Search

OBJECTIVE: Acute rheumatic fever (ARF) results from an autoimmune response to infection with group A streptococci. Serum concentrations of two anti-inflammatory cytokines, interleukin-I receptor antagonist (IL-IRa) and human soluble tumor necrosis factor receptor I (sTNF-RI) were determined in patients with ARF at the time of admission and 3 months after treatment in order to evaluate changes in cytokine concentrations occurring during different stages of the disease. METHODS: Serum concentrations of two anti-inflammatory cytokines, IL-I Ra and sTNF-RI , were investigated in children with ARF at the time of admission (n=21) and after 3 months following the cessation of treatment (n=15). The sTNF-RI and sIL-IRa were measured quantitatively in serum using enzyme-linked immunosorbent assay (ELISA). RESULTS: Levels of IL-1Ra and sTNF-RI were found to be significantly higher during acute phase and remission period of ARF when compared to age-matched healthy controls (p=0.001 and p=0.0001, respectively). CONCLUSION: Our study demonstrated that two anti-inflammatory cytokines, serum sTNFRI and IL-1Ra, are increased in acute and remission stages of ARF reflecting activation of the cellular immune response. We suggest this increase might probably be generated in an effort to counteract the already increased concentrations of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Abstract Background Severe combined immunodeficiency is within a heterogeneous group of inherited defects throughout the development of T- and/or B-lymphocytes. Mutations in recombinase-activating genes 1 or 2 (RAG1/2) represent approximately 10% of all SCID cases. RAG1/2 are essential for V(D)J rearrangement of the B- and T-cell receptors. Objectives The aim of this study was to review clinical, immunological and molecular findings of Turkish SCID patients with RAG1 defects and to draw attention to novel mutations, genotype-phenotype correlations and the high rate of BCG infections within this group. Methods Eleven patients (F/M: 6/5) were included. Molecular, immunological and clinical data were evaluated. Results Five patients were classified as T-B-NK + SCID, four patients as T + B-NK + SCID (two of these patients were diagnosed as classical Omenn syndrome) and two patients as T + B + NK + SCID with respect to clinical presentations and immunological data. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were: 33.0 ± 42.8, 3.1 ± 3.3 and 10.4 ± 13.5 months, respectively. Consanguinity rate was 54%. Some novel mutations were found in RAG1 gene in addition to previously reported mutations. Genotype-phenotype correlation was not significantly apparent in most of the cases. BCG infection was observed in 36.4% of patients (two BCG-osis and two BCG-itis). Conclusion Epigenetic factors such as compound genetic defects, enviromental factors, and exposure to recurrent infections may modify phenotypical characteristics of RAG deficiencies. Inoculation of live vaccines such as BCG should be postponed until primary immunodeficiency disease is excluded with appropriate screening tests in suspected cases.

Abstract Introduction Chronic recurrent multifocal osteomyelitis is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown. Case presentation A two-year-old Caucasian boy, diagnosed with chronic recurrent multifocal osteomyelitis with granulomatous pyoderma following routine vaccinations is presented for the first time in the literature. Conclusion We conclude that antigen exposures might have provoked this inflammatory condition for our case. Skin and/or bone lesions following vaccinations should raise suspicion of an inflammatory response such as chronic recurrent multifocal osteomyelitis only after thorough evaluation for chronic infection, autoimmune, immunodeficiency or vasculitic diseases.

Background: Major histocompatibility complex class II deficiency, a combined immunodeficiency, results from loss of HLA class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation stands as the sole curative approach, although factors influencing patient outcomes remain insufficiently explored., Objectives: To elucidate the clinical, immunologic, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates., Methods: In this multicenter retrospective analysis, we gathered data from 35 patients with a diagnosis of MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes., Results: Predominant symptoms observed were pneumonia (n = 29; 82.9%), persistent diarrhea (n = 26; 74.3%), and severe infections (n = 26; 74.3%). The RFXANK gene mutation (n = 9) was the most frequent, followed by mutations in RFX5 (n = 8), CIITA (n = 4), and RFXAP (n = 2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared with those with RFX5 mutations (P =.0008 and .0006, respectively), alongside a more significant diagnostic delay (P = .020). A notable founder effect was observed in five patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n = 10), showing a significantly higher proportion in individuals with hematopoietic stem cell transplantation (n = 8; 80%). Early death and higher CD8 + T-cell counts were observed in patients with the RFX5 mutations compared with RFXANK-mutant patients (P = .006 and .009, respectively)., Conclusions: This study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCү2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Due to the high rate of post-operative sepsis and other infectious complications, a routine immunological screening protocol has been initiated since 2015 in our paediatric surgery clinic for all patients admitted with oesophageal atresia (EA) and warrant a delayed definitive treatment. In our study, we aimed to evaluate the immunodeficiencies in EA patients, by comparing them to healthy age-matched controls. As a prospective cohort study, EA patients admitted between 2015 and 2022, who had their definitive operation after the newborn period (>28 days of age) were included. On admission, serum concentrations of IgG, IgA, IgM, lymphocyte subset levels, C3 and C4 levels, specific IgG antibody responses against hepatitis B, hepatitis A, measles, varicella zoster were evaluated. The patients were age-matched with healthy controls to compare the results and followed up until three years of age. If a humoral immunodeficiency was detected, intravenous immunoglobulin treatment was administered before major oesophageal surgery and during follow-up. 31 EA patients (18 M/13F) with a mean age of 13.3 ± 9.0 months were compared with 40 age-matched healthy controls. Mean serum IgG levels were found to be statistically lower than controls in all age groups (P < .05). Transient hypogammaglobulinemia of infancy (THI) and unclassified syndromic immunodeficiencies (USI) were found to be strikingly high, accounting for 29.0% and 22.5%, respectively, adding up to 51.5% of EA patients. This is the first study evaluating immunodeficiencies in EA patients found in the reviewed literature. More than half of EA patients that required delayed surgery had humoral immunodeficiency, so preoperative screening and immunology referral may improve patient outcomes., (© 2023 The Scandinavian Foundation for Immunology.)

