title: 16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus.
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.
authors.affiliation: The Zabludovicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, 2 Derech Sheba St,, Ramat Gan, 52621, Israel. kivitys@gmail.com
authors.forename: Shaye
authors.initials: S
authors.lastname: Kivity
authors.forename: Aviva
authors.initials: A
authors.lastname: Katzav
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Arango
authors.forename: Moran
authors.initials: M
authors.lastname: Landau-Rabi
authors.forename: Yaron
authors.initials: Y
authors.lastname: Zafrir
authors.forename: Nancy
authors.initials: N
authors.lastname: Agmon-Levin
authors.forename: Miri
authors.initials: M
authors.lastname: Blank
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.forename: Edna
authors.initials: E
authors.lastname: Mozes
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000633:toxicity*; D001921:Brain / Q000473:pathology; D060825:Cognitive Dysfunction / Q000139:chemically induced*; D004660:Encephalitis / Q000139:chemically induced*; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H
chemical_list: D000906:Antibodies
references.citation: Immunol Lett. 1988 Sep;19(1):77-83
references.pmid: 3263949
references.citation: N Engl J Med. 1987 Jul 30;317(5):265-71
references.pmid: 3496538
references.citation: Immunol Lett. 1986 Jun;12(5-6):313-9
references.pmid: 3525398
references.citation: Isr J Med Sci. 1992 Jul;28(7):422-7
references.pmid: 1506165
references.citation: Ann N Y Acad Sci. 2010 Apr;1193:70-7
references.pmid: 20398010
references.citation: J Autoimmun. 2009 Aug;33(1):77-82
references.pmid: 19346102
references.citation: Arthritis Rheum. 2008 Nov;58(11):3286-98
references.pmid: 18975345
references.citation: Behav Brain Res. 1999 Mar;99(2):191-200
references.pmid: 10512585
references.citation: Clin Rheumatol. 2005 Aug;24(4):394-7
references.pmid: 15662488
references.citation: J Alzheimers Dis. 2013;33(2):317-21
references.pmid: 22954670
references.citation: J Immunol. 1985 Jul;135(1):261-4
references.pmid: 3873490
references.citation: Autoimmun Rev. 2005 Jul;4(6):329-44
references.pmid: 16081024
references.citation: Clin Exp Immunol. 1986 Nov;66(2):255-61
references.pmid: 3102132
references.citation: J Clin Invest. 1985 Jul;76(1):287-94
references.pmid: 3874881
references.citation: Proc Natl Acad Sci U S A. 1988 Apr;85(7):2260-4
references.pmid: 3258423
references.citation: Nat Med. 2001 Nov;7(11):1189-93
references.pmid: 11689882
references.citation: Autoimmunity. 1989;4(4):277-87
references.pmid: 2518831
references.citation: Prog Neurobiol. 2011 Nov;95(3):301-33
references.pmid: 21889967
references.citation: Trends Immunol. 2009 Aug;30(8):409-14
references.pmid: 19643667
references.citation: Lancet. 1984 Aug 25;2(8400):417-22
references.pmid: 6147499
references.citation: Autoimmunity. 1988;1(1):67-75
references.pmid: 2979607
references.citation: J Exp Med. 1983 Sep 1;158(3):718-30
references.pmid: 6886627
references.citation: J Immunol. 1997 Aug 15;159(4):2033-41
references.pmid: 9257871
references.citation: Semin Arthritis Rheum. 2007 Apr;36(5):297-315
references.pmid: 17258299
references.citation: J Exp Med. 2007 Dec 24;204(13):3221-34
references.pmid: 18056288
references.citation: FASEB J. 1990 Jun;4(9):2646-51
references.pmid: 2140806
references.citation: Autoimmun Rev. 2010 Nov;10(1):22-6
references.pmid: 20659591
references.citation: Arthritis Rheum. 2007 Mar;56(3):938-48
references.pmid: 17328071
references.citation: Clin Immunol Immunopathol. 1984 May;31(2):261-71
references.pmid: 6370522
references.citation: Lupus. 2003;12(6):436-42
references.pmid: 12873044
references.citation: Rheumatology (Oxford). 2001 Jul;40(7):750-6
references.pmid: 11477279
references.citation: Arthritis Rheum. 1999 Apr;42(4):599-608
references.pmid: 10211873
references.citation: Neurology. 2002 Apr 23;58(8):1214-20
references.pmid: 11971089
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14515-20
references.pmid: 15452348
references.citation: Eur J Neurosci. 2007 Jan;25(1):281-90
references.pmid: 17241289
references.citation: J Autoimmun. 2008 Dec;31(4):393-8
references.pmid: 18947972
references.citation: Lupus. 2001;10(7):496-9
references.pmid: 11480848
references.citation: Semin Arthritis Rheum. 2011 Aug;41(1):1-11
references.pmid: 20965549
references.citation: N Engl J Med. 1983 Feb 24;308(8):414-20
references.pmid: 6823251
references.citation: FASEB J. 1994 Dec;8(15):1296-301
references.pmid: 8001742
references.citation: Clin Immunol Immunopathol. 1987 May;43(2):265-72
references.pmid: 3568459
references.citation: Ann N Y Acad Sci. 2009 Sep;1173:422-6
references.pmid: 19758181
references.citation: Semin Arthritis Rheum. 2004 Oct;34(2):501-37
references.pmid: 15505768
references.citation: Rheumatol Int. 2000;19(3):83-8
references.pmid: 10776685
references.citation: Neurology. 2001 Aug 14;57(3):496-500
references.pmid: 11502919
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18569-74
references.pmid: 20921396
references.citation: Autoimmun Rev. 2011 May;10(7):389-96
references.pmid: 21241830
references.citation: J Clin Invest. 1982 Jul;70(1):205-8
references.pmid: 7085884
references.citation: Arthritis Rheum. 2009 Dec;60(12):3744-54
references.pmid: 19950283
references.citation: Immunol Lett. 1988 Mar;17(3):285-91
references.pmid: 3372009
references.citation: Arthritis Rheum. 2006 Aug;54(8):2505-14
references.pmid: 16868971
references.citation: Arch Int Pharmacodyn Ther. 1977 Oct;229(2):327-36
references.pmid: 596982
references.citation: Autoimmun Rev. 2007 Jan;6(3):119-25
references.pmid: 17289545
references.citation: Autoimmunity. 2002 Mar;35(2):79-86
references.pmid: 12071439
references.citation: Immunity. 2004 Aug;21(2):179-88
references.pmid: 15308099
references.citation: Autoimmun Rev. 2012 Jun;11(8):596-603
references.pmid: 22041579
references.citation: Isr Med Assoc J. 2008 Jan;10(1):37-9
references.pmid: 18300569
references.citation: Clin Exp Rheumatol. 1998 Nov-Dec;16(6):717-20
references.pmid: 9844765
references.citation: Int Immunol. 1995 Apr;7(4):689-96
references.pmid: 7547696