Search

The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients., This work was supported by the Swedish Research Council (VR) and grants provided by the Stockholm County Council (ALF).

Background Malacoplakia is a rare acquired, infection-related granulomatous disorder, that may affect many systems, but typically occurs in the urinary tract. Cutaneous involvement is less prevalent, and most commonly presents with a perianal or genital region localization. Cutaneous malacoplakia is believed to be caused by an acquired bactericidal defect of macrophages in the setting of chronic infections and immunocompromised states. A diagnosis of cutaneous malacoplakia should be considered when encountering non-specific granulomatous lesions that are refractory to treatment. Histologic findings are marked by the presence of foamy macrophages containing the pathognomonic Michaelis-Gutman bodies. Objectives The aim of this review is to discuss the current perspectives on the pathophysiology, clinical features, diagnosis, and treatment of this disease. We would also like to emphasize that the integration of clinical information, microscopic findings, and exclusion of other cutaneous granulomatous processes is necessary to accurately diagnose this exceedingly rare disease and provide opportunity for therapeutic intervention. Patients/methods Data for this work were collected from the published literature and textbooks. Results Combined surgical excision and protracted antibiotic courses appear to have the highest success rate. Antibiotics should be culture specific, but drugs that easily permeate the macrophages appear to be the best choice.

Summary The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4·2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: ‘predominantly antibody disorders’ are the most common diseases observed (n = 217/348, 62%), followed by ‘phagocytic disorders’ (n = 31/348, 9%). As expected, ‘predominantly antibody disorders’ are more prevalent in adults than in children (78 versus 31%). Within this category, ‘common variable immunodeficiency disorder’ (CVID) is the most prevalent PID (n = 98/217, 45%), followed by ‘other hypogammaglobulinaemias’ (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among ‘phagocytic disorders’, ‘chronic granulomatous disease’ is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for ‘other hypogammaglobulinaemias’.

Maintaining an airway clear of inhaled particles, pathogens, and cellular debris is paramount for lung homeostasis. In healthy individuals, the phagocytes of the innate immune system act as sentinels to patrol the airway and ensure sterility. However, in airways diseases, including asthma, COPD, and cystic fibrosis, there is a propensity for bacterial colonization that may contribute to disease worsening. Evidence suggests that this may be due to dysfunctional phagocytosis. In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations; however, the literature is currently contradictory and requires further clarification. In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies. The identification of this and other mechanisms underlying phagocyte dysfunction may present novel therapeutic opportunities for the treatment of many of these intractable diseases and improve patient morbidity and mortality.

Chronic granulomatous disease (CGD) is an uncommon congenital immunodeficiency seen approximately in 1 of 250,000 individuals. It is caused by a profound defect in a burst of oxygen consumption that normally accompanies phagocytosis in all myeloid cells (neutrophils, eosinophils, monocytes, and macrophages). This “respiratory burst” involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide, which in turn gives rise to hydrogen peroxide, hypochlorous acid, and hydroxyl radicals. These oxygen derivatives play a critical role in the killing of pathogenic bacteria and fungi. As a result of the failure to activate the respiratory burst in their phagocytes, the majority of CGD patients suffer from severe recurrent infections and rather unexplained prolonged inflammatory reactions that may result in granulomatous lesions. Both may cause severe organ dysfunction depending on the tissues involved. Preventive measures as well as rapid (invasive) diagnostic procedures are required to successfully treat CGD. Hematopoietic stem cell transplantation may be a serious option in some of the patients.

An important task for both dentists and pediatricians dealing with patients manifesting different oral lesions is to be able to differentiate changes signaling systemic disease from those appearing without any concomitant serious health problem. In this article, symptomatology of selected primary immune deficiency diseases are discussed with particular emphasis on oral manifestations reported in this group of disorders. Facial, dental, and oral findings compose a constellation of symptoms observed in immunodeficiency diseases. Predisposition to bacterial invasion, cytokine dysregulation, tissue inflammatory process, and necrosis lead to early-onset oral lesions and periodontitis. Developmental abnormalities, periodontal disease, and oral lesions may accompany immunodeficiency and require particular awareness directed toward diagnosis of an underlying disease of the immune system.

