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Editor Keloids are benign growths representing a disrupted wound healing process involving abnormal collagen proliferation. Keloids are most prevalent in African American (AA)1 and Asian populations,2 and greatly impact quality of life.3 Keloids show high recurrence rates and current therapies (intralesional steroids, bleomycin, surgical excision, etc.) have limited efficacy,4 thus, presenting a high unmet need for better treatments. Genetic studies have identified chromosome variants associated with keloid formation in AAs and Asians.1, 5 A genomic profiling study on lesional and non‐lesional keloid skin from three AA patients identified bone/cartilage abnormalities,6 but did not assess inflammatory pathways. Recently, atopic dermatitis (AD) has been indicated as an independent risk factor for developing keloids.7 Increases in IL‐4 and IL‐13 receptors have been detected through laser capture microdissection in lesional keloid skin, but increases in cognate ligands were not detected.

Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a "cytokine" are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8(+) T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4(+) T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response.

Two-particle azimuthal correlations have been measured in neutral current deep inelastic ep scattering with virtuality Q(2)> 5 GeV2 at a centre-of-mass energy root s = 318 GeV recorded with the ZEUS detector at HERA. The correlations of charged particles have been measured in the range of laboratory pseudorapidity -1.5 < eta < 2.0 and transverse momentum 0.1 < p(T)< 5.0 GeV and event multiplicities N-ch up to six times larger than the average < N-ch >approximate to 5. The two-particle correlations have been measured in terms of the angular observables c(n{2})=<< cosn Delta phi >>, where n is between 1 and 4 and phi is the relative azimuthal angle between the two particles. Comparisons with available models of deep inelastic scattering, which are tuned to reproduce inclusive particle production, suggest that the measured two-particle correlations are dominated by contributions from multijet production. The correlations observed here do not indicate the kind of collective behaviour recently observed at the highest RHIC and LHC energies in high-multiplicity hadronic collisions.

Background The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. Conclusions We estimate that similar to 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed similar to 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.

Purpose Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. Methods Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. Results Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. Conclusions The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

BACKGROUND: Evidence of T(H)1/IFN-gamma overactivation as a major pathogenic driver somewhat conflicts with data supporting robust allergic background in patients with alopecia areata (AA). Previous investigations of immunological dysregulations show that both T(H)1- and T(H)2-related markers are overexpressed in AA. Clinical correlations in large populations may shed light on the immune pathways most likely to result in the clinical phenotype of AA. OBJECTIVE: To investigate the atopic comorbidities among patients with AA in a large population-based study. METHODS: This is a cross-sectional retrospective study of patients with AA and a matched comparison group, analyzing the associations between AA and 4 atopic comorbidities: asthma, atopic dermatitis (AD), allergic rhinitis, and allergic conjunctivitis. chi(2) and t tests were used for univariate analysis, and logistic regression model was used for multivariate analysis. The study was performed using the computerized database of the Clalit Health Services, encompassing more than 4.4 million subjects. RESULTS: The study population included 51,561 patients with AA and 51,410 matched control subjects. The prevalence of asthma (7.8% vs 6.5%; odds ratio [OR], 1.22; 95% CI, 1.17-1.28; P < .001), AD (3.9% vs 2.6%; OR, 1.55; 95% CI, 1.44-1.66; P < .001), allergic rhinitis (16.0% vs 12.8%; OR, 1.29; 95% CI, 1.25-1.34; P < .001), and allergic conjunctivitis (23.5% vs 19.6%; OR, 1.27; 95% CI, 1.23-1.30; P < .001) was significantly higher among patients with AA as compared with matched control subjects. Patients with AA also had a significantly higher probability of having more than 1 atopic comorbidity, with increasing OR as the number of concomitant atopic conditions increased. CONCLUSIONS: Our analysis supports the previous literature and provides strong generalizability of significant atopy in patients with AA, suggesting T(H)2 pathogenicity in AA, and challenging the traditional view of AA as a single-axis, T(H)1-centered disease. (C) 2020 American Academy of Allergy, Asthma & Immunology

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

alpha-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro-inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN-7000, the activity of which can be modulated with light. Based on established structure-activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro-inflammatory cytokines, such as IFN-gamma. The azobenzene derivative alpha-GalACer-4 proved to be more potent than KRN-7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.

CD4(+) T cells integrate well-defined signals from the T-cell receptor (TCR) (signal 1) and a host of costimulatory molecules (signal 2) to initiate clonal expansion and differentiation into diverse functional T helper (Th) subsets. However, our ability to guide the expansion of context-appropriate Th subsets by deploying these signals in vaccination remains limited. Using cell-based vaccines, we selectively amplified signal 1 by exclusive presentation of an optimized peptide:MHC II (pMHC II) complex in the absence of classic costimulation. Contrary to expectations, amplified signal 1 alone was strongly immunogenic and selectively expanded high-affinity TCR clonotypes, despite delivering intense TCR signals. In contrast to natural infection or standard vaccines, amplified signal 1, presented by a variety of professional and nonprofessional antigen-presenting cells (APCs), induced exclusively polyfunctional Th1 effector and memory cells, which protected against retroviral infection and tumor challenge, and expanded tumor-reactive CD4(+) T cells otherwise rendered unresponsive in tumor-bearing hosts. Together, our findings uncover a default Th1 response to ample signal 1 and offer a means to selectively prime such protective responses by vaccination.

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.