The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4+ T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4+ T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly.

Genome-wide association analysis for chronic venous disease identifies EFEMP1 and KCNH8 as susceptibility loci.

Chronic venous disease (CVD) is a multifactorial condition representing one of the most common disorders among populations of Western countries. The heritability of about 17% suggests genetic risk factors in CVD etiology. However, so far the genetic causes are unknown. We undertook the hitherto first genome-wide association study (GWAS) for CVD, analyzing more than 1.93 M SNPs in 4,942 German individuals, followed by replication in two independent German data sets. The combined analysis of discovery and replication stages (2,269 cases and 7,765 controls) yielded robust associations within the two genes EFEMP1 and KCNH8 (rs17278665, rs727139 with P < 5 × 10-8), and suggestive association within gene SKAP2 (rs2030136 with P < 5 × 10-7). Association signals of rs17278665 and rs727139 reside in regions of low linkage disequilibrium containing no other genes. Data from the ENCODE and Roadmap Epigenomics projects show that tissue specific marks overlap with the variants. SNPs rs17278665 and rs2030136 are known eQTLs. Our study demonstrates that GWAS are a valuable tool to study the genetic component of CVD. With our approach, we identified two novel genome-wide significant susceptibility loci for this common disease. Particularly, the extracellular matrix glycoprotein EFEMP1 is promising for future functional studies due to its antagonistic role in vessel development and angiogenesis.

Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d 1.

BACKGROUND: Cross-reactivity between the major birch pollen allergen, Bet v 1, and the apple protein, Mal d 1, frequently causes food allergy. OBJECTIVE: To investigate the effects of successful sublingual immunotherapy (SLIT) with birch pollen extract on apple allergy and the immune response to Bet v 1 and Mal d 1. METHODS: Before and after 1 year of SLIT, Bet v 1-sensitized patients with oral allergy syndrome to apple underwent nasal challenges with birch pollen and double-blind placebo-controlled food challenges with apple. Bet v 1-specific and Mal d 1-specific serum antibody levels and proliferation in PBMCs and allergen-specific T-cell lines (TCLs) were determined. Bet v 1-specific TCLs were mapped for T-cell epitopes. RESULTS: In 9 patients with improved nasal provocation scores to birch pollen, apple-induced oral allergy syndrome was not significantly reduced. Bet v 1-specific IgE and IgG(4) levels significantly increased. Bet v 1-specific T-cell responses to all epitopes and those cross-reactive with Mal d 1 significantly decreased. However, neither Mal d 1-specific IgE and IgG(4) levels nor Mal d 1-induced T-cell proliferation changed significantly. In contrast, Mal d 1-specific TCLs showed increased responses to Mal d 1 after 1 year of SLIT. CONCLUSION: This longitudinal study indicates that pollen SLIT does not efficiently alter the immune response to pollen-related food allergens, which may explain why pollen-associated food allergy is frequently not ameliorated by pollen immunotherapy even if respiratory symptoms significantly improve. CLINICAL IMPLICATIONS: SLIT with birch pollen may have no clinical effect on associated apple allergy.

Uptake of antineoplastic agents in pharmacy personnel. Part II: study of work-related risk factors.

OBJECTIVES: This study aimed to find working conditions related to internal exposure of substances handled in centralised cytostatic drug preparation units in hospitals. Recommendations to avoid this uptake should be deduced from the results. METHOD: In a longitudinal study over 3 years, 87 pharmacy technicians and pharmacists of 14 different hospitals in Germany provided 24-h urine samples separately up to three times (three sampling cycles: cycles 1-3) at the end of a working week. Additional samples were taken after 2 days and after at least 3 weeks of absence. Cyclophosphamide and ifosfamide, doxo-, dauno- epi-, and idarubicin, and platinum deriving from cis- and carboplatin were determined in urine samples by gas chromatography/mass spectrometry, liquid chromatography (HPLC) and voltammetry. The following working conditions were assessed by questionnaire: working tasks, different ways that the workbenches were run, cleaning conditions, waste disposal, number of preparations, amount of substances handled, and use of gloves (material, thickness and changing interval). RESULTS: Two-thirds of the subjects showed at least one positive result with regard to all three cycles (56 of initially 87 subjects). Employees who only pass material that is needed for processing are affected, just as are those who only prepare administrations and those alternating in both functions (25% vs. 24.1% vs. 50.6%, respectively). The storage of waste in containers that could be opened to add waste tends to increase the risk of internal exposure of ifosfamide and cyclophosphamide (odds ratios (95% confidence interval): 0.08 (0.013-0.5) and 0.19 (0.03-1.12), respectively). The amount handled and number of preparations of cyclophosphamide for "manufacturers" were associated with internal exposure of cyclophosphamide (28.04 (1.75-448.74) and 1.22 (1.03-1.44), respectively). The total number of preparations handled by assistants seemed to increase the risk of intake of any of the substances under study [1.04 (1.00-1.08)]. CONCLUSION: Since employees who pass materials are affected in the same way as those who prepare administrations, both have to be included in reviewing protective measures. Further studies must be carried out to verify the generated hypotheses of factors related to internal exposure found in this study.