A 13-year-old girl with no previously known predisposing disease developed phycomycosis involving the left lung, pleura and shoulder, the left side of the neck, the left thigh, the kidney sand the brain. Prolonged amphotericin B therapy resulted in clinical improvement, but the disease was wide-spread when the patient died 5 months after debut of symptoms from a subarachnoid haemorrhage due to fungal destruction of the basilar artery. During hospitalization, a marked reduction in the bactericidal activity of circulating neutrophil granulocytes was repeatedly demonstrated and the endotoxin stimulated nitroblue tetrazolium test was negative. Together with the demonstration of granuloma formation and the accumulation of lipid-laden histiocytes in the spleen, lymph nodes, bone marrow and the thymus, these findings indicate that the patient had a less severe form of chronic granulomatous disease.

The ingestion and killing of Staphylococcus aureus by peripheral blood leucocytes from 130 patients with infectious and non-infectious diseases have been determined, using an improved technique for the evaluation of neutrophil granulocyte function in vitro. A reversible defect in intraleucocytic killing could be demonstrated in granulocytes from patients with severe bacterial infections whereas granulocytes from patients with viral infections and non-infectious diseases showed only minor deviations from normal function by this technique. This defect could furthermore be attributed to malfunction of myeloperoxidase-mediated bactericidal systems and was found to be positively related to the degree of “shift to the left” of circulating myeloid cells. A similar defect could also be demonstrated in some patients with non-infectious granulocytosis. It is suggested that this defect may be caused by malfunction of a subpopulation of immature myeloid cells and/or by altered granulocyte function caused by in vivo activation of the cells due to immune reactions.

Carriers for chronic granulomatous disease (CGD) and patients with lupus erythematosus (LE) share several characteristics: They are mostly females, they reduce nitroblue tetra-zolium (NBT) poorly in their neutrophils, and, in some cases, they have similar skin lesions. We thus investigated 19 female LE patients for the presence of laboratory findings characteristic of the carrier state for CGD. None of these patients turned out to have the combined abnormality of neutrophil bactericidal activity and neutrophil NBT-reduction that is diagnostic of CGD carrier state in the X-linked form. An increased frequency of CGD carriers among female LE patients thus appears to be unlikely. Why some CGD carriers develop skin lesions typical of LE remains unexplained.

There is considerable evidence that Negroes have a tendency toward overgrowth of those connective-tissue components concerned with two functions—protection against infection (macrophages and plasma cells) and repair after injury (fibroblasts and their products). Thus, adaptation to the tropical environment in Africans may have involved a tendency toward connective-tissue overgrowth, as well as hypertrophy of the pigmentary apparatus. Both tendencies may have consequences in terms of: (1) susceptibility to certain chronic diseases; and (2) responses to disease processes or drug therapies. Some of these possible consequences are discussed.

TABLE OF CONTENTS I. Preface S1 II. Executive Summary S2 III. Algorithms S7 IV. Summary Statements S14 V. General Considerations S20 VI. Humoral Immunodeficiencies S24 VII. Cellular Immunodeficiencies S30 VIII. Combined Immunodeficiencies S33 IX. Phagocytic Cell Disorders S40 X. Complement Deficiencies S43 XI. Acknowledgments S45 XII. References S45 XIII. Appendix S61

This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47phox to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47phox and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.

Macrophages are normal targets for Salmonella during natural infections, and it has been demonstrated that attenuated bacteria can deliver nucleic acid vaccine constructs. Therefore, we assessed if attenuated Salmonella can be used for the in vivo delivery of transgenes to their natural cellular target, in an attempt to correct genetic defects associated with monocytes/macrophages. This system would offer the distinct advantage of achieving a specific targeting of defective cells in a non-invasive form. Using a reporter gene, we demonstrated that attenuated Salmonella could be used as an effective in vitro delivery system to transfer genetic material into nondividing cells like murine macrophages. In vivo, the oral administration of attenuated Salmonella allows targeted delivery of transgenes to macrophages and subsequently expression of transgenes at a systemic level. IFNgamma-deficient mice (GKO) were thus selected as a model for the in vivo validation of the Salmonella-based delivery approach. Attenuated Salmonella, used as the carrier for a eukaryotic expression vector encoding the murine IFNgamma gene, was able to restore the production of this cytokine in GKO macrophages. Their oral administration to IFNgamma-deficient mice also re-established, in these immunocompromised animals, the natural resistance to bacterial infections. These results demonstrate, for the first time, that attenuated Salmonella can be successfully used in vivo as a DNA delivery system for the correction of a genetic defect associated with monocyte/macrophages.

