A group B streptococcal extract reduces neutrophil counts and induces neutrophil aggregation

The possibility that group B streptococci (GBS) may induce neonatal neutropenia by promoting neutrophil aggregation and the entrapment of aggregates in the lung was studied in vivo and in vitro utilizing a cell free GBS extract [(GBS)-trichloroacetic acid (TCA)]. The intravenous infusion of the extract into neonatal lambs induced reductions of circulating white blood cells (0 time, 3.1 X 10(3)/mm3 +/- 0.5 versus 2.2 X 10(3)/mm3 +/- 0.7) 5 min after infusion (p less than 0.01). At necropsy these lambs had prominent accumulation of polymorphonuclear leukocytes in their pulmonary interstitium. Subsequently, neutrophil aggregation was studied by incubating GBS-TCA in human serum or phosphate-buffered saline with subsequent addition to human polymorphonuclear leukocytes in an aggregometer. GBS-TCA incubated in human serum induced prompt polymorphonuclear leukocyte aggregation (mean delta T 12.3% +/- 2.8 in human serum versus delta T 2.5% +/- 2.1 in phosphate-buffered saline, p less than 0.001). Preincubation of GBS-TCA followed by incubation in human serum with human GBS hyperimmune IgG significantly reduced aggregation (GBS-TCA in serum mean delta T 14.9 +/- 2.44 versus 5.42 +/- 1.80, p = 0.002). Cell-free GBS products may induce polymorphonuclear leukocyte aggregation in the presence of whole serum. This phenomenon might contribute to the pulmonary injury experienced by infants with GBS pneumonia and sepsis.     

Hyperimmunoglobulin-E-associated recurrent infection syndrome accompanied by chemotactic inhibition of polymorphonuclear leukocytes and monocytes

An 8-yr-old girl with a history of severe recurrent infections including perinephritic, pulmonary, and hepatic abscesses had elevated serum IgE levels. Her serum inhibited chemotaxis of polymorphonuclear leukocytes (PMN) and monocytes. Exchange blood transfusion or plasma exchange at the time of severe infection resulted in normalization of chemotactic activity of PMN shown by the skin window method. Although this effect became negative 1 wk after the treatment, the procedures improved her clinical course. The patient's serum, obtained by exchange blood transfusion, 1) inhibited normal PMN chemotaxis toward cultured supernatant of E. coli, zymosan-activated serum, and formyl methionyl-leucyl-phenylalanine (f . Met-Leu-Phe), a synthetic chemotactic peptide; 2) inhibited monocyte chemotaxis, 3) showed an absence of digestive activity of f . Met-Leu-Phe, 4) was heat stable at 56 degrees C for 30 min and 5) showed an absence of antigenicity of IgE in a partial purified inhibitor with a molecular weight of 30,000-40,000. The inhibitory effect seemed to be reversible.     

Histamine suppression of the non-immunological release of slow reacting substances from neutrophils of asthmatics

Slow reacting substance is released from cytochalasin B treated human polymorphonuclear leukocytes by incubation with zymosan and fresh autologous serum. It is reversed by FPL 55712, a specific endorgan antagonist of SRS-A and the process is confirmed to involve LTC₄, LTD₄, LTE₄ by High-Performance Liquid Chromatography. The levels of SRS from PMN by the non-immunological stimuli are significantly higher in asthma group than in control group. SRS is inhibited with pretreatment of theophylline and histamine, and the suppressed release of SRS is recovered by adding cimetidine, H2-brocker. Histamine appears to inhibit SRS release through H2-receptor. The role of neutrophils in IgE mediated hypersensitivity was discussed.     

The chemoluminescence response of human polymorphonuclear leukocytes to Escherichia coli O and K antigens

The interactions between Escherichia coli O or K antigens and polymorphonuclear leukocyte function were studied. Five types of O antigen and three types of K antigen were extracted from E. coli . These included O1, O6, O75 and K1 antigens from pyelonephritopathogenic strains, O44 and K74 antigens from an enteropathogenic strain and O14 and K7 antigen from a standard strain. The antigens all reacted specifically to their specific antisera and no cross-reactions were observed. The O1 or O44 antigen stimulated a significantly greater chemoluminescence response in polymorphonuclear leukocytes obtained from normal volunteers than O75, O6 or O14 antigen. In addition, the K1 or K74 antigen stimulated polymorphonuclear leukocytes significantly more than K7 antigen. These results suggest that pyelonephritopathogenic or enteropathogenic E. coli may produce severe tissue damage as a result of the response to their O or K antigens, as well as via adhesive agents such as pyelonephritopathogenic P-pili or the enteroadhesive factor, and exotoxins such as hemolysin or verotoxin.     

Activity and characteristics of inflammatory effector cells in newborns

To investigate the aspecific activity of inflammatory effector cells (mononuclear and polymorphonuclear leukocytes) of newborn babies, a comparative study was performed of chemotactic and random filter motility, phagocytic activity, and bactericidal capacity of these cells, of the electron microscopic counterparts of these activities, the serum factors influencing motility and of the content and ratio of cyclic nucleotides present in the cells of subjects of different ages. It was found that chemotaxis of the mononuclear and polymorphonuclear leukocytes is a gradually maturing function; its deficiency observed during the neonatal period is not caused by a depressed excitability by chemical agents, by the presence of inactivators of chemotactic factors or of chemotaxis inhibitors. It is the low serum levels of total complement, C 3, IgG, IgM and properdin that explain the reduced chemotactic mobility. In addition to these factors reduced leukocyte flexibility, condition and activity of the flexibility, condition and activity of the microtubular and microfilamentary system depending on calcium ion and cyclic nucleotide concentrations, and an eventual immaturity or exhaustion of certain intracellular enzymes also play a part. In respect to orientation towards chemical stimuli, the leukocytes of the newborn largely differ from those of children or adults. Similarly, a difference in uptake and elimination of bacteria and in ultrastructural changes accompanying these processes can be demonstrated between newborn and adult cells. The aspecific cellular functions, the reduction of which plays an important part in the weak resistance of the newborn, also depend on certain properties of the infective agents.     

Osteochondritis dissecans in a patient with hyperimmunoglobulin E syndrome

Hyperimmunoglobulin E syndrome (hyper-IgE) is a rare immunodeficiency disease associated with recurrent pyogenic infections, chronic eczematoid dermatitis and osteopenia. We present here a 13-year-old girl with hyperimmunoglobulin E syndrome, who developed osteochondritis dissecans (OCD) of the lateral femoral condyle, which is rare. Osteopenia, which is frequently associated with hyper IgE, may predispose the patient to the development of OCD.     

Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism.

Leukocyte adhesion deficiency II has been described in only 2 patients; herein we report extensive investigation of another patient. The physical stigmata were detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex) was absent from the surface of polymorphonuclear neutrophils, and cell binding to E- and P-selectin was severely impaired, causing an immunodeficiency. The elevation of peripheral neutrophil counts occurred within several days after birth. A severe hypofucosylation of glycoconjugates bearing fucose in different glycosidic links was present in all cell types investigated, demonstrating that leukocyte adhesion deficiency II is not only a disorder of leukocytes but a generalized inherited metabolic disease affecting the metabolism of fucose.     

Pathophysiology, diagnosis and therapy of disorders of granulocyte function

Congenital disorders of polymorphonuclear leukocytes can be seen as a tool to learn more about the function of these cells. In this paper the pathophysiology of leukocyte adhesion deficiency and of chronic granulomatous disease is reported in detail, partly at the molecular level. Patients with leukocyte adhesion deficiency can be treated by bone marrow transplantation, whereas in chronic granulomatous disease the therapy is restricted to antibiotic treatment or surgical intervention. In some cases of chronic granulomatous disease an increase of polymorphonuclear leukocyte function by immunomodulators (gamma-interferon) may be a new therapeutic approach.     

Hyper-IgE syndrome

The Hyper-IgE-syndrome (Job-, Buckley-) is characterized by recurrent staphylococcal infections of the skin, the ears and the lungs, by an eczematoid dermatitis from early infancy on, and by extreme elevation of serum IgE. The inconstantly found decreased chemotaxis of the polymorphonuclear leukocytes seems to be a secondary sign of a so far unknown deficiency possibly of the T-cell mediated immunity. Thus, therapy is restricted to antibiotic and surgical treatment. Many patients have a typical coarse face and some involvement of the bones (osteoporosis, craniosynostosis).     

Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity

OBJECTIVE: The autosomal-dominant form of the hyperimmunoglobulin E syndrome (AD-HIES) has been described as a multisystem disorder including immune, skeletal, and dental abnormalities. Variants of AD-HIES are known but not well defined. METHODS: We evaluated 13 human immunodeficiency virus-seronegative patients from six consanguineous families with an autosomal-recessive form of hyperimmunoglobulin E syndrome (AR-HIES) and 68 of their relatives. RESULTS: Persons affected with AR-HIES presented with the classical immunologic findings of hyperimmunoglobulin E syndrome, including recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. In addition, severe recurrent fungal and viral infections with molluscum contagiosum, herpes zoster, and herpes simplex were noted. Autoimmunity was seen in two patients. Central nervous system sequelae, including hemiplegia, ischemic infarction, and subarachnoid hemorrhages, were common and contributed to high mortality. Notably, patients with AR-HIES did not have skeletal or dental abnormalities and did not develop pneumatoceles, as seen in AD-HIES. In lymphocyte proliferation assays, patients' cells responded poorly to mitogens and failed to proliferate in response to antigens, despite the presence of normal numbers of lymphocyte subpopulations. CONCLUSION: The autosomal-recessive form of hyperimmunoglobulin E syndrome is a primary immunodeficiency with elevated immunoglobulin E, eosinophilia, vasculitis, autoimmunity, central nervous system symptoms, and high mortality. AR-HIES lacks several of the key findings of AD-HIES and therefore represents a different, previously unrecognized disease entity.     

Promoting effect of colostrum on the phagocytic activity of bovine polymorphonuclear leukocytes in vitro

Bovine colostrum contains a variety of essential nutrients, antibodies, cytokines, hormones, and growth factors that are important for nutrient supply, host defense, growth and for general neonatal adaptation. We have investigated the effect of bovine colostrum on the phagocytic activity for latex particles by normal peripheral blood polymorphonuclear leukocytes using flow cytometric analysis. The phagocytosis promoting effect was observed in colostrum. The promoting activity showed dose-dependent increase up to 25% at a concentration of colostrum. This activity was maximum in the colostrum obtained at parturition and gradually decreased with the time course of lactation as well as IgG level. Colostrum possessed the higher promoting activity than milk and normal serum. These results indicate that bovine colostrum strongly activates polymorphonuclear leukocyte phagocytosis, suggesting the concernment with development of nonspecific immune system in newborns.     

Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome

OBJECTIVE: Patients with the hyperimmunoglobulinemia E (hyper-IgE) syndrome are reported to have defective production of interferon gamma (IFN-gamma). Because IFN-gamma is a major activator of polymorphonuclear leukocytes (PMNs), this could result in defective PMN chemotaxis and markedly elevated IgE levels because of the unopposed action of interleukin (IL)-4. IL-12, an important enhancer of IFN-gamma production, also suppresses IgE production. This study assessed the IL-12/IFN-gamma pathway in patients with hyper-IgE syndrome. METHODS: Production of IL-12 and IFN-gamma by mononuclear cells from 10 patients with hyper-IgE syndrome in response to a number of stimuli was determined, as well as the effect of IL-12 on IFN-gamma release and cell proliferation. RESULTS: IL-12 and IFN-gamma production by the patients' cells was similar to that of control subjects independent of the stimulus used, except for Staphylococcus aureus, with which cells of patients with hyper-IgE syndrome released markedly less IFN-gamma (19.8%; P <.002). The ability of recombinant IL-12 to enhance IFN-gamma release from patients' cells in response to all stimuli was, however, significantly lower than with control cells (12% to 51%; P <.03). CONCLUSION: The lymphocytes of patients with hyper-IgE syndrome have an impaired response to IL-12, resulting in decreased IFN-gamma production, which may be of key importance in the pathogenesis of the immune abnormalities of hyper-IgE syndrome.     

Evaluation of visceral larva migrans by radioimmunoassay systems.

A 9-year-old child with miliary pulmonary infiltrates, eosinophilia, and hyperimmunoglobulinemia E recovered rapidly cover a four-week period. Subsequent analysis of serum samples by a solid phase radioimmunoassay technique demonstrated IgM, IgE, and IgG antibodies to Ascaris suum antigen which declined following the acute phase of the illness in parallel with a decline in serum IgM, IgE, and IgG concentrations. Precipitating antibodies in serum against Ascaris antigen were demonstrated. The diagnosis is considered to be toxocariasis or ascariasis. The application of sensitive radioimmunoassay techniques of this type should provide a method of earlier diagnosis and the demonstration of rapidly changing antibody levels a method of confirming the diagnosis in parasitic diseases.     

Improved survival of newborns receiving leukocyte transfusions for sepsis

To determine the role of polymorphonuclear (PMN) leukocyte transfusions in neonates with sepsis, 23 consecutive newborns were prospectively randomly selected during an 18-month period in a treatment plan to receive polymorphonuclear leukocyte transfusions with supportive care or supportive care alone. Thirteen neonates received transfusions every 12 hours for a total of five transfusions. Each transfusion consisting of 15 mL/kg of polymorphonuclear leukocytes was subjected to 1,500 rads of radiation. The polymorphonuclear leukocytes were obtained by continuous-flow centrifugation leukapheresis and contained 0.5 to 1.0 X 10(9) granulocytes per 15 mL with less than 10% lymphocytes. Pretreatment demographic, clinical, and laboratory variables that were found to be insignificant in prognosis between newborns who received transfusions and newborns who did not receive transfusions included weight, gestational and postnatal age, hypoxia, acidosis, hypotension, initial absolute granulocyte count (AGC), initial levels of immunoglobulins (IgA, IgG, and IgM), and total hemolytic complement. Positive findings on blood cultures were obtained in 14/23 patients and seven were randomly selected for each treatment group. Absolute granulocyte counts were less than 1,500/microL in 13 patients but tibial bone marrow examinations revealed that the neutrophil supply pool was depleted in only three patients. The survival was significantly greater in the treatment group (13/13, 100%) compared with the group that did not receive transfusions (6/10, 60%, P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myeloperoxidase deficiency as a cause of recurrent infections

Myeloperoxidase (MPO) deficiency is a common hereditary leukocyte function defect. A two year old girl with MPO-deficiency suffered from recurrent skin infections. No MPO-activity was detectable in leukocytes of her peripheral blood smears, while NBT reduction and chemotactic activity was normal. The quantitative enzyme determination in leukocyte sonicates confirmed the total MPO-deficiency in the girl's leukocytes and a partial MPO-deficiency in the cells of her mother. The patient leukocytes demonstrated also an impaired chemiluminescence.     

Cerebrospinal fluid values in the very low birth weight infant

The cerebrospinal fluid values obtained in the first 12 weeks of life from 43 infants with birth weights of 1500 gm or less were analyzed to determine the ranges for leukocyte count and chemistry values. All these neonates had birth weights appropriate for gestational age, negative cerebrospinal fluid culture for bacteria, and no evidence of intracranial bleeding by head ultrasound examination. The mean birth weight was 1002 gm (range 550 to 1500 gm), and mean gestational age was 27 weeks (range 24 to 33 weeks). The mean cerebrospinal fluid leukocyte count was 5 cells/mm3 (range 0 to 44 cells/mm3); leukocyte differential was 7% polymorphonuclear leukocytes (range up to 66%) and 85% mononuclear leukocytes (range 13% to 100%). Additional values included protein concentration, 142 mg/dl (range 45 to 370 mg/dl); and glucose, 60 mg/dl (range 29 to 217 mg/dl). Knowledge of these measurements should help in the interpretation of the cerebrospinal fluid values of the very low birth weight infant undergoing examination of a central nervous system disorder.     

