University of Iowa professor of microbiology and immunology Gail Bishop has been named a fellow of the American Association for the Advancement of Science for her work in the field of immunology.

After a long career in science, University of Iowa professor of microbiology and immunology Gail Bishop was named a 2019 fellow of the American Association for the Advancement of Science after nomination from her peers.

Bishop has worked at the UI for 30 years and studied T and B lymphocytes, which are white blood cells that moderate the bodys defense against pathogens. Through her work, she discovered one of the molecules she was studying was important in preventing a certain type of lymphocyte from turning into a tumor.

Bishop first came to the UI in 1989 as an assistant professor and became active in the cancer center. She was then named the Associate Director for Basic Science Research in the Holden Comprehensive Cancer Center.

The lymphocytes she studies are the microbes in the body that remember what immunizing factors they encounter through vaccinations or natural infection, Bishop said. She is interested in signals the lymphocytes get from other cells and environmental cues that regulate an immune response, she said.

Her research on B lymphocytes led her to her work in the cancer center, Bishop said. Using mouse models, she and the research team removed the molecule that regulates the amount of B lymphocytes in the mouses system, she said.

The mice had large lymph nodes and developed a type of tumor called cell lymphoma, which is the most common type of white blood cell cancer in humans, Bishop said.

Related: UI professor receives grant to train medical field in collaboration with language interpreters

I think you have to really enjoy the science itself and not be in it for prizes or fame or anything like that, Bishop said, because although those things do occasionally come, theyre so intermittent and so unpredictable that if that was your goal, youd be miserable all the time.

Through her time as a researcher, a number of people have worked in her lab. Bruce Hostager, a current researcher in her lab, started working with Bishop when he was a postdoctoral student and has been working with her continuously for 25 years.

Through his time working with Bishop, Hostager has seen the way they conduct research change, he said. The technology used in editing the genetics in mice models has evolved to make their work easier, he added.

Her research is one thing that shes being recognized for, but also for some of her service to the scientific community, both nationally and here at the university, Hostager said.

Stanley Perlman, one of Bishops colleagues at the UI, nominated her to be honored as a fellow in the American Association for the Advancement of Science because of her contributes to immunology.

There is not a large number of women working in biology, Perlman said. More and more women are working in biology at the college level, but as you go up the hierarchy there are a lot of men, he added.

Seeing Bishop be honored as a fellow of the American Association for the Advancement of Science may allow her to serve as a role model for women in science, Perlman said.

I just think recognizing Gails talents and contributions is important, even without it being a role model for anyone or affecting anyone else, Perlman said.

Read more here:
University of Iowa professor honored for her work in immunology - UI The Daily Iowan

Interferon Insight

Uncontrolled type I IFN activity has been linked to several human pathologies, but evidence implicating this cytokine response directly in disease has been limited. Here, Duncan et al. identified a homozygous missense mutation in STAT2 in siblings with severe early-onset autoinflammatory disease and elevated IFN activity. STAT2 is a transcription factor that functions downstream of IFN, and this STAT2R148W variant was associated with elevated responses to IFN/ and prolonged JAK-STAT signaling. Unlike wild-type STAT2, the STAT2R148W variant could not interact with ubiquitin-specific protease 18, which prevented STAT2-dependent negative regulation of IFN/ signaling. These findings provide insight into the role of STAT2 in regulating IFN/ signaling in humans.

Excessive type I interferon (IFN/) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN/, which manifest as prolonged Janus kinasesignal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN/ signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN/ signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN/ activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Type I interferons (including IFN/) are antiviral cytokines with pleiotropic functions in the regulation of cellular proliferation, death, and activation. Reflecting their medical importance, type I IFNs have been shown to be essential to antiviral immunity in humans (1), whereas their potent immunomodulatory effects have been exploited to treat both cancer and multiple sclerosis (2, 3).

IFN/ also demonstrates considerable potential for toxicity, which became apparent in initial studies in rodents (4) and subsequent clinical experience in patients (5, 6). Thus, the production of and response to type I IFNs must be tightly controlled (7). Transcriptional biomarker studies increasingly implicate dysregulated IFN/ activity in a diverse spectrum of pathologies ranging from autoimmune to neurological, infectious and vascular diseases (811).

The immunopathogenic potential of IFN/ is exemplified by a group of monogenic inborn errors of immunity termed type 1 interferonopathies, wherein enhanced IFN/ production is hypothesized to be directly causal (12). Neurological disease is typical of these disorders, which manifest as defects of neurodevelopment in association with intracranial calcification and white matter changes on neuroimaging, suggesting that the brain is particularly vulnerable to the effects of excessive type I IFN activity (9). A spectrum of clinical severity is recognized, from prenatal-onset neuroinflammatory disease that mimics in utero viral infectionAicardi-Goutires syndrome (13)to a clinically silent elevation of IFN activity (14).

However, the central tenet of the type I interferonopathy hypothesis, namely, the critical pathogenic role of type I IFNs (12), has yet to be formally established (15). Evidence for an IFN-independent component to disease includes (i) recognition that other proinflammatory cytokines are also induced by nucleic acid sensing, which might contribute to pathogenesis (16); (ii) imperfect correlations between IFN biomarker status and disease penetrance (14); (iii) the absence of neuropathology in mouse models of Aicardi-Goutires syndrome despite signatures of increased IFN activity (17); and (iv) the observation that crossing to a type I IFN receptor deficient background does not rescue the phenotype in certain genotypes (e.g., STING and ADAR1) (18, 19), although it does in others (e.g., TREX1 or USP18) (20, 21). Here, we provide concrete evidence of the pathogenicity of type I IFNs in humans, shedding new light on the critical importance of signal transducer and activator of transcription 2 (STAT2) in the negative regulation of this pathway.

We evaluated two male siblings, born in the United Kingdom to second cousin Pakistani parents. Briefly, patient II:3, born at 34 weeks + 6 days with transient neonatal thrombocytopenia, was investigated for neurodevelopmental delay at 6 months (which was attributed to compensated hypothyroidism). Aged 8 months, he presented with the first of three episodes of marked neuroinflammatory disease, associated with progressive intracranial calcification, white matter disease, and, by 18 months, intracranial hemorrhage (Fig. 1A). These episodes were associated with systemic inflammation and multiorgan dysfunction, including recurrent fever, hepatosplenomegaly, cytopenia with marked thrombocytopenia, raised ferritin, and elevated liver enzymes. Latterly, acute kidney injury with hypertension and nephrotic range proteinuria developed (see Table 1, Supplementary case summary, and table S1).

(A) Neuroimaging demonstrating calcifications [brainstem/hypothalamus (proband II:3, top), cerebral white matter/basal ganglia/midbrain/optic tract (sibling II:4, top and middle)], hemorrhages [occipital/subdural/subarachnoid (proband II:3, middle)], and cerebral white matter and cerebellar signal abnormality with parenchymal volume loss (both, bottom), accompanied by focal cystic change and cerebellar atrophy (sibling II:4). (B) Whole blood RNA-seq ISG profiles: controls (n = 5); proband II:3 (n = 4); and patients with mutations in: TREX1 (n = 6), RNASEH2A (n = 3), RNASEH2B (n = 7), RNASEH2C (n = 5), SAMHD1 (n = 5), ADAR1 (n = 4), IFIH1 (n = 2), ACP5 (n = 3), TMEM173 (n = 3), and DNASE2 (n = 3). (C) IFN scores (RT-PCR) of patients, parents, and n = 29 healthy controls. ****P < 0.001, ANOVA with Dunnetts posttest. (D) Renal histopathology in proband (400 magnification) showing TMA with extensive double contouring of capillary walls (silver stain, top left); endothelial swelling, mesangiolysis, and red cell fragmentation (top right); arteriolar fibrinoid necrosis (bottom left); and myxoid intimal thickening of an interlobular artery (bottom right, all hematoxylin and eosin). (E) Transcriptional response to JAK inhibitor (JAKi) ruxolitinib in both patients (RT-PCR).

HLH, hemophagocytic lymphohistiocytosis; EEG, electroencephalogram.

This clinical phenotype was reminiscent of a particularly severe form of type I interferonopathy. In keeping with this observation, IFN-stimulated gene (ISG) transcripts in whole blood, measured by RNA sequencing (RNA-seq) and reverse transcription polymerase chain reaction (RT-PCR), were substantially elevated over multiple time points at similar magnitudes to recognized type I interferonopathies (Fig. 1, B and C), notably without evidence of concomitant induction of IFN-independent inflammatory pathways (fig. S1). Disease in the proband, which not only met the diagnostic criteria for hemophagocytosis but also included features of a thrombotic microangiopathy (TMA) (Fig. 1D), was partially responsive to dexamethasone and stabilized with the addition of the Janus kinase (JAK) inhibitor ruxolitinib (Fig. 1E and fig. S2). Sadly, however, this child succumbed to overwhelming Gram-negative bacterial sepsis during hematopoietic stem cell transplantation.

Patient II:4, his infant brother, presented with abnormal neurodevelopment and neuroimaging in the neonatal period, characterized by apneic episodes from 3 weeks of age in conjunction with parenchymal calcifications and hemorrhage, abnormal cerebral white matter, and brainstem and cerebellar atrophy (Fig. 1A). Blood tests revealed an elevated ISG score (Fig. 1, B and C), anemia, elevation of D-dimers, and red cell fragmentation on blood film, together with proteinuria and borderline elevations of ferritin and lactate dehydrogenase; renal function was normal, and blood pressure was on the upper limit of the normal range for gestational age. Introduction of ruxolitinib led to prompt suppression of ISG expression in whole blood (Fig. 1E) and an initial reduction in apneic episodes, but neurological damage was irretrievable, and he succumbed to disease at 3 months of age. Mothers pregnancy with patient II:4 had been complicated by influenza B at 23 weeks gestation.

Whole-exome sequencing analysis of genomic DNA from the kindred, confirmed by Sanger sequencing (Fig. 2, A and B), identified an extremely rare variant in STAT2 (c.442C>T), which substituted tryptophan for arginine at position 148 in the coiled-coil domain (CCD) of STAT2 (p.Arg148Trp, Fig. 2C). The Arg148Trp variant was present in the homozygous state in both affected children and was heterozygous in each parent and one healthy sibling, consistent with segregation of an autosomal recessive trait (table S2). This variant was found in the heterozygous state at extremely low frequency in publicly available databases of genomic variation [frequency < 0.00001 in Genome Aggregation Database (22)], and no homozygotes were reported. A basic amino acid, particularly arginine, at position 148 is highly conserved (fig. S3). In silico tools predicted that this missense substitution was probably deleterious to protein function (table S2). STAT2 protein expression in patient cells was unaffected by the Arg148Trp variant, in contrast to the situation for pathogenic loss-of-expression STAT2 variants, which resulted in a distinct phenotype of heightened viral susceptibility (Fig. 2D) (23, 24). Filtering of exome data identified an additional recessive variant in CFH (c.2336A>G and p.Tyr779Cys; fig. S4) present in the homozygous state in II:3 but absent from II:4. We considered the possibility that this contributed to TMA in the proband, but functional studies of this variant showed negligible impact on factor H function (fig. S5).

(A) Pedigree, (B) capillary sequencing verification, (C) protein map, and (D) immunoblot (fibroblasts) showing normal expression of STAT2 protein. DBD, DNA binding domain; LD, linker domain; SH2, Src homology 2 domain; TAD, trans-activation domain.

The transcription factor STAT2 is essential for transcriptional activation downstream of the receptors for the innate IFN-/ (IFNAR) and IFN- and their associated JAK adaptor proteins. In the current paradigm (25), STAT2 is activated by tyrosine phosphorylation, associated with IFN regulatory factor 9 (IRF9) and phosphorylated STAT1 (pSTAT1) to form the IFN-stimulated gene factor 3 (ISGF3) to effect gene transcription by binding to IFN-stimulated response elements in the promoters of ISGs. Although loss-of-function variants in STAT2 increase susceptibility to viral disease (23, 24), evidence here suggested pathological activation. Germline gain-of-function variants have been reported in STAT1 (26, 27) and STAT3 (28, 29) but not hitherto STAT2. Consistent with the apparent gain of IFN activity associated with mutant STAT2R148W, we observed in patient fibroblasts (Fig. 3, A and B) and peripheral blood mononuclear cells (PBMCs; fig. S6) the enhanced expression of ISG protein products across a range of IFN concentrations. However, basal and induced production of IFNB mRNA by fibroblasts was indistinguishable from controls (Fig. 3C); nor was IFN protein substantially elevated in patient samples of cerebrospinal fluid (II:3) or plasma (II:4) as measured by a highly sensitive digital enzyme-linked immunosorbent assay (ELISA) assay (30), albeit samples were acquired during treatment (table S3). Thus, the response to type I IFNs, but not their synthesis, was exaggerated. This heightened IFN sensitivity was accompanied by enhancement of key effector functions, as revealed by assays of IFN-mediated viral protection (Fig. 3D) and cytotoxicity (Fig. 3E). Collectively, these data indicated that STAT2R148W was not constitutively active but rather resulted in an exaggerated response upon IFN exposure. To confirm that the Arg148Trp variant was responsible for this cellular phenotype, we transduced STAT2-null U6A cells (31) and STAT2-deficient primary fibroblasts (23) with lentiviruses encoding either wild type (WT) or STAT2R148W, recapitulating the heightened sensitivity of cells expressing the latter to IFN (Fig. 3, F and G, and fig. S7).

Unless stated, all data are from patient II:3 and control fibroblasts. (A) ISG expression (immunoblot, IFN for 24 hours) and (B) densitometry analysis (n = 3, t test). MX1, MX dynamin like GTPase 1; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; RSAD2, radical S-adenosyl methionine domain containing 2. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (C) IFNB mRNA (RT-PCR) external polyinosinic:polycytidylic acid (poly I:C) treatment (25 g/ml for 4 hours; n = 3, t test). US, unstimulated. (D) Antiviral protection assay (mCherry-PIV5). Twofold dilutions from IFN (16 IU/ml), IFN (160 IU/ml) n = 7 replicates, representative of n = 2 experiments (two-way ANOVA with Sidaks posttest). (E) Cytopathicity assay (IFN for 72 hours; n = 3, t test). (F) As in (A), ISG expression in STAT2/ U6A cells reconstituted with STAT2WT or STAT2R148W (immunoblot, IFN for 24 hours). (G) As in (B), n = 3 to 4, t test. Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., nonsignificant.

To explore the underlying mechanism for heightened type I IFN sensitivity, we first probed STAT2 activation in IFN-stimulated fibroblasts. In control lysates, levels of pSTAT2 had almost returned to baseline between 6 and 24 hours of treatment despite the continued presence of IFN (Fig. 4, A and B). In contrast, pSTAT2 persisted for up to 48 hours in patient cells. This abnormally prolonged pSTAT2 response to IFN was also observed in PBMCs of both patients (fig. S8). Consistent with immunoblot data, immunofluorescence analysis showed persistent ( 6 hours) nuclear localization of STAT2 in patient fibroblasts after IFN treatment, at times when STAT2 staining was predominantly cytoplasmic in control cells (Fig. 4, C and D, and fig. S9). This was accompanied by continued expression of ISG transcripts for 36 hours after the washout of IFN in patient cells as measured by RNA-seq and RT-PCR (Fig. 4, E and F). Thus, the type I IFN hypersensitivity of patient cells was linked to prolonged IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) pSTAT2 time course [immunoblot, IFN (1000 IU/ml)] and (B) densitometry analysis (n = 5 experiments, two-way ANOVA with Sidaks posttest). (C) Immunofluorescence analysis [IFN (1000 IU/ml); scale bar, 100 m; representative of n = 3 experiments] with (D) image analysis of STAT2 nuclear translocation (n = 100 cells per condition, ANOVA with Sidaks posttest). A.U., arbitrary units. (E) RNA-seq analysis of IFN-regulated genes (n = 3 controls) with (F) validation by RT-PCR (n = 3, two-way ANOVA with Sidaks posttest). CPM, read counts per million. (G) pSTAT2 decay (immunoblot). IFN (1000 IU/ml; 30 min) followed by extensive washing and treatment with 500 nM staurosporine (STAU). Times relative to STAU treatment. (H) No significant differences by densitometry analysis (n = 3, t test). Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

The IFNAR signaling pathway is subject to multiple layers of negative regulation that target STAT phosphorylation directlythrough the action of tyrosine phosphatasesor indirectly by disrupting upstream signal transduction (7). Prolonged tyrosine phosphorylation is reported with gain-of-function mutations in STAT1, in association with impaired sensitivity to phosphatase activity (27). By contrast, we observed no impairment of dephosphorylation of STAT2R148W in pulse-chase assays with the kinase inhibitor staurosporine (Fig. 4, G and H), implying instead a failure of negative feedback upon the proximal signaling events that generate pSTAT2.

To localize this defect, we analyzed by phosflow and immunoblot the successive activation steps downstream of IFNAR ligand binding in Epstein-Barr virus (EBV)transformed B cells from the proband (II:3) and a heterozygous parent (I:2). As was the case for STAT2 phosphorylation, we also observed prolonged phosphorylation of both JAK1 and STAT1 after IFN treatment (Fig. 5, A to D). This points to a defect in regulation of the most proximal IFNAR signaling events, upstream of STAT2 (7). We observed no evidence of this phenotype in cells bearing STAT2R148W in the heterozygous state, consistent with autosomal recessive inheritance and the lack of clinical disease or up-regulation of IFN activity in heterozygous carriers. This genetic architecture provides a notable contrast to gain-of-function mutations affecting other STAT proteins, all of which are manifest in the heterozygous state (2629).

Time course of IFN stimulation (1000 IU/ml) in EBV B cells from patient II:3 [homozygous (hom)], parent I:2 [heterozygous (het)], and n = 3 controls. (A) Immunoblot and (B) densitometry analyses. (C) Representative histograms (flow cytometry) and (D) mean fluorescence intensity (MFI). Data are means SEM of three repeat experiments (*P < 0.05, **P < 0.01, t test).

Known negative regulators of IFNAR signaling are suppressor of cytokine signaling (SOCS) 1 and SOCS3 (32) and the ubiquitin-specific protease 18 (USP18) (33). SOCS1 and SOCS3 participate in regulation of additional JAK-STAT signaling pathways, such as those activated by IFN and interleukin 6 (IL-6) (34, 35), whereas USP18 acts specifically upon IFNAR signaling (33). To better localize the molecular defect in patient cells, we examined the signaling responses to IFN (STAT1 phosphorylation) and IL-6 (STAT3 phosphorylation), based on the prediction that defects of SOCS1 or SOCS3 regulation would manifest under these conditions. These experiments revealed that regulation of STAT1 and STAT3 phosphorylation was normal in patient fibroblasts (fig. S10). Together with the absence of evidence of up-regulation of the IFN and IL-6 pathways in the analysis of whole blood RNA-seq data (fig. S1), these observations effectively ruled out the involvement of SOCS1 and SOCS3 in the clinical phenotype, leading us to suspect a defect of USP18 regulation.

