Dalia H. El-Ghoneimy

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

The use of inhaled corticosteroids in pediatric asthma: update

Despite the availability of several formulations of inhaled corticosteroids (ICS) and delivery devices for treatment of childhood asthma and despite the development of evidence-based guidelines, childhood asthma control remains suboptimal. Improving uptake of asthma management plans, both by families and practitioners, is needed. Adherence to daily ICS therapy is a key determinant of asthma control and this mandates that asthma education follow a repetitive pattern and involve literal explanation and physical demonstration of the optimal use of inhaler devices. The potential adverse effects of ICS need to be weighed against the benefit of these drugs to control persistent asthma especially that its safety profile is markedly better than oral glucocorticoids. This article reviews the key mechanisms of inhaled corticosteroid action; recommendations on dosage and therapeutic regimens; potential optimization of effectiveness by addressing inhaler technique and adherence to therapy; and updated knowledge on the real magnitude of adverse events.

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Differences in B and T cell repertoires in patients with RAG deficiency associate with clinical severity. Taking SCID genetics to the clinic Mutations that lead to deficiencies in the recombination-activating genes RAG1 and RAG2 result in a spectrum of immunodeficiencies ranging from loss of T and/or B cell repertoire diversity to a complete lack of T and B cells—severe combined immunodeficiency (SCID). Here, Lee et al. perform next-generation B and T cell repertoire sequencing on 12 patients with RAG mutations who have immunodeficiencies of varying severity. They found that the level of repertoire skewing was associated with the severity of disease and that specific repertoire deficiencies were associated with particular phenotypes. These data support a genotype-phenotype connection for primary immunodeficiencies. Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations

Perforin, encoded by PRF1, is a pore‐forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early‐onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later‐onset disease and more variable manifestations.

Evaluation of banana hypersensitivity among a group of atopic egyptian children: relation to parental/self reports.

PURPOSE To evaluate the frequency of banana sensitization and allergy among a group of atopic Egyptian children in relation to parental/self reports. METHODS This is a case-control study included 2 groups of allergic children with and without history of banana allergy, each included 40 patients. They were subjected to skin prick test (SPT) using commercial banana allergen extract and prick-prick test (PPT) using raw banana, in addition to measuring the serum banana-specific IgE. Oral banana challenge was performed in suspected cases. RESULTS Banana allergy was diagnosed in 3 (7.5%) patients based on positive history of allergy on exposure to banana, positive SPT/PPT and elevated banana-specific IgE. The 3 patients had bronchial asthma with exacerbation upon banana exposure. The PPT results conform with those of SPT both in diagnosis of banana allergy and in the skin reactivity to banana. Serum banana-specific IgE was detectable in the whole studied sample with higher serum level among those without history of banana allergy (P=0.005). Oral banana challenge was negative for 20 patients with history of banana allergy and positive serum banana-specific IgE but negative SPT and PPT. CONCLUSIONS Self/parental reports of banana allergy is high while the actual banana allergy is uncommon. The PPT seems as reliable as SPT in diagnosis of banana allergy unlike specific IgE which reflects sensitization rather than allergy. Oral food challenge remains the most helpful tool for diagnosis of food allergy in suspected cases.

A Rare Association Between Leukocyte Adhesion Deficiency Type I and Psoriasis in Humans

The β2 integrins are expressed exclusively on leukocytes and participate in many immune and inflammatory processes. This subfamily comprises four heterodimeric glycoproteins with a common β-subunit, designated β2 (CD18). Spontaneous mutations of the CD18 gene result in leukocyte adhesion deficiency type I (LAD-I). Low level of CD18 expression has also been implicated in the pathogenesis of psoriasis. We here describe a child with recurrent skin infections without pus formation, persistent gingivitis and periodontitis. His blood counts showed persistent leukocytosis (neutrophilia). CD11b expression was defective on neutrophils, while that of CD18 was normal. So, our patient represents a mild variant of LAD-I with possible dysfunctional CD18. Moreover, he developed psoriasis with reduced CD18 expression on CD4+ T-cells. Psoriasiform dermatitis has been described before in association with LAD-I, however, clinically and histologically confirmed psoriasis in association with LAD-I has been described only in CD18 hypomorphic mice. Therefore, our patient represents the first clinically and histopathologically documented association between LAD-I and psoriasis in humans. It lends support to the role of β2 integrins in the etiopathogenesis of psoriasis.

Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration

BackgroundRheumatic diseases in children are associated with significant morbidity andpoor health-related quality of life (HRQOL). There is no health-relatedquality of life (HRQOL) scale available specifically for children with lesscommon rheumatic diseases. These diseases share several features withsystemic lupus erythematosus (SLE) such as their chronic episodic nature,multi-systemic involvement, and the need for immunosuppressive medications.HRQOL scale developed for pediatric SLE will likely be applicable tochildren with systemic inflammatory diseases.FindingsWe adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters(SMILEY©) to Simple Measure of Impact of Illness in Youngsters(SMILY©-Illness) and had it reviewed by pediatric rheumatologists forits appropriateness and cultural suitability. We tested SMILY©-Illnessin patients with inflammatory rheumatic diseases and then translated it into28 languages.Nineteen children (79% female, n=15) and 17 parents participated. The meanage was 12±4 years, with median disease duration of 21 months (1-172months). We translated SMILY©-Illness into the following 28 languages:Danish, Dutch, French (France), English (UK), German (Germany), German(Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil),Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish(Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans,Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian,Japanese, Romanian, Serbian and Xhosa.ConclusionSMILY©-Illness is a brief, easy to administer and score HRQOL scale forchildren with systemic rheumatic diseases. It is suitable for use acrossdifferent age groups and literacy levels. SMILY©-Illness with itsavailable translations may be used as useful adjuncts to clinical practiceand research.