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"Holland, Steven M."
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Host susceptibility to non-tuberculous mycobacterial infections
Non-tuberculous mycobacteria cause a broad range of clinical disorders, from cutaneous infections, such as cervical or intrathoracic lymphadenitis in children, to disseminated infections at all ages. Recognition of the underlying immune defect is crucial for rational treatment, preventive care, family screening, and, in some cases, transplantation. So far, at least seven autosomal mutations (in IL12B, IL12RB1, ISG15, IFNGR1, IFNGR2, STAT1, and IRF8) and two X-linked mutations (in IKBKG and CYBB), mostly presenting in childhood, have been reported to confer susceptibility to disseminated non-tuberculous mycobacterial infection. GATA2 deficiency and anti-interferon γ autoantibodies also give rise to disseminated infection, typically in late childhood or adulthood. Furthermore, isolated pulmonary non-tuberculous mycobacterial infection has been increasing in prevalence in people without recognised immune dysfunction. In this Review, we discuss how to detect and differentiate host susceptibility factors underlying localised and systemic non-tuberculous mycobacterial infections.
Journal Article
The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity
Abstract The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.
Journal Article
Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability progression slopes compared with the remaining TRAP-MS participants. Quantification of approximately 7,000 proteins in CSF samples collected before and after clemastine treatment showed significant increases in purinergic signaling and pyroptosis. Mechanistic studies showed that clemastine with sublytic doses of extracellular adenosine triphosphate (ATP) activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell-derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7, which is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally, reanalysis of published single-nucleus RNA-Seq (snRNA-Seq) studies revealed increased P2RX7 expression and pyroptosis transcriptional signature in microglia and oligodendrocytes in the MS brain, especially in chronic active lesions. The CSF proteomic pyroptosis score was increased in untreated MS patients, was higher in patients with progressive than relapsing-remitting disease, and correlated significantly with the rates of MS progression. Collectively, this identifies pyroptosis as a likely mechanism of CNS injury underlying PIRA even outside of clemastine toxicity.
Journal Article
Spatial Clusters of Nontuberculous Mycobacterial Lung Disease in the United States
Prevalence of pulmonary nontuberculous mycobacterial (PNTM) disease varies by geographic region, yet the factors driving these differences remain largely unknown.
To identify spatial clusters of PNTM disease at the county level and to describe environmental and sociodemographic factors predictive of disease.
PNTM cases identified from a nationally representative sample of Medicare Part B beneficiaries from 1997 to 2007 were geocoded by county and state of residence. County-level PNTM case counts and Medicare population data were then uploaded into SaTScan to identify significant spatial clusters and low-risk areas of disease. High-risk and low-risk counties were then compared to identify significant sociodemographic and environmental differences.
We identified seven significant (P < 0.05) clusters of PNTM cases. These high-risk areas encompassed 55 counties in 8 states, including parts of California, Florida, Hawaii, Louisiana, New York, Oklahoma, Pennsylvania, and Wisconsin. Five low-risk areas were also identified, which encompassed 746 counties in 23 states, mostly in the Midwest. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, although lower manganese levels.
Specific environmental factors related to soil and water exposure appear to increase the risk of PNTM infection. Still, given that environmental sources of NTM are ubiquitous and PNTM disease is rare, both host susceptibility and environmental factors must be considered in explaining disease development.
Journal Article
Primary Immunodeficiency Diseases: Current and Emerging Therapeutics
Primary immunodeficiency diseases (PID) result from defects in genes affecting the immune and other systems in many and varied ways (1, 2). Until the last few years, treatments have been largely supportive, with the exception of bone marrow transplantation. However, recent advances in immunobiology, genetics, and the explosion of discovery and commercialization of biologic modifiers have drastically altered the landscape and opportunities in clinical immunology. Therapeutic options and life expectancy of PID patients have also improved dramatically, in large part as a result of better prevention and treatment of infections as well as better understanding and treatment of autoimmune complications (3). As early-life infection-related mortality declines we should anticipate the emergence of other conditions that were previously not appreciated, including malignancies and degenerative disorders unmasked by increasing longevity (4). The genomic revolution has identified literally hundreds of new genetic etiologies of immune dysfunction, many of which are or will soon be eligible for targeted therapies. These emerging immunomodulatory agents represent new therapeutic options in PIDs (5).
Journal Article
Cis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 limits antibody-mediated neutrophil recruitment
Vascular-deposited IgG immune complexes promote neutrophil recruitment, but how this process is regulated is still unclear. Here we show that the CD18 integrin Mac-1, in its bent state, interacts with the IgG receptor FcγRIIA in
cis
to reduce the affinity of FcγRIIA for IgG and inhibit FcγRIIA-mediated neutrophil recruitment under flow. The Mac-1 rs1143679 lupus-risk variant reverses Mac-1 inhibition of FcγRIIA, as does a Mac-1 ligand and a mutation in Mac-1’s ligand binding αI-domain. Sialylated complex glycans on FcγRIIA interact with the αI-domain via divalent cations, and this interaction is required for FcγRIIA inhibition by Mac-1. Human neutrophils deficient in CD18 integrins exhibit augmented FcγRIIA-dependent recruitment to IgG-coated endothelium. In mice, CD18 integrins on neutrophils dampen IgG-mediated neutrophil accumulation in the kidney. In summary,
cis
interaction between sialylated FcγRIIA and the αI-domain of Mac-1 alters the threshold for IgG-mediated neutrophil recruitment. A disruption of this interaction may increase neutrophil influx in autoimmune diseases.
Deposited immune complexes (IC) promote neutrophil recruitment, but the fine tuning of this process is still unclear. Here the authors show that the
cis
interaction of the IC receptor, FcγRIIA and CD18 integrin, Mac-1, on the neutrophil surface modulates neutrophil adhesion, with FcγRIIA sialylation specifically implicated in this interaction.
Journal Article
Anti-cytokine autoantibodies: mechanistic insights and disease associations
Anti-cytokine autoantibodies (ACAAs) are increasingly recognized as modulating disease severity in infection, inflammation and autoimmunity. By reducing or augmenting cytokine signalling pathways or by altering the half-life of cytokines in the circulation, ACAAs can be either pathogenic or disease ameliorating. The origins of ACAAs remain unclear. Here, we focus on the most common ACAAs in the context of disease groups with similar characteristics. We review the emerging genetic and environmental factors that are thought to drive their production. We also describe how the profiling of ACAAs should be considered for the early diagnosis, active monitoring, treatment or sub-phenotyping of diseases. Finally, we discuss how understanding the biology of naturally occurring ACAAs can guide therapeutic strategies.This Review covers the biology of anti-cytokine autoantibodies and their varied roles in causing, preventing and treating diseases. Recent reports of anti-type I interferon autoantibodies in critical COVID-19 have led to renewed interest in this topic, which offers fascinating insights into the reversibility of immune tolerance and the origins of autoimmunity in otherwise healthy individuals.
Journal Article
Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype
Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.
Journal Article
The non-uniformity of fossil preservation
The fossil record provides the primary source of data for calibrating the origin of clades. Although minimum ages of clades are given by the oldest preserved fossil, these underestimate the true age, which must be bracketed by probabilistic methods based on multiple fossil occurrences. Although most of these methods assume uniform preservation rates, this assumption is unsupported over geological timescales. On geologically long timescales (more than 10 Myr), the origin and cessation of sedimentary basins, and long-term variations in tectonic subsidence, eustatic sea level and sedimentation rate control the availability of depositional facies that preserve the environments in which species lived. The loss of doomed sediments, those with a low probability of preservation, imparts a secular trend to fossil preservation. As a result, the fossil record is spatially and temporally non-uniform. Models of fossil preservation should reflect this non-uniformity by using empirical estimates of fossil preservation that are spatially and temporally partitioned, or by using indirect proxies of fossil preservation. Geologically, realistic models of preservation will provide substantially more reliable estimates of the origination of clades.
This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
Journal Article