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Objective Kawasaki disease (KD) is an acute systemic vasculitis that is one of the major causes of acquired heart disease especially in young children. The pathogenesis of KD is still unclear. The increased incidence of the disease among Japanese children and siblings of affected patients suggests a genetic component to KD susceptibility. Several reports have studied human leukocyte antigen (HLA) polymorphisms in different populations with KD and found various results. In the present study, we aimed to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in Turkish children with KD. Methods The study was conducted between January 2016 and February 2018. HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) alleles of patients and healthy controls were studied using the low-resolution DNA-based sequence-specific oligonucleotide method. Results Fifty children with KD and 500 healthy controls were included in this study. In the analysis of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, no statistical difference was found in the frequency of alleles between the patients with KD and the control group. However, a significantly lower frequency of the HLA-DQB1*03 allele was observed in the KD group than in the control group (p < 0.001, odds ratio [OR]: 0.29, 95% confidence interval [CI]: 0.15–0.55). When the patients with KD were divided into two subgroups with or without coronary artery lesions (CALs), the frequency of the HLA-DQB1*03 allele was also found lower in the KD group with CALs than the KD group without CALs (p = 0.008, OR: 0.19, 95% CI: 0.05–0.68). Conclusion The study may guide future studies on HLA-DQB1*03 whether it is a protective allele for KD and CALs in Turkish children. [ABSTRACT FROM AUTHOR]

We investigated the effects of vitamin D on the ocular surface, tear functions, corneal imaging, and tear film cytokine levels. Fifty-two patients with vitamin D levels were examined in 3 groups according to serum vitamin D levels; 28 in group 1 (<12 ng/ml), 10 in group 2 (12–20 ng/ml), and 14 in group 3 (>20 ng/ml). Ocular surface disease index (OSDI), tear break up time (BUT), lissamine green (LG) staining, Schirmer test, in vivo confocal microscopy (IVCM), and tear collection for cytokine analysis were performed. The mean OSDI score was 35.2 ± 23.3, 36.2 ± 17.7, 24.4 ± 18.2 (p =.253), TBUT was 6.7 ± 2.5 sec, 9.3 ± 1.8 sec, 11.1 ± 2.8 sec (p <.001), Schirmer test was 16.7 ± 8.5 mm, 18.7 ± 7.6 mm, and 20.2 ± 7 mm (p =.254), median LG staining grade was 1 (0–3), 1 (0–2), 0 (0–1) (p =.008) in group 1, group 2, and group 3, respectively. Basal epithelial cell density was 4 027 ± 512 cells/mm2, 4 673 ± 451 cells/mm2, 5 067 ± 817 cells/mm2 (p = < 0.001), sub-basal nerve density was 978 ± 204 μm/frame, 1 236 ± 172 μm/frame, 1 425 ± 290 μm/frame (p = <0.001), median number of long nerve fibers was 3 (2–4) nerve/frame, 4 (3–4) nerve/frame, 4 (3–6) nerve/frame (p =.001), and median grade of nerve fiber tortuosity was 2 (0–3), 2.5 (2–3), 3 (2–4) (p <.001) in group 1, group 2, and group 3, respectively. Mean IL-1 β (82.62 ± 15.26, 85.57 ± 17.41, and 66.44 ± 11 ng/ml in group 1, 2 and 3, respectively, p =.002), IL-17 (77.80 ± 24.91, 64.46 ± 25.47, 55.42 ± 12.05 ng/ml in group 1, 2 and 3, respectively, p =.012), and IL-2 (75.7 ± 18.4, 66.13 ± 26.78, and 59.65 ± 16.04 ng/ml in group 1, 2 and 3, respectively, p =.048) levels were significantly lower in group 3, whereas, IL-13 levels were significantly higher in group 3 (16.12 ± 5.24, 19.20 ± 4.90, and 21.6 ± 5.55 ng/ml in groups 1, 2, and 3, respectively, p =.010). Vitamin D deficiency/insufficiency is associated with ocular surface changes shown with significant TBUT, LG staining, and tear film cytokine contents. Besides, significant corneal basal epithelial, sub-basal nerve density, and structural sub-basal nerve changes were associated with lower Vitamin D levels. [ABSTRACT FROM AUTHOR]

Objective: Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. Materials and Methods: After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. Results: We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. Conclusions: Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests. [ABSTRACT FROM AUTHOR]

Background: To evaluate the cytokine profile in gingival crevicular fluid (GCF) and serum of pediatric inflammatory bowel disease (IBD) patients and determine the cluster patterns of cytokines.Methods: Fifty IBD patients and 21 systemically healthy children were enrolled in the study. The GCF samples were collected from the participants during periodontal examination and periodontal indices were recorded. Based on activity indexes and response to conventional treatment, patients with IBD were further categorized into subgroups as: remission, active disease, and treatment-resistant. Serum samples were obtained from IBD patients to determine serum levels of cytokines. The levels of pro- (interleukin (IL)-1β, IL-12, IL-21, IL-22, IL-23, IL-17A, IL-17F) and anti-inflammatory (IL-4, IL-10) cytokines in serum and GCF were measured using Enzyme-linked Immunosorbent Assay (ELISA) kits.Results: Among 50 IBD patients, 58% were in remission, 20% had active disease, and 22% were defined as treatment-resistant. The severity of gingival inflammation measured by the criteria of Löe had increasing trends in IBD patients with active disease and treatment resistance. GCF IL-1β level was lower and GCF IL-4 and GCF IL-23 levels were higher in IBD patients compared to healthy controls. In the active disease group, more cytokine clusters occurred compared to the control group and other IBD subgroups, as explained by increased cytokine-cytokine interactions.Conclusions: Considering the increased complexity of cytokine interactions and the increased severity of gingival inflammation in patients with active disease, it can be concluded that disease activity might have an impact on gingival inflammation in pediatric patients with IBD. [ABSTRACT FROM AUTHOR]