To investigate this possibility, we primed patient and control cells with IFN for 12 hours, washed them extensively, and rested and restimulated them with IFN or IFN after 48 hours. In these experiments, IFN-induced pSTAT2 and pSTAT1 were strongly inhibited by priming in control cells, consistent with desensitization, a well-established phenomenon of type I IFN biology (Fig. 6, A and B) (36). In marked contrast, the response to IFN restimulation in patient cells was minimally suppressed, indicating a failure of desensitization. Desensitization has been shown to be exclusively mediated by USP18, an IFN-induced isopeptidase (37), through its displacement of JAK1 from the receptor subunit IFNAR2 (38, 39)a function that is independent of its isopeptidase activity toward the ubiquitin-like protein ISG15 (33). STAT2 plays a critical role as an adaptor protein by supporting binding of USP18 to IFNAR2 (Fig. 6C) (40). Both the clinical and cellular effects of STAT2R148W resemble homozygous USP18 deficiency, which was recently described as the molecular cause of a severe pseudo-TORCH syndrome associated with elevated type I IFN expression (table S4) (41). Although this STAT2:USP18 interaction has been shown to be essential for negative regulation of type I IFN signaling in vitro (40), its significance in vivo has not previously been examined. Furthermore, the precise residue(s) of STAT2 that bind USP18 were unresolved, although this interaction had been localized to a region including the CCD and/or DNA binding domain(s) of STAT2 (40).

(A) Desensitization assay (immunoblot, fibroblasts) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 4, ANOVA with Sidaks posttest). (C) Schematic of USP18 mechanism of action and proposed model of STAT2R148W pathomechanism. (D) Modeling of exposed WT (R148)/mutant (W148) residue, demonstrating charge-change (blue, positive; red, negative) and possible steric restriction. (E) Coimmunoprecipitation of USP18 by STAT2 in U6A cells expressing STAT2WT or STAT2R148W with (F) densitometry analysis (USP18/STAT2, ratio to WT; one-sample t test). Data are means SEM (**P < 0.01, ****P < 0.0001). IB, immunoblot.

Because USP18 was induced normally in patient cells (Fig. 6, A and B) and in vivo (Fig. 1B), our data implied that STAT2R148W impedes the proper interaction of STAT2 with USP18, compromising its regulatory function (Fig. 6C). Molecular modeling of STAT2R148W placed the substituted bulky aromatic tryptophan, and resulting charge change, at an exposed site within the CCD (Fig. 6D). Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, coimmunoprecipitation experiments in U6A cells stably expressing WT or STAT2R148W demonstrated a statistical significance reduction of USP18 pull down STAT2R148W compared with WT (Fig. 6, E and F), providing a molecular mechanism for the USP18 insensitivity of patient cells.

Although disruption to the STAT2R148W:USP18 interaction was the most plausible explanation for the clinical and molecular phenotype, we also considered the contribution of alternative regulatory functions of STAT2. Beyond the role of tyrosine phosphorylated STAT2 in innate IFN signal transduction, the unphosphorylated form of STAT2 (uSTAT2) has additional, recently described functions in the regulation of other cytokine signaling pathways. For example, uSTAT2 negatively regulates the activity of IFN (and other inflammatory cytokines that signal via STAT1 homodimers) by binding to uSTAT1 via its CCD (42). This interaction appears to limit the pool of STAT1 available for incorporation into transcriptionally active (tyrosine phosphorylated) STAT1 homodimers. Conversely, uSTAT2, induced by type I IFN signaling, has been reported to promote the transcriptional induction of IL6 through an interaction with the nuclear factor B subunit p65 (43). To investigate the potential relevance of these regulatory functions of STAT2, we first examined the induction of IL6 by RT-PCR analysis of RNA isolated from whole blood of patients, their heterozygous parents, and healthy controls. We found no evidence of increased expression of IL6 or its target gene SOCS3 (fig. S11, A and B), consistent with our previous pathway analysis of RNA-seq data (fig. S1) and implying that STAT2R148W does not influence IL-6 induction. Next, to explore any impact on STAT2s negative regulatory activity toward STAT1, we examined the transcriptional responses to IFN in patient fibroblasts and in U6A cells expressing STAT2R148W. Although we were able to reproduce the previously reported findings of heightened transcription of the IFN-regulated gene CXCL10 in U6A cells lacking STAT2, alongside a nonsignificant trend for IRF1 (fig. S12, A and B) (42), STAT2R148W did not enhance transcript levels of either CXCL10 or IRF1 above WT, in agreement with the data showing the preserved ability of STAT2R148W to bind STAT1 in a coimmunoprecipitation assay (fig. S12, C and D). Together, these studies effectively exclude a contribution of the USP18-independent regulatory functions of STAT2 to the disease phenotype.

To conclusively demonstrate the impairment of STAT2:USP18-mediated negative regulation in patient cells, we tested the impact of overexpression or knockdown of USP18. First, we probed IFNAR responses in fibroblasts stably expressing USP18. As predicted, USP18 was significantly impaired in its ability to suppress IFN signaling in patient cells, relative to controls, both in terms of STAT phosphorylation (Fig. 7, A and B) and STAT2 nuclear translocation (Fig. 7, C and D), recapitulating our prior observations with IFN priming (Fig. 6A). The reciprocal experiment, in which USP18 expression was stably knocked down using short hairpin RNA (shRNA), revealed significantly prolonged STAT2 phosphorylation in control cells at 24 hours, recapitulating the phenotype of patient cells (Fig. 7, E and F). In contrast, there was no effect of USP18 knockdown in patient cells, demonstrating that they are USP18 insensitive. Incidentally, we noted that the early peak (1 hour) of STAT2 phosphorylation in USP18-knockdown control fibroblasts was marginally reduced (Fig. 7E). This subtle reduction was also apparent in STAT2R148W patient fibroblasts (Fig. 4B), although not in EBV B cells (Fig. 5). We speculate that the cell typespecific induction of other negative regulator(s) of IFNAR signaling at early times after IFN treatment, such as SOCS1, might be responsible for this observation. RT-PCR analysis confirmed the increased expression of SOCS1 mRNA in whole blood of patients (fig. S11C), whereas examination of RNA-seq data from IFN-treated fibroblasts revealed an eightfold enhancement of SOCS1 expression at 6 hours in patient cells as compared with controls (Padj = 0.0001; Fig 4E). Together, these data provide preliminary support for the hypothesis that alternative negative regulator(s) of IFNAR signaling may be up-regulated in patient cells. Nevertheless, such attempts at compensation are clearly insufficient to restrain IFNAR responses in the context of STAT2R148W, reflecting the nonredundant role of STAT2/USP18 in this process (39). Collectively, these data support a model in which the homozygous presence of the Arg148Trp STAT2 variant compromises an essential adaptor function of STAT2 toward USP18, rendering cells USP18 insensitive and culminating in unrestrained, immunopathogenic IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) STAT phosphorylation in USP18 and vector expressing fibroblasts (immunoblot) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 3, ANOVA with Sidaks posttest). (C) Immunofluorescence analysis of STAT2 nuclear translocation [IFN (1000 IU/ml 30 min); representative of n = 3 experiments] with (D) image analysis (n = 100 cells per condition, ANOVA with Sidaks posttest). (E) Time course of STAT phosphorylation upon IFN stimulation (1000 IU/ml for 0, 1, 6, and 24 hours) of cells transduced with USP18 shRNA or nontargeting (NT) shRNA with (F) densitometry analysis of pSTAT2 (n = 3, t test). Data are means SEM (**P < 0.01, ***P < 0.001, ****P < 0.0001).

We report a type I interferonopathy, caused by a homozygous missense mutation in STAT2, and provide detailed studies to delineate the underlying molecular mechanism. Our data indicate the failure of mutant STAT2R148W to support proper negative regulation of IFNAR signaling by USP18revealing an essential regulatory function of human STAT2. This defect in STAT2 regulation results in (i) an inability to properly restrain the response to type I IFNs and (ii) the genesis of a life-threating early-onset inflammatory disease. This situation presents a marked contrast with monogenic STAT2 deficiency, which results in heightened susceptibility to viral infection due to the loss of the transcription factor complex ISGF3 (23, 24). Thus, just as allelic variants of STAT1 and STAT3 are recognized that either impair or enhance activity of the cytokine signaling pathways in which they participate (44), we can now add to this list STAT2. Our findings also highlight an apparently unique property of human STAT2: That it participates directly in both the positive and negative regulation of its own cellular signaling pathway. Whether this is true of STAT2 in other species remains to be determined. Our findings also localize the interaction with USP18 to the CCD of STAT2, indicating a specific residue critical for this interaction. This structural insight may be relevant to efforts to therapeutically interfere with the STAT2:USP18 interaction to promote the antiviral action of IFNs.

This monogenic disease of STAT2 regulation provides incontrovertible evidence of the pathogenic effects of failure to properly restrain IFNAR signaling in humans. The conspicuous phenotypic overlap with existing defects of IFN/ overproduction, particularly with regard to the neurological manifestations, provides compelling support for the type I interferonopathy hypothesis, strengthening the clinical rationale for therapeutic blockade of IFNAR signaling (15). JAK1/2 inhibition with ruxolitinib was highly effective in controlling disease in the proband; however, the damage that already accrued at birth in his younger brother was irreparable, emphasizing the importance of timely IFNAR blockade in prevention of neurological sequelae. A notable aspect of the clinical phenotype in patient II:3 was the occurrence of severe TMA. Our studies did not support a pathogenic contribution of the coinherited complement factor H variant in patient II:3. This evidence, together with clinical hematological and biochemical results suggestive of incipient vasculopathy in patient II:4who did not carry the CFH variantsuggests that type I IFN may have directly contributed to the development of TMA. Although it is not classically associated with type I interferonopathies, TMA is an increasingly recognized complication of both genetic (41, 42) and iatrogenic states of IFN excess (43), consistent with the involvement of vasculopathy in the pathomechanism of IFN-mediated disease. The fact that STAT2R148W is silent in the heterozygous state at first sight offers a confusing contrast with gain-of-function mutations of its sister molecules STAT1 and STAT3, both of which produce autosomal dominant disease with high penetrance (2629). However, the net gain of IFNAR signaling activity results from the isolated loss of STAT2s regulatory function, which evidently behaves as a recessive trait. There are other examples of autosomal recessive loss-of-function disorders of negative regulators, including USP18 itself (41, 45); the unique aspect in the case of STAT2R148W is that the affected molecule is itself a key positive mediator within the regulated pathway.

In light of the intimate relationship between STAT2 and USP18 revealed by these and other recent data (40), it is reasonable to conclude that the clinical manifestations of human USP18 deficiency are dominated by the loss of its negative feedback toward IFNAR rather than the STAT2-independent functions of USP18 including its enzymatic activity (40, 46, 47). In mouse, white matter pathology associated with microglia-specific USP18 deficiency is prevented in the absence of IFNAR (21). There are now three human autosomal recessive disorders that directly compromise the proper negative regulation of IFNAR signaling and thus produce a net gain of signaling function: USP18 deficiency, which leads to embryonic or neonatal lethality with severe multisystem inflammation (41); STAT2R148W, which largely phenocopies USP18 deficiency; and ISG15 deficiency, in which there is a much milder phenotype of neurological disease without systemic inflammation (45). ISG15 stabilizes USP18, and human ISG15 deficiency leads to a partial loss of USP18 protein (41). Thus, a correlation is clearly evident between the extent of USP18 dysfunction and the clinical severity of these disorders, with STAT2R148W closer to USP18 deficiency and ISG15 on the milder end of the spectrum (table S4). Those molecular defects that result in a failure of negative regulation of IFNAR signaling (i.e., STAT2R148W and USP18/) lead to more serious and extensive systemic inflammatory disease than do defects of excessive IFN/ production (41), suggesting that the STAT2:USP18 axis acts to limit an immunopathogenic response toward both physiological (48) and pathological (41) levels of IFN/. Thus, variability in the efficiency of this process of negative regulation might be predicted to influence the clinical expressivity of interferonopathies. Determining the cellular source(s) of physiological type I IFNs and the molecular pathways that regulate their production are important areas for future investigation.

Some limitations of our results should be acknowledged. Although strenuous efforts were made, we were only able to identify a single kindred, which probably reflects the rarity of this variant. As more cases are identified, our understanding of the clinical phenotypic spectrum will inevitably expand. Furthermore, for practical and cultural/ethical reasons, limited amounts of cellular material and tissues were available for analysis. As a result, we were unable to formally evaluate the relevance of STAT2 regulation toward type III IFN signaling; however, existing data suggest that USP18 plays a negligible role in this context (38). Together, our findings confirm an essential regulatory role of STAT2, supporting the hypothesis that type I IFNs play a causal role in a diverse spectrum of human disease, with immediate therapeutic implications.

We investigated a kindred with a severe, early-onset, presumed genetic disease, seeking to determine the underlying pathomechanism by ex vivo and in vitro studies. Written informed consent for these studies was provided, and ethical/institutional approval was granted by the NRES Committee North East-Newcastle and North Tyneside 1 (ref: 16/NE/0002), South Central-Hampshire A (ref: 17/SC/0026), and Leeds (East) (ref: 07/Q1206/7).

Dermal fibroblasts from patient II:3 and healthy controls were obtained by standard methods and cultured in Dulbeccos modified Eagles medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (DMEM-10), as were human embryonic kidney 293 T cells and the STAT2-deficient human sarcoma cell line U6A (31). PBMCs and EBV-transformed B cells were cultured in RPMI medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (RPMI-10). Unless otherwise stated, cytokines/inhibitors were used at the following concentrations: human recombinant IFN-2b (1000 IU/ml; Intron A, Schering-Plough, USA); IFN- (1000 IU/ml; Immunikin, Boehringer Ingelheim, Germany); IL-6 (25 ng/ml; PeproTech, USA); and 500 nM staurosporine (ALX-380-014-C250, Enzo Life Sciences, NY, USA). Diagnostic histopathology, immunology, and virology studies were conducted in accredited regional diagnostic laboratories to standard protocols.

Whole-exome sequencing analysis was performed on DNA isolated from whole blood from patients I:1, I:2, II:3, and II:4. Capture and library preparation was undertaken using the BGI V4 exome kit (BGI, Beijing, China) according to manufacturers instructions, and sequencing was performed on a BGISEQ (BGI). Bioinformatics analysis and variant confirmation by Sanger sequencing are described in the Supplementary Materials.

RNA was extracted by lysing fibroblasts in TRIzol reagent (Thermo Fisher Scientific) or from whole blood samples collected in PAXgene tubes (PreAnalytix), as described previously (49). Further details, including primer/probe information, are summarized in the Supplementary Materials and table S5.

Whole-blood transcriptome expression analysis was performed using nine whole blood samples, from the proband taken before and during treatment, and five controls. In addition, the four patient II:3 samples taken before treatment and samples from six patients with mutations in TREX1, three with mutations in RNASEH2A, seven with mutations in RNASEH2B, five with mutations in RNASEH2C, five with mutations in SAMHD1, four with mutations in ADAR1, two with mutations in IFIH1, three with mutations in ACP5, three with mutations in TMEM173, and three with mutations in DNASE2 were analyzed, as described in the Supplementary Materials. RNA integrity was analyzed with Agilent 2100 Bioanalyzer (Agilent Technologies). mRNA purification and fragmentation, complementary DNA (cDNA) synthesis, and target amplification were performed using the Illumina TruSeq RNA Sample Preparation Kit (Illumina). Pooled cDNA libraries were sequenced using the HiSeq 4000 Illumina platform (Illumina). Fibroblasts grown in six-well plates were mock-treated or treated with IFN for 6 or 12 hours, followed by extensive washing and 36-hour rest, before RNA extraction. The experiment was performed with patient II:3 and control cells (n = 3) in triplicate per time point. RNA was extracted using the ReliaPrep RNA Miniprep kit (Promega) according to manufacturers instructions and processed as described above, before sequencing on an Illumina NextSeq500 platform. Bioinformatic analysis is described in the Supplementary Materials. PMBC and fibroblast STAT2 patient and control data have been deposited in ArrayExpress (E-MTAB-7275) and Gene Expression Omnibus (GSE119709), respectively.

Details of lentiviral constructs, mutagenesis, and preparation are included in the Supplementary Materials. Cells were spinoculated in six-well plates for 1.5 hours at 2000 rpm, with target or null control viral particles, at various dilutions in a total volume of 0.5 ml of DMEM-10 containing hexadimethrine bromide [polybrene (8 g/ml); Sigma-Aldrich]. Cells were rested in virus-containing medium for 8 hours and then incubated in fresh DMEM-10 until 48 hours, when they were subjected to selection with puromycin (2.0 g/ml) or blastocidin (2.5 g/ml) (Sigma-Aldrich). Antibiotic-containing medium was refreshed every 72 hours.

EBV B cells were seeded at a density of 8 105 cells/ml in serum-free X-VIVO 15 medium (Lonza, Basel, Switzerland) and stimulated with IFN (1000 IU/ml) for the indicated times. After staining with Zombie UV (BioLegend, San Diego, CA, USA), cells were fixed using Cytofix buffer (BD Biosciences, Franklin Lakes, NJ, USA). Permeabilization was achieved by adding ice-cold PermIII buffer (BD Biosciences, Franklin Lakes, NJ, USA), and cells were incubated on ice for 20 min. After repeated washing steps with phosphate-buffered saline (PBS)/2% fetal bovine serum (FBS), cells were stained for 60 min at room temperature with directly conjugated antibodies (table S6). Samples were acquired on a Symphony A5 flow cytometer (BD Biosciences) and analyzed using FlowJo (FlowJo LLC, Ashland, OR, USA). The gating strategy is shown in fig. S13.

Immunoblotting was carried out as previously described (1) and analyzed using either a G:BOX Chemi (Syngene, Hyarana, India) charge-coupled device camera with GeneSnap software (Syngene) or a LI-COR Odyssey Fc (LI-COR, NE, USA). Densitometry analysis was undertaken using ImageStudio software (version 5.2.5, Li-COR). For complement studies, sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis (PAGE) under nonreducing conditions was performed on patient/parental serum [diluted 1:125 in nonreducing buffer (PBS)] or affinity-purified factor H (diluted to 200 ng in nonreducing buffer), separated by electrophoresis on a 6% SDS-PAGE gel, and transferred to nitrocellulose membranes for immunoblotting (antibodies in table S6). Blots were developed with Pierce ECL Western blotting substrate (Thermo Fisher Scientific) and imaged on a LI-COR Odyssey Fc (LI-COR).

U6A cells were lysed in immunoprecipitation buffer [25 mM Tris (pH 7.4), 1 mM EDTA, 150 mM NaCl, 1% Nonidet P-40, 1 mM sodium orthovanadate, and 10 mM sodium fluoride, with complete protease inhibitor (Roche, Basel, Switzerland)]. Lysates were centrifuged at 13,000 rpm at 4C for 10 min. Soluble fractions were precleared for 1 hour at 4C with Protein G Sepharose 4 (Fast Flow, GE Healthcare, Chicago, USA) that had been previously blocked with 1% bovine serum albumin (BSA) IP buffer for 1 hour. Precleared cell lysates were immunoprecipitated overnight with blocked beads that were incubated with anti-STAT2 antibody (A-7) for 1 hour and then washed three times in IP buffer before boiling with 4 lithium dodecyl sulfate buffer at 95C for 10 min to elute the absorbed immunocomplexes. Immunoblot was carried out as described above.

Fibroblasts grown on eight-well chamber slides (Ibidi, Martinsried, Germany) were fixed with 4% paraformaldehyde in PBS for 15 min at room temperature before blocking/permeabilization with 3% BSA/0.1% Triton X-100 (Sigma-Aldrich) in PBS. Cells were incubated overnight with anti-STAT2 primary antibody (10 g/ml; C20, Santa Cruz Biotechnology, Dallas, USA) at 4C, and cells were washed three times with PBS. Secondary antibody [goat anti-rabbit Alexa Fluor 488 (1 g/ml), Thermo Fisher Scientific] incubation was performed for 1 hour at room temperature, followed by nuclear staining with 4,6-diamidino-2-phenylindole (DAPI; 0.2 g/ml; Thermo Fisher Scientific). Cells were imaged with an EVOS FL fluorescence microscope with a 10 objective (Thermo Fisher Scientific). The use of STAT2-deficient cells (23) demonstrated the specificity and lack of nonspecific background of the staining approach. Image analysis was performed in ImageJ. The DAPI (nuclear) image was converted to binary, and each nucleus (object) was counted. This mask was overlaid onto the STAT2 image, and the mean fluorescence intensity of STAT2 within each nucleus was calculated (see also fig. S9). About n = 100 cells were analyzed per image.

The structure of human STAT2 has not been experimentally determined. We therefore used comparative modeling to predict the structure. The sequences of both the WT and mutant were aligned to mouse STAT2 (Protein Data Bank code 5OEN, chain B). For each sequence, 20 models were built using MODELLER (50), and the one with the lowest discrete optimized protein energy score was chosen. Protein structures and electrostatic surfaces were visualized with PyMOL (Schrodinger, USA).

Fibroblasts grown on 96-well plates were treated with IFN (1000 or 10,000 IU/ml) or DMEM-10 alone for 72 hours. Cells were fixed in PBS containing 5% formaldehyde for 15 min at room temperature and then incubated with crystal violet stain. Plates were washed extensively then allowed to air dry. The remaining cell membrane-bound stain was solubilized with methanol and absorbance at 595 nm measured on a TECAN Sunrise plate reader (Tecan, Switzerland). Background absorbance was subtracted from all samples, and the results were expressed as a percentage of the absorbance values of untreated cells.

Fibroblasts grown on 96-well plates were pretreated in septuplicate for 18 hours with twofold serial dilutions of IFN and IFN, followed by infection with mCherry-expressing parainfluenza virus 5 (PIV5) in DMEM/2% FBS for 24 hours. Monolayers were fixed with PBS containing 5% formaldehyde, and infection was quantified by measuring mean fluorescence intensity of mCherry (excitation, 580/9; emission, 610/20) using a TECAN Infinite M200 Pro plate reader (Tecan, Switzerland). Background fluorescence was subtracted from all samples, and the results were expressed as a percentage of the fluorescence values of untreated, virus-infected cells.

Unless otherwise stated, all experiments were repeated a minimum of three times. Data were normalized/log10-transformed before parametric tests of significance in view of the limitations of ascertaining distribution in small sample sizes and the high type II error rates of nonparametric tests in this context. Comparison of two groups used t test or one-sample t test if data were normalized to control values. Comparisons of more than one group used one-way analysis of variance (ANOVA) or two-way ANOVA as appropriate, with posttest correction for multiple comparisons. Statistical testing was undertaken in GraphPad Prism (v7.0). All tests were two-tailed with 0.05.

immunology.sciencemag.org/cgi/content/full/4/42/eaav7501/DC1

Materials and Methods

Supplementary case summary

Fig. S1. Ingenuity pathway analysis of whole blood RNA-seq data.

Fig. S2. Longitudinal series of laboratory parameters.

Fig. S3. Multiple sequence alignment of STAT2.

Fig. S4. Factor H genotyping and mutant factor H purification strategy.

Fig. S5. Functional analysis of factor H Tyr779Cys variant.

Fig. S6. Immunoblot analysis of MX1 expression in PBMCs.

Fig. S7. Transduction of STAT2-deficient primary fibroblasts.

Fig. S8. Prolonged STAT2 phosphorylation in PBMCs.

Fig. S9. STAT2 immunofluorescence image analysis.

Fig. S10. STAT phosphorylation is not prolonged in patient cells in response to IFN or IL-6.

Fig. S11. RT-PCR analysis of gene expression in whole blood.

Fig. S12. STAT2R148W does not impair regulation of STAT1 signaling.

Fig. S13. Phosflow gating strategy.

Table S1. Laboratory parameters, patients II:3 and II:4.

Table S2. Rare variants segregating with disease.

Table S3. Digital ELISA detection of IFN protein concentration.

Table S4. Phenotypes of monogenic defects of USP18 expression and/or function.

Table S5. RT-PCR primers and probes.

Table S6. Antibodies.

Data file S1. Raw data (Excel).

References (5159)

Acknowledgments: We are grateful to the patients and our thoughts are with their family. Funding: British Infection Association (to C.J.A.D.), Wellcome Trust [211153/Z/18/Z (to C.J.A.D.), 207556/Z/17/Z (S.H.), and 101788/Z/13/Z (to D.F.Y. and R.E.R.)], Sir Jules Thorn Trust [12/JTA (to S.H.)], UK National Institute of Health Research [TRF-2016-09-002 (to T.A.B.)], NIHR Manchester Biomedical Resource Centre (to T.A.B.), Medical Research Foundation (to T.A.B.), Medical Research Council [MRC, MR/N013840/1 (to B.J.T.)], MRC/Kidney Research UK [MR/R000913/1 (to Vicky Brocklebank)], Deutsche Forschungsgemeinschaft [GO 2955/1-1 (to F.G.)], Agence Nationale de la Recherche [ANR-10-IAHU-01 (to Y.J.C.) and CE17001002 (to Y.J.C. and D.D.)], European Research Council [GA 309449 (Y.J.C.); 786142-E-T1IFNs], Newcastle University (to C.J.A.D.), and ImmunoQure for provision of antibodies (Y.J.C. and D.D.). C.L.H. and R.S. were funded by start-up funding from Newcastle University. D.K. has received funding from the Medical Research Council, Wellcome Trust, Kidney Research UK, Macular Society, NCKRF, AMD Society, and Complement UK; honoraria for consultancy work from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Novartis, and Idorsia; and is a director of and scientific advisor to Gyroscope Therapeutics. Author contributions: Conceptualization: C.J.A.D., S.H., and T.A.B. Data curation: C.F., G.I.R., A.J.S., J.C., A.M., R.H., Ronnie Wright, and L.A.H.Z. Statistical analysis: C.J.A.D., B.J.T., R.C., G.I.R., F.G., D.F.Y., S.C.L., V.G.S., A.J.S., L.A.H.Z., C.L.H., D.K., and T.A.B. Funding acquisition: C.J.A.D., D.D., Y.J.C., R.E.R., D.K., S.H., and T.A.B. Investigation: C.J.A.D., B.J.T., R.C., F.G., G.I.R., D.F.Y., Vicky Brocklebank, V.G.S., B.C., Vincent Bondet, D.D., S.C.L., A.G., M.A., B.A.I., R.S., Ronnie Wright, C.L.H., and T.A.B. Methodology: C.J.A.D., B.J.T., R.C., F.G., D.F.Y., A.J.S., D.D., K.R.E., Y.J.C., R.E.R., C.L.H., and D.K. Project administration: C.J.A.D., K.R.E., S.H., and T.A.B. Resources: S.M.H., Robert Wynn, T.A.B., J.H.L., J.P., E.C., S.B., K.W., and D.K. Software: C.F., A.J.S., M.Z., L.A.H.Z., and Ronnie Wright. Supervision: C.J.A.D., K.R.E., Y.J.C., D.D., C.L.H., R.E.R., D.K., S.H., and T.A.B. Validation: B.J.T., R.C., A.J.S., V.G.S., and C.L.H. Visualization: C.J.A.D., B.J.T., R.C., and S.C.L. Writing (original draft): C.J.A.D., with B.J.T., R.C., S.H., and T.A.B. Writing (review and editing): C.J.A.D., G.I.R., A.J.S., S.C.L., M.Z., S.M.H., K.R.E., R.E.R., D.K., S.H., and T.A.B. Competing interests: The authors declare that they have no competing interests. Data and materials availability: GEO accession: GSE119709. ArrayExpress accession: E MTAB-7275. Materials/reagents are available on request from the corresponding author(s). MBI6 is available from Claire Harris under a material agreement with Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

View post:
Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 - Science

The immune system. Fantastic when it works terrible when it doesn't.

In this episode of the Health Report, we canvas the new frontiers of knowledge of the immune system from infancy through to adulthood and problems like allergy and cancer.

And we begin with a primer on the immune system what is it and how does it work?

This panel discussion was recorded at the World Science Festival Brisbane 2019.

Presenter:

Dr Norman Swan

Guests:

Professor Nigel McMillanCancer biologist, Menzies Health Institute Queensland

Professor Katie Allen

Paediatric allergist; gastroenterologist, Murdoch Children's Research Institute

Professor Mark SmythSenior scientist, immunology coordinator, QIMR Berghofer Research Institute

Producer:

James Bullen

The rest is here:
New frontiers in allergy, cancer and the immune system - ABC News

Michael W. Russell, professor emeritus in the Department of Microbiology and Immunology in the Jacobs School of Medicine and Biomedical Sciences at UB and the Department of Oral Biology in the School of Dental Medicine, has been awarded the distinction of fellow by the American Association for the Advancement of Science.

Russell, whose specialty is mucosal immunology and vaccine development, was recognized for his novel approaches to mucosal immunization, and the induction and function of secretory and serum IgA antibodies, the AAAS said.

I was very pleased to receive this honor, and especially gratified by the citation for distinguished contributions to the field of mucosal immunology, which is the major discipline governing my research career for over 50 years, Russell said.

He was nominated by Thomas Van Dyke of the Forsyth Institute in Boston, who is a UB School of Dental Medicine alumnus.

Russell, who has been a member of the AAAS for 15 years, is one of 443 AAAS members elected as fellows this year. These individuals have attained this rank because of their efforts on behalf of the advancement of science, or its applications are scientifically and socially distinguished, the association said.

The new fellows were announced in the AAAS News & Notes section of the Nov. 28 issue of the journal Science.

The 2019 recipients will be recognized on Feb. 15 at the Fellows Forum during the AAAS Annual Meeting at the Washington State Convention Center in Seattle. They each will receive an official certificate and a gold and blue rosette pin. The two colors represent science and engineering, respectively.

The distinction of fellow is a lifetime honor. Fellows are expected to maintain the highest standards of professional ethics and scientific integrity.

Russell attended the University of Cambridge in England, where he studied natural sciences/biochemistry, and the University of Reading, also in England, where he studied microbiology. He was a postdoctoral research fellow at Guys Hospital Medical and Dental School in London. He held several positions at the University of Alabama at Birmingham and served as a visiting associate professor at the Royal Dental College in Aarhus, Denmark.

Russell began his career at UB in 2000. He retired in 2016. His research was funded by grants from the National Institutes of Health from 1984 to 2013.

He has published 143 peer-reviewed research papers and reviews in scientific journals, and 90 book chapters and conference reports, and was an editor of the fourth edition of Mucosal Immunology (Academic Press/Elsevier, 2015). He and his colleagues have been awarded five patents.

View post:
UB researcher named AAAS fellow - UB Now: News and views for UB faculty and staff - University at Buffalo Reporter

The research report Immunology Market Global Industry Analysis 2019 2025 offers precise analytical information about the Immunology market. The report identifies top players in the global market and divides the market into several parameters such as major drivers market strategies and imposing growth of the key players. Worldwide Immunology Industry also offers a granular study of the market dynamics, segmentation, revenue, share forecasts and allows you to make superior business decisions. The report serves imperative statistics on the market stature of the prominent manufacturers and is an important source of guidance and advice for companies and individuals involved in the Immunology industry.

This Immunology market report bestows with the plentiful insights and business solutions that will support our clients to stay ahead of the competition. This market report contains categorization by companies, region, type, and application/end-use industry. The competitive analysis covered here also puts light on the various strategies used by major players of the market which range from new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and many others that leads to increase their footprints in this market. The transparent research method carried out with the right tools and methods makes this Immunology market research report top-notch.

Interesting? Apply for a sample report: http://www.intenseresearch.com/market-analysis/global-immunology-market-2018-by-manufacturers-countries-type.html#request-sample

Competitive Landscape

Global Immunology market is highly split and the major players have used numerous tactics such as new product launches, acquisitions, innovation in products, expansions, agreements, joint ventures, partnerships, and others to increase their footprints in this market.

Key players profiled in the report include: AbbVie, Amgen, F. Hoffmann-La Roche, Johnson & Johnson, Bionor Pharma, Celgene, Cellectar Biosciences, eFFECTOR Therapeutics

Market Segmentation

Immunology Market report segmentation on Major Product Type:Immuno Boosters, Immunosuppressants

Market by Application: Here, various application segments of the global Immunology market are taken into account for the research study.

Autoimmune Diseases, Oncology, Organ Transplantation, Others

Enquire Here For Queries Or Report Customization: http://www.intenseresearch.com/market-analysis/global-immunology-market-2018-by-manufacturers-countries-type.html#inquiry-for-buying

Regional Analysis

The Immunology market report keenly emphasizes on industrial affairs and developments, approaching policy alterations and opportunities within the market. The regional development methods and its predictions are explained in every key point that specifies the general performance and issues in key regions such as North America, Europe, Asia Pacific, Middle East, South America, and Middle East & Africa (MEA). Various aspects such as production capability, demand, product value, material parameters and specifications, distribution chain and provision, profit and loss, are explained comprehensively in the market report.

Key Questions Answered in Global Immunology Market Report:-

What will the market growth rate, overview, and analysis by type of global Immunology Market in 2026?

What are the key factors driving, analysis by applications and countries Global Immunology Market?

What are dynamics, this summary includes analysis of the scope and price analysis of top players profiles of Global Immunology Market?

Who are the opportunities, risk and driving forces of the global Immunology Market?

Who are the opportunities and threats faced by the vendors in the Global Immunology Market?

What are the Global Immunology market opportunities, market risk and market overview of the Market?

Thanks for reading this article, you can also get individual chapter wise section or region wise report versions like North America, Europe or Asia. Also, If you have any special requirements, please let us know and we will offer you the report as you want.

Here is the original post:
Global Immunology Market 2019 by Manufacturers, Countries, Type and Application, Forecast to 2025 - E-Industry News

Food allergy refers to the bodys abnormal immune reaction to foods that would usually be harmless. In the case of food-allergic individuals, the immune system incorrectly identifies food proteins as harmful and launches an immune response to attack them. The severity of a reaction ranges from mild itchiness of the mouth, for example, through to severe and life-threatening anaphylaxis.

Image Credit: Evan Lorne / Shutterstock.com

According to estimates, 32 million Americans are living with a food allergy, 5.6 million of whom are children under the age of 18. Approximately 40% of food-allergic children are allergic to more than one food.

To help Americans avoid risky foods and allergic food reactions, the FDA enforced the Food Allergen Labeling and Consumer Protection Act of 2004, which requires that food labels name any major food allergens that are used to make the product.

While more than 170 foods have been recognized as reaction-inducing among people with an allergy, the eight most common allergenic foods recognized by the law are described below. These foods account for 90% of reactions and are often the foods from which other allergenic ingredients are derived.

Between 2% and 3% of children younger than three years of age are allergic to milk. Although experts used to think most infants would outgrow this allergy by the time they turned three, recent studies have shown that fewer than one-fifth outgrow it by age four. Still, approximately 80% of children are likely to have outgrown the allergy before the age of sixteen.

People who are allergic to cows milk may also be allergic to milk from other animals such as sheep and goats.

Milk allergy is not the same thing as lactose intolerance, which is very common. Lactose intolerance is the inability to digest the sugar in milk because some people lack the lactase enzyme. The associated discomfort and diarrhea are not an allergic reaction.

Egg allergy is the second most common food allergies among children in US, next to cows milk. The majority of children eventually outgrow the allergy. People who are allergic to chicken eggs may also be allergic to other types of eggs, such as duck, goose, or quail.

Eggs are an ingredient found in many foods, ranging from salad dressing, canned soups, and ice cream through to meat-based dishes such as meatballs and meatloaf. Even some egg substitutes on the market can contain egg protein. People with an egg allergy, therefore, need to be extremely vigilant about checking food labels and the ingredients in foods people have prepared for them.

Whether a person has an allergy to egg whites or egg yolks, they should avoid eggs altogether because it is impossible to ensure complete separation of egg white from egg yolk.

The estimated prevalence of finned fish allergy in the United States is 0.4%, and the allergy is usually lifelong. Around 40% of those with this allergy first experience a reaction to fish during adulthood. The most common culprits are salmon, tuna, and halibut. More than 50% of people who are allergic to one type of fish are also allergic to other types of fish. Finned fish allergy is not connected to shellfish allergy; having one of these allergies does not necessarily mean a person has both allergies. However, people who are allergic to fish should avoid seafood restaurants, where there is a high risk of cross-contact between finned fish and shellfish. Fish markets and any areas where fish are being cooked should be also be avoided.

Shellfish allergy most commonly arises during adulthood but is also the third most common allergy among children in the United States. About 60% of people with this allergy first experience a reaction as adults, and the allergy is usually lifelong.

There are two groups of shellfish: crustacea (e.g., shrimps, crabs and lobster) and mollusks (e.g., clams, mussels, and oysters). The crustacean allergies account for the greatest number of reactions, which tend to be severe. Many people with an allergy to crustacea can eat mollusks without experiencing any problems, but anyone with a specific shellfish allergy should consult an allergist before eating any other type of shellfish. Fish restaurants or markets where different types of shellfish are often stored together should be avoided.

Tree nut allergy affects about 1.1 % of children and 0.5 % of adults in the United States. It is the second leading cause of severe allergic food reactions, and the estimated prevalence of tree nut anaphylaxis (life-threatening reaction) among children is 0.25% to 0.95%

Allergies to tree nuts such as almonds, walnuts, or cashews usually last a lifetime, with fewer than 10% of people with a tree nut allergy outgrowing it.

People often confuse peanut allergy with a tree nut allergy, but peanuts are legumes that grow underground and not true nuts. However, studies show that up to 40% of people with a peanut allergy also react to at least one type of tree nut. People with a tree nut allergy do not need to avoid coconuts, which is a fruit rather than a nut, even though the FDA classifies coconut as a tree nut. Although coconut allergies have been recorded, most people with a tree nut allergy can safely eat coconuts.

An allergy to peanuts is among the most common food allergies found in children in the United States, and peanut is one of the food allergens most commonly associated with anaphylaxis. Since awareness about the number of peanut allergy cases reported has risen, many schools have chosen to be nut-free or have designated seating areas for children with peanut allergy to eat their meals so that they will not contact others food that may contain peanuts.

In 2017, the National Institute for Allergy and Infectious Disease released updated guidelines about how to classify infants as high, moderate, or low risk for peanut allergy, as well as how to proceed with introducing peanuts to the diet based on the risk level.

Wheat allergy is most common in children, with prevalence amongst the United States pediatric population somewhere between 0.4% to 1.0%. Most children outgrow the allergy before they reach adulthood; one-third outgrow it by age four, and two-thirds outgrow it by age twelve.

Wheat is the most commonly produced grain in the United States. Children with a wheat allergy can still eat a wide variety of foods, but the source of grain must be something other than wheat, such as barley, corn, oat, rice, or rye.

As is the case with adults, soy allergy prevalence among children is the lowest of the eight major allergens. The allergy affects about 0.4% of children in the United States. Children often outgrow the allergy by the age of three, and the majority have usually outgrown it by the age of ten.

Soybeans are a member of the legume family, but being allergic to soy does not mean an increased risk of allergy to other legumes such as beans, peas, lentils, and peanuts.

Epidemiology of wheat allergy. Dr. Schr Institute. Available at: https://www.drschaer.com/us/institute/a/epidemiology-wheat-allergy

What You Need to Know about Food Allergies. U.S Food and Drug Administration. Available at: http://www.fda.gov/.../what-you-need-know-about-food-allergies

Food allergies: Understanding food labels. Mayo Clinic. Available at: http://www.mayoclinic.org/.../art-20045949

Facts and Statistics. FARE: Food Allergy Research & Education. Available at: http://www.foodallergy.org/.../facts-and-statistics

Food Allergy & Anaphylaxis Public Declaration. EAACI: European Academy of Allergy and Clinical Immunology. Available at: http://www.eaaci.org/.../...ergy&AnaphylaxisPublicDeclarationCombined.pdf

Warren, C et al. Prevalence and characteristics of adult shellfish allergy in the United States. The Journal of Allergy and Clinical Immunology 2019. DOI: https://doi.org/10.1016/j.jaci.2019.07.031 Available at: https://www.jacionline.org/article/S0091-6749(19)31027-9/abstract

All About Tree Nut Allergies. Allergic Living. Available at: http://www.allergicliving.com/2010/08/19/nut-main-about-tree-nut-allergy/

Allergy Prevalence: Useful facts and figures. Allergy UK. Available at: http://www.allergyuk.org/.../Stats_for_Website_original.pdf?1505209830

Soy Allergy. FARE: Food Allergy Research & Education. Available at: https://www.foodallergy.org/common-allergens/soy-allergy

Wheat Allergy. FARE: Food Allergy Research & Education. Available at: https://www.foodallergy.org/common-allergens/wheat-allergy

Shellfish allergy. FARE: Food Allergy Research & Education. Available at: https://www.foodallergy.org/common-allergens/shellfish-allergy

Fish Allergy. FARE: Food Allergy Research & Education. Available at: https://www.foodallergy.org/common-allergens/fish-allergy

Wheat Allergy. Mayo Clinic. Available at: http://www.mayoclinic.org/.../syc-20378897

Egg Allergy. Mayo Clinic. Available at: http://www.mayoclinic.org/.../syc-20372115

Peanut Allergy. American College of Allergy, Asthma and Immunology. Available at: acaai.org/.../peanut-allergy

Tree nut Allergy. American College of Allergy, Asthma and Immunology. Available at: acaai.org/.../tree-nut-allergy

Shellfish Allergy. American College of Allergy, Asthma and Immunology. Available at: acaai.org/.../shellfish-allergy

Milk & Dairy Allergy. American College of Allergy, Asthma and Immunology. Available at: acaai.org/.../milk-dairy-allergy

Egg allergy. American College of Allergy, Asthma and Immunology. Available at: acaai.org/.../egg-allergy

Go here to see the original:
Most Common Food Allergies in the USA - News-Medical.net

Wonder Drake of Vanderbilt University in Nashvillein her lab with some of the students she supports through the National Institutes of Healths diversity supplements

By Jeffrey MervisDec. 13, 2019 , 4:10 PM

Wonder Drake knows how being poor can hinder someones dream of becoming a biomedical researcher.

Raised in rural Alabama by a single mother who never graduated from high school, Drake overcame those obstacles by finding mentors willing to take her under their wing. Now a professor of medicine at Vanderbilt University in Nashville, Drake has repeatedly returned that favor by participating in a National Institutes of Health (NIH) program aimed at improving the diversity of the biomedical workforce.

Under the program, NIH grantees such as Drake can win additional funding, called diversity supplements, to aid students from one of several groups underrepresented in biomedical research. Some 90% of the awards made in 2018 serve students who are Hispanic or African American, whereasfewer than 1% of investigators cite the category of economically disadvantaged when applying for a diversity supplement.

NIH officials think that tiny slice should be bigger. So last month, the agency tweaked its definition of the word disadvantaged in hopes that the diversity supplements would serve a broader swath of that population.

Diversity supplements can be used to support students from high school through postdoctoral training. NIHs previous definition of disadvantaged referred to students whose pursuit of a research career was hampered by living in an educational environment such as those found in certain rural or inner-city environments. But that language may have confused people, says Michael Lauer, who leads NIHs office of extramural research. What does [that] mean? Lauer asked in a 26 November blog announcing the change, adding that the phrase is nearly impossible to evaluate.

NIHs new definition of disadvantagedwhich applies to all of the agencys programs meant to foster diversityhas seven components. A person is eligible if they have been homeless, or qualified for a free or reduced-priced lunch in elementary or high school, or if they meet the income level requirements to receive a federal Pell grant to help finance their college education. NIH also invites in those who were in foster care, whose parents never graduated from college, or who grew up in a rural area or a region with a shortage of health professionals.

We wanted to make it easy for students to self-identify while not being overly redundant, says Jon Lorsch, director of the National Institute of General Medical Sciences in Bethesda, Maryland, the hub of NIHs diversity activities. The goal of the supplements remains the same, he says: helping students overcome barriers caused by their low economic status.

Drake, for one, applauds NIHs move. The new definition may attract more students who are immigrants, or poor Caucasians, she speculates. Just think how useful their input would be in finding solutions to the opioid crisis, which is ravaging so many low-income communities.

Drake notes that she would have met several of the new eligibility criteria when she was a student. I certainly grew up disadvantaged, she says. She is also African American, so she would have qualified in that category as well.

Drake, who has received many diversity supplements, typically chooses students from a racial or ethnic minority because its obvious. Students of color at Vanderbilt who want a research experience tend to seek her out, Drake adds.

But she also contacts nearby institutions that educate large numbers of students who fit NIHs definition of diversity. I call up the chair of the basic science department and I tell them, I need your best student, she says. Then I give them the chance to see what its like to be a scientist. The goal is to have them complete a research project over the summer, she says, and then present a poster session at a scientific conference.

The new definition of disadvantaged could help more students tap into such experiences. And Drake says, Based on my experience, the economically disadvantaged students are sometimes the most talented because they have had to overcome so much adversity.

A National Institutes of Health diversity program helped Matthew Bruce begin to trainfor a career as a biomedical researcher after he spent 4 years in prison for armed robbery.

Some diversity experts fear eligible students could shy away from identifying themselves as economically disadvantaged because of the stigma associated with the term. I was a single mother on Medicaid and food stamps during part of my student years, and also the first in my family to go to college, but I never thought of it as being a disadvantage, says a researcher who has led diversity efforts at her institution. I am also averse to playing the hardship card.

But others arent too worried. I think that students with the potential to succeed in graduate school would not be dissuaded, says Jacqueline Tanaka, a professor emeritus of biology at Temple University in Philadelphia, Pennsylvania, and former director of its Minority Access to Research Careers (MARC) program, one of NIHs longest running diversity initiatives. They are probably already carrying a lot of student debt, and this is an opportunity to get the type of research experience they need to move ahead.

In fact, Tanaka would like to see NIH broaden the definition even more to include students with backgrounds like that of Matthew Bruce, now a third-year graduate student in immunology at the University of California, Davis. In 2008, Bruce used a gun to rob a convenience store for money to support his drug habit. A few months, later he turned himself in, pleaded guilty, and served 4 years in a Pennsylvania state prison.

After his release, Bruce juggled work and a full load of courses at a local community college before transferring to Temple. There, Tanaka recruited him to the MARC program, which offers high-achieving, upper-level undergraduate students the type of research experiences they need to get into a good graduate program, the first rung on an academic career.

It may sound corny, Bruce says, but being in the MARC program was everything to me. I was feeling the imposter syndrome times 100, he says about the well-documented phenomenon of students from disadvantaged backgrounds underestimating their ability to make it in science.

I didnt come from the same background as my peers, and I hadnt really paid much attention in school [because of his drug dependency], Bruce continues. When Dr. Tanaka told me that, as a scientist, I would essentially get paid to solve problems, I said, That sounds phenomenal. Sign me up. In 2017 he graduated from Temple with a near-perfect academic record.

Bruce grew up in rural Pennsylvania, was the first in his family to attend college, and received a Pell grant, so he would likely qualify as disadvantaged under NIHs new definition. But what really sold Tanaka on Bruce was how he had overcome a huge obstacleincarcerationthat is not included in the definition.

Lorsch saysNIH is open to further revisions of the criteria for disadvantaged. Our goal is to give students as many on-ramps as possible, he says.

And money is not an impediment. Lorsch estimates that NIH could, without straining its budget, accommodate a 10-fold increase in the number of supplement applications that cite the disadvantaged category; in 2018 there were fewer than 11 such applications.

Given that NIH funds nearly two-thirds of the proposals it receives for diversity supplements, Drake doesnt understand why more of her colleagues dont apply. I think [the diversity supplements] are one of the best-kept secrets at NIH, she says. And were doing everything we can at [Vanderbilt] to spread the word.

View post:
NIH clarifies meaning of 'disadvantaged' in bid to boost diversity in science - Science Magazine

On 9 December, 1979, health officials declared smallpox as the first and only human disease to be eradicated in what is considered the greatest achievement of modern medicine. Four decades on, the U.S. and Russia still maintain samples of the potentially deadly virus, and the debate on whether they should be kept or destroyed rages on.

We don't know where smallpox came from. But the infectionwhich is caused by two related variola virusesis thought to date back to the Egyptian Empire in the 3rd Century BCE, with its pustules found on the head of the Egyptian Pharaoh Ramses V. Trade and the expansion of civilizations helped the disease, found only in humans, spread. Characterized by symptoms including a fever, a widespread rash of fluid-filled blisters, vomiting and diarrhea, smallpox is estimated to have killed as many as 300 million people in the 20th century alone.

Following a failed attempt to wipe out the disease in 1959, efforts were renewed in 1967. Thanks to a worldwide vaccination program, the last person to ever be naturally infected by smallpox fell ill in Somalia, on October 12, 1977. By 9 December, 1979, the WHO had concluded the virus had been eradicated worldwide. And on May 8, 1980, the 33rd World Health Assemblythrough which the World Health Organization is governed by its member statesdeclared the world free of smallpox. Amid the Cold War, the body decided it would be wise to have two smallpox repositories in the West and one in the Soviet Bloc, in the interests of political neutrality.

To this day, only two remaining stocks of the variola virus are known to exist. They are kept under high-security conditions at a U.S. Centers for Disease Control and Prevention laboratory in Atlanta, and at Russia's State Research Centre of Virology and Biotechnology (Vector) in the Siberian city of Novosibirsk. Everything known about their location is in the public domain except for the exact rooms and freezers where the samples are kept, David Relman, professor of microbiology and immunology at Stanford University, told Newsweek.

Experts agreed on keeping the virus in case the disease reappears, and in order to help to improve vaccines, create treatments, antivirals and improve diagnostics methods. Any work on variola must be pre-approved by the World Health Organization, which takes inventories on samples every year, and inspects the labs biennially.

Until these objectives are met, the World Health Organization agrees the stocks should not be destroyed. Professor Grant McFadden, director of the Biodesign Center for Immunotherapy, Vaccines, and Virotherapy at Arizona State University, told Newsweek: "There remains debate about how close each of these goals is to completion."

So far, the decision to retain the samples has been somewhat fruitful. In 2018, for instance, the FDA approved the first drug that it believes could treat smallpox. Following a meeting in September 2018, members of the WHO's Advisory Committee on Variola Virus Research were divided, but once again concluded the repositories are still needed to develop an antiviral drug different from the one approved by the FDA.

While some argue the aims of the research agenda have been essentially achieved, McFadden said, others point to the fact only one new drug is now available, the animal models to test the new vaccines are currently inadequate, and the new generation of diagnostics remain unproven, he said.

The virus is needed to test the efficacy of new vaccines and drugs, David Relman, professor of microbiology and immunology at Stanford University, told Newsweek. "And chemical synthesis of the virus, in the event of destruction and then unexpected re-emergence and the need for new testing with the virus, would take too long," he said.

But what ifothers arguethe virus was released by accident, or on purpose? As people are no longer vaccinated against smallpox, this could potentially spark a large and deadly epidemic or pandemic, Amesh A. Adalja, a senior scholar at Johns Hopkins Center for Health Security, told Newsweek. Its potential as a tool of bioterrorism adds another layer to the controversial question of smallpox stock retention.

Concerning incidents have reignited the debate over the years. Previously unknown smallpox vials were found in an FDA building at the NIH Bethesda campus back in 2014. Last year, biosecurity experts feared the publication of a study that detailed the replication of the horsepox virus could provide terrorists with a recipe for making a pathogen that causes smallpox. And in September of this year, an explosion occurred at the Vector lab, (during which the smallpox samples were unscathed).

Relman told Newsweek that while he believes it is safe, but "not foolproof," to keep the repositories, he is "much more worried about the re-synthesis of smallpox from chemicals in the library and re-booting the virus with methods that have now been published."

McFadden is also concerned by that prospect, as well as the potential existence of any undeclared stocks.

For Adalja, the time has come to get rid of smallpox once and for all. "The virus should be destroyed," he said. "As time passes, the initial reason for keeping viable virus has less support."

Read more

"In 2019, we now have achieved most of those milestones so it has become increasingly unnecessary to keep viable virus, especially since its genetic sequence is known and the virus could be recreated if needed," he argued.

"Keeping the viable stocks and working with them could lead to laboratory accidents with resultant infection and spread. The stocks could also be misused or fall into the wrong hands and be used nefariously," Adalja said.

Relman countered that in his view, the arguments for retention are stronger than the arguments for destruction. Not until re-synthesis can happen overnight and is reliable "will the balance of the arguments shift, and by then, by definition, we're back to the same or greater danger despite destruction," he said.

McFadden, meanwhile, said remains agnostic on the issue. "A great deal has been achieved on the original research goals, but the argument that more remains to be done is hard to refute," he said.

"I believe that a fully unanimous opinion of the research community and public health experts familiar with variola virus will be hard to achieve in the near future, and so the destruction decision will need to be political," he said. "It is important to have these debates about whether mankind should deliberately eliminate feared pathogens, or study them."

Follow this link:
Smallpox Was Eradicated 40 Years Ago, So Why Are the U.S. and Russia Still Holding Stocks of the Virus? - Newsweek

Viral and bacterial infections are not the only causes of inflammation of body tissue. It has been known for some time that certain fat molecules in our bloodstream can also trigger an inflammatory response. Patients with higher levels of these fats in their blood have a significantly greater chance of dying early from kidney damage or vascular disease. This causal link has now been clearly demonstrated by an international team of researchers led by Dr. Timo Speer of Saarland University.

The research team was able to show how these fat molecules interact with body cells and how they can mobilize the body's own immune system to damaging effect. The study's findings have now been published in the highly respected medical journal 'Nature Immunology'.

Doctors interested in ways to minimize the risk of cardiovascular disease have long had blood cholesterol levels in their sights. But other types of blood fats (also known as 'lipids') can also be damaging to health.

Our work has involved studying a special group of lipids, the triglycerides. We've been able to show that when these naturally occurring fats are present at elevated concentrations they can alter our defense cells in such a way that the body reacts as if responding to a bacterial infection. This leads to inflammation, which, if it becomes chronic, can damage the kidneys or cause atherosclerosis - the narrowing of arteries due to a build up of deposits on the inner arterial wall. And atherosclerosis is one of the main causes of heart attacks and strokes."

Timo Speer, Saarland University

Speer, who has doctorates in medicine as well as biology, is the lead author of the work just published in Nature Immunology.

The large-scale study was able to demonstrate that patients with elevated levels of triglycerides in their blood had a significantly higher mortality rate than comparison groups with a similar health history. 'Put another way, we can now say that adopting a low-fat diet can significantly extend the life expectancy of high-risk patients, such as those with diabetes or those whose blood pressure is too high,' says Timo Speer. Blood triglyceride levels rise substantially in people who eat a high-fat diet. 'As a result of biochemical changes, the triglycerides develop toxic properties that activate the body's innate immune system. This initiates a series of self-destructive processes including those in which the walls of the arteries are attacked and the blood vessels become occluded, reducing blood flow,' explains Speer. The study has established a definitive link between the chronic inflammation triggered by an elevated triglyceride concentration in the blood and secondary diseases such as kidney failure or heart attack. 'We hope that our results will help in developing new strategies for treating and preventing these life-threatening diseases,' says Timo Speer.

The publication in Nature Immunology is one of the results of the diverse range of scientific investigations being carried out as part of a Transregional Collaborative Research Centre between Saarland University and RWTH Aachen University. The focus of the work performed within the Collaborative Research Centre is to discover which cardiac and vascular diseases can be caused by chronic kidney disease. The German Research Foundation (DFG) is funding this major research programme with ten million euros over a three-year period. Timo Speer is the lead researcher for one the research projects. He is also a senior physician at Saarland University Hospital and laboratory director for experimental and translational nephrology.

Source:

Journal reference:

Zewinger, S., et al. (2019) Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nature Immunology. doi.org/10.1038/s41590-019-0548-1.

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Apolipoprotein, Atherosclerosis, Blood, Blood Pressure, Blood Vessels, Cardiovascular Disease, Cholesterol, Chronic Kidney Disease, Diabetes, Diet, Heart, Heart Attack, Hospital, Immune System, Immunology, Inflammasome, Inflammation, Kidney, Kidney Disease, Kidney Failure, Laboratory, Life Expectancy, Lipids, Medicine, Mortality, Nephrology, Research, Triglyceride, Vascular

View original post here:
Research shows how high levels of blood fat induce inflammation and organ damage - News-Medical.net

La Jolla, California-based immunology specialist Equillium has inked a deal with Biocon, expanding an existing collaboration and license agreement.

The deal builds on the firms research into Biocons novel biologic itolizumab, granting Equillium exclusive rights for developing and commercializing the candidate in Australia and New Zealand. The firm secured rights to the US and Canadian markets in May 2017.

Itolizumab is a novel first-in-class humanized anti-CD6 monoclonal antibody, which Biocon developed and launched in India under the brand name Alzumab, to treat moderate to severe plaque psoriasis in 2013.

The firms are working to develop the candidate for a wide range of autoimmune disorders.

More here:
BRIEFEquillium and Biocon expand itolizumab deal - The Pharma Letter