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"Smith, Kenneth"
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Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia
Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states.
We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls.
Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage.
Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.
Journal Article
T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
CD8 T-cell exhaustion, although a negative prognostic indicator during persistent infections, is shown to be associated with a good outcome in autoimmune and inflammatory diseases.
T-cell exhaustion a plus in autoimmunity
CD8 T-cell exhaustion occurs in chronic viral infections, which inhibits the immune response and facilitates viral persistence. Here Kenneth Smith and colleagues show that, in contrast, CD8 T-cell exhaustion is associated with a good outcome in autoimmune and inflammatory diseases. As in infections, exhaustion in autoimmunity correlates with a lack of CD4 co-stimulation. These findings raise the possibility that therapeutic manipulation of exhaustion might be used to suppress autoreactivity, an action that the authors demonstrate to be possible
in vitro
.
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence
1
. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory ‘help’ signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells
in vitro
, suggesting that each process plays a role in dictating outcome in autoimmune disease. The ‘non-exhausted’ T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.
Journal Article
Microelectronic circuits
CD-ROM contains: free student version of PSpice 9.2 Lite Edition (SPICE simulator) and new industry-based design examples.
Book
FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
Key Points
Fc receptor IIB for IgG (FcγRIIB) is the only inhibitory Fc receptor, is expressed on many cell types in the immune system and controls humoral responses, pro-inflammatory cytokine release, antigen uptake and presentation, immune complex handling and many other functions.
A role for FcγRIIB in controlling B cell tolerance and autoimmunity has been suggested by studies using FcγRIIB-deficient mice and confirmed by
in vivo
overexpression studies.
Spontaneous polymorphic variants alter the expression and/or function of FcγRIIB in both mice and humans, and have been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases.
FcγRIIB balances bacterial clearance and the risk of septic shock in mouse models.
Genetic studies have shown that an inhibitory, SLE-associated polymorphism of FcγRIIB can protect children from severe malaria, which could drive the high frequency of this polymorphism observed in sub-Saharan Africa and Southeast Asia, and thus begin to explain the increased susceptibility to SLE seen in people of African and Asian ethnicity.
The immunosuppressive effect of intravenous immunoglobulin is at least in part dependent on FcγRIIB, and the receptor itself is being investigated as a therapeutic target.
FcγRIIB is the only inhibitory Fc receptor for IgG, common genetic variants of which are associated with susceptibility to autoimmune disease but, also, with protection from severe malaria. Furthermore, understanding the function of FcγRIIB has important implications for the use of therapeutic antibodies.
FcγRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcγRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcγRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcγRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target.
Journal Article
Inkling
When an inkblot, who can write, listen, learn, and draw, jumps out of Mr. Rylance's sketchbook, Ethan believes he may be the answer to their problems and names him Inkling.
Book
Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease
Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46) and healthy controls (n = 43), revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.
Journal Article
Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19
Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.
Smith and colleagues find that a multivariate signature of unresolved inflammation and altered iron homeostasis detected beyond 2 weeks following acute COVID-19 onset was the strongest early differentiator of those who report long COVID symptoms at 3–10 months.
Journal Article