Deficiency of adenosine deaminase type 2 (DADA2) is an autoinflammatory disease characterized with immunologic, hematologic, and neurological features. Here, we presented two patients with severe persistent chronic neutropenia, which required differential diagnosis of congenital and autoimmune neutropenia, myelodysplastic syndrome (MDS), and primary immunodeficiency diseases, including autoimmune lymphoproliferative disease. The therapy of the disease except hematopoietic stem cell transplantation is a challenging experience. [ABSTRACT FROM AUTHOR]

Defects in genes that have role in apoptotic pathways result in development of Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS related disorders. Germline and somatic FAS mutations, FASL and CASPIO mutations constitute other genetic defects in ALPS. Patients who fulfill ALPS diagnostic criteria and do not have any identified known disease causing mutations are classified as ALPS-unknown or ALPS phenotype and comprise about one third of all patients. CASP8, NRAS and KRAS gene mutations were reported for ALPS related diseases. We performed DNA sequence analysis in 25 unrelated patients with probable ALPS for FAS, FASL and CASP8 gene defects. Pathogenic mutations could not be found in the FAS, FASL and CASP8 genes. However, we found that the frequencies of SNPs rs 2234978 and rs 1045487 of FAS and CASP8 genes were significantly higher in the patients. Our results suggest that CASP8 and FAS gene polymorphisms in particular, may contribute to the susceptibility to development of ALPS phenotype. [ABSTRACT FROM AUTHOR]

Objective: To determine the vitreous and serum concentrations of TNF-α, IL-6, VEGF, IL-1β, IL-8, IL-17, MCP-1, IL-1Ra, IL-10 in patients with proliferative diabetic retinopathy (PDR) and to investigate the effect of adipose tissue on the pathogenesis of PDR. Methods: Twenty-two patients with PDR were prospectively evaluated. Seven cadavers and 11 patients with idiopathic epiretinal membrane or macular hole served as the controls. Multiplex bead array technology was employed to assess the concentrations of the cytokines. Results: The intravitreal levels of VEGF, IL-8, IL-6 were significantly higher in PDR group than control groups. In PDR group, the levels of IL-17, IL-8, IL-6 were significantly elevated in the vitreous, whereas the intravitreal levels of IL-10, IL-1Ra were found to be significantly lower than the serum concentrations. No significant correlation was found between cytokine levels and body mass index (BMI), fasting blood glucose (FBG), or glycated haemoglobin (HbA1c) of diabetic patients. Conclusion: In PDR the balance between the intravitreal pro- and anti- inflammatory adipo- cytokines is disturbed in favor of proinflammatory and proangiogenic cytokines in the vitreous humour. This study supports the role of adipocytokines in vascular pathology in PDR. It seems that PDR is a local inflammatory disease. However, obesity may not be the root of the inflammatory mediators in PDR. [ABSTRACT FROM AUTHOR]

ABSTRACT IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12 RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12 RB1. All these variants have been deposited in the online IL12 RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12 Rβ1 and molecular genetics of human IL12 RB1. [ABSTRACT FROM AUTHOR]

Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms and a high prevalence of autoimmune diseases, most often systemic lupus erythematosus (SLE). Here, we report a 29- month-old boy who presented with facial rash and history of early death of a sibling with infections, who was found to have a selective deficiency of C1q. The facial rash was composed of patchy erythematous plaques and centrally hypopigmented macules and desquamation. Two siblings had died of severe bacterial infections and his uncle had died of meningitis. Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation. [ABSTRACT FROM AUTHOR]

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder which is characterized by susceptibility to infections with weakly virulent mycobacteria, including Mycobacterium bovis and Bacille Calmette-Guerin (BCG). These patients are also susceptible to infections with Salmonella and M. tuberculosis. Nine disease-causing genes have been described (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, NEMO, ISG15, IRF8, and CYBB). Defect in IL12RB1 gene is the most common cause of the disease. We screened 3 families with patients with BCG infection, a feature compatible with MSMD, for IL12RB1 deficiency. First we screened 3 probands and 18 family members by flow cytometry (the surface expression of IL12Rβ1 was studied on activated lymphocyte) than Sangers sequencing. In 11 individuals surface expression of IL12Rβ1 was absent (<1%). Among these only 5 had clinical features compatible with MSMD and all were found to have homozygous c64+1G mutation. Two siblings, two parents and two grandparents without surface expression of IL12Rβ1 were asymptomatic, among those only one sibling had homozygous c64+1G mutation while the rest of the family members were heterozygous both for the mutation and Arg156His polymorphism (rs11575926) which allele frequency is 0.79. It seems that the antibody we use cannot detect IL12Rβ1 with Arg156His polymorphism suggesting that the epitope recognized by the antibody to be around the position of the polymorphism. Among the 6 affected (one died before family screening was performed) from 3 families carrying the same mutation the severity of the infections varied considerably, from transient axillary drained BCG lymphadenitis without any further infections to severe disseminated BCG infection. One patient who was BCG vaccinated had only mild oral moniliasis. In conclusion: Testing with two different antibodies may be better for screening by flow cytometry. There is a wide range of clinical presentation in patients with the same mutation and even within the same family. The penetrance of MSMD in IL-12Rβ1 deficiency seems to be incomplete for BCG infection. So even healthy siblings of the proband should be investigated for the defect. [ABSTRACT FROM AUTHOR]

Background: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings., Objective: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis., Methods: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry., Results: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia., Conclusions: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.