Open Access Research article

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus

Shaye Kivity12*, Aviva Katzav13, Maria Teresa Arango145, Moran Landau-Rabi1, Yaron Zafrir1, Nancy Agmon-Levin1, Miri Blank1, Juan-Manuel Anaya4, Edna Mozes6, Joab Chapman13 and Yehuda Shoenfeld17

Author Affiliations

1 The Zabludovicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, 2 Derech Sheba St., Ramat Gan, 52621, Israel

2 Rheumatic Disease Unit, Sheba Medical Center, Tel-Hashomer, 2 Derech Sheba St., Ramat Gan, 52621, Israel

3 Department of Neurology, Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, 2 Derech Sheba St., Ramat Gan, 52621, Israel

4 Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Kr 24 N°63C-69, Bogotá, DC, 111221, Colombia

5 Doctoral Program in Biomedical Sciences, Universidad del Rosario, Kr 24 N°63C-69, Bogotá, DC, 111221, Colombia

6 Department of Immunology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot, 76100, Israel

7 Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel-Aviv University, Haim Lebanon St., Ramat Aviv, 69978, Israel

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BMC Medicine 2013, 11:90  doi:10.1186/1741-7015-11-90

Published: 4 April 2013

Abstract

Background

The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naïve mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intra-cerebra-ventricularly (ICV) with the 16/6-Id antibody.

Methods

C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes.

Results

16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression–like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control.

Conclusions

Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus.

See related Commentary article: http://www.biomedcentral.com/1741-7015/11/91 webcite

Keywords:
Systemic lupus erythematosus; 16/6 idiotype; Anti-DNA; Neuropsychiatric lupus; Cognitive impairment