Himmet Haluk Akar

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion.

A patient developing anaphylaxis and sensitivity to two different GnRH analogues and a review of literature.

Abstract Gonadotropin-releasing hormone analogues are used in the treatment of prostate cancer, breast cancer, endometriosis, and uterine leiomyomas in adults and often in the treatment of precocious puberty in children. Many adverse effects have been reported for gonadotropin-releasing hormone analogues, but anaphylaxis is rarely reported as an adverse effect. Frequent cross-reactions, particularly during childhood, and diversity of the time of onset of anaphylactic manifestations complicate the diagnosis. A patient who exhibited anaphylactic allergic reactions to two different agents used in the treatment of central precocious puberty presented here because the case has an atypical course and is the first in the literature.

Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak–Higashi Syndrome Patients

Chediak–Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK cell- and T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.

Three faces of recombination activating gene 1 (RAG1) mutations

Severe combined immune deficiency (SCID) is a group of genetic disorder associated with development of T- and/or B-lymphocytes. Recombination-activating genes (RAG1/2) play a critical role on VDJ recombination process that leads to the production of a broad T-cell receptor (TCR) and B-cell receptor (BCR) repertoire in the development of T and B cells. RAG1/2 genes mutations result in various forms of primary immunodeficiency, ranging from classic SCID to Omenn syndrome (OS) to atypical SCID with such as granuloma formation and autoimmunity. Herein, we reported 4 patients with RAG1 deficiency: classic SCID was seen in two patients who presented with recurrent pneumonia and chronic diarrhoea, and failure to thrive. OS was observed in one patient who presented with chronic diarrhoea, skin rash, recurrent lower respiratory infections, and atypical SCID was seen in one patient who presented with Pyoderma gangrenosum (PG) and had novel RAG1 mutation.

The Role of Irisin, Insulin and Leptin in Maternal and Fetal Interaction

Objective: Insulin is an important hormone for intrauterine growth. Irisin is an effective myokine in the regulation of physiological insulin resistance in pregnancy. Leptin and insulin are associated with fetal growth and fetal adiposity. In this study, we aimed to investigate the relationships between irisin, insulin and leptin levels and maternal weight gain, as well as anthropometric measurements in the newborn. Methods: Eighty-four mothers and newborns were included in the study. Irisin, leptin and insulin levels were measured in the mothers and in cord blood. Anthropometric measurements in the newborn, maternal weight at the beginning of the pregnancy and at delivery were recorded. Results: Birth weight were classified as small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA). There was no difference in irisin levels among the groups. Leptin and insulin levels were found to change significantly according to birth weight (p=0.013, and p=0.012, respectively). There was a negative correlation between the anthropometric measurements of the AGA newborns and irisin levels. This correlation was not observed in SGA and LGA babies. Leptin levels were associated with fetal adiposity. Conclusion: While irisin levels are not affected by weight gain during pregnancy nor by birth weight, they show a relationship with anthropometric measurements in AGA infants. These results may lead to the understanding of metabolic disorders that will occur in later life.

Increased Levels of Plasma Soluble Human Leukocyte Antigen G in Persistent Wheezy Infants

Human leukocyte antigen (HLA)‐G is a non‐classical major histocompatibility complex class I antigen characterized by limited polymorphism in its coding region, unique tissue expression pattern in physiologic conditions and immunomodulatory properties. Recently, the level of soluble (s)HLA‐G was found to be higher in atopic asthma and allergic rhinitis, but this remains to be clarified in wheezy infants. The aim of the present study was therefore to investigate sHLA‐G in wheezy infants.

DOCK8 deficiency in a boy who presented with a giant aortic aneurysm between aortic root and iliac bifurcation.

Dedicator of cytokinesis 8 protein (DOCK8) deficiency is an autosomal recessive, inherited form of hyper-immunoglobulin E (hyper-IgE) syndrome, characterized by persistent cutaneous viral infections, elevated IgE, eosinophilia, and allergic manifestations. The case of a 10-year-old boy who presented with giant aortic aneurysm between the aortic root and iliac bifurcation is described in the present report. Aortic aneurysm of this size has not yet been reported.

