Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity

ObjectiveTo isolate and characterize muscle-specific kinase (MuSK) monoclonal antibodies from patients with MuSK myasthenia gravis (MG) on a genetic and functional level.MethodsWe generated recombinant MuSK antibodies from patient-derived clonal MuSK-specific B cells and produced monovalent Fab fragments from them. Both the antibodies and Fab fragments were tested for their effects on neural agrin-induced MuSK phosphorylation and acetylcholine receptor (AChR) clustering in myotube cultures.ResultsThe isolated MuSK monoclonal antibody sequences included IgG1, IgG3, and IgG4 that had undergone high levels of affinity maturation, consistent with antigenic selection. We confirmed their specificity for the MuSK Ig-like 1 domain and binding to neuromuscular junctions. Monovalent MuSK Fab, mimicking functionally monovalent MuSK MG patient Fab-arm exchanged serum IgG4, abolished agrin-induced MuSK phosphorylation and AChR clustering. Surprisingly, bivalent monospecific MuSK antibodies instead activated MuSK phosphorylation and partially induced AChR clustering, independent of agrin.ConclusionsPatient-derived MuSK antibodies can act either as MuSK agonist or MuSK antagonist, depending on the number of MuSK binding sites. Functional monovalency, induced by Fab-arm exchange in patient serum, makes MuSK IgG4 antibodies pathogenic

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory disease

Passive transfer models of myasthenia gravis with muscle-specific kinase antibodies

Neurological Motor DisordersParoxysmal Cerebral Disorder

Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression

OBJECTIVES Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). METHODS Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. RESULTS Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1β or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1β, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). CONCLUSIONS Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment

Activity Impairment, Work Status, and Work Productivity Loss in Adults 5-7 Years after Burn Injuries

An important aspect of the rehabilitation of burn patients is social participation, including daily activities and work. Detailed information on long-term activity impairment and employment is scarce. Therefore, we investigated activity impairment, work status, and work productivity loss in adults 5-7 years following burn injuries, and investigated associations with burn-specific health-related quality of life (HRQL) domains. Adult participants completed the Work Productivity and Activity Impairment General Health questionnaire and the Burn Specific Health Scale-brief (BSHS-B) 5-7 years post-burn. Outcomes were compared between participants with mild/intermediate and severe burns (>20% total body surface area burned). Seventy-six (36%) of the 213 participants experienced some degree of activity impairment due to burn-related problems 5-7 years post-burn. Seventy percent of the population was employed; 12% of them experienced work productivity loss due to burn-related problems. Nineteen percent reported changes in their work situation (partly) because of the burn injury. A higher proportion of participants with severe burns had activity impairments (56% vs 29%; P =. 001) and work productivity loss (26% vs 8%; P <. 001) compared to participants with mild/intermediate burns. Activity impairment and work productivity loss were both associated with burn-related work problems and lower mood, measured with the BSHS-B. In conclusion, a substantial part of the study population experienced activity impairment and work productivity loss, was unemployed, and/or reported changes in their work situation due to their injury. Particularly patients with severe burns reported productivity loss and had lower employment rates. This subscribes the importance of addressing work-related functioning in the rehabilitation of burn patients

Regulation of Tie2 and Tie1 expression during macrophage polarization.

<p>(A) FACS analysis of macrophages polarized for 7 d with the indicated cytokines, using Ig control (filled grey area) and Tie2 antibodies (open area). Experiments shown are representative of 7 independent experiments. (B) Quantification of relative Tie2 surface expression (geomean) and Tie2 mRNA expression (C) by macrophages differentiated in medium alone or with the indicated cytokine. (D) Quantification of relative Tie1 mRNA expression and (E) Tie2 mRNA expression relative to Tie1 by macrophages differentiated in medium alone or with indicated cytokine. qPCR data is shown as relative quantity, as described in material and methods Values are the mean ± SEM of 5–7 independent experiments. ^*P<0.05. ^**P<0.01 versus macrophages differentiated in medium alone. Kruskal-Wallis test was used for statistical analyses.</p