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Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

X‐linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro‐inflammatory signalling downstream of the nucleotide‐binding oligomerization domain containing (NOD)‐1 and ‐2 pattern recognition receptors. Mutations in XIAP cause X‐linked lymphoproliferative syndrome type‐2 (XLP2), an immunodeficiency associated with a potentially fatal deregulation of the immune system, whose aetiology is not well understood. Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2. We demonstrate that XLP2‐BIR2 mutations severely impair NOD1/2‐dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP‐deficient cell lines. XLP2‐BIR2 mutations abolish the XIAP‐RIPK2 interaction resulting in impaired ubiquitylation of RIPK2 and recruitment of linear ubiquitin chain assembly complex (LUBAC) to the NOD2‐complex. We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM‐binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a general defect in XLP2 and demonstrate that the XIAP BIR2‐RIPK2 interaction may be targeted pharmacologically to modulate inflammatory signalling. Graphical Abstract The X‐linked lymphoproliferative syndrome type‐2 is an immunodeficiency disease caused by mutations in the XIAP gene. BIR2 domain mutations in patients impair RIPK2 binding and NOD2‐dependent innate immune signaling, explaining some of the pathology.

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on a neonatal dried blood spot (DBS) by real-time PCR, which showed remarkably reduced T-cell receptor and kappa-deleting recombination excision circles (TREC/KREC). Retesting was delayed due to communication difficulties with the family. Whole exome sequencing on a new DBS confirmed the diagnosis. The newborn was a candidate for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment. HSCT is a complex procedure still ongoing in Ukraine despite the conflict. However, due to the psychosocial strain, the family sought medical support in Germany, where HSCT was performed successfully at 6 months. As part of a collaborative initiative with Italy, PNP biomarkers were quantified on the same DBSs using tandem mass spectrometry, according to the protocols established for SCID NBS in Tuscany, serving as a proof of concept of its diagnostic performance. This case highlights the importance of sustaining preventive and life-saving healthcare services, and reflects the key role of international partnerships in upholding the right to healthcare in times of crisis.

Phosphorene, a puckered 2D allotrope of phosphorus, has sparked considerable interest in recent years due to its potential especially for optoelectronic applications with its layer‐number‐dependant direct band gap and strongly bound excitons. However, detailed experimentalcharacterization of its intrinsic defects as well as its defect creation characteristics under electron irradiation are scarce. Here, the creation and stability of a variety of defect configurations under 60 kV electron irradiation in mono‐ and bilayer phosphorene are reported including the first experimental reports of stable adatom‐vacancy‐complexes. Displacement cross section measurements in bilayer phosphorene yield a value of 7.7 ± 1.4 barn with an estimated lifetime of adatom‐vacancy‐complexes of 19.9 ± 0.7 s, while some are stable for up to 68 s under continuous electron irradiation. Surprisingly, ab initio‐based simulations indicate that the complexes should readily recombine, even in structures strained by up to 3%. The presented results will help to improve the understanding of the wide variety of defects in phosphorene, their creation, and their stability, which may enable new pathways for defect engineered phosphorene devices. The stability of adatom‐vacancy‐complexes in mono‐ and bilayer phosphorene is shown via atomically‐resolved scanning transmission electron microscopy (STEM). With the help of density‐functional theory (DFT) simulations also several additional defect configurations were identified. Simulations are also used to understand defect dynamics. However, it remains unclear why the adatom‐vacancy‐complexes are stable.

Heterozygous mutations in lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and . Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by mutation carriers. The seroprevalence between affected and unaffected mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

[This corrects the article DOI: 10.3389/fimmu.2022.1011646.].

Inherited defects in MyD88 and IRAK4, two regulators in Toll-like receptor (TLR) signaling, are clinically highly relevant, but still incompletely understood. MyD88- and IRAK4-deficient patients are exceedingly susceptible to a narrow spectrum of pathogens, with ∼50% lethality in the first years of life. To better understand the underlying molecular and cellular characteristics that determine disease progression, we aimed at modeling the cellular response to pathogens in vitro . To this end, we determined the immunophenotype of monocytes and macrophages derived from MyD88- and IRAK4-deficient patients. We recognized that macrophages derived from both patients were particularly poorly activated by streptococci, indicating that both signaling intermediates are essential for the immune response to facultative pathogens. To characterize this defect in more detail, we generated induced pluripotent stem cells (iPSCs) of fibroblasts derived from an MyD88-deficient patient. The underlying genetic defect was corrected using Sleeping Beauty transposon vectors encoding either the long (L) or the short (S) MYD88 isoform, respectively. Macrophages derived from these iPSC lines (iMacs) expressed typical macrophage markers, stably produced either MyD88 isoform, and showed robust phagocytic activity. Notably, iMacs expressing MyD88-L, but not MyD88-S, exhibited similar responses to external stimuli, including cytokine release patterns, as compared to genetically normal iMacs. Thus, the two MyD88 isoforms assume distinct functions in signaling. In conclusion, iPSC technology, in combination with efficient myeloid differentiation protocols, provides a valuable and inexhaustible source of macrophages, which can be used for disease modeling. Moreover, iPSC-derived macrophages may eventually aid in stabilizing MyD88-deficient patients during pyogenic infections.