Objective: Immunoglobulin-A vasculitis (IgAV) is an inflammatory disease that affects small blood vessels. This study was performed to identify an association between protein tyrosine phosphatase non-receptor type 22 (PTPN22) + 788G > A (rs33996649), transforming growth factor-beta (TGF-β) -509C > T (rs18004069), interleukin 1-beta (IL-1β) -511C > T (rs16944), interleukin 5 (IL-5) -746C/T (rs2069812), and angiotensin-converting enzyme (ACE) I/D (rs4646994) gene polymorphisms, susceptibility to IgAV, as well as the mRNA levels of IL-1β, IL-1β, and TGF-β., Method: A total of 53 patients with IgAV and 50 healthy controls were enrolled. PTPN22, TGF-β, IL-1β, ACE gene polymorphisms, ACE gene I/D polymorphisms, and mRNA expression levels were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, allele-specific PCR, and real-time PCR with TaqMan kits, respectively., Results: PTPN22, TGF-β, IL-1β, IL-5, and ACE variants showed no genotype or allele differences between patients with IgAV and controls. Increased levels of IL-1β and TGF-β mRNA expressions were observed in patients with IgAV (p < 0.001). Patients with the IL-1β AG genotype showed significantly increased amounts of arthritis than patients with non-AG (p = 0.004). Age at disease onset was found to be significantly different in patients with IgAV according to the presence of TGF-β TT genotype (p = 0.047)., Conclusion: Polymorphisms in PTPN22, TGF-β, IL-5, IL-1β, and ACE genes are unlikely to confer susceptibility to IgAV. However, the presence of the AG genotype of IL-1β is associated with susceptibility to IgAV-related arthritis. This is the first study to report a significant increase in serum mRNA levels of IL-1β and TGF-β in IgAV patients, supporting a susceptibility to IgAV in childhood., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: LPS-responsive beige-like anchor (LRBA) deficiency (LRBA -/- ) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4 +/- ) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown., Objective: Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up., Methods: The 98 patients (63 LRBA -/- and 35 CTLA4 +/- ) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies., Results: The LRBA -/- patients exhibited a more severe disease course than did the CTLA4 +/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA -/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival., Conclusions: Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Autosomal recessive dedicator of cytokinesis 8 (DOCK8 -/- ) and autosomal dominant signal transducer and activator of transcription 3 (STAT3 -/+ ) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8 -/- and STAT3 -/+  early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8 -/- or STAT3 -/+ from AD., Methods: This multicenter study involved 100 patients with DOCK8 -/- and STAT3 -/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8 -/- or STAT3 -/+ from AD., Results: There were 43 patients with DOCK8 -/- , 23 with STAT3 -/+ , and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8 -/- and STAT3 -/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3 + , CD4 + , and CD8 + T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8 -/- or STAT3 -/+ and AD via PCA., Conclusions: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Immune dysregulation as a result of an inborn error of immunity (IEI) leads to the complicated symptoms of refractory multi-organ immune dysregulation. B lymphocytes with immune regulatory capacity (Breg) are activated by environmental triggers and act as regulators of the immune response as observed in several autoimmune diseases., Objective: We sought to investigate the Breg profile and the CD21 low expressing B cells of patients with LRBA deficiency (N = 6) and non-LRBA deficiency IEI (N = 13) with overlapping clinical symptoms of immune dysregulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N = 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N = 5)., Methods: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts (CD27 + CD38 hi ), transitional B cells (CD24 hi CD38 hi ), and B10 cells (CD24 hi CD27 + ), and additionally the CD21 low B cells (CD21 low CD38 low ) were analyzed. Breg function was assessed by the interleukin-10 expression within the CD19 + population. Additionally, B cell cytokines were measured in cell culture supernatants., Results: We observe significant alterations of B cell/Breg subpopulations in the LRBA deficient cohort including a severe lack of memory B cells (P = 0.031) and B10 cells (P = 0.031) as well as a tendency towards higher CD21 low B cells (P = 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P = 0.012), and a tendency towards elevated levels of CD21 low expressing B cells (P = 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21 low B cells over time (P = 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P = 0.02) and lower IL-12p70 secretion upon stimulation (P = 0.020) in the LRBA cohort., Conclusion: Aberrant maturation of Breg subsets and the pathological expansion of CD21 low B cells in patients with IEI may have therapeutic implications. Patients suffering from LRBA deficiency show a lack of memory B cells, insufficient expansion of B10 cells, increased BAFF levels as well as an increase in circulating CD21 low B cells. Abatacept treatment results in a steady decrease in CD21 low B cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction and Objectives: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease., Material and Methods: Thirty-three pediatric patients with 22q11.2 deletion syndrome diagnosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children's Education and Research Hospital were evaluated., Results: This study includes the largest case series reported from Turkey. Congenital cardiac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syndrome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogammaglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up., Conclusions: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any difference in terms of numbers and severity of infections and autoimmunity., Competing Interests: The authors declare that they have no conflict of interest.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant., Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant., Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices., Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome., Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established., Objective: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations., Methods: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry., Results: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy., Conclusions: Long-term abatacept therapy is effective in most patients with LRBA deficiency., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by susceptibility to bacterial and fungal infections resulting from the inadequacy of phagocytic leucocytes to produce reactive oxygen radicals. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB (OMIM #300481) gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA (OMIM #608508), NCF1 (OMIM #608512), NCF2 (OMIM #608515) and NCF4 (OMIM #601488) genes encoding p22(phox), p47(phox), p67(phox) and p40(phox), respectively. The genetic mutation of one of the cytosolic p47phox/p67phox proteins and membrane-bound gp91phox/p22phox proteins, which constitutes the NADPH oxidase enzyme complex, causes the disease. In this study, we evaluated the clinical, laboratory and genetic findings and the prognostic effects of molecular inheritance of our 24 CGD cases (14 XR, 10 autosomal recessive-AR). Consanguinity (three XR and all AR cases) showed statistically significant relationship with the type of hereditary inheritance (P < 0.001). 83% patients had an infection since early infancy. The mean age of initiation of symptoms was earlier in XR cases, and 78% patients had respiratory tract infections. Bone marrow transplantation was performed in five XR cases (two ex) and four AR (one ex) cases. Three of nine XR and two of six AR cases deceased on medical follow-up. In countries especially with high consanguinity rates, the early diagnosis for appropriate prophylactic treatment of CGD is quietly important to avoid from recurrent severe infections, early death and fatal complications of late transplantation., (© 2018 The Foundation for the Scandinavian Journal of Immunology.)

