Regulation of the immune response in lymphatic filariasis: perspectives on acute and chronic infection with Wuchereria bancrofti in South India

Delineating the immune responses in lymphatic filariasis has been complicated not only by the rapidly expanding knowledge of new immunological mediators and effortors, but also by new methodologies (in particular, circulating filarial antigen detection) for defining and categorizing filarial-infected individuals. By using assays for circulating antigen in the sera collected as part of the many immunological studies performed on individuals in a Wuchereria bancrofti-endemic region of South India, we have attempted to explore the influence of patency on the antigen-driven proliferative and cytokine responses seen in peripheral blood mononuclear cells of individuals with varying clinical manifestations of lymphatic filarial infection. Moreover, we have provided perspectives on the differences between acute and chronic infection with W. bancrofti and suggested mechanisms that may underly the modulation of the immune response as patency occurs.     

Transgenic Leishmania and the immune response to infection

Genetic manipulation of single-celled organisms such as the Leishmania parasite enables in depth analysis of the consequences of genotypic change on biological function. In probing the immune responses to infection, use of transgenic Leishmania has the potential to unravel both the contribution of the parasite to the infection process and the cellular interactions and mechanisms that characterize the innate and adaptive immune responses of the host. Here, we briefly review recent technical advances in parasite genetics and explore how these methods are being used to investigate parasite virulence factors, elucidate immune regulatory mechanisms and contribute to the development of novel therapeutics for the leishmaniases. Recent developments in imaging technology, such as bioluminescence and intravital imaging, combined with parasite transfection with fluorescent or enzyme-encoding marker genes, provides a rich opportunity for novel assessment of intimate, real-time host-parasite interactions at a previously unexplored level. Further advances in transgenic technology, such as the introduction of robust inducible gene cassettes for expression in intracellular parasite stages or the development of RNA interference methods for down-regulation of parasite gene expression in the host, will further advance our ability to probe host-parasite interactions and unravel disease-promoting mechanisms in the leishmaniases.     

Worms: Pernicious parasites or allies against allergies?

Type 2 immune responses are most commonly associated with allergy and helminth parasite infections. Since the discovery of Th1 and Th2 immune responses more than 30 years ago, models of both allergic disease and helminth infections have been useful in characterizing the development, effector mechanisms and pathological consequences of type 2 immune responses. The observation that some helminth infections negatively correlate with allergic and inflammatory disease led to a large field of research into parasite immunomodulation. However, it is worth noting that helminth parasites are not always benign infections, and that helminth immunomodulation can have stimulatory as well as suppressive effects on allergic responses. In this review, we will discuss how parasitic infections change host responses, the consequences for bystander immunity and how this interaction influences clinical symptoms of allergy.     

Lymphatic filariasis: parallels between the immunology of infection in humans and mice

Mouse models of Brugia infection have provided much useful quantitative and qualitative information on the immune response elicited by different life cycle stages of filarial worms. Many parallels exist between the immune response in the mouse and the infected human and in this review we highlight areas of topical interest, including the induction of specific cytokine responses and their role in immunomodulation and protective immunity. These studies have reinforced the concept that different life cycle stages of filarial parasites each have their own mechanism of modulating responses so that potentially inflammatory IFN-gamma responses are downregulated. While the precise mechanisms of protective immunity remain to be defined, studies in the mouse have suggested novel pathways, including a possible role for granulocytes.     

Human lung immunity against Mycobacterium tuberculosis: insights into pathogenesis and protection

The study of human pulmonary immunity against Mycobacterium tuberculosis (M.tb) provides a unique window into the biological interactions between the human host and M.tb within the broncho-alveolar microenvironment, the site of natural infection. Studies of bronchoalveolar cells (BACs) and lung tissue evaluate innate, adaptive, and regulatory immune mechanisms that collectively contribute to immunological protection or its failure. In aerogenically M.tb-exposed healthy persons lung immune responses reflect early host pathogen interactions that may contribute to sterilization, the development of latent M.tb infection, or progression to active disease. Studies in these persons may allow the identification of biomarkers of protective immunity before the initiation of inflammatory and disease-associated immunopathological changes. In healthy close contacts of patients with tuberculosis (TB) and during active pulmonary TB, immune responses are compartmentalized to the lungs and characterized by an exuberant helper T-cell type 1 response, which as suggested by recent evidence is counteracted by local suppressive immune mechanisms. Here we discuss how exploring human lung immunity may provide insights into disease progression and mechanisms of failure of immunological protection at the site of the initial host-pathogen interaction. These findings may also aid in the identification of new biomarkers of protective immunity that are urgently needed for the development of new and the improvement of current TB vaccines, adjuvant immunotherapies, and diagnostic technologies. To facilitate further work in this area, methodological and procedural approaches for bronchoalveolar lavage studies and their limitations are also discussed.     

