Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

Characterization of the expression pattern for a putative toxin in black widow silk glands

Studies have shown that Latrodectus hesperus, black widow spiders, produce silks that illustrate remarkable strength and toughness that can be compared to steel. The ultimate goal, in the future, is to decipher the exact primary sequence for the silk protein so that it may be mass produced and integrated into many beneficial products, such as bullet-proof vests or a new type of medical suture. Using the silk could not only make our industrial products stronger, more elastic, cheaper, but also biodegradable, which would reduce much waste produced from non-bio-degradable products and be environmentally friendly.However, there has been an interesting discovery in recent years regarding black widow spider silk. Our lab has recently discovered that there may be neurotoxin proteins present in black widow spider silk-producing glands. This was discovered when researchers where analyzing the components that constitute black widow silk. However the glands that are responsible for producing toxins are located in glands near the fangs of the spider in the cephalic region, by the head. The glands that are responsible for producing silk are in the abdominal region of the spider, clearly away from where toxin proteins are produced.For our research we have decided to confirm if toxin proteins are being produced in web glands. We have selected to study the tubuliform gland, aggregate gland, major ampullate gland, and minor ampullate glands to look for the expression of toxin RNAs where they are not typically expressed. We have designed an experiment where we have created primers that use real time PCR to amplify the mRNA sequences in each of the glands. Using this analysis, we will examine whether some recently identified putative toxin proteins are expressed in silk-producing glands. Results will be discussed

Clinical phenotype and allergen sensitization in the first 2 years as predictors of atopic disorders at age 5 years

Introduction From a birth cohort of at-risk Asian infants, we prospectively investigated the role of early onset allergen sensitization and clinical phenotypes as risk factors for atopic disorders at the age of 5 years.Methods and materials The study recruited 253 families with a history of allergic disease in a first degree relative from an antenatal clinic in Singapore. The children were followed prospectively to assess clinical outcomes and skin prick test was performed at 2 and 5 years of age.Results Allergen sensitization (food and/or house dust mites) alone at 2 years of age was not associated with increased risk of wheeze and eczema at 5 years. However, the clinical phenotype (eczema and wheeze) with or without the presence of concomitant allergen sensitization at 2 years increased this risk. For eczema, eczema alone at year 2 increased the risk of eczema at year 5 (adjOR = 7.1; 95 % CI: 1.8–27.8) and this was further increased by the presence of allergen sensitization (adjOR = 25.4; 95 % CI: 4.7–138.5) and the concomitant presence of both wheeze and allergen sensitization (adjOR = 64.9; 95 % CI: 4.7–900.0). For wheeze, wheeze alone at 2 years (adjOR = 4.5; 95 % CI: 1.4 -14.8), and wheeze with concomitant allergen sensitization and eczema (adjOR = 13.9; 95 % CI: 1.2–168.5) increased the risk of wheeze at 5 years. The exception was rhinitis, where allergen sensitization alone at 2 years (adjOR = 5.6; 95 % CI: 1.1–29.2) increased the risk of rhinitis at 5 years. Early onset of eczema at 2 years also increased the risk of rhinitis (adjOR = 6.8; 95 % CI: 2.0–23.1).Conclusion In this Asian birth cohort, the clinical phenotype (eczema and wheeze) with or without concomitant allergen sensitization in the first 2 years of life were strong predictors of atopic disorders at 5 years. Keywords: Eczema, Wheeze, Rhinitis, Allergen sensitizatio