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    Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease
    (Nature Portfolio, 2021) Ozen, Ahmet; Kasap, Nurhan; Vujkovic-Cvijin, Ivan; Apps, Richard; Cheung, Foo; Karakoc-Aydiner, Elif; Akkelle, Bilge
    CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.
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    Consensus Middle East and North Africa Registry on Inborn Errors of Immunity
    (Springer/Plenum Publishers, 2021) Aghamohammadi, Asghar; Rezaei, Nima; Yazdani, Reza; Delavari, Samaneh; Kutukculer, Necil; Topyildiz, Ezgi; Ozen, Ahmet
    Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.
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    Glucocorticoid Receptor-? Is Downregulated by Vitamin D Treatment in Children with Low Vitamin D Levels but Not in Allergic Asthma
    (Mary Ann Liebert, Inc, 2015) Guner, Sukru Nail; Sancak, Recep; Gulten, Sedat; Ozen, Ahmet; Kilic, Mehtap; Bedir, Abdulkerim
    Background: Vitamin D (VitD) enhances the anti-inflammatory effects of glucocorticoids (GC) in vitro. It was hypothesized that VitD3 (colecalciferol) treatment could have an impact on the expression of glucocorticoid receptors (GRs) in a group of children with low VitD levels, with or without asthma. Methods: Asthmatic children and healthy controls, all with low serum VitD levels (25-hydroxyvitamin D [25(OH)D] level <30 ng/mL) were recruited. VitD3 treatment at a dose of 300,000 IU was given orally. Blood samples were obtained at admission and 1 month after the treatment to examine serum 25(OH)D levels and the relative gene expression (RGE) of GR-alpha and -beta in peripheral blood mononuclear cells. Results: Twenty-four children with asthma (M-age 11.1 +/- 2.1 years) and 14 healthy controls (M-age 11.5 +/- 1.7 years) were studied. The expression of GR-beta was significantly higher in the control group at baseline compared with those with asthma (p = 0.006). With VitD3 treatment, there was a decrease in GR beta expression at 1 month in the control group (p = 0.05), but not in the asthma group. When analyzing the change in the relative expression of GR beta (change in 1st month to baseline), the decrease in GR beta was significantly higher in the control group compared with the asthma group (p = 0.002). A negative correlation was detected between the change in the asthma control test score (ACT) and the change in 25(OH)D values (r = -0.51, p = 0.01). Conclusion: VitD3 supplementation led to a decrease in the expression of GR beta in control subjects with low baseline VitD levels, whereas no such change was observed in asthmatic children. Meanwhile, better asthma control was achieved by VitD3 treatment, possibly through mechanisms not related to GR expression.
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    Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency
    (Wiley, 2017) Uygun, Dilara Fatma K.; Uygun, Vedat; Reisli, Ismail; Keles, Sevgi; Ozen, Ahmet; Yilmaz, Mustafa; Sayar, Esra H.
    DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.