Immune mechanisms in human and canine demodicosis: A review

Demodex mites are saprophytic parasites of the mammalian skin, mostly found in or near pilosebaceous units of hairy regions. While they can be found in healthy humans and animals without causing any clinical manifestations, they were suggested to create pathogenic symptoms when they appear in high densities under favourable conditions (ie, demodicosis). Nevertheless, their role as the primary causative agent of the pathogenic conditions in humans is debated today. Canine demodicosis, which is highly prevalent in certain dog breeds, provides a valuable tool for studying the pathogenesis of human demodicosis. Canine and human demodicosis are caused by different Demodex species, and the clinical manifestations in former could be life‐threatening. Nevertheless, current literature suggests similar immune responses and immune evasion mechanisms in human and canine demodicosis; cellular immunity appeared to have a central role in protection against demodicosis, and Demodex mites were shown to influence both innate and adaptive immune response to escape immune attack. The aim of this review is to summarize the relevant literature on demodicosis obtained from studies conducted on both organisms, and draw the attention to the effect of mite‐associated factors (eg, microbiota) on the different clinical manifestations displayed during human and canine demodicosis.     

What can transgenic parasites tell us about the development of Plasmodium‐specific immune responses?

Malaria infects 500 million people and kills an estimated 2.7 million annually, representing one of the most significant diseases in the world. However, efforts to develop effective vaccines have met with limited success. One reason is our lack of basic knowledge of how and where the immune system responds to parasite antigens. This is important as the early events during induction of an immune response influence the acquisition of effector function and development of memory responses. Our knowledge of the interactions of Plasmodia with the host immune system has largely been derived through in vitro study. This is a significant issue as the component parts of the immune system do not work in isolation and their interactions occur in distinct and specialized micro- and macro-anatomical locations that can only be assessed in the physiological context, in vivo. In this context, the availability of transgenic malaria parasites over the last 10 years has greatly enhanced our ability to understand and evaluate factors involved in host-parasite interactions in vivo. In this article, we review the current status of this area and speculate on what parasite transgenesis approaches will tell us about the development of Plasmodium-specific immune responses in the future.     

Immune responses in parasitic diseases. Part B: mechanisms

A number of host defenses provide variable resistance against parasites. From the biological point of view, invading parasites must not eliminate the susceptible host population; therefore, antiparasite immunity plays an essential role in limiting the invasion and proliferation of parasites. Several differences exist between immune responses to parasites and immune responses to other microorganisms. Effector mechanisms include T lymphocyte-mediated inflammatory granuloma formation and encapsulation involving the deposition of fibrous tissue. In some instances, passive immunity can be transferred by serum antibodies. Antibodies may act via complement fixation, granulocyte adhesion, opsonization, inhibition of invasion, or mast cell degranulation. Of the nonspecific factors, macrophage activation, natural killer cells, and serum factors other than antibodies are critical in the battle against parasites. The net result of these immune responses may be antiparasitic, proparasitic, of no consequence to either host or parasite, or harmful to the host.     

Consequences of HIV infection on malaria and therapeutic implications: a systematic review

Despite recent changes in the epidemiology of HIV infection and malaria and major improvements in their control, these diseases remain two of the most important infectious diseases and global health priorities. As they have overlapping distribution in tropical areas, particularly sub-Saharan Africa, any of their clinical, diagnostic, and therapeutic interactions might have important effects on patient care and public health policy. The biological basis of these interactions is well established. HIV infection induces cellular depletion and early abnormalities of CD4+ T cells, decreases CD8+ T-cell counts and function (cellular immunity), causes deterioration of specific antigen responses (humoral immunity), and leads to alteration of innate immunity through impairment of cytolytic activity and cytokine production by natural killer cells. Therefore, HIV infection affects the immune response to malaria, particularly premunition in adolescents and adults, and pregnancy-specific immunity, leading to different patterns of disease in HIV-infected patients compared with HIV-uninfected patients. In this systematic review, we collate data on the effects of HIV on malaria and discuss their therapeutic consequences. HIV infection is associated with increased prevalence and severity of clinical malaria and impaired response to antimalarial treatment, depending on age, immunodepression, and previous immunity to malaria. HIV also affects pregnancy-specific immunity to malaria and response to intermittent preventive treatment. Co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis and antiretroviral treatment reduce occurrence of clinical malaria; however, these therapies interact with antimalarial drugs, and new therapeutic guidelines are needed for concomitant use.     

