Genotype-Phenotype Correlations in Chronic Granulomatous Disease: Insights From a Large National Cohort.

Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic Granulomatous Disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the NADPH oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyper-inflammatory manifestations. We report a multi-center cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2,918 patients suffering from frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD, 56 of Jewish ancestry, 48 of Arabic ancestry and 6 non-Jewish/non-Arabic. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyper-inflammatory manifestations are described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39/110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multi-professional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management and prevention.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Hypoparathyroidism-Retardation-Dysmorphism Syndrome due to a Variant in the Tubulin-Specific Chaperone E Gene as a Cause of Combined Immune Deficiency.

BACKGROUND: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome is a disease composed of hypoparathyroidism, growth retardation, severe developmental delay, and typical dysmorphic features caused by the tubulin-specific chaperone E gene variant. Many patients succumb in infancy to HRD due to overwhelming infections mainly caused by Pneumococcus spp. Knowledge related to the immune system in these patients is scarce. PURPOSE: To define the immune phenotype of a cohort of HRD patients including their cellular, humoral, and neutrophil functions. METHODS: The study included HRD patients followed at Soroka University Medical Center. Clinical and immunological data were obtained, including immunoglobulin concentrations, specific antibody titers, lymphocyte subpopulations, lymphocyte proliferation, and neutrophil functions. RESULTS: Nine patients (5 females and 4 males) were enrolled, aged 6 months to 15 years. All received amoxicillin prophylaxis as part of a routine established previously. Three patients had bacteremia with Klebsiella, Shigella spp., and Candida. Three patients had confirmed coronavirus disease 19 (COVID-19), and two of them died from this infection. All patients had normal blood counts. Patients showed high total IgA and IgE levels, low anti-pneumococcal antibodies in spite of a routine vaccination schedule, and reduced frequency of naive B cells with increased frequency of CD21lowCD27- B cells. All patients had abnormal T-cell population distributions, including reduced terminally differentiated effector memory CD8, inverted CD4/CD8 ratios, and impaired phytohemagglutinin (PHA)-induced lymphocyte proliferation. Neutrophil superoxide production and chemotaxis were normal in all patients tested. CONCLUSION: HRD is a combined immunodeficiency disease with syndromic features, manifesting in severe invasive bacterial and viral infections.

SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma.

Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

Unusual phenotype in patients with a hypomorphic mutation in the DCLRE1C gene: IgG hypergammaglobulinemia with IgA and IgE deficiency.

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.

Efficacy of omalizumab treatment for pediatric chronic spontaneous urticaria: A multi-center retrospective case series.

BACKGROUND: Chronic urticaria is defined by the presence of itchy wheals, sometimes accompanied by angioedema, lasting for at least 6 weeks. In children, most cases occur without an eliciting factor and are defined as chronic spontaneous urticaria (CSU). CSU affects up to 0.75% of children with a negative impact on quality of life and school performance. CSU is treated in adults with second-generation antihistamines, increased up to four times normal doses for second-line treatment. Omalizumab (a monoclonal antibody to IgE) may be recommended as third-line therapy. A similar protocol is used in children, yet little is known of its efficacy and safety. OBJECTIVES: To summarize our multi-center experience in treating children with recalcitrant CSU with omalizumab. METHODS: A retrospective multi-center case series conducted in 5 tertiary care centers in Israel. Patients included were children <18 years old diagnosed with recalcitrant CSU who were treated with omalizumab. Patients were followed up throughout the duration of omalizumab therapy/symptom remission. Patients' electronic medical records were used to gather data. RESULTS: Nineteen participants (11 F; 8 M) presented with CSU between ages 6 and 16.9 years. Sixteen (84%) responded to omalizumab, including children <12 years old, although two became non-responsive after 6-12 months of therapy. Another three patients (16%) were resistant to treatment, achieving remission through fourth-line (Cyclosporine A) or other therapies. CONCLUSION: Children with recalcitrant CSU, even those <12 years old, respond well to standard-dose, third-line omalizumab therapy at rates similar to adults. Yet, some cases may become non-responsive with ongoing treatment.

Gastric Drainage in the Treatment of Near-Fatal Food-Induced Anaphylaxis.

