiac disease characterized by the destruction of myocardial cells, infiltration of interstitial inflammatory cells, and fibrosis, and is becoming a major public health concern. The aetiology of myocarditis continues to broaden as new pathogens and drugs emerge. The relationship between immune checkpoint inhibitors, severe acute respiratory syndrome coronavirus 2, vaccines against coronavirus disease-2019, and myocarditis has attracted increased attention. Immunopathological processes play an important role in the different phases of myocarditis, affecting disease occurrence, development, and prognosis. Excessive immune activation can induce severe myocardial injury and lead to fulminant myocarditis, whereas chronic inflammation can lead to cardiac remodelling and inflammatory dilated cardiomyopathy. The use of immunosuppressive treatments, particularly cytotoxic agents, for myocarditis, remains controversial. While reasonable and effective immunomodulatory therapy is the general trend. This review focuses on the current understanding of the aetiology and immunopathogenesis of myocarditis and offers new perspectives on immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

This review presents data on the characteristics of the varicella-zoster virus (VZV), the clinical manifestations of CNS lesions in acute and chronic VZV infection in children and adults, and the mechanisms of interaction of the pathogen with the immune system during development of disease. The question of whether neurological disorders in VZV infection should be regarded as a complication or a manifestation of the disease, caused by a defective virus or the presence of subclinical immunodeficiency – as has been confirmed by contemporary scientific studies – is discussed. The critical mechanisms of immune defense against VZV, the main cause of penetration of the virus into the CNS and the development of neurological disorders, and the relationship between VZV genotypes and the presence of mutations in the gE gene and the nature of the course of illness are described; the review also addresses detection of rare variants of the POLR3A, POLR3C, POLR3E, and POLR3F genes, which are associated with impaired interferon induction and the development of severe VZV infection, in which vasculopathy also occurs and is the basis for the use of complex vascular drugs such as Cytoflavin, whose efficacy has been evidenced by the authors. Particular emphasis is given to analysis of intrathecal immunopathogenesis, which may be associated with the presence and severity of neurological manifestations. The causes of severe disease in patients vaccinated against chicken pox are discussed, along with resistance to specific antiviral drugs, which is probably associated with mutations responsible for therapeutic resistance of the virus. [ABSTRACT FROM AUTHOR]

The first part of this paper presented the current knowledge on two very significant respiratory diseases with high pandemic potential, COVID-19 and influenza. The second part reviews other pathogens that cause acute respiratory viral infections, ARVI, including parainfluenza viruses, adenoviruses, pneumoviruses and specifically respiratory syncytial virus, enteroviruses, rhinoviruses, bocaviruses, and seasonal coronaviruses. The review presents modern data on the structure and replication of viruses, epidemiology and immunopathogenesis of diseases, diagnostics, preventive vaccination, and antiviral drugs. Topical issues regarding ARVI vaccination and the search for new broad-spectrum antiviral drugs are discussed. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE), the most common form of lupus, is a multisystemic rheumatic disease with different clinical features that generally affect women of childbearing age. The common symptoms of SLE are very similar to other autoimmune and non-autoimmune disorders, thereby it is known as a thousand faces disease. In this article, we are going to discuss some of the most updated information about immune system-related factors, cells, and cytokines involved in SLE pathogenesis. Methods: Different electronic databases, especially PubMed/MEDLINE, Scopus, and Google Scholar, were searched to review and analyze relevant literature on the role of innate and adaptive immune cells and cytokines in the pathogenesis of SLE. A search for relevant literature was accomplished using various keywords including systemic lupus erythematosus, apoptosis, autoantibodies, immunopathogenesis of SLE, adaptive and innate immune cells, inflammatory cytokines, hormones, etc. Results and conclusion: The most important characteristic of SLE is the production of antibodies against different nuclear autoantigens like double-strand DNA and RNA. The depositions of the immune complexes (ICs) that are generated between autoantibodies and autoantigens, along with aberrant clearance of them, can lead to permanent inflammation and contribute to tissue or organ damage. Related mechanisms underlying the initiation and development of SLE have not been clarified yet. Although, defects in immune tolerance, enhanced antigenic load, hyperactivity of T cells, and inappropriate regulation of B cells contribute to the pathogenic autoantibodies generation. Besides, sex hormones that influence the immune system seem to act as triggers or protectors of SLE development. [ABSTRACT FROM AUTHOR]

