Biomedical subjects
Publications and source records attributed to Amos Etzioni.
A 2-year-old girl with recurrent severe varicella infections had a fatal outcome. Studies of cellular and humoral immunity were normal. No natural killer (NK) cells were detected, and NK activity was markedly decreased. The interleukin (IL)15/IL15R signaling pathway was intact. This case emphasizes the role of NK cells in controlling herpes viral infection.
OBJECTIVES: Supplementation of probiotics and supplementation of zinc during acute gastroenteritis in children have been shown to exert positive effects on diarrhea duration and severity. Our aim was to evaluate a new diet enriched with zinc and probiotic bacteria in the treatment of acute gastroenteritis in young children. METHODS: In a double blind prospective study, 65 children aged 6-12 months were randomized to receive 6 x 10(9) colony forming units of Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus (2 x 10(9) of each strain), 10 mg of zinc/day, and 0.3 grams of fructo-oligosaccharides in the supplemented group (n = 33) or placebo (n = 32), given in a soy protein based rice cereal. For each child, age, sex, weight, degree of dehydration, the presence of fever or vomiting, stool frequency and consistency were recorded daily until diarrhea resolution. RESULTS: Diarrhea resolution occurred after 1.43 +/- 0.71 days in the supplemented group vs. 1.96 +/- 1.24 in the control group (p = 0.017). In the subset of children who presented with vomiting, time to vomiting resolution was 0.27 +/- 0.59 vs. 0.81 +/- 0.91 days in the supplemented and control groups, respectively (p = 0.06). On day 3, there was only 1 child with watery stools in the supplemented group versus 10 children in the control group (p = 0.02). CONCLUSIONS: In our series, the feeding of a cereal containing Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus and zinc, reduced the severity and duration of acute gastroenteritis in young children. However, whether this combination is better than either the addition of probiotics or zinc alone is yet to be determined.
Analysis of gene-targeted mice and patients with severe combined immunodeficiency due to mutations of the alpha chain of the interleukin-7 receptor (IL-7Ralpha) has shown important differences between mice and humans in the role played by IL-7 in lymphoid development. More recently, it has been shown that IL-7Ralpha is also shared by the receptor for another cytokine, thymic stromal lymphopoietin (TSLP). In this review, we discuss recent advances in IL-7- and TSLP-mediated signaling. We also report on the clinical and immunological features of 16 novel patients with IL-7Ralpha deficiency and discuss the results of hematopoietic stem cell transplantation.
Intravenous immunoglobulin (IVIg) has been used successfully for hypogammaglobulinemic states for more than 20 yr. In both primary and secondary situations when hypogammaglobulinemia is of clinical significance, IVIg should be the first line of treatment. In most cases, 400 mg/kg infused every 3 to 4 wk will lead to a trough level higher than 500 mg/dL, which in most cases provides good protection against bacterial infections. Higher doses may be needed in patients with known lung damage. Side effects include headache, nausea, chills, and fever but can be minimized by lowering the infusion speed rate. Rarely, aseptic meningitis may develop but it is always reversible. Although all products have been shown to be beneficial, differences among the various products have still been reported. In this regard, all products should be standardized according to common accepted international parameters. The route of immunoglobulin G replacement (intravenously vs subcutaneously) was reported to be of similar benefit. However, guidelines for usage and choice of route should be established and might be of help.
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The hyper IgM syndromes (HIGM) are a group of primary immune deficiency disorders characterized by defective CD40 signaling by B cells affecting class switch recombination and somatic hypermutation. As a consequence, patients with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections. The most common HIGM syndrome is X-linked and due to mutations of CD40 ligand (CD40L) expressed by activated CD4(+) T lymphocytes. Four other genes, expressed by B cells, have been associated with the HIGM phenotype. Mutations of CD40, the receptor for CD40L, cause a rare autosomal form of HIGM with a clinical phenotype similar to CD40L deficiency. Mutations of Activation-Induced Cytidine Deaminase (AICDA) and Uracil (DNA) Glycosylase (UNG), both expressed by follicular B lymphocytes, lead to defective class switch recombination and somatic hypermutation. Mutations of Nuclear Factor kappa B Essential Modulator (NEMO), an X-chromosome associated gene, result in hypohidrotic ectodermal dysplasia and immune deficiency. Thus, the molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes.
