No abstract

Previous studies indicate that 30-50% of chronic urticaria patients have an autoimmune etiology. Clinical diagnosis of autoimmune urticaria is supported with the autologous serum skin test. The purpose of this study was to compare two laboratory tests for measurement of IgG autoantibodies to IgE or IgE receptors and compare the results with the autologous serum and plasma skin tests. We performed skin tests and two functional in vitro tests, basophil histamine release, and CD63 up-regulation to detect autoantibodies relevant to autoimmune urticaria. Both sera and citrated plasma were evaluated in the autologous skin test and histamine release assay. Thyroid autoantibodies were also measured. Basophils were incubated with patient plasma, sera, buffer, or anti-IgE. The cells were analyzed for CD63 expression and the supernatants were recovered for histamine analysis. There was high correlation between CD63 up-regulation and histamine release assays, but histamine release was more sensitive. There was a high concordance between sera and citrated plasma for the skin test. Sera from chronic urticaria patients produced higher mean histamine release (23%) compared with citrated plasma (12%). Thirty-one percent of patients positive in the histamine release assay were also positive for thyroid autoantibodies. This compares with 12% who were negative in the histamine release assay. These data show that in vitro basophil histamine release can be used to measure antibodies to FceRI, FceRII/CD23, or IgE and identify patients with autoimmune urticaria.

Background: Alpha-gal syndrome (AGS) is an emerging immunoglobulin E (IgE)emediated allergy to galactose-alpha-1,3-galactose (alpha-gal). The geographic distribution and burden of AGS in the United States are unknown. Objective: To characterize alpha-gal IgE testing patterns and describe the trends and distribution from 2010 to 2018 in the United States. Methods: This retrospective analysis included all persons tested for alpha-gal IgE antibodies by Viracor-IBT Laboratories (Lee's Summit, Missouri), the primary site of testing in the United States. Data included age and sex of person tested, specimen state of origin, collection date, and result value; persons with at least 1 positive test result (!0.1 kU/L) were compared with negatives. Proportions tested and with positive test results were calculated using the US Census population estimates. Results: Overall, 122,068 specimens from 105,674 persons were tested for alpha-gal IgE during July 1, 2010, to December 31, 2018. Nearly one-third (34,256, 32.4%) had at least 1 positive result. The number of persons receiving positive test results increased 6-fold from 1110 in 2011 to 7798 in 2018. Of those receiving positive test results, mean [SD] age was 46.9 (19.8) years; men were more likely to test positive than women (43.3% vs 26.0%). Arkansas, Virginia, Kentucky, Oklahoma, and Missouri had the highest number of persons who were tested and had a positive result per 100,000 population. Conclusion: More than 34,000 persons, most presumably symptomatic, have received positive test results for IgE antibodies to alpha-gal, suggesting AGS is an increasingly recognized public health problem. The geographic distribution of persons who tested positive is consistent with exposure to Amblyomma americanum ticks.

Background BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. Methods In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1–4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. Results We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1–4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. Conclusions Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.