Interactions between host and oral commensal microorganisms are key events in health and disease status.

The oral cavity has sometimes been described as a mirror that reflects a person's health. Systemic disease such as diabetes or vitamin deficiency may be seen as alterations in the oral mucosa. A variety of external factors cause changes in the oral mucosa, thus altering mucosal structure and function, and promoting oral pathologies (most frequently bacterial, fungal and viral infections). Little is known, however, about immune surveillance mechanisms that involve the oral mucosa.There is no direct contact between specific immune cells in the basal epithelium and microorganisms in the upper layers of the oral mucosa. The author's hypothesis is that the protective immunity is conveyed through epithelial cells. The present brief review assesses the oral mucosa's role as the main defense in the interactions between the host and the oral microbial community. A unique model was used to investigate these interactions as the cause of oral disease and to develop new treatments that exploit our knowledge of the host-microorganism relationship.     

Worms and malaria: noisy nuisances and silent benefits

The burden of malaria mortality has been a major evolutionary influence on human immunity. The selection of the most successful immune responses against malaria has been in populations concomitantly infected by intestinal helminths. Animal models have shown that coinfections with helminths and protozoa in the same host elicit a range of antagonist and synergistic interactions. Recent findings suggest similar interactions take place between helminths, Plasmodium falciparum and humans. However, as the threat of HIV and tuberculosis becomes a major selective force, what used to be a successful ecological system may now prove detrimental. Nevertheless, the understanding of the ecological forces at play may expose new intervention targets for malaria control, and give a new perspective on our shortcomings against the deadliest of human parasites.     

The Interplay between Bluetongue Virus Infections and Adaptive Immunity

Viral infections have long provided a platform to understand the workings of immunity. For instance, great strides towards defining basic immunology concepts, such as MHC restriction of antigen presentation or T-cell memory development and maintenance, have been achieved thanks to the study of lymphocytic choriomeningitis virus (LCMV) infections. These studies have also shaped our understanding of antiviral immunity, and in particular T-cell responses. In the present review, we discuss how bluetongue virus (BTV), an economically important arbovirus from the Reoviridae family that affects ruminants, affects adaptive immunity in the natural hosts. During the initial stages of infection, BTV triggers leucopenia in the hosts. The host then mounts an adaptive immune response that controls the disease. In this work, we discuss how BTV triggers CD8⁺ T-cell expansion and neutralizing antibody responses, yet in some individuals viremia remains detectable after these adaptive immune mechanisms are active. We present some unpublished data showing that BTV infection also affects other T cell populations such as CD4⁺ T-cells or γδ T-cells, as well as B-cell numbers in the periphery. This review also discusses how BTV evades these adaptive immune mechanisms so that it can be transmitted back to the arthropod host. Understanding the interaction of BTV with immunity could ultimately define the correlates of protection with immune mechanisms that would improve our knowledge of ruminant immunology.     

Immunopathogenesis: role of innate and adaptive immune responses

Hepatitis B virus (HBV) infection in immunocompetent adults usually results in a self-limited, transient liver disease and viral clearance, with only a small percentage (5 to 10%) developing chronic hepatitis associated with viral persistence. In contrast, when neonates are infected, more than 90% become persistently infected, suffering differing degrees of chronic liver disease. Activation of immunity plays a central role in host-virus interactions, greatly influencing viral replication and the clinical outcome of infection. Although all of the specific mechanisms and consequences of this interaction have not been elucidated, the purpose of this article is to describe the basic arms of the immune system as they interact with the HBV and describe the present state of knowledge in this area. These arms may be divided broadly into innate and specific immune responses, and they have different roles and responses in acute and chronic infection.     

Nutritional signals and reproduction

There is extensive evidence that nutrition influences reproductive function in various mammalian species (agricultural animals, rodents and human). However, the mechanisms underlying the relationship between nutrition, energy metabolism and reproductive function are poorly understood. This review considers nutrient sensors as a molecular link between food molecules and consequences for female and male fertility. It focuses on the roles and the molecular mechanisms of some of the relevant hormones, such as insulin and adipokines, and of energy substrates (glucose, fatty acids and amino acids), in the gonadotropic axis (central nervous system and gonads). A greater understanding of the interactions between nutrition and fertility is required for both better management of the physiological processes and the development of new molecules to prevent or cure metabolic diseases and their consequences for fertility.     

Influenza Virus RNA Synthesis and the Innate Immune Response

Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In this review, we will focus on the interplay between influenza virus RNA synthesis and the detection of influenza virus RNA by our innate immune system. Specifically, we will discuss the generation of various RNA species, host pathogen receptors, and host shut-off. In addition, we will also address outstanding questions that currently limit our knowledge of influenza virus replication and host adaption. Understanding the molecular mechanisms underlying these factors is essential for assessing the pandemic potential of future influenza virus outbreaks.     

Cellular immunity and immunopathology in autoimmune Addison's disease

Autoimmune adrenocortical failure, or Addison's disease, is a prototypical organ-specific autoimmune disorder. In common with related autoimmune endocrinopathies, Addison's disease is only manageable to a certain extent with replacement therapy being the only treatment option. Unfortunately, the available therapy does not restore the physiological hormone levels and biorhythm. The key to progress in treating and preventing autoimmune Addison's disease lies in improving our understanding of the predisposing factors, the mechanisms responsible for the progression of the disease, and the interactions between adrenal antigens and effector cells and molecules of the immune system. The aim of the present review is to summarize the current knowledge on the role of T cells and cellular immunity in the pathogenesis of autoimmune Addison's disease.     

Vacunas antiinfecciosas de mucosas en la profilaxis de infecciones recurrentes: más allá de las vacunas convencionales

An urgent search is currently underway for alternatives to antibiotics to prevent infections, due to the accelerated evolution and increase in antibiotic resistance. This problem is more serious for patients with recurrent infections, since they have to use many cycles of antibiotics per year, so the risk for antibiotic resistance is higher and can be life-threatening. In recent years, the use of prophylactic vaccines via the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections. The new knowledge about mucosal immunity and trained immunity, a form of innate immunity memory that can enhance the response to different infectious threads, has made it easier to extend its use. The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections. In this review, we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients.     

Dendritic cells--immunodeficiency virus (HIV): early interactions

Since 1973, when Steinman and Cohn highlighted the importance of dendritic cells as mediators of immunity, a large series of subsequent researches have been registered concerning these amazing cells and their implications in different pathologies. Although in small number, they are widely distributed and represent crucial elements in immune responses against pathogens. Data gathered in the last period, mostly based on in vitro studies, helped us understand the early events of HIV-host interactions, the important roles of dendritic cells in this phase, but fails to fully explain the complex mechanisms underlying these interactions, such as the ways developed by HIV to evade the immune system and to facilitate viral dissemination. Improved knowledge of these mechanisms may provide a basis in the attempt to find new therapeutic targets and elaborate immunologic therapies.     

Teladorsagia circumcincta in the sheep abomasum: defining the role of dendritic cells in T cell regulation and protective immunity

Parasitic nematodes of the small-ruminant gastrointestinal tract pose a problem worldwide. The impact of these pathogens is worsened by the emergence of anthelmintic resistance to all three available classes of drugs. In addition to causing considerable economic loss, these parasites are detrimental to the health and welfare of sheep and goats. Vaccination offers an alternative approach to drug-based control and a great deal of investment has gone into the investigation of protective antigens for some of these nematode species. However, attempts at vaccination are hindered by a lack of understanding of how best to promote protective immunity to nematode species, such as Teladorsagia circumcincta , which inhabits the abomasum of sheep. This situation contrasts with that in murine models of gastrointestinal nematode infection, where the basis of protective immunity is increasingly well understood. In this review, we discuss the current knowledge of the immune effector mechanisms elicited by T. circumcincta and consider the probable role of dendritic cells in the initiation of both effector and regulatory responses in the abomasum.