Idiopathic nephrotic syndrome (INS) is a common glomerular disease in childhood, and the immunological involvement in the pathogenesis of non-genetic INS, although not fully elucidated, is evident. This narrative review aims to offer a concise and in-depth view of the current knowledge on the immunological mechanisms of the development of INS as well as the role of the immunological components of the disease in the responsiveness to treatment. T cell immunity appears to play a major role in the INS immunopathogenesis and has been the first to be linked to the disease. Various T cell immunophenotypes are implicated in INS, including T-helper-1, T-helper-2, T-helper-17, and T regulatory cells, and various cytokines have been proposed as surrogate biomarkers of the disease; however, no distinct T helper or cytokine profile has been conclusively linked to the disease. More recently, the recognition of the role of B cell mediated immunity and the various B cell subsets that are dysregulated in patients with INS have led to new hypotheses on the underlying immunological causes of INS. Finally, the disambiguation of the exact mechanisms of the INS development in the future may be the key to the development of more targeted personalized approaches in managing INS.Conclusions: INS demonstrates particularly interesting immunopathogenetic pathways, in which multiple interactions between T cell and B cell immunity and the podocyte are involved. The disambiguation of these pathways will provide promising novel therapeutic targets in INS.What Is Known: • INS is the most common glomerular disease in the paediatric population, and its onset and relapses have been linked to various immunological triggers. • Multiple immunological mechanisms have been implicated in the pathogenesis of INS; however, no single distinct immunological profile has been recognized.What Is New: • Th17 cells and Treg cells play an important role in the immune dysregulation in INS. • Transitional B cell levels as well as the transitional/memory B cell ratio have been correlated to nephrotic relapses and have been proposed as biomarkers of INS relapses in SSNS patients. [ABSTRACT FROM AUTHOR]

The paper briefly reviews pathogens causing acute respiratory viral infections (ARVIs), including influenza viruses; coronaviruses, including SARS-CoV-2; parainfluenza viruses, adenoviruses, pneumoviruses, and specifically respiratory syncytial virus and metapneumoviruses, enteroviruses, rhinoviruses, and bocaviruses. This review presents modern data on the structure and replication of viruses, epidemiology, and immunopathogenesis of diseases and on diagnostics, preventive vaccination, and antiviral drugs for the treatment of ARVIs. Special attention is paid to the SARS-CoV-2 virus caused COVID-19 pandemic with analyses of similarities and differences between COVID-19 and other ARVIs, first of all, influenza virus. Topical issues regarding ARVI vaccination and the search for new broad-spectrum antiviral drugs are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Myositis as a rare manifestation of COVID-19 is only recently being reported. This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era. Recent Findings: COVID-19 is associated with a viral myositis attributable to direct myocyte invasion or induction of autoimmunity. COVID-19-induced myositis may be varied in presentation, from typical dermatomyositis to rhabdomyolysis, and a paraspinal affliction with back pain. It may or may not present with acute exponential elevations of enzyme markers such as creatine kinase (CK). Virus-mediated muscle inflammation is attributed to ACE2 (angiotensin-converting enzyme) receptor–mediated direct entry and affliction of muscle fibers, leading on to innate and adaptive immune activation. A greater recognition of the stark similarity between anti-MDA5-positive myositis with COVID-19 has thrown researchers into the alley of exploration — finding common etiopathogenic basis as well as therapeutic strategies. For patients with established myositis, chronic care was disrupted during the pandemic with several logistic challenges and treatment dilemmas leading to high flare rates. Teleconsultation bridged the gap while ushering in an era of patient-led care with the digital transition to tools of remote disease assessment. Summary: COVID-19 has brought along greater insight into unique manifestations of COVID-19-related myositis, ranging from direct virus-induced muscle disease to triggered autoimmunity and other etiopathogenic links to explore. A remarkable shift in the means of delivering chronic care has led patients and caregivers worldwide to embrace a virtual shift with teleconsultation and opened doorways to a new era of patient-led care. [ABSTRACT FROM AUTHOR]

Objective: Adenosine deaminase (ADA) associated with cell-mediated immune responses is involved in many diseases. But little is known about the value of ADA activity in the progression of different diabetes types. The purpose of this study was to compare the ADA level between latent autoimmune diabetes in adults (LADA), type 2 diabetes (T2D) patients, and healthy controls (HC) and analyze its correlation with glycemic parameters and systemic cytokines. Methods: This hospital-based study included 28 LADA patients, 52 T2D patients, and 50 HC. Serum ADA activity and concentrations of inflammatory cytokines were measured. Correlations of ADA level with different indicators were assessed by using spearman's correlation method. Results: Serum ADA activity was significantly higher in T2D patients compared with LADA (p = 0.008) and HC (p < 0.001). Correlation analysis of ADA with HbA1c% (r = 0.34, p = 0.003) and inflammatory cytokines (IL-6, r = 0.31, p = 0.007; IL-10, r = 0.22, p = 0.049) showed significant positive correlations. Conclusions: Serum ADA activity may reflect the different immunopathogenesis between LADA and T2D patients. [ABSTRACT FROM AUTHOR]

This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions. [ABSTRACT FROM AUTHOR]

