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Abstract: Recurrent respiratory tract infections are a common motif of pædiatric consultations. Most of the time, children are healthy and their immune system has a delayed but normal maturation. Sometimes, paediatricians have to rule out an underlying pathology, especially a primary immunodeficiency when a child presents a higher susceptibility to infections. Oriented by the medical history and the physical examination, some laboratory tests will have to be performed. However, their interpretation can be uneasy because it depends on the age, the vaccine status and the infectious medical history. A precise diagnosis should be made in order to rule out a severe primary immunodeficiency. These children may also need a specialized medical environment. [Copyright &y& Elsevier]

Our social environment shapes our eating habits, notably our consumption of fruit and vegetables rich in micronutrients (vitamins and trace elements), essential for regulating the immune system. Ensuring a balanced intake of micronutrients could prove to be particularly beneficial for patients with severe forms of COVID-19 suffering from critical immune dysregulation., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Over the past ten years, an increased knowledge of tumor biology and immunology allowed the design and development of novel therapeutic antibody and protein scaffold formats, where bispecific antibodies (Abs) play a major role. The latter molecules can (1) bring novel pharmacological properties through the co-engagement of two targets, (2) increase the safety profile as compared to a combination of two antibodies thanks to a targeted relocation to the tumor and (3) reduce development and manufacturing costs associated with single drug product. This review analyzes the different bispecific antibodies and scaffolds described in the field of immuno-oncology, their structure and major pharmacological and physico-chemical properties., (© 2019 médecine/sciences – Inserm.)

The Milieu Intérieur project aims to define the boundaries of a healthy immune system in steady state and upon immune stimulation, and to elucidate environmental and hereditary determinants of its variability. The project is based on an in-depth immune phenotyping of 1 000 healthy donors. By correlating the cytometry measurements of peripheral blood immune cell composition in homeostasis, with the associated metadata, we have defined reference values of phenotypes related to sex and age, and found a significant impact of latent cytomegalovirus infection and smoking on measured phenotypes. In addition, we identified eleven novel Single-Nucleotide Polymorphisms (SNPs) associated with immune cell phenotypes. Immune response signatures were measured upon stimulation of fresh peripheral blood by 40 immune stimuli. Robust and standardized pipelines were established to quantify expression of 29 proteins and 572 genes and to explore genetic and non-genetic determinants of the variability of healthy immune response. The analytical approaches established by Milieu Intérieur and the collected data set represent an ideal reference for comparison studies of disease populations., (© 2019 médecine/sciences – Inserm.)

Major progress in preventing, delaying or curing various pathologies normally encountered in old age results in a continuous improvement in life expectancy. However, understanding the underlying cause of the disparate comorbidities occurrence with aging remains a priority in order to propose adapted care for the older population. In one hand, aging profoundly impairs the immune system; it is characterized by many changes in haematopoiesis, adaptive and innate systems, and is associated with pro-inflammatory environment. In another hand, stressful events (acute or chronic) can also impact the immune system through the secretion of hormones, which are also altered with aging. Blooming evidences from psychoneuroimmunology field suggest that, in acute medical conditions, elderly people are not equal in their responses to stressors depending on many extrinsic and intrinsic parameters. These factors could interfere with elderly's ability to mount an effective immune response. The objective of this review is to provide an overview of the literature (from fundamental to clinical observations) to draw a global picture of immunosenescence. Understanding this process could enable us to target fundamental age-related pathways and thus open new avenues in improving both lifespan and health span., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens., State of the Art: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints., Perspectives: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker., Conclusions: Numerous challenges still remain in developing research approaches for the development of immunotherapies., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Mast cells are immune cells that mature within the host tissue. The acquired phenotype is dictated by the tissue microenvironment, giving rise to diverse tissue-dependent phenotypes and functions. The lack of cellular models reflecting phenotypes found in vivo and important differences between human and rodent mast cells are obstacles to the understanding of their exact role in several pathophysiological processes. Studies published over the past few years showed that mast cells' role lies far beyond their involvement in allergy and anaphylaxis. Studies demonstrating their participation in innate immune responses as well as tissue scaring and vascular pathologies allowed the understanding of their role in several diseases, but also gave contradictory results, especially concerning tissue response to ionizing radiations. Nevertheless, therapeutic tools exist to target mast cells, such as degranulation inhibitors, antihistamine, protease inhibitors or tyrosine kinase receptors antagonists, and may offer some interesting new therapeutic perspectives to manage acute and chronic after-effects of radiation therapy., (© 2018 médecine/sciences – Inserm.)

Genetic evolution of multicellular organisms occurred as a response to environmental challenges, in particular competition for nutrients, climatic change, physical and chemical stressors and pathogens. However organism fitness depends on both the efficiency of its defences and its capacities for benefiting from its symbiotic organisms. Indeed microbes not only engender pathogenies, but enable efficient uptake of host non-self biodegradable nutriments. Furthermore, microbes play an important role in the development of host immunity. We shall review here the associations between some specific genes of the host, microbiota and the immune system. Recent genome-wide association studies disclose that symbiosis between host and microbiota results from a stringent genetic co-evolution. On the other hand, a microbe subset isolated from murine and human microbiotes has been identified on the basis of its interaction with both the host genetics and immunity. Remarkably, microbes which have two such connections are taxonomically related. The best performing bacterial genuses in these two perspectives are Bifidobacterium, Lactobacillus and Akkermansia. We conclude that future therapies targeting microbiota within the framework of chronic inflammatory diseases must consider together host immune and genetic characters associated with microbiota homeostasis., (© Société de Biologie, 2017.)

The microbiota designates the various flora of commensal microbes of living species. Most research in human focusing mainly on the intestinal microbiota, we will limit ourselves to its description and role in physiology and pathology. The intestinal microbiota acts on digestion and the immune system. It seems responsible, at least in part, for obesity, digestive cancers, several autoimmune and allergic pathologies, and pathologies of the nervous system. The role of prebiotics, probiotics, xenobiotics and stool transplantations will be discussed., (© Société de Biologie, 2017.)

The aim of the review is to discuss about the role played by the defence crosstalk between the gut microbiota and the intestinal immune system, in the development of metabolic disease focusing on obesity and diabetes. Starting from physiological and pathological stand points and based on the latest published data, this review is addressing how the concept of the hologenome theory of evolution can drive the fate of metabolic disease. The notion of "metabolic infection" to explain the "metabolic inflammation" is discussed. This imply comments about the process of bacterial translocation and impaired intestinal immune defense against commensals. Eventually this review sets the soil for personalized medicine. The monthly increase in the number of publications on the gut microbiota to intestinal immune defense and the control of metabolism demonstrate the importance of this field of investigation. The notion of commensal as "self or non-self" has to be reevaluated in the light of the current data. Furthermore, data demonstrate the major role played by short chain fatty acids, secondary bile acids, LPS, peptidoglycans, indole derivatives, and other bacteria-related molecules on the shaping of cells involved in the intestinal protection against commensals is now becoming a central player in the incidence of metabolic diseases. The literature demonstrates that the onset of metabolic diseases and some specific co-morbidities can be explained by a gut microbiota to intestinal immune system crosstalk. Therefore, one should now consider this avenue of investigation as a putative source of biomarkers and therapeutic targets to personalize the treatment of metabolic disease and its co-morbidities. Gut microbiota is considered as a major regulator of metabolic disease. This reconciles the notion of metabolic inflammation and the epidemic development of the disease. In addition to evidence showing that a specific gut microbiota characterizes patients with obesity, type 2 diabetes, and hepatic steatosis, the mechanisms causal to the disease could be related to the translocation of microbiota from the gut to the tissues, which induces inflammation. The mechanisms regulating such a process are based on the crosstalk between the gut microbiota and the host immune system. The hologenome theory of evolution supports this concept and implies that therapeutic strategies aiming to control glycemia should take into account both the gut microbiota and the host immune system. This review discusses the latest evidence regarding the bidirectional impact of the gut microbiota on host immune system crosstalk for the control of metabolic disease, hyperglycemia, and obesity. To avoid redundancies with the literature, we will focus our attention on the intestinal immune system, identifying evidence for the generation of novel therapeutic strategies, which could be based on the control of the translocation of gut bacteria to tissues. Such novel strategies should hamper the role played by gut microbiota dysbiosis on the development of metabolic inflammation. Recent evidence in rodents allows us to conclude that an impaired intestinal immune system characterizes and could be causal in the development of metabolic disease. The fine understanding of the molecular mechanisms should allow for the development of a first line of treatment for metabolic disease and its co-morbidities., (© Société de Biologie, 2017.)

