Evaluation of Keratoconus Disease with Tear Cytokine and Chemokine Levels Before and After Corneal Cross-Linking Treatment.

OBJECTIVES: To compare tear cytokine and chemokine levels of keratoconus (KC) patients with controls to perceive etiology distinctly and to clarify the molecular changes after cross-linking (CXL). METHODS: Tear samples were gathered from 34 participants in this prospective study. Participants underwent anterior and posterior segment examinations with slit-lamp biomicroscopy. Patients were assessed by corneal topography before and 3 months after CXL. Flat (K1), steep (K2), and average keratometry (Kmean), cylinder (CYL), and central corneal thickness (CCT) values were evaluated. After 3 months from CXL, samples were re-collected, and comparisons were made with preoperative values. RESULTS: Levels of IFN-gamma, IL-8, IL-12, IL-17, TNF-α, IL-4 and IL-13 were detected higher in KC patients (p= 0.008, p= 0.047, p= 0.001, p= 0.001, p= 0.001, p= 0.001, p= 0.027, respectively). After CXL IL-4, IL-5, IL-6, IL-7, IL-8, TNF-α levels showed significant decrease (p= 0.005, p= 0.045, p= 0.010, p= 0.022, p= 0.001, p=0.002, respectively). As for the topographic measurements, postoperative CCT values were increased whereas Kmean reduced after CXL (p < 0.001, p = 0.015, respectively). (p= 0.001, p= 0.027, respectively).Our findings imply that inflammation plays a key role in the development of KC and that this link is influenced by CXL therapy.

Ocular Changes and Tear Cytokines in Individuals with Low Serum Vitamin D Levels: A Cross-Sectional, Controlled Study.

BACKGROUND: We investigated the effects of vitamin D on the ocular surface, tear functions, corneal imaging, and tear film cytokine levels. METHODS: 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. RESULTS: 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 ß (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). CONCLUSIONS: 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.

Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.

Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

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.

Influence of video display terminal use and meibomian gland dysfunction on the ocular surface and tear neuromediators.

OBJECTIVE: To evaluate the effects of video display terminal (VDT) work and meibomian gland dysfunction (MGD) on ocular surface parameters, tear cytokine and substance P (SP) levels, and their association with dry eye disease (DED). METHODS: This cross-sectional study included 60 patients with evaporative DED and 20 healthy individuals. The DED patients were divided into three groups according to daily VDT work time and presence of MGD. The ocular surface and tear film were assessed using the Ocular Surface Disease Index questionnaire (OSDI), tear film break-up time (TBUT), ocular surface staining, Schirmer II test, and corneal sensitivity. MGD was evaluated with meibography. Corneal nerve alterations were evaluated using in vivo confocal microscopy (IVCM). The tear levels of 30 cytokines and SP were examined. RESULTS: Compared to controls, DED patients had higher OSDI score (p < 0.001), increased corneal staining with fluorescein and lissamine green (p = 0.046, p = 0,038), and lower TBUT (p < 0.001). Tear interleukin-6 levels were higher in DED patients, while tear SP levels did not differ between the groups (p = 0.265). VDT work time showed a weak positive correlation with OSDI (r = 0.274, p = 0.014) and SP level (r = 0.284, p = 0.011). CONCLUSION: The results of this study show that VDT use and MGD have an adverse effect on the ocular surface. It was also observed that the combination of VDT use and MGD did not significantly increase the ocular surface disease, but longer VDT exposure may be associated with more complaints of ocular discomfort.

Evaluation of periodontal status and cytokine response in children with familial Mediterranean fever or systemic juvenile idiopathic arthritis.