Despite the ability of combination antiretroviral therapy to dramatically suppress viremia, the brain continues to be a reservoir of HIV-1 low-level replication. Adding further complexity to this is the comorbidity of drug abuse with HIV-1 associated neurocognitive disorders and neuroHIV. Among several abused drugs, the use of opiates is highly prevalent in HIV-1 infected individuals, both as an abused drug as well as for pain management. Opioids and their receptors have attained notable attention owing to their ability to modulate immune functions, in turn, impacting disease progression. Various cell culture, animal and human studies have implicated the role of opioids and their receptors in modulating viral replication and virus-mediated pathology both positively and negatively. Further, the combinatorial effects of HIV-1/HIV-1 proteins and morphine have demonstrated activation of inflammatory signaling in the host system. Herein, we summarized the current knowledge on the role of opioids on peripheral immunopathogenesis, viral immunopathogenesis, epigenetic profiles of the host and viral genome, neuropathogenesis of SIV/SHIV-infected non-human primates, blood-brain-barrier, HIV-1 viral latency, and viral rebound. Overall, this review provides recent insights into the role of opioids in HIV-1 immunopathogenesis. [ABSTRACT FROM AUTHOR]

Lacaziosis is a cutaneous chronic mycosis caused by Lacazia loboi. Macrophages are important cells in the host immune response in fungal infections. The macrophage population exhibits strong plasticity that varies according to the stimuli in the microenvironment of lesions M1 profile promotes a Th1 pattern of cytokines and a microbicidal function and M2 is related to Th2 cytokines and immunomodulatory response. We investigated the population of M1 and M2 polarized macrophages in human cutaneous lesions. A total of 27 biopsies from human lesions were submitted to an immunohistochemistry protocol using antibodies to detect M1 and M2 macrophages (Arginase-1, CD163, iNOS, RBP-J and cMAF). We could observe high number of cells expressing Arginase1, CD163 and c-MAF that correspond to elements of the M2 profile of macrophage, over iNOS and RBP-J (elements of the M1 profile). The results suggest a predominant phenotype of M2 macrophages, which have an immunomodulatory role and probably contributing to chronicity of Lacaziosis. [ABSTRACT FROM AUTHOR]

Copyright of Der Hautarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 × 106 pfu, i.m.) and challenged with RSV-A2 (3 × 106 pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI-RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1α, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI-RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-γ, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies. [ABSTRACT FROM AUTHOR]

The role of B lymphocytes in the pathogenesis of type 1 diabetes in humans is not entirely evident. These cells are presumed to be important, but this assumption is largely based on animal models of autoimmune diabetes, where compelling evidence for the contribution of both B lymphocytes and insulin-specific autoantibodies to this disease is in place. For humans, this is much less the case; the exact way in which B lymphocytes and/or autoantibodies may contribute to type 1 diabetes is not yet known but the possibilities include a pathogenic function ('fire'), or they may represent a surrogate of loss of immune tolerance to beta cells ('smoke') or, indeed, they could be a marker of an attempt at immune regulation ('ice water'). In this issue of Diabetologia, a study by Willcox et al (DOI: ) adds new information but no greater clarity on the relevance of B lymphocytes in type 1 diabetes, showing a decrease in germinal centre frequencies in donors with recent-onset type 1 diabetes compared with control donors and donors with longstanding type 1 diabetes. These new findings may guide the research community to design experiments to unambiguously define whether B lymphocytes or their products function as fire, smoke or perhaps ice water in the immunopathogenesis of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Vitamin A, considered to be an essential nutrient, has important actions in immunological responses and the central nervous system (CNS). Neuroimmunological functions of vitamin A are mediated through its active metabolite, retinoic acid (RA). In the CNS, RA contributes to regeneration and plasticity, while also playing a key role in enhancing tolerance and reducing inflammatory responses by regulating T cell, B cell and dendritic cell populations. However, evidence has indicated lower plasma levels of vitamin A in patients with multiple sclerosis (MS). Vitamin A deficiency leads to dysregulation of immune tolerance and pathogenic immune cell production in this disease. Vitamin A may ameliorate MS pathogenesis through numerous mechanisms including a reduction in inflammatory processes by re-establishing the balance between pathogenic (Th1, Th17, Th9) and immunoprotective cells (Th2, Tregs), modulating B cell and dendritic cell function as well as increasing tolerance of autoimmunity and regeneration in the CNS. Thus, the results from the current review suggest that vitamin A can be considered as a potential treatment in MS disease management. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection is a worldwide health problem, with approximately one third of populations have been infected, among which 3-5 % of adults and more than 90 % of children developed to chronic HBV infection. Host immune factors play essential roles in the outcome of HBV infection. Thus, ineffective immune response against HBV may result in persistent virus replications and liver necroinflammations, then lead to chronic HBV infection, liver cirrhosis, and even hepatocellular carcinoma. Cytokine balance was shown to be an important immune characteristic in the development and progression of hepatitis B, as well as in an effective antiviral immunity. Large numbers of cytokines are not only involved in the initiation and regulation of immune responses but also contributing directly or indirectly to the inhibition of virus replication. Besides, cytokines initiate downstream signaling pathway activities by binding to specific receptors expressed on the target cells and play important roles in the responses against viral infections and, therefore, might affect susceptibility to HBV and/or the natural course of the infection. Since cytokines are the primary causes of inflammation and mediates liver injury after HBV infection, we have discussed recent advances on the roles of various cytokines [including T helper type 1 cells (Th1), Th2, Th17, regulatory T cells (Treg)-related cytokines] in different phases of HBV infection and cytokine-related mechanisms for impaired viral control and liver damage during HBV infection. We then focus on experimental therapeutic applications of cytokines to gain a better understanding of this newly emerging aspect of disease pathogenesis. [ABSTRACT FROM AUTHOR]