Anaphylaxis should be treated with early administration of intramuscular Adrenalin; however, fatalities may still occur even with this therapy. We report a patient with near-fatal anaphylaxis due to milk whose symptoms persisted and were resistant to any therapeutic attempt; however, the patient had a prompt resolution of the anaphylaxis shortly after a nasogastric tube placement with gastric drainage, suggesting that this procedure ended the ongoing absorption of additional allergen from the gastrointestinal tract. We suggest that nasogastric drainage of gastric contents should be considered as part of the therapy in severe food-induced anaphylaxis.

Neutrophil Functions in Immunodeficiency Due to DOCK8 Deficiency.

Neutrophil chemotactic defects have been reported previously in patients with hyper-IgE syndrome. Bi-allelic mutations in dedicator of cytokinesis 8 (DOCK8) gene usually cause an autosomal recessive hyper-IgE syndrome phenotype. Data are lacking about expression of DOCK8 protein in neutrophils or the possible role of DOCK8 in neutrophil function. We sought to determine if DOCK8 protein is expressed in neutrophils and if DOCK8 plays a role in neutrophil function. The expression of DOCK8 protein was assessed in neutrophils from healthy volunteers with and without activators. Neutrophil chemotaxis, phagocytosis and superoxide generation were studied in neutrophils from DOCK8-deficient patients compared to neutrophils from healthy controls before and after stimulation with activators: phorbol 12-myristate 13-acetate (PMA) or N-Formylmethionyl-leucyl-phenylalanine (fMLP). DOCK8 protein is expressed in resting neutrophils from healthy controls, with a significant increase in DOCK8 expression after stimulation. Neutrophil functions were assessed in 6 DOCK8-deficient patients. All patients had the same non-sense mutation (c.C5134A, p.S1711X). Normal chemotaxis was recorded in 4/6 patients while a mild to moderate chemotaxis defect was recorded in 2/6. Superoxide generation was mainly normal in neutrophils from all six patients and phagocytosis was normal in five patients tested. We conclude that DOCK8 protein is expressed in resting human neutrophils and DOCK8 expression is increased after stimulation with either PMA or fMLP. Most patients with a disease-causing mutation in DOCK8 have normal neutrophil functions, while a minority showed a mild to moderate chemotactic defect.

Risk factors for congenital heart defects in two populations residing in the same geographic area: a long-term population-based study, Southern Israel.

BACKGROUND: Congenital Heart Defects (CHD) are the most common structural defects of newborns. Southern Israel's population is comprised of Jews (75%) and Arab-Bedouins (25%). The latter has a high rate of consanguinity and low abortion rate compared with the Jewish population, which led us to suspect a higher CHD prevalence in this population. Our aim was to compare maternal risk factors that are associated with CHD in these populations. METHODS: All births during 1991-2011 in Soroka University Medical Center (n = 247, 289) with 6078 newborns having CHD were included. To account for same-woman deliveries, general estimating equation models adjusted for ethnicity, gender and birth number were used. RESULTS: The total prevalence of CHD was 24.6/1000 live births, with 21.4 and 30 among Jewish and Bedouin populations, respectively, (p = 0.001). Multi-variant analysis of risk factors for CHD revealed that risk factors common to both populations included conception with fertility medications, sibling CHD, maternal CHD, diabetes mellitus, hypertension and anaemia. Risk factors that were specific for the Bedouin population were - maternal age over 35 years, recurrent pregnancy loss and in vitro fertilisation. However, sibling CHD was more common as a CHD risk factor in the Jewish compared with the Bedouin population (Adjusted OR 10.23 versus 3.19, respectively). CONCLUSIONS: The prevalence of CHD is higher in both the Bedouin and Jewish populations than previously reported. Several maternal factors were associated with CHD specifically for a certain population. Risk factors for CHD vary in populations residing in the same geographic area.

Analysis of Chronic Granulomatous Disease in the Kavkazi Population in Israel Reveals Phenotypic Heterogeneity in Patients with the Same NCF1 mutation (c.579G>A).

PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47phox deficiency. METHODS: Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47phox by immunoblotting and molecular confirmation by DNA sequence analysis. RESULTS: Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47phox deficiency. CONCLUSIONS: Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusive.

Incidence of typically Severe Primary Immunodeficiency Diseases in Consanguineous and Non-consanguineous Populations.