PURPOSE OF REVIEW: In the last 2-3 years our understanding of leukocyte adhesion cascades has increased, mainly in defining new pathways by which integrin activation occurs on circulating leukocytes recruited to sites of inflammation. While defects in the integrin structure (leukocyte adhesion deficiency (LAD) I) and in the selectin glycoprotein ligand biosynthesis (LAD II) have been described in the past few decades, a newly recognized defect in the activation of integrins (LAD III) was only recently delineated. The clinical manifestations and molecular basis of this syndrome and related cases will be reviewed. RECENT FINDINGS: While in LAD I and II the defect in the adhesion cascade is restricted to leukocytes, all four cases of LAD III described to date also had defects in platelet aggregation. These patients suffered from recurrent bacterial infections and a severe bleeding tendency. All cases were reported to have activation defects in all major integrin subfamily members expressed in circulating leukocytes and platelets. In one case there was a defect in Rap1, which is a crucial protein in the inside-out and outside-in (ligand-induced) signaling underlying integrin activation mainly by cytokines. In this case, both chemokines and cytokines were unable to activate Rap1 leading to severe adhesive defects analyzed in vitro. SUMMARY: While in LAD I and II the primary genetic defect is known, in the newly described LAD III the primary event leading to the defect is still unknown, despite a clear biochemical defect in Rap1 activation. The molecular basis or the defect in integrin activation may be different in the various cases described so far. It seems logical, however, to assume that in all reported cases, a key component of inside-out signaling to integrins activation is involved.
Recently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.(1) We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it "LAD-III."
LAD II/CDG IIc is a rare autosomal recessive disease characterized by a decreased expression of fucosylated antigens on cell surfaces that results in leukocyte adhesion deficiency and severe neurological and developmental abnormalities. Its molecular basis has been identified as a defect in the transporter of GDP-l-fucose into the Golgi lumen, which reduces the availability of the substrate for fucosyltransferases. During metabolic radiolabeling experiments using [3H]fucose, LAD II fibroblasts incorporated significantly less radiolabel compared with control cells. However, fractionation and analysis of the different classes of glycans indicated that the decrease in [3H]fucose incorporation is not generalized and is mainly confined to terminal fucosylation of N-linked oligosaccharides. In contrast, the total levels of protein O-fucosylation, including that observed in Notch protein, were unaffected. This finding demonstrates that the decrease in GDP-l-fucose levels in the fibroblast Golgi caused by the LAD II defect does not impair bulk protein O-fucosylation, but severely affects the bulk addition of fucose as a terminal modification of N-linked glycans. These data suggest that the severe clinical abnormalities including neurological and developmental ones observed in at least some of the LAD II patients may be related to alteration in recognition systems involving terminal fucose modifications of N-glycans and not be due to a defective O-fucosylation of proteins such as Notch.
Leukocyte arrest on vascular endothelium under disruptive shear flow is a multistep process that requires in situ integrin activation on the leukocyte surface by endothelium-displayed chemoattractants, primarily chemokines. A genetic deficiency of leukocyte adhesion to endothelium associated with defective beta2 integrin expression or function (LAD-1) has been described. We now report a novel severe genetic disorder in this multistep process associated with functional defects in multiple leukocyte integrins, reflected in recurrent infections, profound leukocytosis, and a bleeding tendency. This syndrome is associated with an impaired ability of neutrophil and lymphocyte beta1 and beta2 integrins to generate high avidity to their endothelial ligands and arrest cells on vascular endothelium in response to endothelial chemoattractant signals. Patient leukocytes roll normally on endothelial selectins, express intact integrins and G protein-coupled chemokine receptors (GPCR), spread on integrin ligands, and migrate normally along a chemotactic gradient. Activation of beta2 integrins in response to GPCR signals and intrinsic soluble ligand binding properties of the very late activation antigen-4 (VLA-4) integrin are also retained in patient leukocytes. Nevertheless, all integrins fail to generate firm adhesion to immobilized ligands in response to in situ GPCR-mediated activation by chemokines or chemoattractants, a result of a primary defect in integrin rearrangement at ligand-bearing contacts. This syndrome is the first example of a human integrin-activation deficiency associated with defective GPCR stimulation of integrin avidity at subsecond contacts, a key step in leukocyte arrest on vascular endothelium under shear flow.
Wiskott-Aldrich syndrome is a rare immunodeficiency characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and an increased incidence of malignancy. Clinical severity is highly variable. As a first step toward the development of therapeutic guidelines, an international study to evaluate current treatment strategies was undertaken. A total of 73 centers from 24 countries participated. These centers provide care for 507 patients with Wiskott-Aldrich syndrome. Treatment strategies were strikingly variable in both small and large centers. Most options were used in at least some patients in the majority of centers, indicating that treatment is individualized; however, there were some clear trends. Most centers use intravenous gammaglobulin and prophylactic antibiotics in the majority of patients. Splenectomy was used more sparingly. Stem cell transplant was more likely to be used in centers providing care for 10 or more patients. Studies that better define prognostic markers and optimal therapy are needed.