We performed a comprehensive analysis of CCR6 and CXCR3 chemokine receptors and their ligands CCL20/MIP-3α, CXCL9/MIG, CXCL10/IP-10, and CXCL11/ITAC in the liver and blood of patients with chronic hepatitis C at different stages of the disease. TaqMan PCR was used to determine mRNA gene expression of chemokines and their receptors in liver specimens, xMAP multiplex analysis was performed to estimate the concentration of chemokines in blood plasma, and fl ow cytofluorometry was used to evaluate CCR6 and CXCR3 expression on peripheral blood lymphocyte populations. In the liver of patients with hepatitis C, mRNA expression of CXCL10, CCR6, and CXCR3 genes increases with fibrosis progression in the liver tissue. In the plasma, concentrations of all studied chemokines increased depending on the stage of liver fibrosis, CCR6 and CXCR3 expression was changed in various lymphocyte populations. Thus, chemokines are involved in the immunopathogenesis and fibrogenesis in chronic viral hepatitis C. The results suggest using these chemokines in the diagnosis and prognosis of the disease. [ABSTRACT FROM AUTHOR]

Cytokines and growth factors are key regulators of immune activation, vascular alteration and excessive production of extracellular matrix which are hallmark events in the pathogenesis of systemic sclerosis (SSc). They modulate cell-cell and cell-matrix interactions. In particular, cytokines play a central role in the immunopathogenesis of SSc on the basis of molecular pathways which are complex and not completely understood. The majority of cytokines that may be involved in SSc pathogenesis have effect upon or are derived from cells of the immune system, including both the innate and adaptive compartments. Novel therapies that block key mediators that drive the fibrotic response are being developed and appear as potential therapeutic tools in the treatment of SSc, highlighting the importance for an effective therapy targeted towards the molecular and cellular pathways. This article reviews cytokine biology in that context, with particular emphasis on immunopathology of the disease, therapeutic targeting and the way that current or emerging treatments for SSc might impact on cytokine biology. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate a possible association between the immunoexpression of interleukin (IL)-4 and clinicopathological parameters with the periodontal breakdown observed in gingival pyogenic granuloma (PG). Materials and methods: Paraffin-embedded samples of gingival PG ( n = 46) were prepared for histological and immunohistochemical assessment. Demographic and clinical parameters were assessed by criteria based on age stratum, gender, smoking habit, evolution course, location, lesion size, macroscopic appearance, predisposing factors, recurrence, and periodontal breakdown. Histological assessment included the appearance of epithelial lining, microvessel density, inflammatory infiltrate density, interstitial fibrosis, and histological arrangement. A staining intensity distribution (SID) score was used to assess IL-4 immunoreactivity. The association between candidate predictor variables and periodontal breakdown was analyzed individually and adjusted for confounding using a bivariate binary logistic regression model. Results: Mean IL-4 SID values were significantly increased for long-standing and large lesions, presence of periodontal breakdown, high microvessel density, and moderate-to-severe inflammatory infiltrate density. While bivariate and univariate analyses revealed a positive association of the evolution course ≥12 months, lesion size >1 cm, high microvessel density, moderate-to-severe inflammatory infiltrate density, and IL-4 SID score ≥8.04 with periodontal breakdown, after bivariate logistic regression analysis, only the evolution course ≥12 months, moderate-to-severe inflammatory infiltrate density, and IL-4 SID score ≥8.04 remained as robust predictors of periodontal damage. Confounding and interaction effects between candidate predictor variables were also noted. Conclusion: These findings suggest that while evolution course, inflammatory infiltrate density, and the overexpression of IL-4 may act as predictors of periodontal breakdown in gingival PG, there are mutual confounding and synergistic biological interactive effects with respect to the lesion size and microvessel density in the susceptible host that may be also associated with the bone resorption and tissue destruction. Clinical relevance: Although the first-line therapy of gingival PG continues to be the surgical excision, this approach poses unwanted complications such as severe mucogingival defects and recurrence. Hence, early diagnosis and detection of these three significant predictor variables as well as timely surgical excision might help prevent the periodontal tissue destruction observed in some of these lesions. [ABSTRACT FROM AUTHOR]