Management of tacrolimus‐associated food allergy after liver transplantation

Increasingly, food allergy associated with tacrolimus after pediatric living‐donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T‐helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus‐associated food allergy after pediatric living‐donor LT. The patient was a 7‐year‐old Japanese girl who had undergone living‐donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post‐transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post‐transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.     

Vitamin E decreases superoxide anion production by polymorphonuclear leukocytes

Pharmacologic serum levels of vitamin E administered to low birth weight infants predispose them to infectious complications. We studied in vitro the effect of vitamin E, its vehicle and buffer (Krebs Ringers phosphate glucose) on the ability of human polymorphonuclear leukocytes (PMN) to produce superoxide anion, an oxygen radical important for bacterial killing. We found that superoxide anion production after a 5-min exposure to phorbol myristate acetate was significantly decreased in vitamin E-treated PMN (76 +/- 15 nM/10(7) PMN) compared to vehicle-treated PMN (289 +/- 109 nM/10(7) PMN). We also found that significantly decreased superoxide anion production was associated with 5.0 and 10.0 mg/dl but not with 3.5 mg/dl vitamin E. Our results support the hypothesis that pharmacologic concentrations of vitamin E depress PMN oxidative activity.     

Cytidine 5'-diphosphate reductase and thymidine kinase activities in phytohemagglutinin-stimulated lymphocytes of normal subjects of various ages and patients with immunodeficiency

The activities of CDP reductase and thymidine kinase in 10(6) to 5 X 10(6) phytohemagglutinin (PHA)-stimulated lymphocytes isolated from 2 to 5 ml of peripheral blood of individual subjects were measured. The activities of CDP reductase (pmol/h/10(7) cells) and thymidine kinase (nmol/h/10(7) cells) were high in infants, 698 +/- 307 and 64.2 +/- 20.2, constant in subjects of 1-40 years old, 401 +/- 181 and 38.1 +/- 15.3, and low in persons of more than 80 years old, 121 +/- 113 and 22.3 +/- 17.8, respectively. The ratio of thymidine kinase to CDP reductase activity increased with age, indicating that dependency on the salvage pathway of DNA synthesis in lymphocytes increased with age. The activities of CDP reductase and thymidine kinase were reduced in patients with the hyperimmunoglobulin E syndrome, congenital cytomegalovirus infection, anhidrotic ectodermal dysplasia with hyperimmunoglobulin A, Bloom's syndrome, immunodeficiency with hyperimmunoglobulinemia, and Down's syndrome. The clinical symptoms of these diseases seem to be due to impaired DNA synthesis of PHA-stimulated lymphocytes, but the degrees of reduction of enzyme activities were generally greater than that of thymidine incorporation in these patients.     

Disseminated Bacillus Calmette-Guérin infection in a girl with hyperimmunoglobulin E syndrome

Disseminated Bacillus Calmette-Guérin infection occurs in few well-defined immunodeficiencies, such as severe combined immunodeficiency, chronic granulomatous disease and paediatric acquired immunodeficiency syndrome. This severe complication of immunization against tuberculosis has been lethal in the majority of children who had primary immunodeficiency. Our patient, a 9-y-old girl with hyperimmunoglobulin E syndrome developed disseminated Bacillus Calmette-Guerin infection in infancy. Patients with hyperimmunoglobulin E syndrome (HIES) are susceptible to serious staphylococcal and fungal infections. Disseminated Bacillus Calmette-Guerin infection has not previously been reported in this rare immunodeficiency.