Background: Primary immunodeficiency disorder (PID), being a chronic disorder, may increase the prevalence of psychopathologies, but there are few studies on the effect of disease-related factors on psychopathology in this population. The aim of this study was therefore to assess and compare three groups: children with PID who receive i.v. immunoglobulin treatment; children with juvenile idiopathic arthritis (JIA); and healthy controls with respect to their mental health status., Methods: Forty-four children with PID, 32 children with JIA and 30 healthy controls, underwent psychiatric evaluation. The Childhood Depression Inventory and the screen for child anxiety-related emotional disorders questionnaire were completed by the participants. The child behavior checklist was completed by the mothers of the participants. In addition, disease-related factors were identified., Results: The frequency of mood disorders between the three groups differed. There was no difference between the PID and JIA groups with respect to the prevalence of mood disorders and other psychopathologies. The disease-related factors were associated with the frequency of mood disorder in PID patients., Conclusion: The rate of psychopathology was similar in patients with PID and JIA and higher than the controls. Some of the disease-related factors were associated with the frequency of mood disorders in the PID patients., (© 2018 Japan Pediatric Society.)

Background: The Transmembrane Activator and Calcium modulator ligand Interactor (TACI), encoded by TNFRSF13B/TACI gene, is mutated in some patients with Common Variable Immunodeficiency (CVID) and IgA Deficiency (IgAD). The purpose of the study was to investigate for the first time in Turkish patients the prevalence of TNFRSF13B alterations in CVID, selective and partial IgAD patients., Methods: Forty two CVID, 36 selective IgAD, 34 partial IgAD and 25 healthy controls were included. All patients were examined for TNFRSF13B gene mutations by PCR., Results: The percentages of TNFRSF13B mutations in CVID, selective and partial IgAD patients were 7.1, 2.7 and 2.9%, respectively. No disease causing TNFRSF13B mutation in healthy controls was found. Patients with TACI mutations had recurrent respiratory tract infections. None of them experienced autoimmunity, bronchiectasis or granulomatous disease. In conclusion, TNFRSF13B mutations were present not only in CVID patients, but also in IgAD cases., Conclusion: Modifier genes as well as their combination with other genetic or environmental factors may play an important role in the development of the immunodeficiency phenotype., Competing Interests: Conflict of Interest The authors declare that they have no conflict on interest.

Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.

Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients., Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients., Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients., Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.

Aim: Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases., Material and Methods: Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/ interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests., Results: A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients including Mycobacterium bovis, Mycobacterium chelonea, Mycobacterium elephantis, Mycobacterium fortuitum , and Mycobacterium tuberculosis . All patients were treated with anti-tuberculosis therapy. Thirty-six percent of these 25 patients underwent hematopoietic stem cell transplantation. Eight patients (five before, three after transplantation) died., Conclusions: Non-tuberculosis mycobacteria including mainly Mycobacterium bovis were observed with a higher rate compared to Mycobacterium tuberculosis in primary immunodeficiencies, especially in those affecting the interleukin 12/interferon gamma pathway. Early diagnosis of primary immunodeficiencies with neonatal screening program and preventing administration of the Bacille Calmette-Guerin vaccine in these patients is important., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

In order to evaluate B-lymphocyte subsets of patients with primary immunodeficiencies, the normal values for national healthy children have to be used as a reference. Recently, B-cell co-receptor markers (CD19, CD21, and CD81) and CD20, CD22, and CD27 deficiencies have been reported in relation with different primary immunodeficiency diseases. The objective of this study was to establish national reference values for B-lymphocyte co-receptors and some surface markers, CD20, CD22, CD27, as well as classic lymphocyte subsets in the peripheral blood of healthy children. A total of 90 healthy children were included in this study. Complete blood counts were performed and cells with CD3, CD4, CD8, CD19, CD16/56, CD20, CD21, CD22, CD27, and CD81 surface markers were simultaneously detected by flow cytometry. The children were evaluated in three age subgroups, 0-1, 1-6, and >6 years, and minimum, maximum, mean, mean minus standard deviation, and 2.5-97.5 percentile values were all determined. By establishing reliable reference ranges for these surface markers, we hoped to help identifying and classifying some primary immunodeficiency patients, especially those defined as unclassified hypogammaglobulinemia and those without definite diagnosis.

Background: The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of T H 17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear., Objective: We sought to elucidate common mechanisms operating in the different forms of HIES., Methods: We analyzed the differentiation of CD4 + T H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T H cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis., Results: There was a profound block in the differentiation of DOCK8-deficient naive CD4 + T cells into T H 17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T H 17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression., Conclusion: DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent T H 17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines - IL-2, IL-4, IL-13, IFN- γ-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-γ in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID. In addition, Th1 cells seem to be more involved in the disease pathogenesis than Th2 cells., (© The Author(s) 2015.)

Background: Severe combined immunodeficiency (SCID) syndromes are a heterogenous group of diseases characterized by impairment in both cellular and humoral immunity with a range of genetic disorders. Complete recombinase activating gene (RAG) deficiency is associated with classical T(-)B(-)NK(+) SCID which is the most common phenotype of Turkish SCID patients. There is a broad spectrum of hypomorfic RAG mutations including Omenn syndrome, leaky or atypical SCID with expansion of γδ T cells, autoimmunity and cytomegalovirus (CMV) infections., Methods: Twenty-one (44%) patients had RAG1 deficiency of all 44 SCID patients followed up by pediatric immunology department. A retrospective analysis was conducted on the medical records of all SCID patients with RAG1 deficiency., Results: Eight patients were classified as T(-)B(-)NK(+) SCID, five patients as T(+)B(-)NK(+) SCID (three of these were Omenn phenotype), and eight patients as T(+)B(+)NK(+) SCID phenotype. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were 87.7 ± 73.8 (12 - 256), 4.4 ± 8.2 (1 - 36) and 29.1 ± 56.8 (1 - 244) months, respectively. Consanguinity was present in 11 (52%) of 21 patients. Autoimmunity was found in six patients (28%). Ten patients (47%) had CMV infection, four (19%) had Epstein-Barr virus (EBV) infections and three (14%) had Bacillus Calmette-Guerin (BCG) infections. Seven patients who had refractory cytopenia (two pancytopenia and five bicytopenia) underwent bone marrow biopsy, three of whom had bone marrow fibrosis. Future evaluations must be considered about bone marrow fibrosis in RAG1 deficiency patients. Eosinophilia was observed in 10 patients, seven of whom did not have Omenn phenotype., Conclusion: Non-Omenn phenotype RAG1 deficiencies can also present with eosinophilia. This report is presented to emphasize that RAG1 mutations may lead to diverse clinical phenotypes.

Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

Background: Patients with transient hypogammaglobulinaemia of infancy (THI) may have mild infections or be asymptomatic. About 20% of THI patients have very severe and recurrent infections and receive intravenous immunoglobulins (IVIg) for replacement therapy and infection prophylaxis. It is still not clear why some THI patients are severely symptomatic; it has been suggested that there might be additional immunologic or environmental factors or other co-morbidities., Objective: As an immunological factor, Fcγ receptor polymorphisms (H/H-131, H/R-131 and R/R-131 for FcγIIa; V/V-158, V/F-158 and F/F-158 for FcγRIIIa; NA1/NA1, NA1/NA2 and NA2/NA2 for FcγRIIIb) were analysed in THI patients who had very severe infections and need hospitalisation (treated with IVIg) (n:18) and in THI patients who were asymptomatic or had mild infections (treated with antibiotics or received no medication) (n:25)., Results: Genotypic distributions between two groups did not deviate significantly from the Hardy-Weinberg equilibrium expectations (p > 0.05) and odds ratios for "disease risk estimate" did not show any dominance for any genotype. Allele frequencies did not show any significant difference between the two groups (p >0.05). The number of infections per year for each Fcγ receptor genotype was not significantly different between both groups., Conclusion: There is no association between the heterogeneous clinical picture of THI patients and Fcγ receptor gene polymorphisms.

Introduction: Interleukin-1 receptor antagonist deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. The underlying genetic abnormality involves a recessive mutation in IL1RN, which encodes interleukin-1 receptor antagonist. In this case report, we describe a case of a 12-year-old Turkish girl who initially was presented at 1 year of age, older than previously reported children with interleukin-1 receptor antagonist deficiency, and with a novel mutation, p.R26X, in ILR1N., Case Presentation: Our patient developed pustular cutaneous lesions at 1 year of age. At the age of 12 years, she was hospitalized for arthralgia of her knees, elbows, and ankles and arthritis of the left knee, with simultaneous pustular cutaneous lesions. She was admitted to the intensive care unit because of septicemia and respiratory insufficiency during follow-up. A skin biopsy of hyperpigmented lesions demonstrated neutrophil infiltration in the epidermis and subepidermal pustular dermatosis. Interleukin-1 receptor antagonist deficiency was suspected, and genetic analysis revealed a homozygous mutation (p.R26X) in IL1RN, which led to a diagnosis of interleukin-1 receptor antagonist deficiency. Treatment with canakinumab (recombinant human anti-human interleukin-1β monoclonal antibody) 150 mg subcutaneously once every 6 weeks was initiated. Our patient did not experience further cutaneous lesions or arthritis. Her post-treatment inflammatory markers were normal; she gained weight; and she was able to walk independently., Conclusions: In this case report, we describe a patient with interleukin-1 receptor antagonist deficiency who responded excellently to canakinumab treatment. We believe more awareness is warranted for interleukin-1 receptor antagonist deficiency in children. It is possible that the mutation in our patient was a founder mutation that may lead to diagnosis of additional cases in Turkey.

Defective adaptive immune responses are well studied in common variable immunodeficiency (CVID) patients; however, more focus is needed on innate immune system defects to explain CVID's clinical and laboratory heterogeneity. This is the first study comparing migratory function of granulocytes, oxidative burst activity of phagocytic cells, surface integrin expressions on neutrophils and lymphocytes, natural killer (NK) cell numbers and cytotoxic activity, natural killer T cells, lymphocyte subsets such as CD8(+)CD28(+), CD4(+)CTLA-4(+) cells in CVID patients (n: 20) and healthy controls (n: 26). The relationship between laboratory findings and some clinical was also investigated. CD3(+)CD8(+) T cytotoxic cells were found to be elevated in CVID patients, but CD3(+)CD8(+)CD28(+) or CD3(+)CD8(+)CD28(-) cells did not show any significant difference. CD4(+)CTLA-4(+) cell percentages were significantly lower in CVID patients compared to healthy controls. Severe CVID patients had decreased percentages of NK cells with increased NK cell cytotoxicity suggesting possibly increased activation. Furthermore, CD3(-)CD16(+)CD56(+)CD28(+) cells of CVID patients were elevated while percentage of CD28(-) NK cells was decreased. Neutrophil migration percentages were lower but and oxidative burst activity was not affected. CD11a expressions on these cells were depressed in contrast to increased expression of CD18. Innate immunity defects may affect the extent of recurrence and severity of infections in CVID. Our observations highlight some of these associations and indicate the need for further similar studies for improving better innate system evaluation batteries for these patients. Further phenotypic correlations of these analyses will help clinicians reach a more definitive target for the molecular genetic diagnostic of pediatric CVID patients.

