A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Recommendation to update the British Society for Cutaneous Allergy corticosteroid series.

BACKGROUND: Patch testing is an important investigation when dermatitis is unresponsive to, or worsened by, topical corticosteroid treatment. There is a balance to be struck between testing too many allergens, which is expensive, time consuming and risks causing sensitization, and testing too few, which risks missing the diagnosis. The current British Society for Cutaneous Allergy (BSCA) corticosteroid series comprises eight allergens and was last updated in February 2007. AIM: To review and update the BSCA corticosteroid series. METHODS: We retrospectively analysed data from 16 patch test centres in the UK and Ireland for all patients who were patch tested to a corticosteroid series between August 2017 and July 2019. We recorded the allergens tested, the number and percentage tested to a corticosteroid series and the number of positive results for each allergen. We identified the allergens that test positive in ≥ 0.1% of selectively tested patients. RESULTS: Overall, 3531 patients were tested to a corticosteroid series in the 16 centres. The number of allergens tested ranged from 7 to 18 (mean 10). The proportion of patch test patients who were tested to a corticosteroid series ranged from 1% to 99%. Six allergens in the 2017 BSCA series tested positive in ≥ 0.1% of patients. Nine allergens not in the BSCA corticosteroid series tested positive in ≥ 0.1% of patients. CONCLUSION: This audit demonstrates the importance of regular review of recommended series and the significant variations in practice. The new BSCA corticosteroid series that we recommend contains 13 haptens, with the addition of the patient's own steroid creams as appropriate.

Bees wax wraps-A novel source of colophonium allergic contact dermatitis.

A patient with recurrent face and eyelid eczema after establishing an eco-friendly refill business, she was selling bees wax wraps as part of her business. This case raises awareness of bees wax wraps being a new potential eco-friendly source of colophonium allergic contact dermatitis.

Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells That Mark Progression to Type 1 Diabetes.

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ("progressors") compared with five children matched for sex, age, and HLA-DR who had not progressed ("nonprogressors"). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.

Ideal proportion of the population to be patch tested: How many should we be doing?

BACKGROUND: How many patients should we be patch testing? A previous study suggested that the minimum proportion of a population to be patch tested for allergic contact dermatitis was 1:700 annually. OBJECTIVES: To evaluate if the current minimum rate for patch testing has changed over the 20 years since the previous study in order to maximize the value. METHODS: In cooperation with the British Society for Cutaneous Allergy, a proforma for collation of retrospective data between January 2015 and December 2017 was sent to patch-test centers in the United Kingdom (UK) and the Republic of Ireland (ROI). The number of positive tests was analyzed against the proportion of population tested to see what proportion of the population would yield the greatest number of positive results. RESULTS: Responses from 11 centers showed that the minimum number needed to patch test had increased to 1:550 per head of population per year using the current criteria. CONCLUSIONS: In agreement with previous studies, we should be patch testing more people than we are. We could reduce the threshold for referral of patients we patch test to derive the most benefit from this investigation.

A survey of members of the European Surveillance System on Contact Allergy and the EU project "StanDerm" to identify allergens tested in cosmetic series across Europe.

BACKGROUND: There is currently no agreed cosmetic series for use across Europe. OBJECTIVES: To establish allergens currently tested in local and national cosmetic series. METHOD: Members of the European Surveillance System on Contact Allergy and the European Cooperation in Science and Technology project TD1206 ("StanDerm") were surveyed to establish their current practice. RESULTS: A wide range of allergens was tested but there was significant variation between centres on the allergens considered to be important in screening for allergy to cosmetics. The number of allergens tested in addition to the baseline series varied between 2 and 50. CONCLUSIONS: There is a need for further investigation to establish the frequency and relevance of reactions to cosmetic allergens to enable an agreed evidence-based cosmetic series to be produced. Criteria for inclusion need to be established.

CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function.

CD52, a glycophosphatidylinositol (GPI)-anchored glycoprotein, is released in a soluble form following T cell activation and binds to the Siglec (sialic acid-binding Ig-like lectin)-10 receptor on T cells to suppress their function. We show that binding of CD52-Fc to Siglec-10 and T cell suppression requires the damage-associated molecular pattern (DAMP) protein, high-mobility group box 1 (HMGB1). CD52-Fc bound specifically to the proinflammatory Box B domain of HMGB1, and this in turn promoted binding of the CD52 N-linked glycan, in α-2,3 sialic acid linkage with galactose, to Siglec-10. Suppression of T cell function was blocked by anti-HMGB1 antibody or the antiinflammatory Box A domain of HMGB1. CD52-Fc induced tyrosine phosphorylation of Siglec-10 and was recovered from T cells complexed with HMGB1 and Siglec-10 in association with SHP1 phosphatase and the T cell receptor (TCR). Thus, soluble CD52 exerts a concerted immunosuppressive effect by first sequestering HMGB1 to nullify its proinflammatory Box B, followed by binding to the inhibitory Siglec-10 receptor, triggering recruitment of SHP1 to the intracellular immunoreceptor tyrosine-based inhibitory motif of Siglec-10 and its interaction with the TCR. This mechanism may contribute to immune-inflammatory homeostasis in pathophysiologic states and underscores the potential of soluble CD52 as a therapeutic agent.

An unusual presentation of a common condition: Allergic contact dermatitis.

Allergic contact dermatitis commonly affects patients with chronic venous leg ulcers and can contribute to impaired wound healing. Many allergens have been identified, and despite the use of advanced dressings, the incidence of allergy has remained high. We discuss an unusual presentation of allergic contact dermatitis in a patient with a chronic wound. The patient's history was consistent with a recurrent venous leg ulcer, but on this occasion, the wound continued to deteriorate despite optimal treatment. This prompted further investigation, which included patch testing. Although the clinical features were not suggestive of allergy, the patch test was positive for several allergens, including Atrauman® dressings, which the patient was using at the time. This case highlights the importance of regular reassessment and accurate diagnosis for the management of chronic wounds. It also demonstrates that allergic contact dermatitis can contribute to delayed wound healing without causing the classical clinical features of inflammation of the surrounding skin, and even hypoallergenic, non-adherent dressings can be sensitising.

Delayed and localized pemphigus vulgaris after breast cancer radiotherapy.

Breast cancer treatment involving ionizing radiation causes characteristic radiation dermatitis in the majority of patients. The DNA damaging effects of radiation can rarely predispose to primary inflammatory dermatoses, such as pemphigus vulgaris. In such cases, the disease presents with all the hallmarks of the primary dermatosis, but the eruption is limited to the field of irradiation and is often amenable to treatment. In contrast, occurrence of generalized pemphigus vulgaris in this setting may mean cancer recurrence. The mechanism by which radiotherapy induces localized disease remains unknown, but there is likely a loss of self-tolerance which maybe coupled to antigen exposure.

Para-phenylenediamine allergy: current perspectives on diagnosis and management.

Para-phenylenediamine (PPD) is the commonest and most well-known component of hair dyes. Oxidative hair dyes and dark henna temporary tattoos contain PPD. Individuals may be sensitized to PPD by temporary henna tattooing in addition to dyeing their hair. PPD allergy can cause severe reactions and may result in complications. In recent years, frequency of positive patch test reactions to PPD has been increasing. Cross-sensitization to other contact allergens may occur, in particular to other hair dye components. Hairdressers are at a high risk for PPD allergy and require counseling regarding techniques to minimize exposure and protective measures while handling hair dye. We focus this review on the current perspectives of diagnosis and management of PPD allergy.

Antigen-based vaccination and prevention of type 1 diabetes.

Insulin-dependent or type 1 diabetes (T1D) is a paradigm for prevention of autoimmune disease: Pancreatic ß-cell autoantigens are defined, at-risk individuals can be identified before the onset of symptoms, and autoimmune diabetes is preventable in rodent models. Intervention in asymptomatic individuals before or after the onset of subclinical islet autoimmunity places a premium on safety, a requirement met only by lifestyle-dietary approaches or autoantigen-based vaccination to induce protective immune tolerance. Insulin is the key driver of autoimmune ß-cell destruction in the nonobese diabetic (NOD) mouse model of T1D and is an early autoimmune target in children at risk for T1D. In the NOD mouse, mucosal administration of insulin induces regulatory T cells that protect against diabetes. The promise of autoantigen-specific vaccination in humans has yet to be realized, but recent trials of oral and nasal insulin vaccination in at-risk humans provide grounds for cautious optimism.