Cell adhesion molecules of the immunoglobulin supergene family as tissue‐specific autoantigens: induction of experimental allergic neuritis (EAN) by PO protein‐specific T cell lines

Abstract

The P0 glycoprotein is a homophilic cell adhesion molecule of the immunoglobulin supergene family which is responsible for maintaining the structure of compact internodal myelin in the peripheral nervous system (PNS). Utilizing a panel of synthetic P0 peptides two distinct T cell epitopes have been identified that can induce T cell-mediated experimental autoimmune neuritis (EAN) in the Lewis rat. One T cell epitope (amino acid residues 56-71), is located within the extracellular, immunoglobulin-like domain of P0, while the other disease-inducing T cell epitope (residues 180-199) is located within the proteins cytoplasmic carboxyterminal domain. The adoptive transfer of 10(6) CD4+ T line cells specific for either of these peptide antigens induced EAN in syngeneic recipients. However, while the pathogenic response induced by both peptide-specific T cell lines was identical, their epitopes differ markedly in their immunologic properties in vivo. In particular while the response to peptide p180-199 was immunodominant in animals immunized with either purified P0 protein or the native membrane-bound P0 protein in autologous rat peripheral nerve myelin, no response to peptide p56-71 was detected, indicating that this epitope is cryptic. This study provides the first experimental evidence that the immunoglobulin-like domains of members of the immunoglobulin supergene family can function as target autoantigens in T cell-mediated autoimmune disease.

Tolerance Induction by Intrathymic Expression of P0

“…Our results seem contradictory to recent data showing that P0-reactive T cells are eliminated in a gene-dosage dependent manner (10). However, those results were obtained using another peptide, P0 180 -199, which was initially described as an immunodominant peptide in Lewis rats (5). Our mapping experiments of the immune response to P0 on BL/6 background prompted us to use the immunodominant determinant of P0 (P0 41-60), which may behave differently compared with the P0 180 -199.…”

“…Studies in these P0-deficient mice revealed the potential of P0 to act as an immune target (2). Moreover, Ab responses to P0 have been detected in patients' sera with chronic polyneuritis (3) and immunization with P0 peptides and adoptive transfer of peptide-specific T cells induce experimental autoimmune neuritis in susceptible animals (4,5).…”

Immune Deficiency in Mouse Models for Inherited Peripheral Neuropathies Leads to Improved Myelin Maintenance

“…Why P 0 appears to be a main immunogenic component in P 0 ϩ/Ϫ mice is presently not known. In experimental autoimmune neuritis (EAN) in rat, P 2 is a much stronger neuritogen than P 0 (Linington et al, 1992), but there might be differences among species. On the other hand, even in heterozygous mutants, P 0 is still the most abundant peripheral myelin protein (Giese et al, 1992) which could explain a substantial role of P 0 as an immunogenic component.…”

Th1-like responses to peptides from peripheral nerve myelin proteins in patients with polyneuropathy associated with monoclonal gammopathy

“…In a study of T cell reactivity in GBS, all these peptides were shown to cause reactivity [23]. P2 57-81 [24], P0 56-71 and P0 180-199 [25] induce experimental allergic polyradiculoneuritis (EAN), which is the animal model of GBS, in rats. P0 56-71 is located in the extracellular immunoglobulin-like domain of P0, while P0 180-199 and P0 194-208 are located in the cytoplasmic carboxyterminal domain of the protein.…”