Human phagocytes (polymorphonuclear neutrophils and monocytes) play a critical role in host defense against invading microorganisms. Recent studies reported that circulating phagocytes undergo a final maturation process, in particular in terms of oxidative burst, during extravasation and migration to local sites of inflammation. This process is known as priming. We report here on a nine-year-old boy with successive disseminated infections due to intracellular microorganisms (Mycobacterium bovis, BCG, and Salmonella typhimurium). No T- or B-cell quantitative or qualitative defects were found. Polymorphonuclear neutrophil (PMN) migration and NADPH oxidase in PMNs and monocytes stimulated with various agents at optimal concentrations were normal, ruling out a leukocyte adhesion deficiency syndrome, a Chediak Higashi syndrome, and a chronic granulomatous disease. Nevertheless, the patient's PMNs and monocytes showed defective priming capacity, as measured by H(2)O(2) production after pretreatment with LPS (5 microg/mL for 30 min), TNFalpha (100 units/mL for 30 min), or IL-8 (50 ng/mL for 30 min) in response to bacterial N-formyl peptides (fMLP 10(-6) M for 5 min). In these conditions, H(2)O(2) production of PMNs and monocytes from the patient did not exceed that of the samples treated with fMLP or LPS alone, while the controls strongly produced H(2)O(2). Moreover, monocytes from the patient showed an impaired capacity to kill S. typhimurium in vitro. Such an impairment could be related at least in part to the priming deficiency of phagocyte oxidative burst. This case suggests, for the first time, that in vivo priming processes are critical in host defence against intracellular pathogens.

One hundred sixty-six cases of primary immunodeficiency diseases (PID) (95 males, 71 females), diagnosed according to WHO criteria, have been registered at the Children's Hospital, University of Sao Paulo, Brazil. The following frequencies were found: predominantly humoral defects, 60.8% (n = 101); T cell defects, 4.9% (n = 8); combined ID, 9.6% (n = 16); phagocyte disorders, 18.7% (n = 31); and complement deficiencies, 6% (n = 10). IgA deficiency was the most frequent disorder (n = 60), followed by transient hypogammaglobulinemia (n = 14), chronic granulomatous disease (n = 14), and X-linked agammaglobulinemia (n = 9). In comparison to other (national) reports, we observed higher relative frequencies of phagocyte and complement deficiencies. Recurrent infections were the cause of death in 12.7%. Allergic symptoms were observed in 41%, mainly in IgA-deficient, hypogammaglobulinemic, or hyper-IgE patients, and autoimmune disorders in 5%, predominantly in IgA and complement deficiencies. Five patients suffered from BCG dissemination; two of them died. This is the first Brazilian report on PID over an observation time of 15 years.

The differential diagnosis for a patient presenting with recurrent infections is formidable, given the complexity of the immune system. The clinical presentation of a patient who has a qualitative neutrophil abnormality may be similar to that of one who has an antibody or complement disorder. In general, evaluation for phagocytic cell disorders (Table) should be initiated among those patients who have at least one of the following clinical features: 1) Two or more systemic bacterial infections; 2) Frequent, serious respiratory infections, such as pneumonia or sinusitis, or frequent bacterial infection, such as cellulitis, draining otitis media, or lymphadenitis; 3) Infections presenting at unusual sites (hepatic or brain abscess); and 4) Infections associated with unusual pathogens (ie, Aspergillus pneumonia, disseminated candidiasis, or infections with Serratia marcescens, Nocardia sp, and Pseudomonas cepacia). Disorders of Neutrophil Function HYPERIMMUNOGLOBULIN E SYNDROME (JOB SYNDROME) Hyperimmunoglobulin E (hyper-IgE) syndrome is an autosomal dominant disorder with incomplete penetrance that is characterized by elevated levels of serum IgE and recurrent staphylococcal abscesses (Table). Neutrophils in these children exhibit impaired chemotaxis, although phagocytic function is normal. Clinically, hyper-IgE syndrome must be distinguished from severe atopic dermatitis. Both disorders are characterized by the development of severe dermatitis in the presence of elevated IgE levels.

A five-and-a-half-month-old male weimaraner with severe recurrent bacterial infections was assessed for immunocompetence. Results revealed a low serum immunoglobulin G concentration and defective neutrophil phagocytosis.

Prospective studies have indicated an age-related impairment of the immune response. Carotenoids have been hypothesised to enhance immune cell function. The aim of the present study was to describe the age-related effects and the impact of in vivo dietary carotenoid depletion and repletion on specific and non-specific immunity. A total of ninety-eight healthy male subjects (aged 20–75 years) received a carotenoid-depleted diet for 3 weeks and were then supplemented daily for 5 weeks with 30 mg β-carotene, 15 mg lycopene and 9 mg lutein. Blood samples were collected at study entry, after depletion and supplementation, and biomarkers of immune status were determined. We found that serum IgA levels were positively correlated with ageing. Lymphocyte phenotyping indicated an increase with age in the memory T-helper cell subpopulation (CD4+CD45RO+) concomitantly with a decrease in naive T-helper cells (CD4+CD45RA+). A significant increase in the natural killer cells subpopulation and a small decrease in B lymphocytes were also observed, especially for the oldest volunteers. From ex vivo cell function exploration, a positive correlation was observed between age and IL-2 production of phytohaemagglutinin-stimulated lymphocytes. Neutrophils' bactericidal activity was significantly impaired with age (from 50 years) and was modulated by carotenoid status. An age effect was found on neutrophils' spontaneous migration but not on directed migration. Immune response in healthy human subjects is mostly affected by age rather than by dietary carotenoid depletion and repletion. Even in carefully selected healthy volunteers, some age-related immune changes occur predominantly from 50 years onwards. This immunosenescence could generate a loss in the immune system adjustment capacity.

A study on the functional ability of polymorphonuclear leucocytes (PMNL) indicates that the total lysosomal enzyme levels viz. Beta-glucuronidase, lysozyme, acid phosphatase and alkaline phosphatase were not altered in diabetics, compared to that in control subjects. However, the findings also reveal that the release of these lysosomal enzymes in response to a particulate stimulus is impaired in diabetics. This suggests that the bactericidal capacity of these cells, which are involved in phagocytosis, is impaired in diabetics, making them more vulnerable to infections.

The immunopathogenesis of human immunodeficiency virus (HIV) infection is characterized by the failure to control opportunistic infections. Here, the direct effect of HIV on macrophage phagocytic function was studied. HIV-1-infected monocyte-derived macrophages expressed as many Fc gamma and complement receptors as did control macrophages. The function of these receptors was not affected by HIV-1 infection since binding and internalization of opsonized Escherichia coli and Staphylococcus aureus were not impaired. Production of reactive oxygen species induced by stimulation of the HIV-1-infected macrophages with opsonized E. coli, zymosan, or PMA was intact. HIV-1-infected macrophages killed opsonized E. coli and Candida albicans as effectively as did control macrophages. These results, therefore, do not support the hypothesis that HIV-1 infection of macrophages causes phagocytic dysfunction and suggest that HIV-induced abnormalities outside the mononuclear phagocyte system may lead to the inability to control opportunistic pathogens.

Patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects.respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia.

The role of leucocyte integrins in phagocyte function has been studied by comparing normal neutrophils with those from a patient with partial leucocyte adhesion deficiency (LAD), in whom the levels of CD11b and CD11c were 10% of controls, whereas CD11a levels were normal. Unstimulated LAD neutrophils exhibited defective adhesion to plastic (4·4 ± 1·5% cf. 14·4 ± 3·8% in controls), but not to human umbilical vein endothelial cells (HUVECs). The adhesion to HUVECs could be further upregulated by granulocyte‐macrophage colony stimulating factor (GM‐CSF), but not by 12‐0‐tetradecanoylphorbol 13‐acetate (TPA) which, in normal cells, is a more potent ‘pro‐adhesive agonist’. The normal neutrophil‐endothelial interaction induced by GM‐ CSF in LAD neutrophils was confirmed in vivo when administration of GM‐CSF resulted in rapid phagocyte marginatum. Neutrophil migration and phagocytosis/killing were defective in LAD neutrophils, and some improvement in phagocytosis/killing was seen following in vivo administration of GM‐CSF. These studies illustrate that the degree to which the leucocyte integrins mediate adherence‐related phagocyte functions varies not only with the particular function, but also with the conditions of stimulation. High levels of CD11b and CD11c expression appear not to be required for unstimulated or GM‐CSF‐stimulated neutrophil‐endothelial interactions, either In vitro or in vivo. Other neutrophil functions, on the other hand, such as migration and phagocytosis/killing are much more dependent on the leucocyte integrins. Copyright © 1991, Wiley Blackwell. All rights reserved

The aims of the present study are: first, to assess the toxic role of serum from thalassemic patients in phagocytosis of PMN from healthy controls, and second, to seek to determine whether serum and cellular disturbances of polymorphonuclear neutrophils (PMN) phagocytosis, observed in thalassemic patients, can be prevented and/or corrected by use of desferrioxamine (DFX). Two kinds of in vitro incubations--without or with DFX--were performed. PMN or serum from thalassemic patients or from healthy controls was used. First, a phagocytosis defect of 3 different bacteria species was induced in PMN from healthy controls by incubation in thalassemic serum. Second, DFX could prevent, already at 1 microM, the phagocytic defect induced in normal PMN by the incubation with thalassemic serum, with disappearance of the toxic role of thalassemic serum at higher concentrations. Third, improvement of the phagocytosis defect of PMN from thalassemic patients was also observed at 1 microM of DFX for the 3 bacteria species. Normalization was obtained at higher concentrations for gram-negative bacteria. In vivo studies revealed, after a 3 hr subcutaneous infusion of DFX into 3 thalassemic patients, an improvement of the phagocytosis results and a decrease of the Prussian Blue reactivity of the PMN. It is concluded first that an iron-mediated defect in phagocytosis can be induced in normal neutrophils by incubation in serum from thalassemic patients, and second that a precautious and intensive chelation therapy seems to be advantageous for increasing PMN defense against infectious agents. Special care must nevertheless be taken in order to detect rapidly opportunistic (such as Yersinia) infections.

There are few reports about congenital indifference to pain or Hereditary and Sensory Autonomic Neuropathy (HSAN). Several investigations for pathophysiology of this syndrome have been performed and different classifications about it. In this report we present a case of HSAN type II with general absence of pain and self amputations and leprosy–like damage of extremities which was suspected to be phagocytic immunodeficiency due to past history of repeated ulcer and abscess formation.

Blau syndrome (BS) is a rare familial granulomatous disease manifested by uveitis, arthritis and skin rash. BS has recently been found to be associated with a distinctive mutation in NOD2, which encodes an intracellular toll-like receptor. We have compared host cell interaction with bacterial challenge in U937 cells expressing wild type human NOD2 (NOD2(wt)), mutant NOD2 (NOD2(Blau)), or a vector control (VC). The cells were incubated with Salmonella typhimurium. Intracellular uptake was assessed by harvesting the cells at different time points following invasion and quantitating the CFU, recovered after gentamicin treatment to kill extracellular organisms. Expression of TNF-alpha, TLR2 and TLR4 was determined by semi-quantitative RT-PCR under resting conditions and after stimulation by bacteria. Invasion of target cells with S. typhimurium was diminished in the presence of NOD2(Blau). Expression of TNF-alpha mRNA was enhanced following bacterial invasion in all cell lines but NOD2(Blau) was associated with a more rapid decline in TNF-alpha expression. Kinetics of intracellular clearance of bacteria indicated a relative defect in NOD2(Blau) compared to controls. This clearance defect may be related to the lack of sustained TNF-alpha seen in the early stages. These events were not related to differential TLR2 or TLR4 expression since there were no significant differences seen between the cell lines after bacterial stimulation. Our findings indicate that the NOD2 mutation associated with this syndrome alters host:microbial interaction, and this may have relevance to triggering factors in the ocular and joint inflammation seen in BS.

Ehrlichioses constitute a group of acute zoonoses caused by the infection with the microorganisms belonging to the genera Ehrlichia, Anaplasma and Neorickettsia (Rickettsiaceae). Presence of human granulocytic ehrlichiosis (HGE) caused by infection with Anaplasma phagocytophila (A. phagocytophila) and transmitted by Ixodes ricinus tick has been confirmed in Poland. All the cases described so far were noted in the area of endemic prevalence of Lyme borreliosis (north-east of Poland). Lack of characteristic symptoms makes the diagnosis of HGE difficult. It should be suspected in patients exposed to tick bites during the preceding few weeks, in whom acute, febrile illness accompanied by leucopenia and thrombocytopenia develops. The course of infection may be serious, or even life-threatening, in patients more than 40 years old; consequences of co-infection with A. phagocytophila and other tick-borne pathogens remain not well known. There is probably no risk of the development of chronic HGE. As specific diagnostic methods are not widely accessible in Poland, empirical therapy with doxycycline may be of benefit in suspected HGE cases.

Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). We have shown that neutrophil recruitment to the lung during P. aeruginosa pneumonia is impaired in uPAR-deficient (uPAR−/−) mice but is normal in uPA−/− mice. However, both uPA−/− mice and uPAR−/− mice have impaired lung clearance of P. aeruginosa compared with wild-type (WT) mice. To determine the role of uPA and uPAR in antibacterial host defense, we compared neutrophil bacterial-phagocytosis, respiratory burst, and degranulation among uPA−/−, uPAR−/−, and WT mice. Nutrophil phagocytosis was significantly diminished comparing uPA−/− and uPAR−/− mice with WT mice at all time points. The generation of superoxide by both uPA−/− and uPAR−/− neutrophils was about half of that seen in WT neutrophils. Degranulation of azurophilic granules was significantly diminished in uPA−/− neutrophils compared with either uPAR−/− or WT neutrophils. By contrast, agonist-stimulated release of specific granules was not diminished in either uPA−/− or uPAR−/− mice compared with WT. We conclude that the uPA/uPAR system modulates several of the crucial steps in neutrophil activation that result in bacterial killing and effective innate host defense.

Stress substantially modulates the mononuclear phagocytic system (its center and periphery), the time of changes in granuloma formation in animals infected with BCG vaccine. This determines the specific features of development of vaccine-induced granulomatous inflammation as a reflection of changes in the host's resistance system and possibly mycobacteria. An additional influence (to Mycobacteria tuberculosis) of stresses during 30 days enhances destructive processes in the hepatic parenchyma.

The field of phagocytic disorders has attained major biologic and clinical significance in the past 40 years. The development of exciting new techniques in molecular biology and the cellular physiology of signal transduction have made it possible to identify the genetic defects involved in many of these disorders. Moreover through immunopharmacologic intervention, bone marrow or peripheral or cord blood stem cell transplantation along with the prospect of gene therapy, we have begun attempts to at least partially correct genetic defects in cell development and activation pathways in the entire spectrum of phagocyte disorders. Carrier detection and prenatal diagnosis employing with chain reaction techniques or direct nucleotide sequencing in fetal blood have made these diseases potentially preventable or treatable in utero or shortly after birth.

To evaluate alterations in the immune system (IS) in patients with different forms of secondary immunodeficiency and design of differentiated programs of reestablishment of defective functions depending on pathogenetically important type of deficiency of immunocompetent cells.Clinicoimmunological examination was made in 678 patients with complicated course of infectious-inflammatory diseases. Immunotropic medicines and physicochemical impacts were used in accordance with types of disorders in the system of immune homeostasis.There was a pathogenetic heterogeneity of IS disorders in complicated course of infectious-inflammatory diseases: generalized forms of infection (bacterial shock, sepsis) are in 75% of cases associated with deficiency of effector functions of peripheral blood polymorphonuclear leukocytes of the second-third degree, progressive fall in production of IgG immunoglobulins (42%), cellular-humoral immunodeficiency (92%). In lingering acute inflammatory diseases activation of phagocytosis occurred in 30%, IgG and/or IgM rise was in 50%, phagocytic function deficiency occurred in 48%, low production of immunoglobulins in 24%, humoral-cellular immunodeficiency in 62%. Purulent infection is associated with secondary cellular-humoral immunodeficiency, lowering of the immunoregulatory index (47%), phagocytic function deficiency (up to 35%), hyperproduction of IgM. Recurrent bacterial-viral diseases form in immunocompromised patients with T-lymphocytopenia (56%) and cellular-humoral immunodeficiency (30%).Protracted chronic inflammatory diseases are characterized by variability of changes in the immune systems. Combined types of disorders were found in 52% of the examinees. Pathogenetic heterogeneity of the disorders are determined by concomitant and previous diseases, occupational hazards and intoxication, environmental conditions, etc.Immunocorrective therapy in secondary immunodeficiency is conducted with allowances for pathogenetically essential types of disorders in the system of immune homeostasis, clinical variant of complication of inflammatory process under control of immunogram.

