No abstract

Background Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated. Methods Female and male A20 heterozygous mice (A20 +/− ) and wildtype littermates were tested in an extensive behavioral battery. This was done at the age of 10±2weeks and 24 ​± ​2 weeks to evaluate the impact of aging. To investigate the contribution of an acute immunological challenge, LPS was injected intracerebroventricularly at the age of 10±2weeks followed by behavioral analysis. Underlying molecular mechanisms were evaluated in gene expression assays on hippocampus and cortex. White blood cell count and blood-brain barrier permeability were analyzed to determine whether peripheral inflammation is a relevant factor. Results A20 heterozygosity predisposes to cognitive symptoms that were observed at the age of 10 ​± ​2 weeks and 24 ​± ​2 weeks. Young A20 +/− males and females showed a subtle cognitive phenotype (10±2weeks) with distinct neuroinflammatory phenotypes. Aging was associated with clear neuroinflammation in female A20 +/− mice only. The genetic predisposition in combination with an environmental stimulus exacerbates the behavioral impairments related to anxiety, cognitive dysfunction and sensorimotor gating. This was predominantly observed in females. Furthermore, signs of neuroinflammation were solely observed in female A20 +/− mice. All above observations were made in the absence of peripheral inflammation and of changes in blood-brain barrier permeability, thus consistent with the CNS-primary hypothesis. Conclusions We show that A20 heterozygosity is a predisposing factor for NPSLE. Further mechanistic insight and possible therapeutic interventions can be studied in this mouse model that recapitulates several key hallmarks of the disease.

No abstract

ADH, α‐GPDH and SOD enzyme activities have been measured in lines of Drosophila melanogaster homozygous and/or heterozygous for chromosomes extracted from two different populatioi Globally the results demonstrate that factors other than structural genes are determining the observed pattern of enzyme activities. ADH and α‐GPDH activities are, however, more affected than SOD by these factors. Geographic origin, sex, chromosome, genetic background of the lines, containing regulatory genes in a broad sense, can be mentioned as the more relevant factors that influencing enzyme activities. A high and significant correlation is detected between ADH and α‐GPDH enzyme activities and it can be interpreted as due to linkage disequilibrium among these two loci. SOD activity shows a lesser correlation with ADH and α‐GPDH because it is less variable within population, i.e. it is a more canalized character. Finally, a principal component analysis, using the three enzyme systems shows that both populations are clearly separated, with a first principal component explaining 71.1 percent of the observed variance.