During their long co-evolution, bacteria and their animal host have developed mutualistic interactions that are regulated by the immune system of the host. A dialogue between bacteria and the host immune system is initiated at birth during microbial colonization. This colonization induces the recruitment of multiple immune cell types that cooperate with the intestinal epithelium to construct a barrier capable of confining the microbes within the intestinal lumen. Regulatory mechanisms avoid deleterious inflammatory reactions that would harm both the host and its microbiota. In mouse, homeostatic activation of the intestinal immune system is recapitulated by a small number of bacteria, and more particularly by the segmented filamentous bacteria., (© 2016 médecine/sciences – Inserm.)

Alpha-radioimmunotherapy (α-RIT) is a targeted anti-tumor therapy using usually a monoclonal antibody specific for a tumor antigen that is coupled to an α-particle emitter. α-emitters represent an ideal tool to eradicate disseminated tumors or metastases. Recent data demonstrate that ionizing radiation in addition to its direct cytotoxic ability can also induce an efficient anti-tumor immunity. This suggests that biologic effects on irradiated tissues could be used to potentiate immunotherapy efficacy and opens the way for development of new therapies combining α-RIT and different types of immunotherapy., (© 2016 médecine/sciences – Inserm.)

Chemerin is a pro-inflammatory adipokine secreted and expressed predominantly by adipocytes. Chemerin is initially involved in the regulation of the immune system, the adipogenesis and the energy metabolism. However, several recent studies show that this adipokine and its receptors are present in the gonads. In vitro, chemerin reduces steroidogenesis in ovarian and testicular cells in rodents and humans. Chemerin and its receptors are also present in the placenta. Chemerin plays an important role in the regulation of fetal and maternal metabolism, fetal growth and metabolic homeostasis during pregnancy. This review describes the role of chemerin in metabolism and reproduction., (© 2015 médecine/sciences – Inserm.)

Although the precise pathogenesis and etiology of Behçet's disease (BD) still remains unknown, current evidence suggests that inflammatory reaction in BD arises from disruption of homeostasis in genetically susceptible individuals, resulting in altered innate and adaptive immunity responses, pathogenic T cell activation in the peripheral blood, and in inflammatory sites. Association with HLA-B51 is known as the strongest genetic susceptibility factor for BD. Recent GWAS (genome-wide association studies) have confirmed this relationship, and reported new susceptibility genes (IL-10, IL-23R, IL-12RB2) for the disease. A triggering infectious agent could operate through molecular mimicry, and the disease could subsequently be perpetuated by an abnormal immune response to an auto-antigen in the absence of ongoing infection. Several potential bacteria have been investigated but the most commonly implicated microorganism is Streptococcus sanguis. Recent data have showed that the T cell homeostasis perturbation consisted mainly of Th1 and Th17 expansions, while regulatory T cell response was suppressed. Cytokine such as IL-17, IL-23 and IL-21 play a significant role in the pathogenesis of BD. Inflammatory cells within BD inflammatory lesions include mostly neutrophils, CD4(+) T cells, and cytotoxic cells. Lastly, endothelium dysfunction has been clearly established. This improved understanding of the pathophysiology of BD will certainly lead to the development of new therapeutic agents, potentially more effective than current therapy. In this review, we have studied the etiopathogenesis of BD in the light of recent advances., (Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

The development of new animal models and functional analysis methods has dramatically changed our understanding of the physiology of microglial cells. These cells which are the resident macrophages of central nervous system have the ability to adapt rapidly to subtle changes of their environment. Recent findings indicate in particular that they can establish contacts with neuronal synapses that they can eliminate and modulate by releasing specific mediators. Here we review the experimental observations that have revealed the occurrence of these interactions not only in pathological conditions but also in the healthy brain and in particular during normal brain development. The discovery of bi-directional communications between synapses and microglia sheds a new light on our understanding of brain functioning and should allow a better understanding of brain functioning and of interactions between immune and nervous systems., (© 2014 médecine/sciences – Inserm.)

Vitamin D acts at several levels in the immune systems to maintain immune tolerance. Vitamin D deficiency is a plausible environmental risk factor for autoimmune disease. Basic, genetic and epidemiological studies indicate a potential role of vitamin D in the prevention and the treatment of autoimmune diseases. Most of the epidemiological studies are cross-sectional, so that they are insufficient to establish a direct link between vitamin D deficiency and both disease risk and disease activity. Randomized, controlled trials are necessary., (Copyright © 2013. Published by Elsevier Masson SAS.)

The etiology of auto-immune disorders is multifactorial. Stress is probably a participating factor. Indeed, a high proportion of patients with auto-immune diseases report uncommon stress before disease onset or disease flare. The biological consequences of stress are increasingly well understood. Glucocorticoids and catecholamines released by hypothalamic-pituitary-adrenal axis during stress will alter the balance Th1/Th2 and the balance Th17/Treg. Stress impairs cellular immunity, decreases immune tolerance and stimulates humoral immunity exposing individuals to autoimmune disease among others. The treatment for autoimmune disease should include stress management., (Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Giant cell arteritis is a large-vessel vasculitis affecting all three layers of the arterial wall. Histopathology of this vasculitis consists of an inflammatory infiltrate with CD4(+) T cells, macrophages, multinucleated giant cells, forming granulomas in the media. This infiltrate is associated with a destruction of the arterial wall, a fragmentation of the internal elastic lamina and a vascular remodeling leading to intimal hyperplasia. Recent studies have clarified the role of Th17 cells in the initial phase of the disease, pro-inflammatory cytokines and vascular smooth muscle cells in vascular remodeling. This review aims to update data on giant cell arteritis pathogenesis and to propose clues of investigation for a better understanding of this condition., (Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Vitamin D plays a clearly defined role in phosphorus, calcium and bone metabolism. In addition to its effects on cellular proliferation and differentiation, and on immunity, it appears to exert other action, poorly understood to date, on human physiology and disease. A number of epidemiological studies have demonstrated a protective role of sun exposure with regard to the incidence of certain immune diseases and cancer, and upon the related mortality rates. Furthermore, over the last 10 years, studies have purported to find levels judged "inadequate" in numerous populations, and, in the absence of any strict scientific arguments, a correlation was established by certain authors between supposedly "inadequate" levels, sun exposure and risk of cancer. However, analysis of the literature shows that there is in fact no precise and consensual definition of normal ranges and that the notion of inadequacy was created artificially using assay techniques lacking in sensitivity and reproducibility. Photosynthesis of vitamin D can in fact be considered perfectly adequate in the majority of populations. However, greater care is needed with elderly subjects and with subjects exposed very little to sunlight. Current studies show that the means of photoprotection used in everyday life do not adversely affect such photosynthesis. In the event of documented vitamin D deficiency, oral supplements should be given, and exposure to natural or artificial UV radiation should not be prescribed. Ultraviolet radiation has been shown to be carcinogenic and responsible for the onset of most skin cancers, and the population must be warned against misleading advertising from the tanning industry. Care should also be taken with regard to the potential harmful effects of inappropriate vitamin D supplementation., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Cancer is a complex disease that affects more and more people around the world. Unfortunately, existing treatments are only partially efficient and often induce major side effects. Thus, the use of viruses to selectively kill cancer cells is a new promising therapeutic approach. Recently, VSV has been used in oncolytic virotherapy because of its capacity to preferentially infect most human tumor cells. However, despite the availability of good oncolytic VSV mutants, the large variability of tumor cell types and the multiple ways in which they can evade viral infection suggests that therapeutic combinations of various viruses will be necessary to efficiently treat most cancers. A better understanding of the infection mechanisms and immune system recruitment by oncolytic viruses will be of great value for the development of safe and efficient strategies for cancer treatment., (© 2013 médecine/sciences – Inserm / SRMS.)

Adipocytokines or adipokines are a group of molecules (such as leptin, adiponectin, visfatine and resistine) mainly produced by adipose tissue. The adipokines are involved in different physiological processes but their participation to inflammatory and immune responses have been recently described. Their contribution to inflammatory diseases such as chronic inflammatory joint diseases and autoimmune diseases, and osteoarthritis as well, is currently growing, suggesting new pathophysiological schema and treatments. Leptin, visfatin and resistin have pro-inflammatory properties while adiponectin is anti-inflammatory, especially for the vascular wall. Adiponectin is considered to be protective for cardiovascular risk. The influence of the treatments given in inflammatory rheumatic diseases and autoimmune diseases (traditional drugs and biologics) on adipokines requires to be studied., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The respiratory system undergoes progressive involution with age, resulting in anatomical and functional changes that are exerted on all levels. The rib cage stiffens and respiratory muscles weaken. Distal bronchioles have reduced diameter and tend to be collapsed. Mobilized lung volumes decrease with age while residual volume increases. Gas exchanges are modified with a linear decrease of PaO(2) up to the age of 70 years and a decreased diffusing capacity of carbon monoxide. Ventilatory responses to hypercapnia, hypoxia and exercise decrease in the elderly. Knowledge of changes in the respiratory system related to advancing age is a medical issue of great importance in order to distinguish the effects of aging from those of diseases., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Bone metabolism is mainly under estrogenic control. Estrogen induces the expression or activation of transcription factors, leading to phenotypic cellular changes that are critical for the balance between bone formation and resorption. The two activities are linked via the RANK ligand/osteoprotegerin pathway. Fine regulation of bone metabolism and the bone-specific response to estrogen deficiency implies the participation of immune cells, and especially T cells. Indeed, T cells are activated by estrogen deficiency and produce pro-inflammatory cytokines such as TNFalpha, which stimulates osteoclastogenesis both directly and indirectly through the RENKL pathway. Antigen hyperactivity mechanisms may potentiate T cell activation. Other cytokines such as IL-1 and IL-7 also participate in the cross-takl between immune cells and osteoclasts. TGFbeta and IFNgamma modulate these redundant and multiple pathways in a more complex fashion. B cells may also participate, especially after IL-7-induced activation. Although many of these findings remain to be validated in humans, they open up the possibility of new therapeutic approaches, especially given the growing evidence that post-menopausal osteoporosis is associated with a mild chronic inflammatory state.

Prion disease pathogenesis has been largely studied since the inter-species transmissibility of the infectious protein (PrPSc), the oral uptake as natural route of infection and the exceptional implication in a problem of public health were highlighted. Two sequential preclinical stages are observed before the development of irreversible and fatal lesions in the central nervous system: the lymphoinvasion and the neuroinvasion. The first is characterized by the accumulation of PrPSc within lymphoid tissues and the second by PrPSc scattering the peripheral nervous system towards the central nervous system. The mechanisms involved in the communication between the immune and the peripheral nervous system are still debated. Recent studies even suggest that neuroinvasion can occur through the hematogenous route, independently of the peripheral nervous system. This review analyses (i) the role of immune cells, implicated in prion pathogenesis: dendritic cells as PrPSc vehicle, follicular dendritic cells as PrPSc accumulator and nerve fibres as PrPSc driver and (ii) the respective relations they maintain with peripheral nerve fibres to migrate to the brain.