PURPOSE: Primary immunodeficiency diseases are considered to be rare diseases; however, data on the exact birth incidences of these diseases are sparse. Southern Israel is inhabited by two major populations: a relatively non-consanguineous Jewish population and a highly consanguineous Muslim Bedouin population. We sought to calculate the incidences of typically severe primary immunodeficiency diseases and compare the incidences in these populations. METHODS: A retrospective analysis of all typically severe primary immunodeficiency diseases evaluated at a single center from January 1, 1996 to December 31, 2016. The amount of live births by population was the denominator for calculating the incidences by population. RESULTS: A total of 95 patients were included, 85 of Bedouin and 10 of Jewish ethnicities. There were 152,331 births in the Bedouin and 160,998 births in the Jewish populations. The total incidence of typically severe primary immunodeficiency diseases was higher in the Bedouin population than expected based on previous studies. The total incidences were 55.8/105 births in the Bedouin population compared with 6.2/105 births in the Jewish population (P < 0.001). The incidences of all combined immunodeficiency diseases, ataxia telangiectasia, and infantile IBD due to interleukin 10 receptor defects were all significantly higher in the Bedouin population (P < 0.001). The incidence of X-linked agammaglobulinemia was not significantly different between both populations (P = 0.11). CONCLUSIONS: Typically, severe primary immunodeficiency diseases are not rare diseases in a consanguineous population; these diseases are significantly more common in the Bedouin population. This finding is probably also applicable to other consanguineous populations, and in these populations, primary immunodeficiency diseases should not be regarded as rare diseases.

Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients.

Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life-threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live-births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR-CGD) and 32 (38%) with X-linked recessive inheritance (XLR-CGD). Consanguinity was detected in 64% of AR-CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR-CGD and 13 in AR-CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long-term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28-36, 2017. © 2016 Wiley Periodicals, Inc.

Anomalous Left Coronary Artery From the Pulmonary Artery in Infants and Toddlers Misdiagnosed as Myocarditis.

OBJECTIVES: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect. Children with this anomaly are usually asymptomatic at birth and develop symptoms later on in life, which may mimic myocarditis. We sought to delineate clinical, laboratory, and epidemiological aspects of this anomaly. METHODS: A retrospective analysis of children with ALCAPA evaluated in a tertiary medical center in southern Israel was performed. A computerized search for all patients with the diagnosis of ALCAPA between 2000 and 2011 was performed. The medical records were reviewed; demographic, clinical, and laboratory data were extracted. RESULTS: A total of 9 patients were included. In 4 patients, acute deterioration required evaluation in the pediatric emergency medicine department; in all 4, the initial clinical suspicion was myocarditis. Failure to thrive was recorded in 7 (77.7%) of the 9 patients and asthma or wheezing were recorded in 5 (55.5%) of the 9 patients. Normal heart size was recorded in 4 (44.4%) of the 9 patients. Electrocardiographic abnormalities were present in all of the patients (100%). A total of 141,675 births were recorded during the study period, giving an incidence of at least 1 case (0.00635%) per 15,741 births. CONCLUSIONS: Children evaluated in the emergency medicine department with suspected myocarditis should be evaluated specifically for ALCAPA. The clinical findings that should raise the suspicion of this anomaly are failure to thrive and either a diagnosis of asthma or recurrent wheezing.

Anaphylactic reactions in adult patients in Southern Israel.

BACKGROUND: Southern Israel is inhabited by Jews and Bedouins. Children from these populations differ in the epidemiology of anaphylactic reactions; however, the effects of ethnicity on the epidemiology of anaphylactic reactions in adults in these populations are unknown. METHODS: Retrospective review of medical records of patients with anaphylactic reactions treated in a single institution during 2008-2012. RESULTS: A total of 192 evaluable cases of anaphylaxis were recorded; 155 (80.7%) anaphylactic reactions occurred in Jews and 37/192 (19.3%) occurred in Bedouins. A trend towards an older mean age of occurrence of anaphylaxis was recorded in Jewish patients compared with Bedouin patients: 48.1 years versus 41.2, respectively (P = 0.053). Anaphylaxis was more common in Jewish female patients than males and more common in Bedouin male patients than females. Overall, 93/155 (60.0%) females in Jewish patients were affected compared with 14/37 (37.8%) in the Bedouin population (P = 0.015). More Jewish patients had more anaphylaxis attributed to food compared with Bedouin patients: 31/155 (20%) versus 2/37 (5.4%) (P = 0.034). The mean yearly incidence of anaphylaxis was similar in Bedouin and Jewish patients: 12.1 ± 5.3 versus 17.6 ± 15.3, respectively (P = 0.466). However, a significant trend towards a higher incidence of anaphylactic reactions was recorded throughout the study years only in Jewish patients (r = 0.906, P = 0.034). CONCLUSIONS: Adult Jewish patients have a significantly higher probability of having anaphylactic reactions due to food compared with Bedouin patients, with females being more affected, and the incidence of anaphylactic reaction is increasing only in the Jewish population. The epidemiology of anaphylactic reactions can differ between populations residing in the same geographical area.

