Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs), conferring a predisposition to life-threatening COVID-19 pneumonia. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52/IκBδ).

Two Very Rare Cases of Metastatic Thymic Carcinoma with Sjogren's Syndrome: A Case Series.

Thymic tumours are rare thoracic malignancies with thymic carcinoma accounting for approximately 12% of all thymic tumours compared to thymomas which account for approximately 86%. Unlike thymomas, it is very rare for thymic carcinomas to be associated with autoimmune disorders or paraneoplastic syndromes. When these phenomena do occur, the vast majority are myasthenia gravis, pure red cell aplasia, or systemic lupus erythematous.

A cell-based functional assay that accurately links genotype to phenotype in familial HLH.

Familial forms of the severe immunoregulatory disease hemophagocytic lymphohistiocytosis (HLH) arise from biallelic mutations in the PRF1, UNC13D, STXBP2, and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding biallelic mutations in patients with HLH symptoms and reduced natural killer (NK)-cell cytotoxicity.

For whom the B cells toll.

Researchers have identified a new monogenic form of systemic lupus erythematosus caused by mutations that result in increased Toll-like receptor 7 (TLR7) signaling.

Standardized testing and written communication improve patient understanding of beta-lactam allergy testing outcomes: A multicenter, prospective study.

Background: Historical penicillin allergy is commonly reported, but the lack of standardized allergy clinic practices may diminish the ability to delabel beta-lactam allergy appropriately.

Objective: We sought to improve beta-lactam allergy testing and patient understanding of their antibiotic allergy status by standardizing testing and communication practices between 7 adult and pediatric hospital centers.

Methods: Phase 1 prospectively described the beta-lactam allergy testing practices at each center.

Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency.

Purpose: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients.

Cerebrospinal fluid free light chain quantitation is a specific biomarker for inflammatory neurological disorders in a paediatric patient cohort.

The analysis of cerebrospinal fluid (CSF) is routinely used in the diagnostic work-up of a range of inflammatory, infective, and congenital neurological conditions. Many diagnostic tests used in this analysis have poor sensitivity; as such, we investigated the utility of CSF free light chain (FLC) analysis as an adjunct to currently used assays in a paediatric population with neurological disorders. Kappa (κ) and lambda (λ) FLC levels were quantitated in blinded CSF samples by two nephelometric platforms.

Systemic lupus erythematosus presenting as Guillain-Barré syndrome.

A 37-year-old woman developed progressive symmetrical weakness with areflexia, consistent with Guillain-Barré syndrome. After initially briefly responding to intravenous immunoglobulin, her weakness progressed markedly. Further investigation identified a new diagnosis of systemic lupus erythematosus with lupus nephritis.

Molecular and cellular mechanisms underlying defective antibody responses.

Primary immune deficiency is caused by genetic mutations that result in immune dysfunction and subsequent susceptibility to infection. Over the last decade there has been a dramatic increase in the number of genetically defined causes of immune deficiency including those which affect B-cell function. This has not only identified critical nonredundant pathways that control the generation of protective antibody responses but also revealed that immunodeficiency and autoimmunity are often closely linked.

Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.

Background: Anti-programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immunotherapy is now routinely used to treat several cancers. Clinical trials have excluded several populations, including patients with solid organ transplant, HIV infection and hepatitis B/C infection. We examined the safety outcomes of these populations treated with anti-PD-1/PD-L1 treatment in a multicentre retrospective study.

Gastric Cancer Screening in Common Variable Immunodeficiency.

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications.

Germline-activating mutations in compromise B cell development and function.

Gain-of-function (GOF) mutations in , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery.

Signal Transducer and Activator of Transcription 3 Control of Human T and B Cell Responses.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of many key cytokine receptors expressed by lymphocytes. As such, it plays a critical role in regulating B cells as well as CD4 and CD8 T cells. Patients with clinically significant immunodeficiency and immune dysregulation resulting from loss-of-function or gain-of-function mutations in STAT3 have been described.

Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines.

STAT3 is a central regulator of lymphocyte differentiation and function.

Signalling in lymphocytes through cytokine receptors is critical for their development, activation and differentiation into effector cells that mediate protection against pathogens and provide the host with protective immunological memory. The essential role of cytokine signalling has been established not only by the generation and examination of gene-targeted mice, but also 'Experiments of Nature' whereby monogenic mutations cause primary immunodeficient conditions characterised by impaired immunity to infectious diseases due to compromised lymphocyte function. Mutations in STAT3 cause autosomal dominant hyper-IgE syndrome.