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Suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.

Background The safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs). Methods This phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs). Results In total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160). Conclusions No safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs. Trial registration number (ClinicalTrials.gov) NCT03116347.

Current understanding of how immunodeficiencies impact protective responses against viral infections and vaccination is primarily derived from adult cohorts that may not accurately reflect the pediatric, adolescent, and young adult population. This cross-sectional study aimed to evaluate immune responses in this underrepresented population affected by various immunodeficiencies after SARS-CoV-2 infection, two doses of the mRNA BNT162b2 vaccine, or after a combination of both. We analyzed blood samples from 102 immunocompromised patients (IC) (5–25 years) categorized into groups of primary immunodeficiencies (PID, n=17), bronchial asthma and allergic rhinitis (BA-AR, n=39), rheumatoid diseases (RD, n=21), and individuals who had undergone hematopoietic stem cell transplantation (HSCT, n=28), as well as 30 healthy individuals (9–26 years). We measured titres of Spike-specific IgM, IgA, and IgG antibody classes (including IgG subclasses) in plasma using ELISA and evaluated their inhibitory potential in a Spike-ACE2 cell-based internalization assay. Spike-specific CD4 T-cells were examined using a flow cytometry-based proliferation assay (FASCIA). In the IC group, all participants except eight generated detectable levels of IgG antibodies. The IgG titres induced by vaccination (Geometric mean titre (GMT vac ) = 205023, 95% CI: 116074-362136) and a combination of vaccination and infection (GMT hyb = 172819, 95% CI: 33133-901403) were higher than after infection (GMT inf = 3323, 95% CI: 578-19109, P vac/inf = .006 and P hyb/inf = .001). On the other hand, the hybrid immunity induced the highest IgA titres (GMT hyb = 2672, 95% CI: 566-12623) compared to vaccination (GMP vac = 275, 95% CI: 97-777, P hyb/vac = .016) and infection (GMT inf = 60, 95% CI: 13-280, P hyb/inf = .002). The IgG titres in vaccinated and hybrid immunity groups strongly correlated (r Spearman = 0.86, P <.0001) with the levels of antibodies inhibiting the internalization of Spike protein (S protein) in a cell-based assay. Most IC patients (except five) also developed above-threshold Spike-specific CD4 T-cell responses, which were not statistically different from the responses in the healthy control group. Our data show that infection and vaccination can induce protective humoral or cellular responses against SARS-CoV-2 in IC patients. The activated cellular response in patients with agammaglobulinemia may assist them in overcoming viral infections.

MEHMO syndrome is a rare X-linked syndrome characterized by Mental retardation, Epilepsy, Hypogenitalism, Microcephaly, and Obesity associated with the defect of protein synthesis caused by the EIF2S3 gene mutations. We hypothesized that the defect in protein synthesis could have an impact on the immune system. We describe immunologic phenotype and possible treatment outcomes in patient with MEHMO syndrome carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. The proband (currently 9-year-old boy) had normal IgG and IgM levels, but had frequent respiratory and urinary tract infections. On subcutaneous immunoglobulin therapy achieving supra-physiological IgG levels the frequency of infections significantly decreased in Poisson regression by 54.5 % (CI 33.2-89.7, p=0.017). The MEHMO patient had had frequent acute infections despite normal IgG and IgM serum levels and responded well to the immunoglobulin treatment.

Allergic diseases have increased in developed countries during the past decades. A cohort of Slovak children was followed from birth to track allergic symptoms dynamics in early childhood. Information on allergic symptoms (atopic dermatitis = AD, rhino conjunctivitis = RC, wheezing = Wh, urticaria = Ur) and food allergies among children was based on clinical evaluation of children by allergists at three developmental stages (infant, toddler, preschool). Out of 320 cases of allergies, 64 infants, 145 toddlers, and 195 preschool children suffered from AD, RC, Wh, Ur, or their combinations (i.e., significant increase with age, p < 0.001). AD first appeared in infants, Wh and/or RC rose mainly in toddlers, and Ur among preschool children. AD in infants or toddlers disappeared in the subsequent developmental stage in approximately one third of all cases. Single AD persistence without remission or extension was not common and accounted only for 6.9% of AD infants’ allergic manifestations. In addition to single-symptom allergic diseases, this study also identified several combinations of atopic symptoms.Conclusions: The proportion of multi-symptom allergies increased while single-symptom forms decreased. The observed temporal trends of allergic symptoms correspond to the atopic march.What is Known:• The observed temporal trends of allergic symptoms correspond to the atopic march.What is New:• Allergic diseases in children were first manifested as single forms, with atopic dermatitis (AD) commonly functioning as the “entry point” to allergies.• The overall proportion of single-symptom allergic disorders decreased over time while the proportion of multi-symptom allergies increased.

Purpose Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. Methods The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. Results Of the 149 NBS patients, 91 (61 %), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin’s lymphomas), were diagnosed in 42 % of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35 %, respectively, and were significantly lower in patients with than without malignancies. Conclusions The extremely high incidence of malignancies, mostly non-Hodgkin’s lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.

Objective To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries. Methods Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire. Results Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients. Conclusions The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries.

Purpose Patients with (X-linked) agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications such as sepsis, meningoencephalitis and chronic lung disease. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for early detection of XLA via newborn screening (NBS). Our international multicenter survey study aimed to evaluate self-reported outcomes and parental perspectives in XLA patients to determine whether an early diagnosis is associated with better quality of life (QoL). Methods QoL-questionnaires included the PedsQL for children and SF-36, CVID_QOL, PADQOL-16 for adults. A new questionnaire was specifically developed for parents about an early diagnosis of XLA. Results In total, 88 adult and 65 pediatric XLA patients, and 69 parents from 14 countries completed the survey. Patients with an early diagnosis reported less severe, recurrent infections and less hospitalization ( p  < 0.05). QoL was significantly lower in multiple health domains for pediatric and adult patients with a late diagnosis compared to the general population. Patients with an early diagnosis reported similar QoL outcomes compared to the general population. Parents showed immense support for NBS for XLA stating that an early diagnosis prevents emotional insecurity, health damage, unnecessary diagnostics and allows early access to medical care and informed family planning. Conclusion Our study has shown supportive evidence to pursue an early diagnosis of XLA from both a self-reported clinical, health related QoL and parental perspective. The main plea from patients and parents is to achieve an early diagnosis for XLA and severe B-lymphocyte deficiencies with NBS.