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Abstract Number: 644

Decreased HVEM Expression in Lupus Patients and Impact of HVEM Knockout Mouse Model of Lupus Suggest a Role for BTLA Signaling in Disease Pathogenesis

Andrew Vendel1, Kimberly Griffiths 1, Antje Rhode-Kurnow 2, Eve Merriman 1, Mark Daniels 1, William Chang 1 and Carl Ware 2, 1Lilly Biotechnology Center, San Diego, CA, 2Sanford Burnham Prebys Medical Research Institute, La Jolla, CA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Lupus and pathogenesis

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Session Information

Date: Sunday, November 10, 2019

Session Title: SLE – Clinical Poster I: Epidemiology & Pathogenesis

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: B and T Lymphocyte Attenuator (BTLA; CD272) is an Ig superfamily member and part of a family of checkpoint receptors that negatively regulate immune cell activation. BTLA is primarily expressed on B cells, T cells, and dendritic cells with highest expression on B and plasmacytoid dendritic cells, followed by CD4+ T cells, then lowest expression on myeloid dendritic cells, gamma-delta (gd) and CD8+ T cells (Murphy & Murphy, 2010).  The natural ligand for BTLA is the TNF receptor superfamily member, herpes virus entry mediator (HVEM; TNFRSF14) and binding of HVEM to BTLA leads to attenuation of lymphocyte activation (Gonzalez, 2005).  In this study we evaluated the role of BTLA and HVEM expression in the pathogenesis of SLE.

Methods: Methods: Healthy volunteer PBMCs were evaluated by mass cytometry (CyToF) to establish baseline expression of BTLA and HVEM on human lymphocytes and compared to SLE patient PBMCs (N=5) acquired by a vendor (SanguineBio) during self-reported flare.  The role of BTLA signaling in a mouse model of lupus was examined using the BM12 lupus model where donor cells were transferred into the HVEM knockout or C57BL/6J control recipient mice (N=11 and 9, respectively).

Results: Results: High levels of BTLA protein was observed on B cells, CD4+ T cells, CD8+ T cells and plasmacytoid dendritic cells in healthy control PBMCs.   HVEM protein levels were lower in SLE patients compared to RA patients and healthy controls, while BTLA levels were similar between SLE and RA and controls.  The BM12 lupus model does not generally present with significant kidney involvement.  However, the HVEM recipient mice had increased prevalence of kidney disease (50%), as measured by albumin/creatinine ratio (ACR) greater than 300 mg/mg, compared to C57BL/6J control mice (22%).

Conclusion: Conclusions: These studies confirmed that BTLA protein is present on key immune cells linked to the pathogenesis of SLE.  Reduced HVEM protein expression in SLE patients in flare compared to RA and healthy donors indicate that SLE is associated with ligand deficiency in the BTLA system.  Furthermore, in a preclinical model of lupus using HVEM knockout mice demonstrate that disrupting this signaling system exacerbates disease pathogenesis.  These data provide clinical rationale for evaluating a BTLA agonist in SLE.  A phase 1 trial with a BTLA agonist antibody in healthy volunteers is in progress.


Disclosure: A. Vendel, Eli Lilly and Company, 1, 3, 4; K. Griffiths, Eli Lilly and Company, 3, 4; A. Rhode-Kurnow, Eli Lilly and Company, 2; E. Merriman, Eli Lilly and Company, 3, 4; M. Daniels, Eli Lilly and Company, 1, 3, 4, Eli Lilly and Company, 3, 4; W. Chang, Eli Lilly and Company, 1, 3, 4; C. Ware, Eli Lilly and Company, 2.

To cite this abstract in AMA style:

Vendel A, Griffiths K, Rhode-Kurnow A, Merriman E, Daniels M, Chang W, Ware C. Decreased HVEM Expression in Lupus Patients and Impact of HVEM Knockout Mouse Model of Lupus Suggest a Role for BTLA Signaling in Disease Pathogenesis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/decreased-hvem-expression-in-lupus-patients-and-impact-of-hvem-knockout-mouse-model-of-lupus-suggest-a-role-for-btla-signaling-in-disease-pathogenesis/. Accessed August 15, 2022.
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