Mutations in CD40 ligand (CD40L) that permit residual CD40L expression typically impair binding of CD40. We report a male patient who presented with recurrent bacterial respiratory tract infections, normal IgM, decreased IgG, absent IgA levels, and CD40L expression at ~50% of the level observed in the normal control. He subsequently developed autoimmunity, inflammatory bowel disease, severe opportunistic infections suggestive of a combined immunodeficiency, and a cervical spine schwannoma. Whole exome sequencing of the patient's genomic DNA revealed a novel missense mutation (p.H47Y) in CD40L. Although this mutation was predicted to be benign in silico, flow cytometry at 13 years of age demonstrated markedly decreased CD40L expression (~32% of normal control) that retained the capacity to bind soluble CD40-Ig, suggesting that the mutation impairs CD40L surface expression without affecting its affinity for CD40. This case highlights the variability in the clinical evolution and phenotype of CD40L deficiency., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Primary immunodeficiency diseases (PIDs) are inherited disorders of the immune system resulting in increased susceptibility to unusual infections and predisposition to autoimmunity and malignancies. The European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This study aimed to provide a minimum estimate of the prevalence of each disorder and to determine the clinical characteristics and outcomes of patients with PID in Turkey., Methods: Clinical features of 1435 patients with primary immunodeficiency disorders are registered in ESID Online Patient Registry by the Pediatric Immunology Departments of the Medical Faculties of Uludag University and Ege University Between 2004 and 2010. These two centers are the major contributors reporting PID patients to ESID database from Turkey., Results: Predominantly antibody immunodeficiency (73.5 %) was the most common category followed by autoinflammatory disorders (13.3 %), other well defined immunodeficiencies (5.5 %), congenital defects of phagocyte number, function or both 3.5 %), combined T and B cell immunodeficiencies (2 %), defects in innate immunity (1 %), and diseases of immune dysregulation (0.7 %). Patients between 0 and 18 years of age constitued 94 % of total and the mean age was 9.2 ± 6 years. The consanguinity rate within the registered patients was 14.3 % (188 of 1130 patients). The prevalance of all PID cases ascertained from the registry was 30.5/100.000. The major cause of the mortality was severe infection which was seen in forty-two of seventy five deceased patients. The highest mortality was observed in patients with severe combined immunodeficiencies and ataxia-telangiectasia., Conclusion: Promoting the awareness of PID among the medical professionals and the general public is required if premature death and serious morbidity occurs due to late diagnosis of the wider spectrum of PID are to be avoided.

B lymphocyte subpopulations, previously defined classification schemes (Freiburg, Paris, EuroClass), TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms were analyzed in 25 common variable immunodeficiency (CVID) patients and 25 healthy controls. Patients were also divided into two subgroups due to some disease severity criteria. SG (severe disease group) (n:11) included patients who have splenomegaly and/or granulomatous diseases and/or bronchiectasis and/or lower baseline IgG values (<270 mg/dl). MG (moderate disease group) (n:14) patients diagnosed as having ESID/PAGID criteria but does not fulfill SG inclusion criteria. The onset of infectious symptoms and age at diagnosis were 50.0 ± 45.7 and 78.5 ± 54.5 months, respectively. Parental consanguinity rate was 54.5% in SG and 7.1% in MG. Switched-memory B cells (CD19 + 27 + IgD-IgM-) showed significant decrease in CVID patients and these cells were also significantly lower in SG compared to MG. CVID patients had significantly higher percentages of CD19 + κ + B cells and CD19 + λ + B cells than healthy controls. Freiburg classification: 87.5% of patients (n:21) were in group I and 12.5% were in Group II. Eighteen (75%) CVID patients with a low percentage of CD21(low) B cells were in Group Ib while three patients classified as Group Ia. The significantly lower levels of IgG and IgA in Group Ia is a novel finding. The percentages of patients for Paris Classification groups MB0, MB1, MB2 were 88%, 4% and 8%, respectively. There was a significant increase of splenomegaly, lymphadenopathy and autoimmune cytopenia in Group MB0. EuroClass: 45.8% of patients were smB+ and 54.2% were smB-. Splenomegaly and lymphadenopathy were significantly higher in smB- group. TACI: One patient carried heterozygous C104R mutation which was known as disease causing. APRIL: G67R and N96S SNPs were detected in most of the patients and healthy controls. BAFF-R: P21R/H159Y compound heterozygous mutation (n:1) and P21R heterozygous mutations (n:3) were detected. +49 A > G changes in exon 1 of CTLA-4 gene: GG and AG genotypes increase the risk of CVID development 1.32 and 2.18 fold, respectively. 1564 T > C polymorphisms on 3'UTR region in exon 2 of ICOS gene was not found to be significantly different in CVID patients. CVID classifications were not helpful in determining the genetic etiology of CVID.

Mutations of the CD40 gene have been found in patients with autosomal recessive hyper-immunoglobulin M (HIGM) syndrome type 3. Five patients from four unrelated families with CD40 mutation have been reported so far. Clinical manifestations include recurrent sinopulmonary infections, Pneumocystis carinii pneumonia and Cryptosporidium parvum infection. Affected patients typically have very low levels of IgG and IgA and normal or high levels of IgM. Flow cytometry analysis of these five patients demonstrated that peripheral blood B lymphocytes lacked expression of surface CD40. Herein, we present two siblings from second-degree consanguineous Turkish parents with homozygous CD40 deletion of four nucleotides including the stop codon resulting presumably to a longer protein. Clinical and immunological profile of these patients is similar to the already reported HIGM3 patients except normal CD40 expression on B lymphocytes. This observation emphasizes the requirement of CD40 mutation analysis for definite diagnosis of HIGM3 despite normal flow cytometric expression of CD40, particularly if the immunological and clinical profile is suggestive for HIGM3., (© 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd.)

Background: IgA deficiency (IgAD) is the most common primary antibody deficiency. Although two-third of the cases are reported to be asymptomatic, some IgAD children may have frequent infections that urge the clinicians to search for prophylactic measures. OM-85 BV is one of these agents that is known to stimulate mucosa associated lymphoid tissue, and upregulate Th-1 response. This study was performed to determine a possible role of OM-85 BV in triggering autoimmunity in IgAD children within a four-year-follow up period., Methods: Sixty-three children (34 males (54%), 29 females (46%)) with sporadic IgAD and recurrent febrile infections were included. Patients were carefully screened for autoimmunity both on admission and in follow-up: Those with autoimmune features or under immunosuppressant treatment were excluded. Patients were randomly divided into two groups: Group I received bacterial lysate propylaxis (OM-85 BV) (n:37), and Group 2 received no prophylactic regimen (n:26). Development of clinical autoimmune findings or autoantibodies (anti-nuclear antibody (ANA), ANA profile (14 antigens), anti-cytoplasmic antibodies (ANCA), anti-cardiolipin antibodies IgG and IgM (aCL), rheumatoid factor (RF), direct Coombs test, anti-thyroglobulin (anti-T) and anti-thyroid microsomal antigen (anti-M)) were evaluated., Results: Mean age of the study group, age at the onset of infectious symptoms and at admission were 102.9±42.2, 27.1±24.9, and 55.2±25.1 months, respectively. Follow-up duration of the whole study group was 48.3±23.1 months. Number of infections was 6.2±2.7 per year in the whole study group. Sixteen patients (25.4%) of the whole study group showed ANA positivity in different patterns and titers. Frequency of ANA, ANCA and RF positivity was 24.3%, 5.4%, 2.7% in Group 1, and 26.9%, 11.5%, 3.8% in Group 2, respectively. Statistical comparisons revealed no significant difference between the two groups., Conclusion: Significant clinical or laboratory markers for autoimmunity in follow-up were not observed between receivers or non-receivers of OM-85 BV. Frequency of ANA positivity was comparable to the previously reported values in IgAD children which was not affected by OM-85 BV usage. Possible effect of triggering autoimmunity with repeated cures of bacterial lysates needs to be further clarified. Side effects requiring the cessation of treatment were not recorded., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Unlabelled: Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 ± 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 ± 13.7 and at 86.6 ± 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4-induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 ± 14.8 months. Ages for normalization of IgG and IgA were 68.2 ± 8.7 and 70.2 ± 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized., Conclusion: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur.

Objective: Patients with some inflammatory diseases have been shown to have increased levels of immunoglobulin light chains. In this study, we measured the concentrations of immunoglobulin kappa and lambda light chains in sera of patients with juvenile idiopathic arthritis (JIA) (study group), familial mediterranean fever (FMF) (disease control group) and in healthy children. Our aim was to compare immunoglobulin light chain levels with other well-known markers of inflammation, such as the erythrocyte sedimentation rate (ESR) and the acute phase reactants (APRs), serum amyloid A (SAA) and C-reactive protein (CRP), to find out if immunoglobulin light chain determinations have any discriminating value in the follow-up of these patients., Results: ESR, CRP, SAA, kappa and lambda chain levels and lambda/IgG ratio showed a statistically significant difference between active and remission stages in JIA patients. Kappa correlated very well with SAA and ESR in both stages. On the other hand, lambda correlated with SAA and ESR only in the remission period. There was no significant difference in kappa and lambda chain levels between active and remission stages in FMF patients. In addition, kappa and lambda chain concentrations showed no correlation with other markers of inflammation and immunoglobulin levels neither in entire FMF group nor in different subgroups with respect to clinical status. Immunoglobulin light chains kappa and lambda as well as levels of three markers of inflammation were found to be significantly higher in JIA patients who were in the active stage of disease when compared to data of healthy children, Conclusion: Ig light chains especially kappa chain concentrations are helpful to determine disease stage in JIA patients but with our current data, they do not exhibit superiority to any of the classical tests for inflammation.