There is evidence that acquired dysfunction of neutrophils, monocytes, or macrophages is an important cause of infection in patients with diabetes mellitus, renal or hepatic failure, alcoholism, autoimmune diseases, influenza or human immunodeficiency virus infection, burns, and trauma. Distinguishable mechanisms of acquired phagocyte dysfunction include inhibitory effects of metabolic disturbances (e.g., hyperglycemia, uremia), chemical toxins (e.g., ethanol), viral proteins on phagocyte activation, and pathologic activation of phagocytes in the circulation (e.g., after hemodialysis, burns, or cardiopulmonary bypass). Although the burden of morbidity and mortality resulting from acquired phagocyte dysfunction appears to be vast, research in this area has been hampered by the complexity of the underlying illnesses and by limitations of laboratory assays and clinical study methodology. Given the advent of improved assays of phagocyte functions and treatments that can enhance these functions, there is a pressing need for more prospective studies of acquired phagocyte dysfunction.

This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9. 1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema.

Acid sulfate-coated solid particles are a significant environmental hazard produced primarily by the combustion of fossil fuels. We have previously described a system for the nascent generation of carbonaceous particles surface coated with approximately 140 microg/m(3) acid sulfate [cpSO(4)(2-); 10 mg/m(3) carbon black (CB) and 10 ppm sulfur dioxide (SO(2)) at 85% relative humidity (RH)]. The effects of inhaled cpSO(4)(2-) on pulmonary host defenses are assessed in the present work. Mice were acutely exposed (4 h) to either 10 mg/m(3) CB, 10 ppm SO(2), or their combination at 10% or 85% RH in a nose-only inhalation chamber. No evidence of an inflammatory response was found following any of the exposures as assessed by total cell counts and differential cell counts from bronchoalveolar lavage fluid. However, alveolar macrophage Fc receptor-mediated phagocytosis decreased only following exposure to 140 microg cpSO(4)(2-), significant suppression occurred after 24 h, maximal suppression occurred at 3 days postexposure, and recovery to preexposure levels required 7-14 days. Intrapulmonary bactericidal activity (IBA) was also suppressed only after exposure to 140 microg cpSO(4)(2-); suppression was maximal at 1 day postexposure and recovered by day 7. To assess the effects of lower cpSO(4)(2-) concentrations, mice were repeatedly exposed to 1 mg/m(3) CB and 1 ppm SO(2) at 85% RH ( approximately 20 microg/m(3) cpSO(4)(2-) for 4 h/day) for up to 6 days. A significant decrement in IBA was observed following 5 and 6 days of exposure. These studies indicated that acute or repeated exposure to cpSO(4)(2-) could alter pulmonary host defense mechanisms.

We have previously shown that polymorphonuclear leucocytes (PMN) harvested from children with cancer and exposed to chemotherapy exhibit defective bactericidal activities against both Gram-positive and Gram-negative microorganisms as well as accelerated apoptosis. In this study, PMN from children with cancer were evaluated to compare in vitro the corrective effects of the two myeloid colony stimulating factors G-CSF and GM-CSF on these defective pathways. Both G-CSF and GM-CSF were able to increase the defective bactericidal activities against S. aureus and E. coli. However, GM-CSF was consistently superior to G-CSF in correcting PMN microbicidal activity; this correction was incomplete since it did not reach the level observed in normal PMN exposed to GM-CSF. The accelerated apoptosis of PMN was not affected by G-CSF. In contrast, GM-CSF significantly prolonged the survival of the PMN although it did not reach the level of survival observed with normal PMN exposed to GM-CSF. These observations were consistent with other studies indicating that in PMN, microbicidal activities and apoptosis are differentially sensitive to the myeloid growth factors G-CSF and GM-CSF.

Neutrophils have a crucial function in the defense against bacteria and fungi. Indeed, during chronic, severe neutropenia and in case of severe neutrophil dysfunctions, the patients may suffer recurrent and sometimes life-threatening infections. This article describes the clinical symptoms, the theory behind the antimicrobial systems of neutrophils, the methods to diagnose the various aberrations, and the possibilities for treating these patients. A few of the most common causes of neutropenia and neutrophil dysfunctions are described in detail, including recent genetic information regarding the cause of these diseases.