Neutropénies auto-immunes

Autoimmune neutropenias (AIN) are classically divided into primary AIN and secondary AIN. The latter are associated with autoimmune disorders, hematologic malignancies, primary immune deficiencies, drug exposure or infections. In this review we will focus on the major aetiologies of AIN, their differential diagnosis, the various methods in biological diagnosis, and the treatment.     

Acute and chronic neutropenias. What is new?

Recently, some of the mechanisms and consequences in the severe chronic neutropenias (e.g. the neutrophil elastase gene mutations and the risk to progress to myelodysplasia and acute leukaemia) and in drug-induced agranulocytosis (e.g. the apoptosis-inducing ability of metabolites of clozapine) have been elucidated, and new aspects of autoimmune and the large granular lymphocyte syndrome were described (e.g. aberrant elaboration of Fas-ligand causing neutrophil apoptosis). Investigations of the mild to moderate chronic neutropenias have shown the significance of interactions between the myeloid development and the immune network (e.g. relations to immunoglobulin aberrations). Granulocyte-colony stimulation factor (G-CSF) is widely used in patients with severe chronic neutropenia, however, its use in other conditions is mostly based on anecdotal evidence. In addition, immune modulating regimens, such as metothrexate, ciclosporine and monoclonal antibodies, are increasingly employed for the autoimmune neutropenias.     

Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection

Tumour necrosis factor alpha (TNFalpha) is a pivotal cytokine in host defences with broad ranging effects on the innate and adaptive immune systems. Clinically, TNFalpha inhibitors have demonstrated remarkable efficacy in a wide range of autoimmune and inflammatory disorders but clearly at the cost of heightened susceptibility to a variety of infections in those treated with these agents. Most reports to date have described increased susceptibility to intracellular pathogens in patients with underlying chronic viral infections, but little in the way of adverse event reporting in these patients has occurred. While the reported experience to date is rather limited, TNFalpha inhibitors have displayed a reasonable safety profile in the setting of some chronic viral infections and in certain circumstances have demonstrated adjunctive activity in the treatment of these infections. Given the high prevalence of chronic viral infections in patients who are candidates for anti-TNF therapy and the potential for these agents in the treatment of chronic viral illness, additional studies are urgently needed to assess the risks and benefits of such therapy in these populations.     

Alcohol, Tumor Necrosis Factor, and Tuberculosis

Alcohol exerts potent suppressive effects on the immune system that significanty increase host susceptibility to a variety of infections, particularly pneumonia. Historically, tuberculosis has been strongly associated with alcohol abuse. Although the relationship between alcohol abuse and tuberculosis is widely appreciated, the basic mechanisms by which alcohol immunosuppresses the host remain to be clarified. A major obstacle in furthering our understanding of this association has been the difficulty in distinguishing between the effects of alcohol per se and the other frequent sequelae of alcoholism such as nutritional deficiencies, liver disease, cigarette smoking, hygienic factors, and lifestyle. This article focuses on the role of tumor necrosis factor-alpha (TNF) in host defense and how alcohol modulates the activity of this important cytokine. While TNF's role in mediating the lethal consequences of infection has been the subject of much conjecture, this review focuses on the emerging evidence that TNF is an essential factor in the normal immune response to numerous infections, including tuberculosis.     

Angeborene Immundefekte

Primary (inborn) immunodeficiency is caused by gene defects that impact both the innate and the adaptive immune system. Individuals with an immunedeficiency primarily come to medical attention with recurrent infections. Most diagnoses are first made in childhood and include cellular immunodeficiency, defects of phagocyte function and other primary immunodeficiencies. Antibody deficiencies, particularly common variable immunodeficiency (CVID) and complement defects may, however, not become manifested until adulthood. A pathological susceptibility to infection in adults is defined as more than three infections per year that require treatment with antibiotics and last longer than 4 weeks each. Clinical clues for immunodeficiency are pathological susceptibility to infections and immune dysregulation. The former is characterized by frequent and severe infections with often unusual pathogens, localization, course and/or intensity. Immune dysregulation comprises granulomas, autoimmune diseases, recurrent fever/chronic inflammation, tendency to eczema, lymphoproliferation and chronic enteritis. There are evidence-based guidelines and consensus documents for the diagnosis and treatment of primary immunodeficiencies. Therapeutic approaches depend on the nature of the immune defect and range from immunoglobulin substitution for antibody deficiencies to bone marrow transplantation for severe cellular immune defects.     

