ABSTRACT
Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.
Subject(s)
Autoimmunity/genetics , Multiple Sclerosis/etiology , Multiple Sclerosis/metabolism , Phenotype , Transcription Factors/genetics , Vitamin D/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers , Case-Control Studies , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Susceptibility , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/immunology , Female , Gene Expression Profiling , Gene Expression Regulation , Genotype , Herpesvirus 4, Human/immunology , Humans , Inheritance Patterns , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Multiple Sclerosis/pathology , Polymorphism, Single Nucleotide , Seasons , Transcription Factors/metabolism , Vitamin D/pharmacology , Young AdultABSTRACT
Common variable immunodeficiency (CVID) is a B cell immunodeficiency disorder characterized frequently by failure of memory B cell development and antibody secretion. A unifying cellular pathogenesis for CVID has not been forthcoming, but given the immunoregulatory role of invariant NK (iNK) T cells and their absence in several other immunodeficiencies, we quantified these cells in the blood of 58 CVID patients. There was a marked decrease in the proportion of iNK T cells in CVID patients compared with controls. This was particularly notable in those with low isotype-switched memory B cells, but subset analysis demonstrated no difference when stratified by specific clinical features. We propose that the decreased proportion of iNK T cells in CVID might be linked to the failure of memory B cell generation, which may contribute to reduced antibody production in these patients.