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Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0–77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with “secondary” hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6–14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0–43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

Abstract Base editing introduces precise single-nucleotide edits in genomic DNA and has the potential to treat genetic diseases such as the blistering skin disease recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by mutations in the COL7A1 gene and type VII collagen (C7) deficiency. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Here, we use ABE8e, a recently evolved ABE, to correct primary RDEB patient fibroblasts harboring the recurrent RDEB nonsense mutation c.5047 C > T (p.Arg1683Ter) in exon 54 of COL7A1 and use a next generation sequencing workflow to interrogate post-treatment outcomes. Electroporation of ABE8e mRNA into a bulk population of RDEB patient fibroblasts resulted in remarkably efficient (94.6%) correction of the pathogenic allele, restoring COL7A1 mRNA and expression of C7 protein in western blots and in 3D skin constructs. Off-target DNA analysis did not detect off-target editing in treated patient-derived fibroblasts and there was no detectable increase in A-to-I changes in the RNA. Taken together, we have established a highly efficient pipeline for gene correction in primary fibroblasts with a favorable safety profile. This work lays a foundation for developing therapies for RDEB patients using ex vivo or in vivo base editing strategies.

Background Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructosederived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants in TKFC are associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs. Methods Whole- exome sequencing identified a homozygous novel variant in TKFC (c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins. Results The individual presented with chronic active Epstein- Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient's immunodeficiency. Conclusion Our report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further. [ABSTRACT FROM AUTHOR]

Background Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. Objectives To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. Methods Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. Results The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3 + Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. Conclusions Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus. [ABSTRACT FROM AUTHOR]

Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.

The aim of the study was to compare mRNA vaccine BNT162b2 with adenovirus vector- based vaccines in terms of presence of adverse reactions, immunogenicity, and protection against COVID-19. A total of 270 individuals were enrolled, of which 135 were vaccinated with adenovirus vector-based vaccines and compared with 135 age- and sex-matched participants who received the BNT162b2 mRNA vaccine. Serum sampling was performed on all participants on days 21, 42, 90, and 180 following the first dose, to evaluate anti-spike IgG and IgA responses. Antibodies were quantified by chemiluminescent microplate and ELISA assays. We demonstrate that both mRNA and adenovirus vector-based vaccines caused mild side-effects and were effective in inducing adequate antibody responses against SARS-CoV-2, although BNT162b2 was superior concerning the intensity of antibody responses and protection against severe COVID-19. Moreover, we identify that IgG and IgA responses depended primarily on both history of previous COVID-19 infection and vaccination platform used, with individuals immunized with a single-dose vaccine having lower antibody titers over time. Lastly, all vaccine platforms had limited side-effects, with the most frequent pain at the injection site. Our results provide useful information regarding antibody responses after vaccination with different vaccine platforms, which can be useful for public health vaccination strategies.

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and

The aim of our study was to investigate the immunogenicity of the BNT162b2 vaccination according to the age and medical status of vaccinated individuals. A total of 511 individuals were enrolled (median age: 54.0 years, range: 19–105); 509 of these individuals (99.6%) received two doses of BNT162b2 at an interval of 21 days. IgG and IgA responses were evaluated on days 21, 42, 90, and 180 after the first dose with chemiluminescent microparticle and ELISA assays. The cell-mediated immune responses were assessed by an automated interferon-gamma release assay. We demonstrated positive antibody responses after vaccination for the majority of enrolled participants, although waning of IgG and IgA titers was also observed over time. We further observed that the intensity of humoral responses was positively correlated with increased age and prior COVID-19 infection (either before or after the first vaccination). Moreover, we found that only a medical history of autoimmune disease could affect the intensity of IgA and IgG responses (3 weeks after the primary and secondary immunization, respectively), while development of systemic adverse reactions after the second vaccination dose was significantly associated with the height of IgG responses. Finally, we identified a clear correlation between humoral and cellular responses, suggesting that the study of cellular responses is not required as a routine laboratory test after vaccination. Our results provide useful information about the immunogenicity of COVID-19 vaccination with significant implications for public health vaccination strategies.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease resulting in reduced mucus clearance and impaired lung function. Here, the authors show that mutations in PIH1D3 are responsible for an X-linked form of PCD, affecting assembly of a subset of inner arm dyneins.