OBJECTIVES: Familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) are chronic inflammatory diseases and anti-inflammatory agents are used in their treatment. This study evaluates the periodontal status and cytokine response in pediatric patients with FMF or sJIA. MATERIALS AND METHODS: Forty-eight FMF/sJIA patients were under treatment/control and in attack-free period; 20 systemically healthy children participated in the study. FMF/sJIA patients were divided into two subgroups based on the treatment they received: receiving anti-IL-1 therapy (anti-IL-1 ( +)) and not receiving anti-IL-1 therapy (anti-IL-1 ( -)). The clinical periodontal indices were recorded. Gingival crevicular fluid (GCF) and serum samples were collected. Cytokine levels (IL-1ß, IL-1α, TNF-α, IL-6, IL-8, IL-10, IL-17, IL-33) in GCF and serum were measured using ELISA kits. RESULTS: There was no significant difference between the groups in terms of GCF IL-1ß and IL-1α levels although, BoP and GI were significantly lower in the anti-IL-1 ( +) group compared to the control group. GCF IL-10 level was higher in the anti-IL-1 ( -) group than in the control group; GCF IL-8 levels were lower in both FMF/sJIA subgroups versus controls. There was no significant difference between serum cytokine levels of FMF/sJIA subgroups. CONCLUSIONS: Considering the significant decrease in GI, BoP, and GCF IL-8 levels in the anti-IL-1 ( +) group, it can be concluded that anti-IL-1 medications may suppress periodontal inflammation clinically and immunologically. CLINICAL RELEVANCE: Anti-IL agents are not currently used in periodontal therapy. However, this study demonstrated the positive effect of anti-IL-1 medications on periodontal inflammation in pediatric patients with FMF or sJIA.

A Rare Central Nervous System Involvement Due to CTLA-4 Gene Defect.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is the defect of one of the checkpoint inhibitory molecules and defined as a primary immunodeficiency characterized by immune dysregulation. A 26-year-old female with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, and hypogammaglobulinemia was admitted with an inability to walk, urinary hesitancy, and bowel incontinence. Neurological examination revealed mild weakness, pyramidal, and deep sensorial involvement of the left lower extremity. Brain MRI revealed periventricular, juxtacortical, and cerebellar inflammatory lesions. Thoracic spinal MRI showed a longitudinaly extensive cord lesion. Additionally, thoracal CT showed parenchymal opacities and bilateral hilar lymph nodes. The biopsy from mediastinal lymph nodes and lung parenchyma demonstrated a low-grade lymphoproliferation and grade 1 "Lymphomatoid granulomatosis". Detailed laboratory analyses indicated the diagnosis of ''common variable immunodeficiency''. Next-generation sequencing with primary immunodeficiency panel revealed a heterozygous mutation in CTLA-4 (c.436G>A(p.G146R)(p.Gly146Arg)). After molecular diagnosis, abatacept therapy was started as a targeted therapeutic approach with subcutaneous immunoglobulin therapy.

Evaluation of the peripheral blood T and B cell subsets and IRF-7 variants in adult patients with severe influenza virus infection.

BACKGROUND AND AIMS: Influenza virus is one of the leading infections causing death among human being. Despite known risks, primary immune deficiency due to Interferon Regulatory Factor-7 (IRF7) gene defect was reported as a possible cause of the risk factors for complicated influenza. We aimed to investigate the changes in peripheral T and B cell subsets in adult patients with severe seasonal influenza virus infection and the investigation of variants of IRF7 gene. METHODS: In this study, 32 patients, hospitalized due to influenza infection-related acute respiratory failure were included. RESULTS: The median age of the patients was 76 years (26-96), and 13/32 (40.6%) were in the intensive care unit. Central memory Th, effector memory Th, TEMRA Th, cytotoxic T lymphocytes (CTL), central memory CTL of the patients were found to be increased, naive CTL were decreased. There was a significant increase in the percentage of effector memory Th, and a decrease in the percentage of naive CTL in patients ≥65 years-old compared to patients <65 years old (P = .039, and P = .017, respectively). IRF7 gene analysis revealed two different nucleotide changes in three patients; c.535 A > G; p.Lys179Glu (K179E) and c584A > T; p.His195Leu (H195L), located in the fourth exon of the IRF7 gene. DISCUSSION: The increases in central and effector memory Th, central memory CTL and decrease of naive CTLs may be secondary to the virus infection. K179E (rs1061502) and H195L (rs139709725) variants were not reported to be related with susceptibility to an infection yet. It is conceivable to investigate for novel variants in other genes related to antiviral immunity.

