title: Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system.
abstract: BACKGROUND
  The cellular prion protein (PrPc) is a host-encoded glycoprotein whose transconformation into PrP scrapie (PrPSc) initiates prion diseases. The role of PrPc in health is still obscure, but many candidate functions have been attributed to the protein, both in the immune and the nervous systems. Recent data show that experimental autoimmune encephalomyelitis (EAE) is worsened in mice lacking PrPc. Disease exacerbation has been attributed to T cells that would differentiate into more aggressive effectors when deprived of PrPc. However, alternative interpretations such as reduced resistance of neurons to autoimmune insult and exacerbated gliosis leading to neuronal deficits were not considered.
  
  
  METHODS
  To better discriminate the contribution of immune cells versus neural cells, reciprocal bone marrow chimeras with differential expression of PrPc in the lymphoid or in the central nervous system (CNS) were generated. Mice were subsequently challenged with MOG35-55 peptide and clinical disease as well as histopathology were compared in both groups. Furthermore, to test directly the T cell hypothesis, we compared the encephalitogenicity of adoptively transferred PrPc-deficient versus PrPc-sufficient, anti-MOG T cells.
  
  
  RESULTS
  First, EAE exacerbation in PrPc-deficient mice was confirmed. Irradiation exacerbated EAE in all the chimeras and controls, but disease was more severe in mice with a PrPc-deleted CNS and a normal immune system than in the reciprocal construction. Moreover, there was no indication that anti-MOG responses were different in PrPc-sufficient and PrPc-deficient mice. Paradoxically, PrPc-deficient anti-MOG 2D2 T cells were less pathogenic than PrPc-expressing 2D2 T cells.
  
  
  CONCLUSIONS
  In view of the present data, it can be concluded that the origin of EAE exacerbation in PrPc-ablated mice resides in the absence of the prion protein in the CNS. Furthermore, the absence of PrPc on both neural and immune cells does not synergize for disease worsening. These conclusions highlight the critical role of PrPc in maintaining the integrity of the CNS in situations of stress, especially during a neuroinflammatory insult.
authors.affiliation: INSERM, UMR S 938, Centre de Recherche Hôpital Saint-Antoine, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gourdain
authors.forename: Clara
authors.initials: C
authors.lastname: Ballerini
authors.forename: Arnaud B
authors.initials: AB
authors.lastname: Nicot
authors.forename: Claude
authors.initials: C
authors.lastname: Carnaud
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology* / Q000528:radiation effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000009:adverse effects; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009474:Neurons / Q000473:pathology*; D010446:Peptide Fragments / Q000009:adverse effects; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D018621:PrPC Proteins / Q000172:deficiency*; D013997:Time Factors; D014916:Whole-Body Irradiation
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018621:PrPC Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse