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Purpose Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. Methods A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. Results Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4–32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. Conclusion This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.

Primary immunodeficiencies (PID) are a group of heterogeneous diseases. Epidemiological studies from databases worldwide show geographical variation. In this study the objective is to determine the spectrum of PID in Saudi Arabia by analyzing the database in a referral tertiary hospital. This is a prospective data collection by interviews and medical chart review for all PID patients followed at the King Faisal Specialist Hospital & Research Center (KFSH&RC) from May 2010 to April 2013. A total of 502 patients presented (53 % male and 47 % female). Combined immunodeficiencies were the most common (59.7 %), followed by predominantly antibody deficiencies (12.3 %), congenital defects of phagocyte (9.4 %), combined immunodeficiencies with associated or syndromic features (6.2 %), disease of immune dysregulation (6 %), complement deficiencies (5.8), and defects in innate immunity (0.6 %). The most common combined immunodeficiencies phenotype was T-B-SCID (17 %). The patients’ ages ranged from less than 1 year old to 78 years, and 394 patients (78.2 %) are in the paediatrics age group (

Complement deficiencies are rare primary immunodeficiency disorders, the diagnosis of which is often underestimated. Only a small number of molecular studies have been carried out for the characterization of the underlying genetic defects in these cases.Reporting the first family from the Arabian Gulf region with multiple members affected by meningococcemia and abscent serum complement 5 (C5). We tried to correlate clinical, biochemical and molecular genetics features of this family.Determination of the serum level of all complement proteins including the terminal cascade (C5-9), followed by mutation analysis on DNA extracted from fresh blood samples of each alive family member.Molecular studies showed a homozygous nonsense mutation in exon 1, with the change of cytosine to thymine at position 55 (55CT) leading to change of the glutamine amino acid at position 19 to a stop codon (Q19X), and serologically absence of C5 in the serum. A similar but compound heterozygous mutation has been reported in one African-American family. previously.Characterization of the underlying mutations in C5 deficient families is important, to understand this uncommon complement deficiency, and try to elucidate structure-function relationships in the C5 gene. This report also highlights the importance of complement screening in cases of sporadic meningococcal Infections, especially in communities with high prevalence of consanguineous marriages, which will ensure timely and adequate clinical interventions.

Asthma is characterized by eosinophilic airway inflammation and remodeling of the airway wall. Features of airway remodeling include increased airway smooth muscle (ASM) mass. However, little is known about the interaction between inflammatory eosinophils and ASM cells. In this study, we investigated the effect of eosinophils on ASM cell proliferation. Eosinophils were isolated from peripheral blood of mild asthmatics and non-asthmatic subjects and co-cultured with human primary ASM cells. ASM proliferation was estimated using Ki-67 expression assay. The expression of extracellular matrix (ECM) mRNA in ASM cells was measured using quantitative real-time PCR. The role of eosinophil derived Cysteinyl Leukotrienes (CysLTs) in enhancing ASM proliferation was estimated by measuring the release of leukotrienes from eosinophils upon their direct contact with ASM cells using ELISA. This role was confirmed either by blocking eosinophil-ASM contact or co-culturing them in the presence of leukotrienes antagonist. ASM cells co-cultured with eosinophils, isolated from asthmatics, but not non-asthmatics, had a significantly higher rate of proliferation compared to controls. This increase in ASM proliferation was independent of their release of ECM proteins but dependent upon eosinophils release of CysLTs. Eosinophil-ASM cell to cell contact was required for CysLTs release. Preventing eosinophil contact with ASM cells using anti-adhesion molecules antibodies, or blocking the activity of eosinophil derived CysLTs using montelukast inhibited ASM proliferation. Our results indicated that eosinophils contribute to airway remodeling during asthma by enhancing ASM cell proliferation and hence increasing ASM mass. Direct contact of eosinophils with ASM cells triggers their release of CysLTs which enhance ASM proliferation. Eosinophils, and their binding to ASM cells, constitute a potential therapeutic target to interfere with the series of biological events leading to airway remodeling and Asthma.

Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation.GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR. Dexamethasone-inhibition of PHA-induced proliferation and Dexamethasone-induced apoptosis were determined by either (3)H-thymidine or CFSE-labelled cells and by Annexin-V staining and flow cytometry.IL-17 and IL-23 cytokines significantly increased GR-beta expression. IL-2/IL-4 significantly decreased GR-alpha expression without affecting GR-beta. IL17, IL-23 and IL2 + 4 stimulations significantly hampered Dexamethasone-inhibition of proliferation (Dex EC(50) for: IL-17A + F = 251 nM; IL-23 = 435 nM; IL2 + 4 = 950 nM; Medium = 90 nM). IL2 + 4 and IL17A + F but not IL-23, significantly hampered Dexamethasone-induced apoptosis (1400 and 320 nM Dex, respectively). Dexamethasone's trans-activation of GILZ and trans-repression of NF-kB-driven IL-6 expression were both inhibited by IL2 + 4; IL17 + IL23 antagonized Dex trans-repression in PBMC from asthmatics.GR-beta up-regulation by IL-17/IL-23 cytokines is associated with induced steroid insensitivity in PBMCs, observed as diminished Dexamethasone's effects on cell proliferation, apoptosis and gene regulation. Steroid resistance induced by IL-2/IL-4 was associated with decreased GR-alpha expression. This study supports the possibility that Th-17 lymphocytes and associated cytokines play a role in the mechanism of steroid hypo-responsiveness in severe asthmatics.

Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis.Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations.Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes.Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disorder. In addition to the juxtacentromeric heterochromatic instability, the disease is characterized by variable reduction in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood as well as exhibit facial dysmorphism including hypertelorism, epicanthal folds, and low-set ears. A case series of five patients with ICF from a major immunodeficiency center in Saudi Arabia were included. Immunological and cytogenetic studies were performed for all the five patients. Molecular data was conducted on three patients. All patients had variable hypogammaglobulinemia and characteristic centromeric instability of chromosomes 1, 16, and sometimes 9. One of the patients had pseudomonas meningitis. Pauciarticular arthritis was noted in one patient, a previously not reported finding in ICF, though it has been reported among patients with humoral immune defect. In addition, we identified a novel homozygous c.2506 G>A (p.V836M) mutation in DNMT3B in one of the three patients tested. This report describes five patients with ICF Saudi Arabia for the first time. ICF should be suspected in children with facial dysmorphism who present with recurrent infections especially in highly inbred populations.

Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency with few reported cases. In this study, we further characterize the clinical, immunological, and molecular profiles of the disease in a cohort of 11 patients.Molecular genetic analysis and a comprehensive clinical review of patients diagnosed with HIGM3 at our tertiary care center from 1994 to 2011 were undertaken.Eleven patients from seven families were enrolled. The patients had a median age of 9 years [ranging from 2 to 22 years old]. All 11 patients had recurrent chest infections at presentation. Pneumocystis jiroveci pneumonia was confirmed in three patients. Five patients had sclerosing cholangitis, and five patients had Cryptosporidium isolated from their stool. Six patients had nasal and sinus infections, and two of these patients had destructive nasal fungal infections. Eight patients had neutropenia. All of the patients had low IgG and normal or high IgM levels. IgA was undetectable in all but three patients. Two novel mutations were found: a splice site for intron 3 and a missense mutation located in the coding region of exon 3. Two patients underwent successful stem cell transplantation from a matched donor. Four patients are doing well on prophylaxis; two are very sick, one with protracted diarrhea and persistent Cryptosporidium and the other with neurological complications. Three patients died early in life as a result of severe sepsis.To our knowledge, this report provides the largest cohort of patients with this disease with a very long follow-up period. Our cohort showed variable disease severity