A new nanosuspension prepared with wet milling method for oral delivery of highly variable drug Cyclosporine A: development, optimization and in vivo evaluation.

Cyclosporine A (CsA) is a cyclic polypeptide, that has been widely used for immunosuppression. This study aims to develop nanosuspension for oral administration of CsA using the wet milling (WM) method one of the top-down technologies. The WM method was optimized by studying the effects of critical process parameters for WM on the particle size (PS), particle size distribution (PDI), and zeta potential (ZP) of nanosuspensions using the Design of Experiment (DoE) approach. Nanosuspension was developed using hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) and in vitro characterization studies were performed. In vitro dissolution and in vivo pharmacokinetic studies were conducted with biorelevant media (fasted and fed state simulated fluids) and fasted and fed states in rats, respectively. In vivo immunological studies were also performed. PS, PDI, and ZP values for nanosuspension were approximately 600 nm, 0.4, -25 mV, respectively. The solubility of CsA was increased by 4.5-folds by nanosuspensions. Dissolution studies showed that nanosuspension had higher dissolution than the commercial product in the FeSSIF medium. The pharmacokinetic study indicated that AUC0-24 values of CsA nanosuspension were to be 2.09 and 5.51-fold higher than coarse powder in fasted and fed conditions, respectively. Immunological studies were carried out after oral administration of nanosuspension for 21 days, the ratio of CD4+/CD8+ was found to be more acceptable than the commercial product. These results demonstrated that nanosuspension is a promising approach for increasing the bioavailability and avoiding the food effect on absorption of CsA which one of the highly variable drugs.

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency.

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.

Adenosine Deaminase Type II Deficiency: Severe Chronic Neutropenia, Lymphoid Infiltration in Bone Marrow, and Inflammatory Features.

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.

Cytokine profile in serum and gingival crevicular fluid of children with inflammatory bowel disease: A case-control study.

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)-1ß, 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-1ß 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.

A single-center study points to diverse features and outcome in patients with Hyperimmunoglobulin M Syndrome and Class- Switch Recombination defects.

Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n = 18), followed by CD40 Ligand (CD40L) (n = 14) and CD40 (n = 3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p = .001 and p = .008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p = .002 and 77.8%, p = .002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n = 4, CD40 deficiency n = 2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.

Differential diagnosis of primary immunodeficiency in patients with BCGitis and BCGosis: A single-centre study.

BCG infections occur more frequently in patients with underlying primary immunodeficiency disease (PIDD). In this study, we aimed to evaluate the ratio of PIDD in the patients with BCG infections. Patients with BCG infections were analyzed in a tertiary referral centre in the 2015-2020 period. Forty-seven patients with BCGitis/BCGosis were evaluated; thirty-four (72.3%) had BCGitis, and 13 (27.7%) had BCGosis. Common tissue and organs affected are lymph nodes (57.4%), skin and subcutaneous tissue (48.9%), lungs (23.4%) and liver (17%). PIDD was shown in 26 patients (55.3%), including 92.3% of patients with BCGosis and 41.2% of patients with BCGitis. Ten patients had Mendelian susceptibility to Mycobacterial disease (MSMD) (21.2%), six had predominantly antibody deficiency (PAD) (12.7%), five had severe combined immunodeficiency (SCID) (10.6%), three had CGD (6.3%), and two had CID (4.2%). Mortality was reported in two patients (4.2%) with CID (ZAP70 deficiency (n = 1) and PIK3R1 deficiency (n = 1)). Parental consanguinity (84%), axillary lymphadenopathy (65%), mycobacterial lung disease (42%), hepatomegaly (30%) and growth retardation (19%) were significantly high in patients with PIDD diagnosis. Isolated vaccination site infection was also recorded in patients with PIDD (CID (n = 1), SCID (n = 1), PAD (n = 5)). BCG vaccination should be planned with caution for the cases with suspected PIDD. This study indicates that almost all patients (92.3%) with BCGosis and one in every two patients (41.2%) with BCGitis have an underlying PIDD. Parental consanguinity, axillary lymphadenopathy, mycobacterial lung disease, hepatomegaly and growth retardation (19%) are important clinical features in the differential diagnosis of PIDD.

