Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). The patients’ susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia

Vet du om det är någon som säljer hasch, någon som kan fixa weed? : En kvalitativ studie om individens upplevelse kring missbruk och nykterhet

Background: In 2017, there were 675,000 individuals aged 17–84 who reported that they had used drugs. Those with addictions are individuals who often encounter social work in one way or another. The contact can be established at an early age, before the abuse has started, and apply to problems surrounding divorced parents and parents with addiction, something that has been shown to have a connection with an individual's later addiction. Aim: The aim of the study is to investigate and create an increased understanding of sober alcoholics and drug addicts' perception of their lives. The aim is to put the interviewees life experiences in connection to their understandings of abusing alcohol and drugs. Method: The study is a qualitative interview study conducted on five people who all had substance abuse problems. The interviewees were chosen based on convenience and snowball sampling. Semi-structured interviews were held, and the analysis method hermeneutics was applied. Results: The study has shown how negative events in childhood can create anxiety and worry in individuals that can later be linked to addiction in adulthood. Conclusions: The development of an addiction can be linked to the availability of drugs, an individual's negative self-image and various types of deviant behaviour. Keywords: addiction, neglect in childhood, motivation, sobriety

Vet du om det är någon som säljer hasch, någon som kan fixa weed? : En kvalitativ studie om individens upplevelse kring missbruk och nykterhet

Background: In 2017, there were 675,000 individuals aged 17–84 who reported that they had used drugs. Those with addictions are individuals who often encounter social work in one way or another. The contact can be established at an early age, before the abuse has started, and apply to problems surrounding divorced parents and parents with addiction, something that has been shown to have a connection with an individual's later addiction. Aim: The aim of the study is to investigate and create an increased understanding of sober alcoholics and drug addicts' perception of their lives. The aim is to put the interviewees life experiences in connection to their understandings of abusing alcohol and drugs. Method: The study is a qualitative interview study conducted on five people who all had substance abuse problems. The interviewees were chosen based on convenience and snowball sampling. Semi-structured interviews were held, and the analysis method hermeneutics was applied. Results: The study has shown how negative events in childhood can create anxiety and worry in individuals that can later be linked to addiction in adulthood. Conclusions: The development of an addiction can be linked to the availability of drugs, an individual's negative self-image and various types of deviant behaviour. Keywords: addiction, neglect in childhood, motivation, sobriety

A role of Lck annular lipids in the steady upkeep of active Lck in T cells

Theoretical work suggests that collective spatiotemporal behaviour of integral membrane proteins (IMPs) can be modulated by annular lipids sheathing their hydrophobic moiety. Here, we present evidence for this prediction in a natural membrane by investigating the mechanism that maintains steady amount of active isoform of Lck kinase (Lck A ) by Lck trans-autophosphorylation offset by the phosphatase CD45. We gauged experimental suitability by quantitation of CD45 and Lck A subcellular localisation, Lck A generation as a function of Lck and pharmacological perturbation. Steady Lck A was challenged by swapping Lck membrane anchor with structurally divergent ones expected to substantially modify Lck annular lipids, such as that of Src or the transmembrane domains of LAT, CD4, palmitoylation-defective CD4 and CD45, respectively. The data showed only small alteration of Lck A , except for CD45 hydrophobic anchor that thwarted Lck A , due to excessive lateral proximity to CD45. The data are best explained by annular lipids facilitating or penalising IMPs’ lateral proximity, hence modulating IMPs protein-protein functional interactions. Our findings can contribute to improve the understanding of biomembranes’ organisation

Role of the membrane anchor in the regulation of Lck activity

International audienceTheoretical work suggests that collective spatiotemporal behaviour of integral membrane proteins (IMPs) should be modulated by boundary lipids sheathing their membrane anchors. Here, we show evidence for this prediction whilst investigating the mechanism for maintaining a steady amount of the active form of IMP Lck kinase (LckA) by Lck trans-autophosphorylation regulated by the phosphatase CD45. We used super-resolution microscopy, flow cytometry, and pharmacological and genetic perturbation to gain insight into the spatiotemporal context of this process. We found that LckA is generated exclusively at the plasma membrane, where CD45 maintains it in a ceaseless dynamic equilibrium with its unphosphorylated precursor. Steady LckA shows linear dependence, after an initial threshold, over a considerable range of Lck expression levels. This behaviour fits a phenomenological model of trans-autophosphorylation that becomes more efficient with increasing LckA. We then challenged steady LckA formation by genetically swapping the Lck membrane anchor with structurally divergent ones, such as that of Src or the transmembrane domains of LAT, CD4, palmitoylation-defective CD4 and CD45 that were expected to drastically modify Lck boundary lipids. We observed small but significant changes in LckA generation, except for the CD45 transmembrane domain that drastically reduced LckA due to its excessive lateral proximity to CD45. Comprehensively, LckA formation and maintenance can be best explained by lipid bilayer critical density fluctuations rather than liquid-ordered phase-separated nanodomains, as previously thought, with "like/unlike" boundary lipids driving dynamical proximity and remoteness of Lck with itself and with CD45

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature

Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αβT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency