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Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (T H ) cell differentiation are associated with risk of developing MS. However, the underlying mechanism by which these risk alleles influence MS susceptibility has remained elusive. Initiation of neuroinflammation in animal models of MS has been shown to be dependent on T H cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human T H cells with MS disease severity. GM-CSF is strongly induced by interleukin 2 (IL-2). We show that an MS-associated polymorphism in the IL-2 receptor alpha ( IL2RA ) gene specifically increases the frequency of GM-CSF-producing T H cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive T H cells and their propensity to develop into GM-CSF-producing memory T H cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of T H cells in MS. Genetic studies have connected polymorphisms in the IL-2 receptor alpha ( IL2RA ) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human T H cells.

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous -mutations including eight patients with the common p.Arg853 nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published -cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4 or CD8 T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of -associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. First‐line therapeutic regimens directed against activated immune cells or secreted cytokines show limited efficacy since they do not target the underlying immunological problem: defective lymphocyte cytotoxicity causing prolonged immune stimulation. A potential rescue strategy would be the adoptive transfer of ex vivo gene‐corrected autologous T cells. However, transfusion of cytotoxicity‐competent T cells under conditions of hyperinflammation may cause more harm than benefit. As a proof‐of‐concept for adoptive T cell therapy (ATCT) under hyperinflammatory conditions, we transferred syngeneic, cytotoxicity‐competent T cells into mice with virally triggered active primary HLH. ATCT with functional syngeneic trigger‐specific T cells cured Jinx mice from active HLH without life‐threatening side effects and protected Perforin ‐deficient mice from lethal HLH progression by reconstituting cytotoxicity. Cured mice were protected long‐term from HLH relapses. A threshold frequency of transferred T cells with functional differentiation was identified as a predictive biomarker for long‐term survival. This study is the first proof‐of‐concept for ATCT in active HLH. Synopsis Primary hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening syndrome characterized by hyperinflammation and caused by impaired lymphocyte cytotoxicity. We established adoptive immunotherapy in HLH animal models under conditions of hyperinflammation. Adoptive immunotherapy with virus‐specific T cells (ATCT) cured mice from virus‐triggered active primary HLH. ATCT was successful without life‐threatening side effects in two different primary HLH mouse models, in Jinx mice and Perforin‐deficient mice. Long‐term chimerism and “functional” differentiation of donor CD8 T cells in the recipients predicted therapeutic success of ATCT. Graphical Abstract Primary hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening syndrome characterized by hyperinflammation and caused by impaired lymphocyte cytotoxicity. We established adoptive immunotherapy in HLH animal models under conditions of hyperinflammation.

Chronic granulomatous disease (CGD) is a severe inborn error of immunity caused by NADPH oxidase defects. Here, we develop CRISPR/Cas9-based gene editing strategies for correction of variants in the CYBA and CYBB genes causing CGD. For X-linked CGD, we also develop a near-universal gene editing strategy by targeted integration of a truncated CYBB cDNA in CD34 + hematopoietic stem and progenitor cells (HSPCs). Throughout, off-target editing and chromosomal translocations are evident, which negatively impact the ability of gene-edited HSPCs to engraft in immunodeficient mice. However, by employing a high-fidelity Cas9 to minimize off-target editing, we demonstrate restoration of the multilineage engraftment potential of gene-edited HSPCs. Moreover, to further improve safety, we develop a D10A Cas9n editing approach with no detectable off-target activity or chromosomal translocations. Collectively, through risk assessments of different gene editing approaches, we present a D10A Cas9n-based strategy with improved safety, offering a potentially curative treatment for CGD patients. Gene editing of hematopoietic stem and progenitor cells offers promise as a curative treatment for chronic granulomatous disease (CGD). Here, the authors develop a D10A Cas9n based gene editing strategy to treat CGD with no detectable off-target activity or chromosomal translocations.

Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A–SLP2-A interaction and RAB27A–MUNC13-4 interaction, but it does not affect the RAB27A–melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A–MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics.

Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH). Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in , Fructose-1,6-bisphosphatase 1 and Acyl-CoA dehydrogenase family member 9 Variants in lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition. Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in and might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions.

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.

Fluctuations in the size of taurine cattle (Bos taurus) have been regularly demonstrated using archaeozoological data from across time and space in Europe, and have been linked to cultural, social and economic changes, but little is known about whether phenotypic change is accompanied by changes in genetic diversity. Here, we performed PCR-typed analysis of the partial mtDNA d-loop fragments of 99 cattle from the Neolithic to Early Medieval times from a number of different sites across Switzerland, combining newly presented data with previously published data (n = 20). We found that most cattle included (84) were members of the common European macro-haplogroup T3. However, cattle belonging to the haplogroups T1, T2, Q and P were identified as early as the Neolithic period, before 2690 cal. BCE. The highest diversity was found in the Neolithic period, during the 1st century CE and during the 7th–8th centuries CE. Bottleneck phases with low genetic diversity were detected during the Late Iron Age and from the fifth to the seventh century CE. Based on the FST values, Horgen, Corded Ware and cattle populations from the seventh to the ninth century CE were plotted away from the clusters of all other populations. The periods with larger-sized cattle correspond with those of high mtDNA d-loop diversity. Phenotype and genotype both appear to respond to the same socio-economic and cultural processes.

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ ΔKRKR ) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ ΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ ΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ ΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation. Here, the authors show that IFNγ binding to heparan sulfate is a mechanism to restrain IFNγ at the site of production, thereby preventing high systemic levels of this cytokine and associated immunopathology.