Human Leucocyte Antigen Genotyping in Celiac Disease: Reasons for Inappropriate Use.

BACKGROUND: Celiac disease (CD) is an autoimmune enteropathy, which may need further Human Leukocyte Antigen (HLA) testing beyond autoantibodies for diagnosis due to the necessity of lifetime gluten restriction. HLA genotyping test is useful in certain scenarios for CD diagnosis and screening. The aim of this study was to evaluate the reasons for inappropriate requesting of HLA testing. METHODS: One hundred and fifteen patients, who had been tested for CD-related HLAs, were included in this study. Final diagnosis, indication of HLA test, serological and histopathological findings were re-evaluated to determine the inappropriate usage of HLA testing. RESULTS: Among all patients, 44 (38.2%) were diagnosed with CD according to their genotyping results. The frequency of DQ 2.5, DQ8 and DQ2.2 haplotypes among these patients was 57.2%, 28.2%, and 14.3%, respectively. HLA test was performed inappropriately in 35 (30.4%) of patients. The most common reason was serology and pathological findings of patients were already conclusive as CD in 15 (42.9%) patients. Serology negative patients were tested without any supporting finding of CD in 11 (31.4%) patients. Last identified reason was that patients whose serology and intestinal biopsy were not conclusive as CD in 9 (25.7%) patients. CONCLUSIONS: Before requesting HLA typing test, patient's data should be thoroughly evaluated to confirm the need for test.

Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey.

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.

Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature.

BACKGROUND: Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency. OBJECTIVE: We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy. METHODS: In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls. RESULTS: In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics. CONCLUSIONS: The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.

Expression of HLA class I and class II genes in patients with multiple skin warts.

Human leukocyte antigens (HLAs), which are genetic markers that have critical roles in the immune response against pathogens, vary greatly among individuals. The aim of the study is to investigate the frequency of HLA class I (HLA-A, HLA-B and HLAC) and class II (HLA-DRB1, HLA-DQB1 and HLA-DQA1) genes in patients with multiple skin warts and to elucidate the role of these genes in the genetic susceptibility to skin warts. Peripheral venous blood samples were collected from 100 patients with multiple skin warts and 300 healthy individuals (controls). HLA typing was performed after DNA isolation from the blood samples. The HLA-A*02 (odds ratio [OR]: 0.12; p = 0.0019), HLA-DQA1*03:01 (OR: 0.45; p = 0.0017) and DQA1*05:01 (OR: 0.17; p < 0.0001) genes were significantly more prevalent in the patients than in the healthy individuals and were thus identified as risk genes. The HLA-DQA1*01:01 (OR: 0.17; p < 0.0001), HLA-DQA1*01:02 (OR: 0.17; p < 0.0001), HLA-DQA1*01:03 (OR: 0.11; p < 0.0001), HLA-DQA1*02:01 (OR:027; p<0.0001) and HLA-DQA1*05:05 (OR:0.16; p<0.0001) genes were classified as protective genes because of their low frequencies in the patients. The limitation of the study is that Human papillomavirus typing could not be performed while investigating the relationship between skin warts and HLA class I and class II genes. Our data suggest the role of HLA genes in the development of skin warts. However, other components of the major histocompatibility complex system and acquired factors of the immune system could also be involved and should be further investigated.

