Clinical improvement in psoriasis with specific targeting of interleukin-23.

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke.

Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

Naturally occurring hypoallergenic Bet v 1 isoforms fail to induce IgE responses in individuals with birch pollen allergy.

BACKGROUND: Engineered hypoallergens are currently being investigated for specific immunotherapy of allergic diseases in preclinical and clinical studies. Naturally occurring hypoallergens have by and large not been considered as a source of vaccine candidates. OBJECTIVE: Evaluation of the antibody response in atopic individuals induced by birch pollen containing isoforms of the major birch pollen allergen Bet v 1. METHODS: Isoform-specific antibody isotype responses for Bet v 1.0101, Bet v 1.0401, and Bet v 1.1001 were determined for 35 sera of individuals with birch pollen allergy. Isoform structures were compared and related to IgE-binding inhibitory capacities and induction of mediator release in human Fcvarepsilon receptor transformed rat basophilic leukemia cells. RESULTS: Bet v 1.0101 induced a predominant IgE response, whereas the significant highest levels of IgG(4) antibodies were directed against Bet v 1.0401. Bet v 1.1001 induced only a minimal antibody response. Structural comparisons revealed that most of the amino acid differences between the isoforms were located on the protein surfaces. IgE induced by Bet v 1.0101 only partly cross-reacted with the 2 other isoforms and bound to them with notably lower affinity. Bet v 1.0401 and Bet v 1.1001 also were poor inducers of mediator release. CONCLUSION: Bet v 1 isoforms possess highly variant immunogenic and allergenic properties. Bet v 1.0101 acts as the sensitizing agent, whereas Bet v 1.0401 and Bet v 1.1001 can induce only a minimal IgE response.

Surgical Elimination of the Gastric Digestion by Roux-en-Y Gastric Bypass Impacts on Food Sensitisation-a Pilot Study.

BACKGROUND: Impairment of gastric digestion due to pH elevation increases the risk for food allergy induction. As patients after Roux-en-Y gastric bypass (RYGB) surgery have lower gastric acidity and less gastric gland secretion, we aimed to analyse in a prospective study the effect of limiting gastric digestion capacity by surgical intervention on the immune response towards allergens. METHODS: Nine patients undergoing RYGB surgery for morbid obesity and one control patient having undergone surgery for treatment of an incisional hernia were enrolled in the study. Before and 1, 3, 6, 9 and 12 months after surgery, blood was collected for analysis of specific IgE antibodies, and patients were subjected to skin prick testing with 16 food and 18 aeroallergens. RESULTS: Skin prick test results revealed an increase of positive reactions indicating sensitisations towards the tested food and aeroallergens in 77.8 and 88.9 % of the patients, respectively, after surgical elimination of gastric digestion. These results were in line with elevated titers of food- and aeroallergen-specific IgE antibodies in 7 out of 9 (7/9) and 5/9 patients, respectively, after RYGB surgery. Serum cytokine levels revealed a mixed response for IFN-γ and were mostly beneath detection limit for IL-4. CONCLUSION: A change of IgE reactivity pattern occurred after impairment of gastric digestion due to surgical elimination underlining the important gastric gatekeeping function during oral sensitisation. Even though this study indicates an increased allergy risk for gastric bypass patients, further studies are needed to investigate in-depth the immunological changes associated with RYGB surgery.

Association of the chromosome 11q13.5 variant with atopic dermatitis in Austrian patients.

BACKGROUND: Recently, the two single nucleotide polymorphisms, rs7927894 on chromosome 11q13.5 and rs877776 within the region of the hornerin gene, were identified as novel susceptibility variants for atopic dermatitis in the first genome wide association study in atopic dermatitis. OBJECTIVE: The aim of our study was to evaluate the influence of these two genetic variants on atopic dermatitis and disease-related phenotypes in the Austrian population. METHODS: 275 atopic dermatitis patients and 243 controls were genotyped for the two variants rs7927894 and rs877776 by using Taqman based allelic discrimination assays. RESULTS: When comparing patients with controls we found a significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis (OR: 1.71; CI 1.14-2.59; p=0.010). Subgroup analysis revealed no significant association of rs7927894 with early age of onset of the disease, concomitant asthma and allergic rhinoconjunctivitis, total serum IgE levels and family history of atopy. The analysis of the rs877776 variant showed neither a relevant difference in the allelic distribution between patients and controls nor a statistically significant association with any of the analyzed atopic dermatitis phenotypes. CONCLUSIONS: In summary our data show a statistically significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis but not with other disease-related phenotypes. Therefore, we assume that the rs7927894 single nucleotide polymorphism selectively influences eczema development. More investigations in distinct study populations are needed to assess the role of this interesting polymorphism in atopic dermatitis.

The IgE-reactive autoantigen Hom s 2 induces damage of respiratory epithelial cells and keratinocytes via induction of IFN-gamma.

Hom s 2, the alpha-chain of the nascent polypeptide-associated complex, is an intracellular autoantigen that has been identified with IgE autoantibodies from atopic dermatitis patients. We investigated the humoral and cellular immune response to purified recombinant Hom s 2 (rHom s 2). rHom s 2 exhibited IgE reactivity comparable to exogenous allergens, but did not induce relevant basophil cell degranulation. The latter may be attributed to the fact that patients recognized single epitopes on Hom s 2 as revealed by IgE epitope mapping with rHom s 2 fragments. In contrast to exogenous allergens, rHom s 2 had the intrinsic ability to induce the release of IFN-gamma in cultured peripheral blood mononuclear cells from atopic as well as non-atopic individuals. IFN-gamma-containing culture supernatants from Hom s 2-stimulated peripheral blood mononuclear cells caused disintegration of respiratory epithelial cell layers and apoptosis of skin keratinocytes, which could be inhibited with a neutralizing anti-IFN-gamma antibody. Our data demonstrate that the Hom s 2 autoantigen can cause IFN-gamma-mediated cell damage.