Copyright of Der Internist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims/hypothesis: Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), is differentially spliced between pancreatic beta cells and the thymus. This may contribute to incomplete elimination of IGRP-specific T lymphocytes in the thymus, predisposing individuals to type 1 diabetes. We tested whether specific splice variation in islets vs thymus correlates with loss of tolerance to IGRP in type 1 diabetes. Methods: Expression of G6PC2 splice variants was compared among thymus, purified medullary thymic epithelial cells and pancreatic islets by RT-PCR. Differential immunogenicity of IGRP splice variants was tested in patients and healthy individuals for autoantibodies and specific cytotoxic T lymphocytes using radiobinding assays and HLA class I multimers, respectively. Results: Previously reported G6PC2 splice variants, including full-length G6PC2, were confirmed, albeit that they occurred in both pancreas and thymus, rather than islets alone. Yet, their expression levels were profoundly greater in islets than in thymus. Moreover, three novel G6PC2 variants were discovered that occur in islets only, leading to protein truncations, frame shifts and neo-sequences prone to immunogenicity. However, autoantibodies to novel or known IGRP splice variants did not differ between patients and healthy individuals, and similar frequencies of IGRP-specific cytotoxic T lymphocytes could be detected in both patients with type 1 diabetes and healthy individuals. Conclusions/interpretation: We propose that post-transcriptional variation of tissue-specific self-proteins may affect negative thymic selection, although this need not necessarily lead to disease. [ABSTRACT FROM AUTHOR]

Substantial advancements in the field of primary biliary cirrhosis (PBC) research have broadened our understanding of this enigmatic disease. Genome-wide studies have identified several new candidate genes involved in the immunoregulatory process, particularly those responsible for antigen presentation and lymphocyte signaling. Examples include the HLA class-II region and genes implicated in IL12-JAK/STAT signaling, and the NF-κB and TNF signaling pathways. Environmental triggers appear to disrupt the pre-existing, unstable immune tolerance in genetically susceptible individuals, and molecular mimics of the PBC-specific autoantigen (PDC) may be derived from microbes or xenobiotic compounds, which modify native proteins, making them immunogenic. Although the vast majority of patients with PBC are AMA-positive, a variety of disease-specific antinuclear antibodies have been recognized in conferring a worse clinical outcome. There has also been a revived interest in the role of antibody-secreting B cells in murine models suggesting that depletion of these cells paradoxically exacerbates cholangiopathy. Biliary specificity in PBC is most likely driven by the uniqueness of cholangiocyte apoptosis in which the PDC-E2 autoantigen undergoes differential glutathiolation. Cholangiocytes also possess the ability to phagocytose neighboring apoptotic cells, present intact immunoreactive antigen, and undergo attack from autoantibodies, the innate immune system, and autoreactive lymphocytes. Cellular senescence and a lack of functioning T-regulatory cells are proposed mechanisms by which this multi-lineage process is thought to be enhanced. This review summarizes these key advances as the true complexities of the disease process begin to be unraveled. [ABSTRACT FROM AUTHOR]

We have previously demonstrated the critical role of C-C chemokine CCL2 in HIV-1 pathogenesis, and circulating monocytes as the major source of CCL2. Since the functional aspect of monocyte subsets in context to CCL2 production is unclear, we investigated the frequency and production of CCL2 by circulating monocyte subsets in a cohort of HIV- therapy naïve patients. A cohort of HIV-infected therapy naïve patients ( n = 9) and healthy controls ( n = 6) were recruited for this study. To examine monocyte subset frequency and CCL2 production, we performed surface and intra-cellular staining of freshly isolated peripheral blood mononuclear cells (PBMC) and subjected to flow cytometry. A preferential expansion of CD14CD16 monocyte subset, coupled with increased intracellular production of CCL2 was observed in HIV-1 patients compared to healthy controls. Interestingly this phenotype was mostly restricted to CD14CD16 monocyte subsets. This study identifies pro-inflammatory CCL2 producing CD14CD16 monocyte subset that expands selectively in HIV-1 infection and could potentially participate in causing immuno-pathology. [ABSTRACT FROM AUTHOR]