The HLA groups and their relationship with clinical features in Turkish children and adolescents with celiac disease.

BACKGROUND: We aimed to investigate the relationship between human leukocyte antigens (HLA)-groups and clinical features, and degree of intestinal injury in children with celiac disease (CD). METHODS: Study group included 73 (50 females, 68.5%) children with CD. Demographic and clinical features, accompanying autoimmune diseases, family history for CD and degree of damage in small intestinal mucosa (according to Marsh classification) at the time of diagnosis were determined. Twenty-two siblings of celiac patients without CD (15 females, 65.2%) consisted control group 1, and 66 (40 females, 60.6%) people from the normal population consisted control group 2. RESULTS: The allele frequencies of HLA B8, B50, C6, C7, DR3, DR7, DQ2, and DR3 homozygosity were higher in the patient group. HLA DQ2 positivity was 89% in the patient group, 73.9 and 45.5% in control groups 1 and 2, respectively (p < 0.0001). HLA A30, C14, DR11, DQ3 frequency were lower in patients compared to both control groups. HLA-DR15 alleles in patient and control group 1 was significantly lower compared to the general population (p < 0.05). Thirty (41.1%) patients had typical, 43 (58.9%) patients had atypical presentation. Thirteen (17.8%) patients had other autoimmune diseases. There was no association between coexisting autoimmune diseases and the HLA antigens. Fifteen patients (20.5%) had a positive family history for CD; patients with HLA A69, B41 and C12 alleles had a higher positive family history (p < 0.05). Intestinal mucosal damage was as follows: 5 patients (6.8%) had Marsh 2, 25 (34.3%) Marsh 3a, 28 (38.4%) Marsh 3b, 15 (20.5%) Marsh 3c. Patients with HLA-DR15 alleles had more frequent Marsh 3a lesions (p < 0.05). CONCLUSIONS: B8, B50, C6, C7, DR3, DR7, DR3/DR3, DQ2 alleles were risk factors for CD in the Turkish population. HLA C14, DR11, DR15, and DQ3 alleles were found to have a protective role in the same population.

Clinical and Immunological Characteristics of 63 Patients with Chronic Granulomatous Disease: Hacettepe Experience.

BACKGROUND: Chronic granulomatous disease (CGD), one of the phagocytic system defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex which generates reactive oxygen species (ROS), which are essential for killing pathogenic microorganisms, especially catalase-positive bacteria and fungi. OBJECTIVE: The objective of our study was to assess the clinical and laboratory characteristics, treatment modalities, and prognosis of patients with CGD. METHODS: We retrospectively reviewed 63 patients with CGD who have been diagnosed, treated, and/or followed-up between 1984 and 2018 in Hacettepe University, Ankara, in Turkey, as a developing country. RESULTS: The number of female and male patients was 26/37. The median age at diagnosis was 3.8 (IQR: 1.0-9.6) years. The rate of consanguinity was 63.5%. The most common physical examination finding was lymphadenopathy (44/63), growth retardation (33/63), and hepatomegaly (27/63). One adult patient had squamous cell carcinoma of the lung. The most common infections were lung infection (53/63), skin abscess (43/63), and lymphadenitis (19/63). Of the 63 patients with CGD, 6 patients had inflammatory bowel disease (IBD). Twelve of the 63 patients died during follow-up. CYBA, NCF1, CYBB, and NCF2 mutations were detected in 35%, 27.5%, 25%, and 12.5% of the patients, respectively. CONCLUSION: We identified 63 patients with CGD from a single center in Turkey. Unlike other cohort studies in Turkey, due to the high consanguineous marriage rate in our study group, AR form of CGD was more frequent, and gastrointestinal involvement were found at relatively lower rates. The rate of patients who treated with HSCT was lower in our research than in the literature. A majority of the patients in this study received conventional prophylactic therapies, which highlight on the outcome of individuals who have not undergone HSCT.