The susceptibility of elderly people to infectious diseases is usually associated to increasing risk factors found in young adults. However, the role of immune function ageing is associated with the decline of immune function but this decline is not homogenous. Some functions such as the cellular immune system are altered but others are enhanced such as innate immunity. The important events of immune ageing are modifications of lymphocyte subsets with accumulation of memory cells, decrease in proliferative response, and a chronic inflammatory state. The chronic antigenic load throughout life is responsible for gaps in the antigenic system with a greater sensitivity to new antigens. These immune system changes are all the more important that diseases are severe and that denutrition is associated. These diseases will speed up the ageing process. The interaction between immunosenescence and pathology is an important phenomenon to consider. This review outlines the immune system changes due to ageing, their relationship with diseases of the aged patient, and the consequences of these modifications on vaccination effectiveness.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is frequently used as treatment for patients with hematological malignancies. Its efficacy depends in part on the destruction of recipient tumor cells by donor immune cells contained in the graft (graft-versus-tumor effects), underlying the interest of studying donor immune recovery after alloHCT. Further, donor immune cells play an important role in the prevention and treatment of infections after alloHCT, and are the cause of graft-versus-host disease (GVHD). This article reviews the mechanisms of immune recovery after allogeneic hematopoietic cell transplantation (alloHCT), as well as techniques currently used to monitor immune function following alloHCT.

Knowledge about vitamin D has greatly improved during the last few years. Vitamin D cannot any more be considered as exclusively necessary to prevent ricket/osteomalacia. Its role in the prevention of some osteoporotic fractures in the elderly (in association with calcium nutrition) is now well demonstrated and many epidemiologic and laboratory data argue for a role in the prevention of several diseases or anomalies (cancer, auto-immune diseases, cardiovascular events, sarcopenia...). A few intervention studies confirming some of these effects also exist. Vitamin D status can easily be assessed by measuring serum 25 hydroxy vitamin D (25OHD) level. However, many experts have claimed that the population-based reference values for 25OHD are too low and that the cut-off value below which vitamin D insufficiency can be present is somewhere between 20 and 40 ng/mL with a clear tendency to target values above 30 ng/mL (75 nmol/L). The main consequences are that vitamin D insufficiency is highly frequent whereas the currently recommended supplementation doses are not sufficient.

Purpose: It was shown that corticosteroids alter the inflammatory and immune responses. Many publications report on serious infections occurring in patients receiving corticosteroids or presenting with Cushing's syndrome. This information is synthesized in this article., Current Knowledge and Key Points: The demonstration of the infectious risk associated with corticosteroids relies on observational data and on biological plausibility. However, this risk remains difficult to quantify, because of many confusing factors such as the patients' associated conditions and immunosuppressive treatments, and the highly variable dose and duration of the corticosteroid treatment. Taking into account the published data, the screening for a chronic infection seems licit among patients receiving a systemic corticosteroid treatment, in particular for those who will receive more than 10 mg of prednisone per day., Future Prospects: Although no clinical trials of prevention of infections in corticosteroid treated patients has been published, a strategy aiming at minimizing the infectious risk of corticosteroid treated patients is proposed, based on the analysis of the literature presented in this article.

In the past years, the importance of sports in everyday life has been increasing rapidly. Rhinitis and asthma account for the most common problems encountered by sport physicians. These pathologies are often linked to atopy and will require an investigation by an allergist. Less frequent, cholinergic urticaria and exercice-induced anaphylaxis require special attention as to therapeutics. Infections of the upper respiratory tract constitute a well-known problem in athletes. In numerous studies attempts were made to correlate susceptibility to infections to the immunological modifications occurring during exercise. Recently, the use of objective methods has made it possible to analyse these aspects and to demonstrate that other factors also affect immunological changes triggered by exercise.

A RARE EVENTUALITY: Although parasite infections are frequent, observations of vasculitis related to parasitosis are, however, very rare. REGARDING THE MECHANISM: The simultaneous occurrence of a parasitosis and vasculitis may be the consequence of either the direct implication of a parasite observed in the histological lesions in the onset of alteration in the vascular wall, or of immunopathological phenomena occuring during the anti-parasite immune response, or a fortuitous association. THE HUMAN PARASITOSIS IMPLIED: In most cases, vasculitis associated with parasitosis is an isolated event with varied clinical aspects. Such cases have been reported in toxoplasmosis, trichinosis, strongyliasis, ascaridiosis, sarcocystosis, amibiasis, leishmaniosis and toxocarosis.

Remarkable progress has been made in antiretroviral therapeutics, as well as in the prophylaxis and treatment of opportunistic infections, since the beginning of the AIDS epidemic. The patient's life expectancy and quality of life have consequently improved, thanks to better management of opportunistic diseases. The introduction of protease inhibitors-containing regimen (i.e. highly active antiretroviral therapy or HAART), since 1996, has drastically reduced the incidence of opportunistic infections by restoring immunity. The large panel of antiretroviral drugs responsible for frequent sustained viral and immune responses has thus allowed a new definition of guidelines for the prophylaxis and treatment of opportunistic infections. A better use of prophylactic drugs should help to reduce the risk of drug-related toxicity and pharmaceutical interactions. It should also decrease the cost of HIV management and eventually increase compliance to treatment and quality of life.

Recent advances in the field of immunobiology have provided many opportunities for anticancer-immunotherapy. Because they express tu-mor antigen, tumor cells can be kill by T cells. Renal Cell Carcinoma (RCC) is an immunogenic tumor and metastatic RCC is presently treated by cytokines. Anticancer immunity may be achieved by different strategies: allogeneic hematopoietic cell transplantation, vaccination with peptides, vaccination with loaded dendritic cells or adoptive cellular therapy in which specific T cells are isolated and expanded in vitro and then infused to patients. In our group, we have chosen the adoptive transfer of in vitro activated T cells with autologous tumor antigen loaded dendritic cells. To determine the best strategy of anticancer-immunotherapy, we need rigorous control of the specificity and the phenotype of the cell therapy product linked with the immunological status of the patient (before and after infusion) and with the clinical response.

Plasmodium falciparum drug resistance has considerably modified the attitude of physicians in terms of malaria case management. However, a bad understanding of the resistance phenomenon can lead to non-appropriate therapeutic and/or public health practices. The objective of this paper was to contribute to clarify the concept of parasitological resistance by analysing the different types of resistance observed in vivo. We showed through some examples that the precision of in vivo parasitological results depends on the type of microscopical technique used. We also showed that the classification system into resistance levels RI, RII, and RIII does not correspond to an increase in the resistance of the parasite itself but rather to an increase in the proportion of the resistant strains compared to the sensitive ones circulating in a given population. Mutant strains are circulating in low proportions as long as there is no selective drug pressure. They can be first detected in vitro and, later on, when their proportion increase, they are detected in vivo, first in non-immune subjects and later in semi-immune subjects. Therefore, the role of the host immunity is important in malaria drug resistance. To conclude, increasing use of antimalarial drugs (especially in monotherapy) cannot thwart the resistance, but rather leads to the selection of mutants strains. As the proportion of the mutant strains increases compared to the sensitive (wild) ones, it will reach the microscopic detection level and then, the clinical level. It is important that physicians involved in malaria case management understand these notions in order to avoid non-appropriate therapeutic decisions., (Copyright John Libbey Eurotext 2003.)

Despite its relative anatomic simplicity, the nematode Caenorhabditis elegans (C. elegans) is a complex multicellular organism. In this review, we describe studies that have contributed to a better understanding of certain aspects of the worm's physiology. We focus on the cellular and molecular basis of the interaction between C. elegans and its environment, including its sensory capacities, the intrinsic biological clock that governs the speed of its life, and on some of the factors that control its life span. We also outline very recent findings that have demonstrated the existence of an innate immune system in C. elegans. Finally, we highlight a number of novel techniques that are transforming the worm from a largely genetic model system into an attractive organism for functional genomic studies.

Telomeres are specialized structures at the end of eukaryotic chromosomes that in vertebrates constain hundreds to thousands of tandem repeats of the sequence TTAGGG. In most human somatic cells, telomeres shorten with each cell division, eventually triggering an irreversible arrest of proliferation called cellular senescence. These observations have led to a model in which telomere length reflects the mitotic history of somatic cells. Further support for this hypothesis has come from the discovery of telomerase, a unique reverse transcriptase ribonucleoprotein that has the ability to extend 3' end of telomeres. In fibroblasts, senescence is induced by telomere attrition and depends on p53 and pRb pathways triggered by one or a few critically short telomeres. Previous studies have shown that the replicative life span of various primary human cells can be prolonged by transduction of the telomerase reverse transcriptase (hTERT) gene. The hTERT expressing cells proliferate indefinitely, without undergoing any changes associated with transformation to malignancy. Rapid progress has been made towards the goal of using tumor-specific cytolytic CD8+ T lymphocytes for the immunotherapy of cancer. These cells can be expanded in vitro and, in principle, could be used for adoptive immunotherapy. One of the major problems that remains to be solved is the finite life span of normal human T lymphocytes. In an attempt to overcome this barrier three groups have introduced hTERT cDNA into human T lymphocytes and monitored its effect on their life span. In two of these studies, hTERT significantly extended the replicative life span of CD8+ T clones, whereas this was not the case in the third study using bulk T lymphocytes. Possible explanations for these discordant results are that better growth conditions avoided culture-induced stress in the study with clones, or that clones had undergone alterations leading, for example, to the inactivation of the pRb pathway during their derivation.

The endocrine and immune systems are interrelated via a bidirectional network in which hormones affect immune function and, in turn, immune responses are reflected in neuroendocrine changes. This bidirectional communication is possible because both systems share a common "chemical language" that results from a sharing of common ligands (hormones and cytokines) and their specific receptors. Cytokines are important partners in this crosstalk. They play a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis responses at all three levels: the hypothalamus, the pituitary gland and the adrenals. Acute effects of cytokines are produced at the central nervous system level, particularly the hypothalamus, whereas pituitary and adrenal actions are slower and are probably involved during prolonged exposure to cytokines such as during chronic inflammation or infection. Several mechanisms have been proposed by which peripheral cytokines may gain access to the brain. They include an active transport through the blood-brain barrier, a passage at the circumventricular organ level, as well as a neuronal pathway through the vagal nerve. The immune-neuroendocrine interactions are involved in numerous physiological and pathophysiological conditions and the interactions with the HPA axis may represent a mechanism through which the immune system, by stimulating the production of glucocorticoids, avoids an overshoot of inflammatory response. They may also be involved in the state of hypogonadism, of hypothyroidism and growth inhibition which can occur during inflammatory and infectious diseases. The crosstalk between the immune and endocrine systems is important to homeostasis, since the interactions can produce various appropriate adaptative responses when homeostasis is threatened.

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).

Immune responses decline with age, as assessed by the increasing role of infections in elderly subjects. This decline is, however, very progressive, and usually only clear-cut after 80 years of age. Major difficulties have been encountered to delineate the cellular basis of this immunodeficiency, which is subtle and inconsistent, at the origin of contradictory reports. This is, however, an important challenge in view of the possible therapeutic perspectives of immunotherapy of aged subjects.