Clinical features of Candidiasis in patients with inherited interleukin 12 receptor ß1 deficiency.

BACKGROUND: Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency. RESULTS: Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS: Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.

The effects of Bruton tyrosine kinase inhibition on chemotaxis and superoxide generation in human neutrophils.

PURPOSE: The role of the Bruton tyrosine kinase (Btk) protein in neutrophil function has been evaluated using neutrophils from healthy volunteers after incubation with a Btk inhibitor, leflunomide metabolite analog (LFM-A13), suggesting an important role for Btk in neutrophil function. We sought to determine the role of Btk protein on neutrophil superoxide generation and chemotaxis stimulated by N-formyl-methionine-leucine-phenylalanine (fMLP). METHODS: Chemotaxis was assayed on agarose gel and superoxide generation by cytochrome C reduction. The affects of LFM-A13 on chemotaxis and superoxide generation in unstimulated and fMLP stimulated neutrophils were studied in Btk deficient neutrophils from XLA patients compared with matched controls analyzed simultaneously. RESULTS: Chemotaxis and stimulated superoxide production were similar in the normal and Btk deficient neutrophils and were similarly inhibited by LFM-A13. In one patient, LFMA13 had no effect on superoxide generation in Btk deficient neutrophils up to a concentration of 25 microM, while inhibited superoxide production by control neutrophils. CONCLUSIONS: Our results suggest that Btk does not have a specific role in neutrophil fMLP-stimulated superoxide generation and chemotaxis since these activities were similarly inhibited by LFM-A13 in Btk deficient and normal neutrophils. The lack of superoxide generation following Btk inhibition by LFM-A13 in Btk deficient neutrophils from one patient may suggest some heterogeneity in the role of Btk in fMLP induced neutrophil superoxide generation.

Thymic function in MHC class II-deficient patients.

BACKGROUND: MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4(+) TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. OBJECTIVE: We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. METHODS: Eight MHC-II-deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. RESULTS: In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vß repertoires of total CD3(+) lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vß repertoire on CD4(+) cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3(+) lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4(+) cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II-deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. CONCLUSIONS: Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program.

[Allergy to non-steroidal antiinflammatory drugs: recommendations of the Israeli allergy and clinical immunology association].

Drug hypersensitivity is an adverse reaction that was brought-about by a specific immunologic response. Some of these reactions are Linked with significant morbidity and mortality. Nowadays, hypersensitivity reactions to most drugs can be well defined and the risk of re-exposure to the culprit drug and/or related drugs can be properly assessed. Medical history, skin, blood and challenge tests, conducted in an allergy clinic, enable the prediction and prevention of repeated events as well as unnecessary avoidance of needed compounds. Non-steroidal anti-inflammatory drugs [NSAID] are the second most prevalent group of drugs that provoke hypersensitivity responses occurring either immediately or later. Immediate type responses to NSAID could be divided into 2 groups, each related to a different mechanism. The most common reaction is not allergic but rather it is mediated by the inhibition of the cyclooxygenase I enzyme pathway. Accordingly, this reaction is not selective to a single chemical compound but rather cross-reacts with other members of this "family" of drugs, depending on their biochemical properties. The clinical distinction between those two subtypes of immediate reaction is hard and sometimes utterly impossible. Moreover, the clinical appearance of an immediate reaction may vary from rhinitis, asthma, new appearance or augmentation of chronic urticaria and up to overt anaphylaxis and death. Furthermore, delayed type reactions may also be life-threatening and typically appear 24 hours and up to days following initiation of therapy. In the current review, we present the recommendations of the Israel Association for Allergy and Clinical Immunology for the evaluation and treatment of patients suspected to suffer from hypersensitivity to NSAIDs.

IL-12Rß1 deficiency: mutation update and description of the IL12RB1 variation database.

IL-12Rß1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rß1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rß1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rß1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rß1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rß1 and molecular genetics of human IL12RB1.