Sabrina Ceeraz1,2, Susan K Eszterhas1,3, Petra A Sergent1,2, David A Armstrong4,5, Alix Ashare4,5, Thomas Broughton1,2, Li Wang6, Dov Pechenick7, Christopher M Burns8, Randolph J Noelle1,2,7, Matthew P Vincenti3,5, Roy A Fava9,10. 1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA. 2. Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH, 03756, USA. 3. Department of Veterans Affairs, Research Service, White River Junction, VT, 05009, USA. 4. Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. 5. Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, NH, 03756, USA. 6. Microbiology and Immunology & Cancer Center Medical College of Wisconsin, Milwaukee, WI, USA. 7. ImmuNext INC, 1 Medical Center Drive, Lebanon, NH, 03756, USA. 8. Department of Medicine, Section of Rheumatology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA. 9. Department of Veterans Affairs, Research Service, White River Junction, VT, 05009, USA. roy.a.fava@dartmouth.edu. 10. Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, NH, 03756, USA. roy.a.fava@dartmouth.edu.
Abstract
BACKGROUND: In addition to activated T cells, the immune checkpoint inhibitor "V domain-containing Ig suppressor of T-cell activation" (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. METHODS: VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages. RESULTS: VISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritis patients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn). CONCLUSIONS: VISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes.
BACKGROUND: In addition to activated T cells, the immune checkpoint inhibitor "V domain-containing Ig suppressor of T-cell activation" (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. METHODS:VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages. RESULTS:VISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritispatients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn). CONCLUSIONS:VISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes.
Authors: Li Wang; Isabelle Le Mercier; Juan Putra; Wenna Chen; Jun Liu; Austin D Schenk; Elizabeth C Nowak; Arief A Suriawinata; Jiannan Li; Randolph J Noelle Journal: Proc Natl Acad Sci U S A Date: 2014-09-29 Impact factor: 11.205
Authors: Thomas W K Broughton; Mohamed A ElTanbouly; Evelien Schaafsma; Jie Deng; Aurélien Sarde; Walburga Croteau; Jiannan Li; Elizabeth C Nowak; Rodwell Mabaera; Nicole C Smits; Anna Kuta; Randolph J Noelle; J Louise Lines Journal: Front Immunol Date: 2019-11-19 Impact factor: 8.786
Authors: Rebeca Hid Cadena; Rosanne D Reitsema; Minke G Huitema; Yannick van Sleen; Kornelis S M van der Geest; Peter Heeringa; Annemieke M H Boots; Wayel H Abdulahad; Elisabeth Brouwer Journal: Front Immunol Date: 2019-07-16 Impact factor: 7.561