Targeting of myelin protein zero in a spontaneous autoimmune polyneuropathy.
Elimination of the costimulatory molecule B7-2 prevents autoimmune diabetes in NOD mice, but leads to the development of a spontaneous autoimmune polyneuropathy (SAP), which resembles the human disease chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, we examined the immunopathogenic mechanisms in this model, including identification of SAP Ags. We found that B7-2-deficient NOD mice exhibit changes in cytokine and chemokine gene expression in spleens over time. There was an increase in IL-17 and a decrease in IL-10 transcript levels at 4 mo (preclinical phase), whereas IFN-gamma expression peaked at 8 mo (clinical phase). There was also an increase in transcript levels of Th1 cytokines, CXCL10, and RANTES in sciatic nerves of mice that developed SAP. Splenocytes from SAP mice exhibited proliferative and Th1 cytokine responses to myelin P0 (180-199), but not to other P0 peptides or P2 (53-78). Adoptive transfer of P0-reactive T cells generated from SAP mice induced neuropathy in four of six NOD.SCID mice. Data from i.v. tolerance studies indicate that myelin P0 is one of the autoantigens targeted by T cells in SAP in this model. The expression of P0 by peri-islet Schwann cells provides a potential mechanism linking islet autoimmunity and inflammatory neuropathy.
Kim
Hye-Jung
HJ
Department of Neurology, The University of Chicago, Chicago, IL 60637, USA.
Jung
Cha-Gyun
CG
Jensen
Mark A
MA
Dukala
Danuta
D
Soliven
Betty
B
D000595:Amino Acid Sequence; D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D018993:Myelin P0 Protein / Q000276:immunology / Q000378:metabolism*; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012584:Sciatic Nerve / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D018993:Myelin P0 Protein