Hematopoietic growth factors for the treatment of inherited cytopenias

The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.     

Interactions of the female hormonal environment,susceptibility to viral infections,and disease progression

Sex hormones influence susceptibility and disease predisposition for many genital tract infections. This review describes the mechanisms by which sex steroids affect mucosal immunity, with particular reference to human immunodeficiency virus (HIV) and genital herpes, and the stage-specific effects of hormonal contraception on human papillomavirus (HPV) infection. Estrogen's role is important in the early stages of several infections as it stimulates antibody- and cell-mediated immune responses. There is increased expression of some cytokines in peripheral blood and vaginal fluids during the follicular phase of the menstrual cycle and with use of hormonal contraception. Whether estrogen exerts a protective or deleterious influence depends on the infecting organism and stage of infection or disease. Estrogen apparently reduces susceptibility to primary HPV infection but in the event of persistent HPV infection, sex steroid hormones (estrogen and/or progesterone) are associated with progression to cervical cancer. It is important that these stage-specific effects are better described because most vaccines will try to prevent either infection or disease. Clinicians with patients at high risk of sexually transmitted infections, especially HIV, require better information on the risks associated with different hormonal contraceptive regimes.     

Genetic Basis for Recurrent Vulvo-Vaginal Candidiasis

Vulvovaginal candidiasis (VVC) is a frequent disease affecting more than 75% of all women at least once in their lifetime. Up to 8% of them suffer from recurrent VVC (RVVC) characterized by at least three episodes each year. Several risk factors, such as antibiotic use, diabetes, or pregnancy, are known, but the vast majority of women with RVVC develop the infection without having any risk factor, implying that a genetic component most likely plays an important role in the susceptibility to RVVC. This review summarizes the immunogenetic alterations that lead to an increased susceptibility to vaginal infections with Candida albicans. Different mutations and polymorphisms in innate immune genes alter the mucosal immune response against fungi and are likely to have an important role in susceptibility to RVVC. A better understanding of the genetic and immunological mechanisms leading to RVVC is important for both the understanding of the pathophysiology of the disease and the design of novel therapeutic strategies.     

The role of immunity and inflammation in lung senescence and susceptibility to infection in the elderly

Advancing age is associated with a decline in the integrity of physical barriers and protection against invading pathogens, and age-related changes in the immune system are associated with increased susceptibility to the emergence of autoimmune phenomena, neoplasia, and infections. Respiratory tract infections can occur at any age, but the incidence of lower respiratory tract infections increases significantly with advanced age such that pneumonia is a leading cause of illness and death in the elderly. Changes in lung physiology and immune function coupled with inflammation induced by environmental exposures or endogenous factors such as predisposition to aspiration may, in part, account for the increase in susceptibility to respiratory infections. Additionally, age-associated alterations in immune regulation ("immunosenescence") with dysregulation of lung homeostasis may allow low-grade inflammatory changes that lead to anatomical and physiological changes that characterize the senescent lung. The presence of disease states in elderly populations, such as chronic obstructive pulmonary disease (COPD) or nonpulmonary organ system diseases, may increase the likelihood of developing severe respiratory infections. This article examines age-related changes in immune function that predispose elderly individuals to lung remodeling but focuses especially on lower respiratory tract infections. It will discuss risk factors, identify pathogens that typically lead to respiratory infections in the elderly, and review current approaches to treatment and prevention of respiratory infections in the elderly population.     

TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans

Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.     

How I investigate neutropenia

Neutropenia is a common laboratory finding in adults and children. Its underlying causes are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. The clinical laboratory plays a central role in the diagnosis of these disorders, including data derived from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry. The purpose of this review is to (a) highlight the clinical, hematologic, and molecular genetic features of the major entities resulting in neutropenia and (b) outline an algorithm‐based approach to permit the classification of neutropenias.     

