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The article presents the discussion on human immune system possessing two fundamental recognition mechanisms as part of acquired immunity to initiate antigen-specific responses against pathogens. Topics include providing insights into previous exposure to specific pathogens and the development of immune responses; and offering insights into existing protective immunity or vaccine efficacy assessment.

Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous CD70 missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Introduction Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. Methods and analysis The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité – Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 μg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. Ethics and dissemination The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité – Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. [ABSTRACT FROM AUTHOR]

Introduction: In 2015, 4062 unaccompanied minor refugees were registered in Berlin, Germany. According to national policies, basic clinical examination and tuberculosis (TB) screening is a prerequisite to admission to permanent accommodation and schooling for every refugee. This article evaluates the use of an interferon-γ-release-assay (IGRA) during the initial examination and TB screening of 970 unaccompanied minor refugees. Results: IGRA test were obtained during TB screening for 301 (31.0%) of 970 adolescents not previously screened for TB. Positive IGRA results were obtained in 13.9% (42/301). Most of the 42 IGRA-positive refugees originated from Afghanistan or Syria (n?20 and 10 respectively). Two IGRA-positive adolescents were lost to follow-up, 2 were diagnosed with TB and the remaining 38 diagnosed with latent TB infection (LTBI). Demographic features of the 40 patients with positive IGRA result were as follows: 39 male, median age 16.8 years (IQR 16.0–17.2y), none meeting underweight criteria (median BMI 21.3kg/m2). On initial chest X-ray 2/40 participants had signs of active TB, while in 38 active disease was excluded and the diagnosis of latent TB infection (LTBI) made. Active hepatitis B-co-infection was diagnosed in 3/38 patients. All patients with LTBI received Isoniazid and Rifampicin for 3 months without occurrence of severe adverse events. The most frequently observed side effect was transient upper abdominal pain (n = 5). Asymptomatic elevation of liver transaminases was seen in 2 patients. 29 patients completed treatment with no signs of TB disease at the end of chemoprevention and 9 were lost to follow up. Conclusion: Screening for TB infection in minor refugees was feasible in our setting with a relatively high rate of TB infection detected. Chemopreventive treatment was tolerated well regardless of underlying hepatitis-B-status. Minor refugees migrating to Germany should be screened for TB infection, instead of TB disease only, regardless of the background TB incidence. [ABSTRACT FROM AUTHOR]

The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect. [ABSTRACT FROM AUTHOR]

SIT is a transmembrane adapter protein that modulates signals emanating from the T-cell receptor (TCR). Here, we have used gene-targeted mice to assess the role of SIT for T-cell development and peripheral T-cell functions. SIT-/- double-positive thymocytes show an upregulation of the activation markers CD5 and CD69, suggesting that SIT negatively regulates TCR-mediated signals at the CD4+ CD8+ stage of thymic development. This assumption is further supported by the observation that in female H-Y TCR transgenic mice, positive selection is enhanced and even converted to negative selection. Similarly, mature peripheral T cells are hyperresponsive towards TCR-mediated stimuli and produce larger amounts of T-helper 1 (TH1) cytokines, and SIT-deficient mice show an increased susceptibility to develop experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. These results demonstrate that SIT is a critical negative regulator of TCR-mediated signaling and finely tunes the signals required for thymic selection and peripheral T-cell activation. [ABSTRACT FROM AUTHOR]

Genetic predisposition and environmental factors modulate the expression of allergic phenotypes. The frequent allergic phenotype 'immediate cutaneous hypersensitivity' was established in mice as a model for atopy. Genetic dissection of this trait requires a robust procedure to assess the allergic phenotype. To this end, different mouse strains were immunized with birch pollen extract. Immediate cutaneous hypersensitivity reactions were induced through intradermal allergen exposure. Wheel formation was quantitated and expressed as a hypersensitivity score according to the bonitur method. This procedure identified A/J and C57BL/6 mice as high– and low–responder strains, respectively. Crosses of A/J and C57BL/6 mice should allow the characterization of mendelian factors responsible for the two extreme phenotypes identified here. [ABSTRACT FROM AUTHOR]

Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families. [ABSTRACT FROM AUTHOR]

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B‐cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa‐deleting‐recombination‐excision circles (KRECs) reliably identifies classical X‐linked agammaglobulinaemia (XLA) patients with profound B‐cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B‐cell lymphopenia with residual B‐cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B‐cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B‐cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size. [ABSTRACT FROM AUTHOR]

The transmembrane adaptor molecule TRIM is strongly expressed within thymus and in peripheral CD4+ T cells. Previous studies suggested that TRIM is an integral component of the T-cell receptor (TCR)/CD3 complex and might be involved in regulating TCR cycling. To elucidate the in vivo function of TRIM, we generated TRIM-deficient mice by homologous recombination. TRIM-/- mice develop normally and are healthy and fertile. However, the animals show a mild reduction in body weight that appears to be due to a decrease in the size and/or cellularity of many organs. The morphology and anatomy of nonlymphoid as well as primary and secondary lymphoid organs is normal. The frequency of thymocyte and peripheral T-cell subsets does not differ from control littermates. In addition, a detailed analysis of lymphocyte development revealed that TRIM is not required for either positive or negative selection. Although TRIM-/- CD4+ T cells showed an augmented phosphorylation of the serine/threonine kinase Akt, the in vitro characterization of peripheral T cells indicated that proliferation, survival, activation-induced cell death, migration, adhesion, TCR internalization and recycling, TCR-mediated calcium fluxes, tyrosine phosphorylation, and mitogen-activated protein family kinase activation are not affected in the absence of TRIM. Similarly, the in vivo immune response to T-dependent and T-independent antigens as well as the clinical course of experimental autoimmune encephalomyelitis, a complex Th1-mediated autoimmune model, is comparable to that of wild-type animals. Collectively, these results demonstrate that TRIM is dispensable for T-cell development and peripheral immune functions. The lack of an evident phenotype could indicate that TRIM shares redundant functions with other transmembrane adaptors involved in regulating the immune response. [ABSTRACT FROM AUTHOR]

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete. [ABSTRACT FROM AUTHOR]

In Germany community-acquired Legionnaires' disease is usually caused by the species Legionella pneumophila. Recurrent cases of Legionnaires' disease are rarely reported and are due either to a second infection (reinfection) or a relapse of a previous case. We report a case of recurrent Legionnaires' disease in an 86-year-old female patient infected with Legionella pneumophila serogroup 1, monoclonal antibody-subtype Knoxville, sequence type unknown. Between the two disease incidents the patient had completely recovered. Legionella pneumophila was detected with the monoclonal antibody-subtype Knoxville, sequence type 182, in the drinking water of the patient's apartment. Exposure to contaminated drinking water was interrupted after the first incident exposure through the application of point-of-use water filters. The filters were later removed due to low water pressure, and the second illness occurred thereafter. It is unclear if immunological predisposition has contributed to this case of probable reinfection of Legionnaires' disease. Clinical, microbiological and epidemiological information combined suggest this is a case of reinfection of Legionnaires' disease. In cases of recurrent Legionnaires' disease complete collection of patient and water samples is necessary to differentiate relapse from reinfection cases, to implicate the source of infection and to gain more evidence for the role of immunological predisposition. [ABSTRACT FROM AUTHOR]

Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2–q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs∗16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome. [Copyright &y& Elsevier]