Background: The immunopathogenesis of dual chronic infection with hepatitis B virus and hepatitis C virus (HBV/HCV) remains unclear. The in vivo suppressive effects of each virus on the other have been reported. In this study we aimed to analyze the virological and immunological parameters of HBV/HCV coinfected patients during pegylated interferon/ribavirin (Peg-IFN/RBV) therapy. Methods: One patient with high HBV-DNA and high HCV-RNA titers (HBV-high/HCV-high) and 5 patients with low HBV-DNA and high HCV-RNA titers (HBV-low/HCV-high) were enrolled. Twenty patients monoinfected with HBV and 10 patients monoinfected with HCV were enrolled as control subjects.. In vitro cultures of Huh 7 cells with HBV/HCV dual infection were used to analyze the direct interaction of HBV/HCV. Results: Direct interaction of HBV clones and HCV could not be detected in the Huh-7 cells. In the HBV-high/HCV-high-patient, the HCV-RNA level gradually declined and HBV-DNA gradually increased during Peg-IFN/RBV therapy. Activated CD4- and CD8-positive T cells were increased at 1 month of Peg-IFN/RBV-therapy, but HBV-specific IFN-γ-secreting cells were not increased and HBV-specific interleukin (IL)-10 secreting cells were increased. The level of HBV- and HCV-specific IFN-γ-secreting cells in the HBV-high/HCV-high-patient was low in comparison to that in the HBV- or HCV-monoinfected patients. In the HBV-low/HCV-high-patient, HCV-RNA and HBV-DNA rapidly declined during Peg-IFN/RBV therapy. Activated CD4- and CD8-positive T cells were increased, and HBV- and HCV-specific IFN-γ-secreting cells were also increased during Peg-IFN/RBV-therapy. Conclusion: The immunological responses of the HBV-high/HCV-high patient were low in comparison to the responses in HBV and HCV monoinfected patients. Moreover, the response of immune cells in the HBV-high/HCV-high patient during Peg-IFN/RBV therapy was insufficient to suppress HBV and HCV. [ABSTRACT FROM AUTHOR]

Neurotropic flaviviruses are important emerging and reemerging arthropod-borne pathogens that cause significant morbidity and mortality in humans and other vertebrates worldwide. Upon entry and infection of the CNS, these viruses can induce a rapid inflammatory response characterized by the infiltration of leukocytes into the brain parenchyma. Chemokines and their receptors are involved in coordinating complex leukocyte trafficking patterns that regulate viral pathogenesis in vivo. In this review, we will summarize the current literature on the role of chemokines in regulating the pathogenesis of West Nile, Japanese encephalitis, and tick-borne encephalitis virus infections in mouse models and humans. Understanding how viral infections trigger chemokines, the key cellular events that occur during the infection process, as well as the immunopathogenic role of these cells, are critical areas of research that may ultimately guide a much needed effort toward developing specific immunomodulators and/or antiviral therapeutics. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum malaria claims 1 million lives around the globe every year. Parasitemia can reach remarkably high levels. The developing parasite digests hemoglobin and converts the waste product to hemozoin alias malaria pigment. These processes occur in a vesicular compartment named the digestive vacuole (DV). Each parasitized cell releases one DV upon rupture. Myriads of DVs thus gain entry into the blood, but whether they trigger pathobiological events has never been investigated. We recently discovered that the DV membrane simultaneously activates the two major enzyme cascades in blood, complement and coagulation. Activation of both is known to occur in patients with severe malaria, so discovery of the common trigger has large consequences. The DV membrane but not the merozoite has the capacity to spontaneously activate the alternative complement and intrinsic clotting pathway. Ejection of merozoites and the DV into the bloodstream, therefore, results in selective opsonization and phagocytosis of the DV, leaving merozoites free to invade new cells. The DV membrane furthermore has the capacity to assemble prothrombinase, the key convertase of the intrinsic clotting pathway. The dual capacity of the DV to activate both complement and coagulation can be suppressed by low-molecular-weight dextran sulfate. This agent protects experimental animals from the detrimental consequences, resulting from intravenous application of purified DVs. Phagocytosis of DVs not only deploys PMN away from merozoites, but also drives the cells into a state of functional exhaustion. This may be one reason for the enhanced susceptibility of patients with severe malaria toward systemic bacterial infections. Together, these findings indicate that the DV may represent a hitherto unrecognized, important determinant of parasite pathogenicity. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated cytokines and chemokine in different regions of the rat brain at different time points following Japanese encephalitis virus (JEV) infection. Design: Twelve-day-old Wistar rats were infected by intracerebral inoculation of 3 × 10 plaque-forming units of JEV 78668A strain. Expression of cytokines and chemokine was assayed using cytokine bead array in different regions of the brain at 3, 6, 10 and 20 days post-inoculation (dpi). Pathological changes including immunohistochemistry for JEV antigen were observed. Results: The cytokine levels were increased in the acute stage and declined on follow-up. In the acute stage (6 dpi), the levels of TNF-α, IFN-γ, IL-6 and IL-10 were maximum in the cortex, whereas the level of IL-4 was maximum in the striatum. Lower levels of these cytokines were observed in mid-brain and thalamus compared to other regions studied. Maximum expression of JEV antigen and histopathological changes as well as cytokines and chemokine were observed at 6 dpi in all the brain regions studied, but declined thereafter. Conclusion: This experimental study revealed maximum expression of cytokines and chemokine at 6 dpi of JEV infection which corresponded with histopathological changes in different brain regions. [ABSTRACT FROM AUTHOR]