Background/aims: Host-related immune factors in childhood chronic hepatitis B and change in the initial profile with interferon (IFN)-α treatment need to be clarified., Methods: Sixteen patients were included in the study, and 10 million units of IFN-α treatment 3 times per week for 6 months was initiated. Pre- and post-treatment percentages of interleukin (IL)-2 and IFN-γ in CD4+ T cells were assessed to determine intracellular T helper cell 1 (Th1) type cytokine expression. Similarly, percentages of intracellular IL-2 and IFN-γ were detected to verify cytotoxic T cell 1 (Tc1) type cytokine expression in CD8+ T cells. Percentages of Th2 and Tc2 type cytokine expression (IL-4 and IL-13) were determined in CD4+ and CD8+ T cells, respectively., Results: Six (50%) of these were evaluated as having no response and the other half with partial/complete response. All patients had higher percentages of Th2 cells with respect to healthy controls pre-treatment. Tc percentages, both Tc1 and Tc2, were significantly different between these groups, being higher in the patient group. When values of the nonresponder group were compared with healthy controls, IL-4 expression was higher and the percentages of Th1 type cells were significantly low. IL13 expression in Th and Tc cells decreased after 6 months of treatment in the unresponsive group. The decrease we observed in Th1 percentages with treatment, in the responsive group, may be due to Th1 deposition shifting from the periphery to liver tissue, as reported before. Intracellular cytokine profiles of treatment responders and normal controls were not different., Results: This is the first study in children comparing baseline and post-treatment intracellular cytokine profiles with values in healthy controls.

Severe combined immunodeficiencies (SCID) comprise a spectrum of genetic defects that involve both humoral and cellular immunities. Defects in recombinating activating gene 1 (RAG1), RAG2, Artemis, or LIG4 can disrupt V(D)J recombination. Defective V(D)J recombination of the T and B cell receptors is responsible for T(-)B(-)NK(+)SCID. Amorphic mutations in RAG1 and RAG2 cause T(-)B(-)NK(+)SCID, whereas hypomorphic mutations cause an immunodeficency characterized by oligoclonal expansion of TCRgammadelta T cells, severe CMV infection and autoimmunity. First patient is a typical T(-)B(-)NK(+)SCID with clinical and immunologic findings while the second is atypical with normal immunoglobulin levels, CD4 lymphopenia, elevated TCRgammadelta T cells, persistent CMV infection, and autoimmune hemolytic anemia. These cases are presented to emphasize that mutations in RAG1 gene may lead to a diverse spectrum of clinical and immunologic findings while hypomorphic mutations may be related with autoimmunity and refractory CMV infection during infancy.

Common variable immunodeficiency (CVID) is associated with recurrent infections and autoimmunity. The most common autoimmune conditions are idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic arthritis, and gastrointestinal inflammation. Relapsing polychondritis (RP) is an episodic and progressive systemic inflammatory disease, characterized by auricular chondritis, polyarthritis, nasal, and respiratory tract chondritis. Autoimmunity to cartilage-related components is thought to be involved in its pathogenesis. So far, RP has not been included within many autoimmune conditions that have been reported in patients with either CVID or any other primary immunodeficiency. In this report, a case of CVID with RP and chronic arthritis is presented.

IgG subclass deficiencies are common immune system disorders during childhood. The aim of this retrospective study was to review clinical findings and laboratory results of patients with IgG subclass deficiencies in order to determine the changes in serum IgG subclass levels during follow-up, the percentage and time span until normalization of the IgG subclass levels to age-corresponding normal levels, the type of infections incurred and the benefits of prophylaxis. Among the 59 pediatric patients reviewed, the most frequent defect was an IgG3 subclass deficiency (77%). Nine percent of the patients had an isolated IgG2 deficiency and 14% had an IgG2+G3 deficiency. The most common clinical presentations were recurrent upper respiratory tract infections, followed by pneumonia, acute gastroenteritis and urinary tract infections. Atopy was present in 15% of the patients. Ninety percent of the patients were given a prophylactic treatment (benzathine penicillin, oral antibiotics, oral bacterial lysate or intravenous immunoglobulin). The frequency of recurrent infections decreased from 13.4 +/- 7.4 per year to 5.7 +/- 3.9 in patients receiving a prophylactic regimen. Serum IgG subclass levels reached normal ranges in 30% of the patients in the IgG3 deficiency group and in 35.7% of the patients in the IgG2+G3 deficiency group. Patients with an isolated IgG2 deficiency did not reach age-related normal levels during the study period. Our study shows that IgG subclass levels may normalize in 30 to 40% of patients at about 6 years of age. We emphasize the need of monitoring IgG levels together with the clinical symptomatology in affected individuals and initiate preventive measures when appropriate.