Immune Reaction to Type XVII Collagen Induces Intramolecular and Intermolecular Epitope Spreading in Experimental Bullous Pemphigoid Models.

Abstract

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is induced by autoantibodies to type XVII collagen (COL17). Previous studies demonstrated that COL17 harbors several epitopes targeted by autoreactive T and B cells and that the target epitopes change sequentially during the disease course. To elucidate the details of the humoral immune response to COL17, we used an active BP mouse model in which BP is induced by the adoptive transfer of spleen cells from wild-type mice immunized with human COL17-expressing skin grafting to immunodeficient COL17-humanized (Rag-2-/-, mouse Col17-/-, human COL17+) mice. By immunoblot analysis, antibodies to the NC16A domain and other extracellular domains (ECDs) of COL17 were detected earlier than antibodies to intracellular domains (ICDs) in the active BP model. Time course analysis by enzyme-linked immunosorbent assay demonstrated a delayed peak of antibodies to ICD epitopes in active BP model. The blockade of CD40-CD40 ligand interaction soon after the adoptive transfer suppressed the production of antibodies to the non-collagenous 16A (NC16A) domain but not to an ICD epitope, suggesting the sequential activation from T and B cells against the ECD epitopes including the NC16A domain to those against ICD epitopes in vivo. Both wild-type mice immunized with a fragment of the NC16A domain and the recipients of those spleen cells produced IgG antibodies to ICD and ECD epitopes, showing intramolecular epitope spreading from the NC16A domain to other epitopes of COL17. Furthermore, we found that a portion of the active BP model mice show intermolecular epitope spreading from human COL17 to murine BP230. The appearance of antibodies to ICD epitopes of COL17 or of antibodies to murine BP230 did not correlate with the skin changes in the mice, suggesting that those antibodies have low pathogenicity. These results suggest that the immune response to the ECD epitopes of COL17, especially to the NC16A domain, triggers intramolecular, and intermolecular epitope spreading to ICD epitopes of COL17 and to murine BP230. These novel findings provide insight into the mechanism of epitope spreading in organ-specific, antibody-mediated autoimmune disorders.

• Authors: Hideyuki Ujiie, Norihiro Yoshimoto, Ken Natsuga, Ken Muramatsu, Hiroaki Iwata, Wataru Nishie, Hiroshi Shimizu
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 1410 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31275329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Autoantigens
• CD40 Antigens
• Epitopes
• Non-Fibrillar Collagens
• CD40 Ligand

Topics

• Animals
• Autoantibodies (immunology)
• Autoantigens (immunology)
• Autoimmunity
• CD40 Antigens (metabolism)
• CD40 Ligand (metabolism)
• Disease Models, Animal
• Disease Susceptibility (immunology)
• Epitopes (immunology)
• Humans
• Immunomodulation
• Mice
• Mice, Knockout
• Mice, Transgenic
• Models, Biological
• Non-Fibrillar Collagens (immunology)
• Pemphigoid, Bullous (etiology, metabolism, pathology)
• Protein Binding
• Collagen Type XVII