Increased circulating and intracardiac levels of proinflammatory cytokines have been associated with chronic heart failure. Following an initial insult, the increased production of proinflammatory cytokines, including TNF-α, IL-6, IL-1, and IL-18, jeopardizes the surrounding tissue through propagation of the inflammatory response and direct effects on the cardiac myocyte structure and function. Cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling contribute enormously to the development and progression of chronic heart failure. Despite the identification of efficacious pharmacological regimens and introduction of mechanical interventions, chronic heart failure remains among the leading causes of mortality worldwide. To introduce novel therapeutic strategies that modulate the inflammatory response in the context of the failing heart, it is of prime importance to determine the contributions of TNF-α, IL-6, IL-1, and IL-18 in mediating cardiac adaptive and maladaptive responses, as well as delineating their downstream intracellular signaling pathways and their potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Minimal change nephrotic syndrome (MCNS) in children is frequently associated with allergy and immunoglobulin E production. T helper subtype 2 cytokines, such as interleukin (IL)-4 and IL-13, may have an important role in the development of atopy. We investigated the association of genetic variations of IL-4 receptor α chain (IL-4Rα), IL-13 and signal transducer and activator of transcription 6 ( STAT6) genes with MCNS. We analyzed these polymorphisms in 85 Japanese children (55 males, 30 females) with MCNS and 127 healthy controls with neither allergic nor renal diseases. Genomic DNA was extracted from peripheral blood leukocytes. The single nucleotide polymorphisms of IL-4Rα (Ile50Val) and IL-13 (R130Q) were detected by primer-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism analysis, respectively. GT repeat polymorphism in STAT6 gene exon 1 was investigated by fragment length analysis. A significant difference in allelic frequencies in the STAT6 gene was detected between the MCNS and control groups. There was no significant difference between the two groups for genetic variations of IL-4Rα and IL-13 genes. We found a significant difference in IL-4Rα gene polymorphism between MCNS subgroups divided according to the number of relapses. These results suggested that the genetic variation in the first exon of the STAT6 gene may be associated with a predisposition to MCNS and that the genetic variation in the IL-4Rα gene may be associated with its clinical course. [ABSTRACT FROM AUTHOR]

Acute and chronic infection with hepatitis B virus (HBV) is associated with an increased risk of developing liver disease including cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The clinical presentation and natural history of HBV infection is mediated through complex interactions between the virus and the host immune response. HBV is not directly cytopathic to heptocytes; however, the interaction between the virus and the host immune response plays a central role in the pathogenesis of necroinflammation and liver fibrosis. Emerging data from immunopathogenesis studies in animal models and in vitro studies of liver biopsies from patients with chronic hepatitis B demonstrate a potentially important interaction between hepatitis B e antigen, HBV, and components of the innate immune response including Toll-like receptors, Kupffer cells, natural killer T-cells, and dendritic cells. These findings suggest that the innate immune response has an important role in influencing the outcome of acute and chronic HBV infection. The current knowledge regarding the interaction between HBV and components of the innate immune response during acute and chronic HBV infection is reviewed. [ABSTRACT FROM AUTHOR]

Major advancements in the field of lung transplantation have occurred over the past thirty-five years. Despite these advancements, limitations in our ability to obtain sufficient numbers of organs and in our comprehension of the problems associated with the procedure persist. The purpose of this article is to review the current understanding of both the surgical procedure and its most unfortunate complication, bronchiolitis obliterans. Even now, after over three decades of experience, this complication remains the most significant cause of morbidity and mortality following lung transplantation. This article is not meant to be an exhaustive review, and certainly there are important topics not covered herein. We have focused the discussion on ongoing studies, which attempt to understand bronchiolitis oblieterans at both the clinical as well as the immunopathological level. [ABSTRACT FROM AUTHOR]

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Nervenarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cutaneous vasculitis is a heterogeneous group of disorders, and may occur with virtually all syndromes of vasculitis. It can occur as an isolated dermatologic disorder or as a manifestation of a potentially life-threatening systemic vasculitis. Cutaneous manifestations vary depending on the underlying cause, the size of the vessel involved and the severity and type of inflammation. In this short review, the classification, the characteristic skin manifestations of the primary vasculitides and new pathogenic aspects are discussed. [ABSTRACT FROM AUTHOR]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Based on a suspected role of the immune system in the pathophysiology of Alzheimer's disease (AD) and the new discoveries of neuroimmune networks, the investigation of certain neuroimmune markers was performed in AD patients, healthy controls, and disease controls. In agreement with our previous immunological research on AD, the assessment of additional immune parameters revealed abnormalities of both cellular and humoral immunity in several AD patients. These include: As analyzed by flow cytometry and enzyme immunoassay, the peripheral blood immunocytes from AD patients showed a significant increase in the expression of the brain-derived S-100 protein. In the cell proliferation assay, the blood immunocytes from healthy subjects responded to stimulation with beta-amyloid protein (βAP), but this response was absent in AD patients. The initial results of our research suggest that the studies of specific markers of the neuroimmune axis may be potentially important for the new development of diagnostic and therapeutic strategies for AD. [ABSTRACT FROM AUTHOR]