Intradermal infections of mice by low numbers of african trypanosomes are controlled by innate resistance but enhance susceptibility to reinfection

Antibodies are required to control blood-stage forms of African trypanosomes in humans and animals. Here, we report that intradermal infections by low numbers of African trypanosomes are controlled by innate resistance but prime the adaptive immune response to increase susceptibility to a subsequent challenge. Mice were found 100 times more resistant to intradermal infections by Trypanosoma congolense or Trypanosoma brucei than to intraperitoneal infections. B cell-deficient and RAG2(-/-) mice are as resistant as wild-type mice to intradermal infections, whereas inducible nitric oxide synthase (iNOS)(-/-) mice and wild-type mice treated with antibody to tumor necrosis factor (TNF) α are more susceptible. We conclude that primary intradermal infections with low numbers of parasites are controlled by innate defense mediated by induced nitric oxide (NO). CD1d(-/-) and major histocompatibility complex (MHC) class II(-/-) mice are more resistant than wild-type mice to primary intradermal infections. Trypanosome-specific spleen cells, as shown by cytokine production, are primed as early as 24 h after intradermal infection. Infecting mice intradermally with low numbers of parasites, or injecting them intradermally with a trypanosomal lysate, makes mice more susceptible to an intradermal challenge. We suggest that intradermal infections with low numbers of trypanosomes or injections with trypanosomal lysates prime the adaptive immune system to suppress protective immunity to an intradermal challenge.     

The role of immunity in susceptibility to respiratory infection in the aging lung

Respiratory tract infections, particularly pneumonia, are a leading cause of death in persons 65 years or older in both developed and developing countries. Because many attributes of immunity wane with advancing age, the elderly may be more susceptible to respiratory infections, even if they appear to be in good health. A decline in the ability of lymphoid tissues to mount an antigen-specific response (adaptive immunity) to specific microorganisms such as influenza virus or Streptococcus pneumoniae is thought to be an important factor in increasing susceptibility to respiratory tract infection with advancing age. However, abnormalities in innate immunity may also contribute to increased susceptibility to respiratory infections and have been poorly characterized in the elderly. Although changes in immune parameters such as T cell subsets and immunoglobulin concentrations have been observed in respiratory secretions from older healthy individuals compared to younger subjects, the significance of these changes for protective immunity in the lung is unknown. The incidence of pneumonia may be lessened by measures such as optimizing treatment of comorbid conditions, optimizing nutrition, and addressing swallowing disorders. The use of vaccines directed against the influenza virus and S. pneumoniae appears to have made an impact on the degree of morbidity and mortality, and perhaps, the incidence, of community-acquired pneumonia. However, better stimulation of specific immune responses with improved vaccines and more widespread use of these vaccines for protection of elderly individuals are needed.     

Obesity, poor prognostic factor in pandemic influenza A (H1N1) 2009: the role of adipokines in the modulation of respiratory defenses

Pandemic influenza A (H1N1), which occurred during 2009, revealed some unexpected epidemiologic characteristics, notably the high number of obese subjects among the severe cases of influenza. Generally, obesity seems to be associated with a weakness when it comes to respiratory infections. This susceptibility may be the result of a concurrence of mechanical and hormonal factors due to the excess weight. Obesity leads to changes in the ventilatory mechanics and an increase in the metabolic load during exercise. It is associated with immune system changes. Adipokines, cytokines produced by adipocytes, including leptin, play a central role by modulating the activity of all the cells of the immune system. Finally, obesity is associated with an increased risk of thrombosis, which has an adverse effect on the prognosis of infections. All of these observations can explain that obesity has been a risk factor in serious cases of influenza.     

