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VISTA deficiency attenuates antibody-induced arthritis and alters macrophage gene expression in response to simulated immune complexes.

VISTA deficiency attenuates antibody-induced arthritis and alters macrophage gene expression in response to simulated immune complexes.
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Ceeraz S, Eszterhas SK, Sergent PA, Armstrong DA, Ashare A, Broughton T, Wang L, Pechenick D, Burns CM, Noelle RJ, Vincenti MP, Fava RA,


Ceeraz S, Eszterhas SK, Sergent PA, Armstrong DA, Ashare A, Broughton T, Wang L, Pechenick D, Burns CM, Noelle RJ, Vincenti MP, Fava RA, (click to view)

Ceeraz S, Eszterhas SK, Sergent PA, Armstrong DA, Ashare A, Broughton T, Wang L, Pechenick D, Burns CM, Noelle RJ, Vincenti MP, Fava RA,

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Arthritis research & therapy 2017 12 0819(1) 270 doi 10.1186/s13075-017-1474-y
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.

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