Copyright of Der Nervenarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immune complexes (ICs) participate in the pathogenesis of various diseases and can be shown in 18% of all hospitalized patients (excluding those with infectious diseases) by means of a sensitive method such as the Raji-cell radioimmune assay. However, before this test can be applied to quantify disease activity in renal, connective tissue and neoplastic diseases, it must be recognized that febrile infections of the upper respiratory tract also induce ICs in 86% of all patients. The immune complexes containing microbial antigens can be reduced or removed by a single injection of human immunoglobulin. This is a simple method to distinguish between the immune complexes of different specifities. The resulting removal of some immune complexes may be the explanation for the claimed therapeutic effect of gammaglobulin injection in normogammaglobulinemic patients. [ABSTRACT FROM AUTHOR]

Takayasu arteritis is a common cause of renovascular hypertension in India. Sensitization to infective agents, particularly mycobacterium tuberculosis or antoimmune disturbances have been incriminated in its pathogenesis. Twenty patients of Takayasu arteritis along with groups of normal individuals, patients of essential hypertension, autoimmune disorders, tuberculosis, and healthy tuberculin reactors were studied. Besides detailed immunological profiles including LE cell phenomenon, serum complement C3 levels, antibodies to single (SS) and double stranded (DS) DNA, rheumatoid factor, lymphocyte subsets, blast transformation to antigens including, phytohemagglutinine, PPD, pokeweed, and purified human aortal antigen (PHAA) were examined. Soluble protein from human aorta was fractionated into 9 peaks by DEASE-52 and Sephadex G-75 chromatography, and 25 µg of major protein fraction-II was used for blast transformation study. Blast transformation by PHAA was higher in Takayasu arteritis as compared to all other groups ( P < 0.05). Blast transformation to PPD showed wide variation in all the groups, and was significantly higher only in tuberculin reactors as compared to controls. These observations support aortal sensitization to PHAA playing a role in pathogenesis of Takayasu arteritis and do not relate tuberculosis to Takayasu arteritis, at least immunologically. In addition, the ratio of CD-4 positive to CD-8 positive lymphocytes changing in favor of the former and the concomitant increase in B lymphocytes favor the presence of autoimmune disturbances in Takayasu arteritis. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a distinct form of acute and chronic inflammatory liver disease in which immune reactions against host antigens are found to be the major pathological mechanism. If left untreated it carries an unfavourable prognosis, and the diagnosis should be made as soon as possible. The diagnostic approach has been greatly facilitated by the establishment of a panel of marker autoantibodies, which do not define distinct therapeutic groups of AIH, but do allow a subgrouping based on differences in patient populations, some clinical features and prognosis. The characterization of organ-specific components of the liver cell surface as targets of cellular and humoral autoimmune reactions give new insights into the pathogenesis of the disease, even though the primary event triggering the disease remains to be defined. The most important diseasepromoting factor seems to be a genetically determined background for autoimmunity. Without this different environmental factors, including viruses, toxins, cytokines and drugs, are only able to induce transient autoimmune phenomena and not autoimmune disease. The histopathology of AIH is in keeping with the present pathogenetic concept. Although there is no pathognomonic feature distinguishing this type of hepatitis from virus-induced forms, some distinct morphological lesions are regarded as characteristic. Clinical research on AIH has benefited greatly from observations of experimental AIH in mice. Recognition of the critical role of autoreactive T-lymphocytes in the pathogenesis and the observation of spontaneous recovery from AIH in the animal model associated with antigen-specific and antigen-non-specific T-cell suppression have made basic contributions to our improved understanding of the natural course of AIH in humans. [ABSTRACT FROM AUTHOR]

Fatty acid anilides, the major xenobiotic found in the cooking oils responsible for the Spanish toxic oil syndrome, are immunogenic for rabbits as ascertained by a skin test reaction, the characterization of specific antibodies against anilides and the immunofluorescent detection of 'anilide dependent antigens' in tissue slices from treated animals. [ABSTRACT FROM AUTHOR]

Infection with human immunodeficiency virus (HIV) causes an extensive array of immunologic abnormalities which ultimately lead to severe immunosuppression, opportunistic disease, and death. Many of the immunologic defects can be attributable to the quantitative and qualitative deficiencies of T4 lymphocytes caused by HIV. Other abnormalities may reflect chronic HIV exposure to or infection of other immunologic cells including B cells and monocyte/macrophages. A summary of the potential mechanisms of pathogenesis of HIV infection is shown in fig. 2. One of the most puzzling aspects of infection with HIV is the length and variability of time between initial infection and disease. It appears that activation of latent or chronic, smoldering infection into active disease may be the result of a variety of factors, including heterologous viruses and cytokines, whose common denominator is the ability to induce the production of DNA-binding proteins that interact with the HIV-LTR and induce transcription of virus. [ABSTRACT FROM AUTHOR]