title: B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells.
abstract: Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T(FH) cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T(FH) cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F(1) mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T(FH) cells and GC B cells as well as an overall decrease in the frequency of ICOS(+) T cells. Coculture experiments of Ag-primed B cells with CXCR5(+) or CXCR5(-) T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T(FH) cell pool is an important mechanism by which ICOS regulates Ab production.
authors.affiliation: Department of Inflammation, Amgen, Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hu
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Metz
authors.forename: James
authors.initials: J
authors.lastname: Chung
authors.forename: Gerald
authors.initials: G
authors.lastname: Siu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000502:physiology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D001323:Autoantibodies / Q000096:biosynthesis* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018122:B7-1 Antigen / Q000276:immunology* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D011897:Random Allocation; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D001323:Autoantibodies; D018122:B7-1 Antigen; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein