ABSTRACT
In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.
Subject(s)
Autoantibodies/blood , Blood-Brain Barrier/metabolism , Mood Disorders/metabolism , Parkinson Disease/metabolism , Receptors, N-Methyl-D-Aspartate/immunology , Schizophrenia/metabolism , Adult , Aged , Animals , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Cerebral Cortex/metabolism , Endocytosis/physiology , Female , Genome-Wide Association Study , Humans , Influenza, Human/genetics , Influenza, Human/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mood Disorders/genetics , Neurons/metabolism , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Receptors, N-Methyl-D-Aspartate/genetics , Schizophrenia/geneticsABSTRACT
Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3'untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia.
Subject(s)
Membrane Glycoproteins/genetics , Nerve Tissue Proteins/genetics , Phobic Disorders/genetics , Adult , Amygdala/chemistry , Animals , Behavior, Animal , Electroretinography , Female , Genetic Engineering/methods , Heterozygote , Humans , Male , Mice , Mice, Inbred C57BL , Psychological Tests , Reflex, Startle/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stress, Psychological/geneticsABSTRACT
OBJECTIVES: Rheumatoid arthritis (RA) is a systemic, inflammatory disease. Renal involvement worsens the course of RA and increases mortality. It is suggested that chronic inflammatory processes may contribute to renal impairment. The aim of this study was to investigate the impact of chronic inflammation and RA activity on glomerular filtration rate (GFR). METHODS: The study population consisted of 140 RA patients. High disease activity was observed in 42 patients (30%), and long-term RA (duration ≥ 10 years) in 64 (45.7%). Measures of renal function included: serum cystatin C, serum creatinine (SCr), and creatinine-based estimated GFR (eGFR) calculated by Cockcroft and Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas. RESULTS: The mean (SD) cystatin C concentration was 0.77 (0.2) mg/L, SCr 0.71 (0.23) mg/dL, eGFR(CG) 110.5 (37.8) mL/min/1.73 m², and eGFR(MDRD) 109.5 (34.5) mL/min/1.73 m². Cystatin C levels correlated positively with creatinine, and negatively with eGFR(CG) and eGFR(MDRD). Cystatin C concentration was significantly higher in patients with high disease activity, long-term RA, and hypertension, and in males. Patients currently being treated with biologics had non-significantly lower cystatin C levels than those treated with conventional modifying drugs. Cystatin C levels were significantly associated with markers of clinical, functional disease activity, and markers of inflammation. By contrast, there were no such correlations with other parameters of renal function. CONCLUSIONS: In patients with RA, cystatin C may be not only an indicator of GFR but also a marker of intensity of chronic inflammatory processes.
