Leukotrienes and leukotriene modifiers in pediatric allergic diseases

Leukotrienes are potent pro-inflammatory lipid mediators derived from arachidonic acid through several enzymatic pathways. They have an essential role in allergic inflammation, where they induce bronchoconstriction, airway edema, and chemotaxis of the inflammatory cells in the airways, nasal and conjunctival tissues. Leukotriene modifiers include leukotriene receptor antagonists (montelukast, zafirlukast and pranlukast) and leukotriene synthesis inhibitors (zileuton). These medications have been extensively used in childhood allergic diseases. This review will highlight the leukotriene pathway and its role in allergy as well as the effects of leukotriene modifiers in different allergic disorders

The effect of serum angiotensin II and angiotensin II type 1 receptor gene polymorphism on pediatric lupus nephritis

Background: Angiotensin II (Ang II) is found to perpetuate inflammation and visceral damage in systemic lupus erythematosus (SLE). It mediates most of its actions through Ang II receptor type I (AT1) whose gene polymorphism A1166C (CC genotype) seems to have pathogenic effects. Objective: To measure serum Ang II and the frequency of AT1 receptor CC genotype among a group of Egyptian patients with pediatric onset lupus nephritis (pLN). Methods: This is a case-control cross sectional study which included 24 patients with pLN and 24 age and sex-matched healthy subjects as controls. Clinical evaluation and routine laboratory markers for SLE patients were done. SLE disease activity index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG)-2004 renal score were measured. Serum Ang II was measured by enzyme linked immunosorbent assay and detection of ATI receptor CC genotype by polymerase chain reaction were done for both patients and controls. Results: Patients had significantly higher serum Ang II than the controls (p=0.0001). The frequency of AT1 receptor CC genotype was significantly higher among patients as compared to the control group (p=0.008). Both serum Ang II and AT1 receptor CC genotype were comparable between patients with proliferative LN class III and IV and those with LN class II (p>0.05). Serum Ang II did not correlate significantly with SLEDAI or BILAG-renal score (p>0.05). Conclusion: Serum Ang II and AT1 receptor CC genotype seem to have pathogenic role in pLN but with no deleterious effects on the phenotype of LN for further assessment.Keywords: Lupus nephritis; Angiotensin II; Angiotensin II type 1 receptor; Polymorphism; Pediatrics

Hen’s egg white hypersensitivity among a group of Egyptian atopic children

Background: Egg allergy is potentially life-threatening. The prevalenceof egg allergy in Egypt is still unclear. This study is to evaluate thefrequency of egg hypersensitivity in a group of Egyptian atopic children.Methods: Eighty allergic children were enrolled, each is subjected toclinical evaluation, skin prick testing (SPT) using a commercial eggwhite extract, and serum egg white specific IgE (SpIgE) estimation. Sixpatients with suspected egg allergy consent to perform open oral eggchallenge. Results: Twenty-eight patients had history of exacerbation oftheir allergic diseases upon exposure to egg white, of these patients, 8had negative SPT and serum egg white SpIgE. SPT was positive in 25(31.2%) patients, of these patients, 3 (4%) were +3, 22 (28%) were +2,of whom 5 patients tolerate eggs without adverse effects. Serum eggwhite SpIgE was positive in 19 (24%) patients with a mean of 0.81 IU/ml(range: 0.35-4.52 IU/ML). Egg white allergy based on positive history,positive SPT and/or egg white SpIgE was detected in 23 (28.8%)patients. Open oral egg challenge was positive in one patient withpositive history but negative tests giving an overall frequency of eggallergy of 30 % (n=24).While egg white SpIgE did not correlate with theages, positive SPT was significantly more frequent among youngerpatients (t= 1.7, p=0.02). Egg sensitization and allergy did not affect theseverity of asthma (p > 0.05). Conclusion: Although positive SPT/ serumspecific IgE to eggs are good tools for diagnosis, oral food challengeremains the gold standard in suspected cases. Further wide-scale studiesare needed to outline the real prevalence of egg allergy in Egypt.Keywords: Egg allergy; children; skin prick test

Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score

Objective To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. Methods The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. Results The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. Conclusion The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency