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Objective: The p.E148Q variant in pyrin is present in different populations at a frequency of up to 29%, and has been associated with diseases, including vasculitis and FMF. The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, pathogenic mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines., Methods: We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC), which were analysed by flow cytometry to visualize inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome-dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors., Results: In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harboured the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1β and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation., Conclusion: The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The objective was to review COVID-19 vaccine allergy advice and guidance requests received and assess the impact of advice outcome on vaccination outcome., Design: A retrospective analysis of requests for advice and guidance regarding COVID-19 vaccine allergy was completed using an electronic referral system from February 2021 to January 2022., Participants: A total of 1265 independent patient requests for advice were received from primary care. Full vaccination information was available on 1210 patients who were included in the analysis., Main Outcome Measures: We evaluated the specific outcome of request for advice (written advice versus allergy consultation), rate of vaccination, vaccination combinations, and tolerance of vaccination., Results: Of the 1210 patients included, 959 (79%) were female. Eight hundred and ninety-six (74%) requests were managed with written advice only and of these 675 (75%) patients went on to be vaccinated. Overall, 891 (74%) of the population were vaccinated with 2 or more doses.Two hundred and nineteen patient consultations were undertaken with 109 (50%) prior to the first vaccination. Forty-nine (45%) consultations prior to vaccination were undertaken due to a label of anaphylaxis to vaccination in the past. Vaccination was recommended for all patients, and 78 (72%) of these received a first dose. Eight of these patients (10%) had symptoms within 1 h of vaccine administration.One hundred and ten (50%) consultations were undertaken for adverse reactions post COVID-19 vaccination, with 84 (76%) concerning immediate symptoms. Thirty patients (27%) who had a consultation had had adrenaline administered post vaccination. One patient had biopsy confirmed Stevens Johnson Syndrome and was referred to Dermatology. All others due for further doses (107 patients) were recommended to have subsequent doses with 49 (45%) offered the same vaccine. Eighty-nine patients had a vaccine administered post adverse reaction and 79 (88%) tolerated the dose.Skin testing and challenge to polyethylene glycol were negative in the 8 patients tested., Conclusions: Over 1000 requests for advice and guidance were received during the review period, managed mainly with written advice. The overwhelming majority of requests for advice and consultations were for females, with equal distribution both pre- and post-COVID-19 vaccine administration. Vaccination was recommended in all but 1 patient (with biopsy confirmed Stevens Johnson Syndrome). Polyethylene glycol allergy was not confirmed in any patient, nor did any patient have confirmed anaphylaxis when the vaccine was administered under our supervision, suggesting that type 1 mediated hypersensitivity is uncommon even in this "high risk" population., (© 2022 The Authors.)

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: B cells play an important role in protection against viral infections, not only through the production of antibodies but also through their ability to act as antigen-presenting cells and produce cytokines., Objectives: To assess whether there is a link between low circulating B-cell counts and a predisposition to viral infections in immunocompromised individuals, we performed a retrospective cohort analysis at 2 National Health Service Clinical Immunology sites in England., Methods: Eligible patients were adults who were either diagnosed with or under investigation for an immunodeficiency and had recorded circulating B-cell counts. Information on viral infections was collected by using the departmental, hospital, and laboratory electronic information systems. A generalized linear model was used to analyze the relationship between B-cell counts and relevant indices of viral infection while controlling for patient age, diagnosis group, and T-cell and natural killer cell counts., Results: A total of 376 eligible patients were identified, 134 of whom had B-cell counts that were below the laboratory-defined refence range (<0.11 ×10 9 /L). Patients with low numbers of circulating B cells had lower pretreatment immunoglobulin levels and poorer antibody responses to vaccines ( Streptococcus pneumonia , Clostridium tetani, and Haemophilus influenzae type B ). An increased number of chronic or recurrent ( P  = .001), severe or unusual ( P  = .001), and PCR-confirmed viral infections ( P  = .04) were recorded in these patients versus in those with normal numbers of circulating B cells., Conclusion: Overall, there was a statistically significant association between low circulating B-cell counts and the incidence of clinically important viral infections in this patient cohort, even when controlling for relevant covariates. Clinicians caring for patients with immunodeficiency should be vigilant for these types of infections, particularly in patients with low peripheral B-cell counts. A prospective study will be required to confirm these findings., (© 2022 The Author(s).)

Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.

Purpose: NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis., Methods: Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal., Results: A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305., Conclusion: NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis., (© 2021. The Author(s).)