Mariona Pascal

Lipid transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular sensitization to plant‐foods and pollens

Multiple plant‐food sensitizations with a complex pattern of clinical manifestations are a common feature of lipid transfer protein (LTP)‐allergic patients. Component‐resolved diagnosis permits the diagnosis of the allergen sensitization profile.

A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal-onset multisystem inflammatory disease: Novel evidence of the role of low-level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases

OBJECTIVE Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only approximately 55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID. METHODS Clinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed. RESULTS The patients CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria-like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in approximately 30-38% of circulating leukocytes. The absence of this variant in healthy controls and in the patients parents suggested a de novo true disease-causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells. CONCLUSION Our findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease-causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low-level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin-associated periodic syndrome.

A novel G6PC3 homozygous 1-bp deletion as a cause of severe congenital neutropenia

To the editor: Hereditary severe congenital neutropenia (SCN) represents a heterogeneous group of diseases characterized by early-onset life-threatening bacterial infections associated with absolute neutrophil counts (ANC) below 500/μL.[1][1],[2][2] In recent years, different studies have

Ovalbumin-specific IgE/IgG4 ratio might improve the prediction of cooked and uncooked egg tolerance development in egg-allergic children

Accurate predictors of natural tolerance development to cooked and uncooked egg are needed in egg‐allergic patients.

Jug r 2–reactive CD4+ T cells have a dominant immune role in walnut allergy

Background Allergic reactions to walnut can be life threatening. While IgE epitopes of walnut have been studied, CD4+ T-cell specific epitopes for walnut remain uncharacterized. Particularly, the relationship of both phenotype and frequency of walnut specific T-cells to the disease have not been examined. Objectives We sought to provide a thorough phenotypic analysis for walnut reactive T-cells in allergic and non-allergic subjects. Particularly, the relationship of phenotypes and frequencies of walnut specific T-cells with the disease. Methods CD154 up-regulation assay was used to examine CD4+ T-cell reactivity towards walnut allergens.Jug r 1, Jug r 2 and Jug r 3. Tetramer-Guided epitope mapping approach was utilized to identify HLA-restricted CD4+ T-cells epitopes in Jug r 2. Direct ex vivo staining with peptide-major histocompatibility complex class II (pMHC-II) tetramers enabled the comparison of frequency and phenotype of Jug r 2-specific CD4+ T-cells between allergic and non-allergic subjects. Jug r 2-specific T-cell-clones were also generated and mRNA transcription factor levels were assessed by RT qPCR. Intracellular cytokine staining (ICS) assays were performed for further phenotypical analyses. Results Jug r 2 was identified as the major allergen that elicited CD4+ T-cell responses. Multiple Jug r 2 T-cell epitopes were identified. The majority of these T-cells in allergic subjects have a CCR4+ TCM (central memory) phenotype. A subset of these T-cells express CCR4+CCR6+ irrespectively of the asthmatic status of the allergic subjects. ICS confirmed these TH2, TH2/TH17 and TH17-like heterogenic profiles. Jug r 2-specific T-cell-clones from allergic subjects mainly expressed GATA3; nonetheless, a portion of T-cell clones expressed either GATA3 and RORC, or RORC, confirming the presence of TH2, TH2/TH17 and TH17 cells. Conclusions Jug r 2 specific responses dominate walnut T-cell responses in subjects with walnut allergy. Jug r 2 central memory CD4+ cells and terminal effector T-cells were detected in peripheral blood with the central memory phenotype as the most prevalent phenotype. In addition to conventional TH2-cells, TH2/TH17 and TH17 cells were also detected in non-asthmatic and asthmatic subjects with walnut allergy. Understanding this T-cell heterogeneity may render better understanding of the disease manifestation.

Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug–dependent from nonsteroidal anti-inflammatory drug–independent food-induced anaphylaxis

BACKGROUND Lipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor. OBJECTIVE We sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A). METHODS Selection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures. RESULTS Expression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG1 and IgG3. Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-γ-regulated genes and IFN-γ levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism. CONCLUSIONS Gene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-γ pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses.

Serum Calprotectin Versus Acute-Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

To compare the accuracy of serum calprotectin and acute‐phase reactants (C‐reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels.

Shellfish allergens: tropomyosin and beyond

IgE‐mediated shellfish allergy constitutes an important cause of food‐related adverse reactions. Shellfish are classified into mollusks and crustaceans, the latter belonging to the class of arthropoda. Among crustaceans, shrimps are the most predominant cause of allergic reactions and thus more extensively studied. Several major and minor allergens have been identified and cloned. Among them, invertebrate tropomyosin, arginine kinase, myosin light chain, sarcoplasmic calcium‐binding protein, and hemocyanin are the most relevant. This review summarizes our current knowledge about these allergens.

Serum Calprotectin More Accurately Discriminates the Inflammatory Disease Activity of Rheumatoid Arthritis Patients Receiving TNF inhibitors than Acute Phase Reactants

To compare the accuracy of serum calprotectin and acute‐phase reactants (C‐reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels.

Serum allergen-specific IgA is not associated with natural or induced tolerance to egg in children.

The role of specific IgA (sIgA) in oral immunotherapy (OIT) and natural tolerance to foods is poorly understood. We aimed to study serum sIgA in induced and natural tolerance to egg. Children aged 5–16 years diagnosed with IgE‐mediated egg allergy were recruited. After egg challenge, patients were classified as transient (TEA) or persistent (PEA) egg‐allergic. PEA children were further divided into oral immunotherapy (PEA‐OIT) or egg avoidance (PEA‐EA). Allergy/tolerance was reassessed 9–12 months later (T1) in PEA‐EA. Serum sIgA to ovalbumin and ovomucoid were determined at inclusion in all patients and repeated in PEA at T1. 21 TEA and 52 PEA children were recruited (28 PEA‐OIT, 24 PEA‐EA). Serum sIgA remained unchanged after OIT. TEA and PEA had similar serum sIgA. No specific trend on serum sIgA was observed in five PEA‐EA who developed natural tolerance over follow‐up. Thus, serum sIgA seems not to be associated with induced or natural egg tolerance.