Plasma glutamine and cystine are decreased and negatively correlated with endomysial antibody in children with celiac disease

BACKGROUND AND OBJECTIVES Glutamine is a nonessential amino acid which improves intestinal mucosal regeneration and absorption. Glutathione is a vital molecule for antioxidant reactions and is synthesized from cystine. The first aim of the study is to measure the plasma glutamine and cystine in children with celiac disease (CD) and compare them with controls. The second aim of this study is to investigate whether these amino acids are correlated with endomysial antibody (EMA) or not. METHODS AND STUDY DESIGN Fifty children with CD were compared to 50 healthy, age, and sex matched normal children as control. Plasma glutamine and cystine levels of the children were measured by using tandem mass spectrometry. RESULTS Plasma glutamine (808 vs 870 μmol/L) and cystine (19 vs 48.5 μmol/L) were significantly lower in the celiac group than the controls (p<0.05). The levels of plasma glutamine (797 vs 928 μmol/L, n=42) and cystine (18 vs 31.5 μmol/L, n=8) were lower (p<0.05) in the EMA-positive than the EMA-negative celiac patients. We could not find any statistically significance between EMA-negative celiac patients and controls for the plasma glutamine (928 vs 870 μmol/L) and cystine (31.5 vs 48.5 μmol/L) (p>0.05). Serum EMA was negatively correlated with plasma cystine (r=-0,321, p=0.023), glutamine (r=-0.413, p=0.003). CONCLUSIONS Our study indicated that plasma glutamine and cystine were significantly lower in the celiac children than the controls. Also, these amino acids were negatively correlated with EMA.

Eosinophilic esophagitis in a girl with pollen allergy who showed trachealization

Because the esophagus is normally devoid of eosinophils, detection of eosinophils in the esophagus often indicates pathological situations (1). Eosinophilic esophagitis (EoE) is a chronic, immunemediated esophageal disease clinically characterized by esophageal dysfunction related to symptoms and histologically by eosinophilpredominant inflammation. The current incidence rate is almost one in 2,500 individuals in pediatric populations. Pediatric patients with EoE present not only with dysphagia and swallowing difficulties, similar to adults with this disease, but also with abdominal pain and refluxlike symptoms (2). In particular, food allergens are believed to be involved in the pathogenesis of EoE. Furthermore, approximately 50% of EoE patients have coexisting atopic diseases (allergic rhinitis, food allergies, asthma, and atopic dermatitis). In addition, aeroallergens have been implicated as a contributing factor. The possible pollen associated mechanism of EoE may explain following the deposition of pollen into the nares and pharynx and the subsequent swallowing of secretions into esophagus (3). On endoscopic examination, EoE has been associated with a variety of abnormalities, such as linear furrowing, white exudates, and trachealization. There is no consensus regarding the treatment of EoE, although treatment strategies include medical management with topical or systemic corticosteroids and elimination diets (4). We present the case involving a 6yearold girl with asthma and allergic rhinoconjunctivitis who had EoE. The patient presented with refractory gastroesophageal reflux symptoms along with abdominal pain and intermittent dysphagia. Because of these symptoms, she had been treated with omeprazole for 1 year. After this period, her upper gastrointestinal endoscopy revealed edematous and pale mucosa, with loss of vascular pattern and ringed characteristic trachealized esophagus (Figure 1). EoE was documented by histopathology showing severe eosinophilic esophageal inflammation (Figure 2). From patient’s history, we also learned that she suffered from asthma attacks and symptoms of rhinoconjunctivitis, particularly during the spring period over the past 3 years. Her skin prick test was strongly positive for grass pollen. Use of inhaled ciclesonide, omeprazole, and montelukast provided temporary symptom resolution; however, the Turk J Gastroenterol 2015; 26: 69-70