Chronic mild neutropenia in adults: relation to IgG3 deficiency and infection susceptibility

OBJECTIVES: Chronic mild neutropenias (NP, i.e. absolute neutrophil blood counts/ANC/0.5-1.5 x 10(9) L(-1)) are accompanied by a variable infection susceptibility, which may or may not be as a result of concomitant conditions. Here, we assessed whether such patients also displayed an immunoglobulin deficiency and if this condition contributed to infection proneness. DESIGN, SETTING AND SUBJECTS: Thirty consecutive adult Caucasian patients with chronic mild NP were followed at one university hospital for up to 28 years. Comparisons were made with 49 IgG3 deficiency patients at an immunodeficiency clinic. MAIN OUTCOME MEASURES: Recorded infections, ANC and serum immunoglobulin levels; flow cytometry assessments of blood lymphocyte subsets and tests for autoimmunity were run to determine neutropenia subtypes. RESULTS: Forty per cent of the NP patients were treated for severe or recurrent infections. The mean IgG3 value for the NP patients was significantly lower than for healthy controls (P < 0.005) and 33% of the patients displayed IgG3 values below the reference values (i.e. below 0.21 g L(-1)), and an additional 13% had IgG3 values within the range others consider low (0.21-0.41 g L(-1)). Unexpectedly, neutropenic IgG3 deficiency patients exhibited less infection proneness than those with normal IgG3 values (P=0.03). Patients with autoimmune, large granular lymphocyte-associated or idiopathic NP had IgG3 deficiency in 63, 44 and 38%, respectively. In addition, none of IgG3 deficiency patients followed at the immunodeficiency clinic displayed neutropenia. CONCLUSION: IgG3 deficiency is common amongst chronic mild neutropenia patients, particularly in those with autoimmune background, but contributes not significantly to infection susceptibility.     

Effects of chronic ethanol feeding on murine dendritic cell numbers, turnover rate, and dendropoiesis

Background: Chronic alcoholics have increased susceptibility to and severity of infection, which are likely to be a result of impaired immune defense mechanisms. The contribution of dendritic cells (DC) to these immune defense changes is not well understood. Alterations in DC numbers, dendropoiesis, and lifespan have not been specifically studied in vivo in chronic ethanol (EtOH) exposure models. As DC play an essential role in initiating immune responses, alterations in these DC characteristics would help explain changes observed in adaptive immune responses. Methods: Mice received 20% EtOH (w/v) in the drinking water for up to 28 weeks, with mouse chow ad libitum. In EtOH‐fed and water control mice, DC were enumerated by flow cytometry. The effect of EtOH on DC precursor numbers was determined by differentiation in vitro in the presence of granulocyte‐macrophage colony‐stimulating factor and interleukin‐4, and the effect of an EtOH environment on untreated DC differentiation was measured following bone marrow transfer to irradiated hosts. DC turnover rate was also examined by bromodeoxyuridine incorporation and loss. Results: The percentage and absolute numbers of DC were decreased in spleen and increased in thymus beginning as early as 4 weeks of EtOH feeding. In addition, the overall cellularity of spleen and thymus were altered by this regimen. However, chronic EtOH consumption did not adversely affect DC precursor numbers, differentiation abilities, or turnover rates. Conclusions: Decreased splenic DC numbers observed following chronic murine EtOH consumption are not because of altered DC precursor numbers or differentiation, nor increased DC turnover rate. Similarly, increased thymic DC numbers are not the result of alterations in DC precursor differentiation or turnover rate. Compartment size plays a role in determining splenic and thymic DC numbers following chronic EtOH feeding. EtOH‐induced alterations in total DC numbers provide several mechanisms to partially explain why chronic alcoholics have increased susceptibility to infections.     

Aging

Respiratory tract infections are a leading cause of morbidity and mortality in the elderly. Many factors, such as malnutrition and the presence of structural lung disease, increase the risk of respiratory infection in older individuals. Aging is also accompanied by a gradual decline in many aspects of immune function, and waning immunity is thought to be an important risk factor for pneumonia in the elderly. Although a generalized decline in both the cell-mediated and humoral aspects of acquired immunity have been described in otherwise normal elderly populations, relatively little is known about the effect of age on compartmentalized pulmonary immune surveillance and immune responses to a challenge with a respiratory pathogen. Changes in immune cell profiles and acellular components of bronchoalveolar secretions have been detected by bronchoalveolar lavage, but the impact of these changes on host defense against respiratory infections is unknown. An improved understanding of the age-associated changes in pulmonary host defense mechanisms and how these might be manipulated to reduce the susceptibility of the elderly to respiratory tract infections may reduce the possibility of severe debilitation and death and the considerable health care burden posed by the increased incidence of pneumonia in this at-risk population.