To extravasate the bloodstream at specific targets, circulating immune cells must activate their integrins to undergo rapid in situ modulation of affinity or avidity for their endothelial ligands. This activation involves specialized sub-second G-protein signal transduction triggered by endothelium-displayed chemoattractants--primarily chemokines--and their cognate leukocyte-expressed G-protein-coupled receptors (GPCRs). Recently, we reported a rare autosomal-recessive leukocyte adhesion deficiency (LAD) syndrome associated with a defective ability of integrins to undergo GPCR-mediated stimulation at endothelial contacts. This LAD shows significant similarities to a group of integrin-activation syndromes reported in leukocytes and platelets. Here, the mechanisms by which GPCRs might regulate leukocyte and platelet integrins are outlined with respect to this new family of LAD cases. We propose to term this the LAD-III family.
Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.
BACKGROUND: The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP. METHODS: Blood for DNA analysis was collected from six unrelated TTP families, consisting of nine patients from four different countries, and was screened for mutations in the ADAMTS13 gene. This gene spans 29 exons encompassing approximately 37 kb. Conventional techniques of DNA extraction, polymerase chain reaction (PCR), and direct cycle sequencing were used. RESULTS: Eight novel ADAMTS13 mutations are presented. Half of the total number of mutant ADAMTS13 alleles are amino acid substitutions. The disease-causing mutations are spread over the gene. The pathogenicity of the individual mutations is based upon their predicted effect on the ADAMTS13 protein and segregation in family members. Although most of the patients (seven out of nine) had symptoms during the neonatal period, they were in a remarkably good condition. Only one of the nine patients had a decreased glomerular filtration rate (GFR) with proteinuria and hematuria. Another patient had epileptic seizures. CONCLUSION: We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions.
BACKGROUND: [corrected] Insulin is substantially present in human milk. Suckling animal models have demonstrated local trophic effects of insulin on the gut mucosa, but the effects of oral insulin in the post-weaning period are controversial. OBJECTIVE: To examine local and systemic effects of oral insulin supplementation in the post-weaning period. MATERIALS AND METHODS: Balb/c mice received oral insulin supplementation in their drinking water (1 U/ml) from beyond weaning during 40 days (S group). Plasma glucose, lipid levels, amylase and insulin were measured. The liver and intestine were weighed and thiobarbituric acid-reactive substance (TBARS) levels were examined in liver tissue. These data were compared to a control group (C group). RESULTS: Fasting glucose levels (mean +/- SD) were lower in the S than in the C group (116. 5 +/- 10.7 vs 143.9 +/- 25.4 mg/dl; p < 0.001), as were prandial glucose levels (123.1 +/- 12.2 vs 145.1 +/- 18.0 mg/dl; p = 0.03). Plasma insulin levels were higher in the S than in the C group (1,110.28 +/- 721.59 vs 308.17 +/- 100.50 pmol/; p = 0.03). Total triglyceride levels (130.4 +/- 32.4 vs 193.6 +/- 48.4 mg/dl; p < 0.02) and total cholesterol levels (83.6 +/- 5.7 vs 93.3 +/- 7.9 mg/dl; p < 0.05) were lower in the S group compared with the C group. Liver weight was significantly higher in the S group compared with C (0.75 +/- 0.1 vs 0. 7 +/- 0.1 g, p = 0.05). CONCLUSIONS: In the post-weaning period, oral insulin supplementation had a significant effect on plasma glucose levels and lipid profile, as well as on liver weight and protein content in Balb/c mice. The application of these findings in humans should be studied.
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Leukocyte adhesion deficiency (LAD) type II is a rare autosomal recessive syndrome characterized by recurrent infections, typical dysmorphic features, the Bombay blood phenotype and severe growth and psychomotor retardation. It is attributed to a general absence of fucosylated glycans on the cell surface. Three Arab Israeli patients and one Turkish child have been reported so far. The primary defect in a specific GDP-L-fucose transporter of the Golgi apparatus has been disclosed recently. All three children reported by us are homozygous for one single founder mutation, different from that reported in the Turkish child. The amount of mRNA of the GDP-L-fucose transporter in cells from Arab patients and their parents are comparable to controls. Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes.