Date: Monday, November 6, 2017
Session Title: T Cell Biology and Targets in Autoimmune Disease Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Activation of polyclonal CD4+ T cells and B cells is a hallmark of human and murine lupus, which suggests a global defect in the maintenance of T and B cell tolerance. Recent studies unveil a central role of T follicular helper (TFH) cells that is critical in providing help to B cells in the overproduction of pathogenic auto-antibodies leading to tissue damage in systemic lupus erythematosus (SLE). Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ubiquitin ligase which has been shown to increase the activation threshold of immune cells. Bcl-6 is the master transcription regulator that controls the differentiation of naïve T cells into TFH cells. A link between Cbl-b/ Bcl-6 and SLE has not been established.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy subjects and patients with active or inactive SLE as determined by SLEDAI scores. CD4+ cells prepared from PBMCs were stained for CXCR5, ICOS, PD-1, and Cbl-b and mean fluorescent intensity (MFI) of Cbl-b was determined for positive cell populations. Additionally, immunoprecipitation (IP) was performed with PBMC lysates from healthy subjects with anti-human Bcl-6 monoclonal antibody, and then probed with rabbit anti-human Cbl-b.
Results: Flow cytometry analysis gating on CXCR5+, ICOS+, PD-1+ TFH cells demonstrated significantly lower MFIs of Cbl-b in SLE patients relative to healthy controls (P < 0.05). Moreover, Cbl-b levels were lower in active SLE patients than those with less disease activity. At the molecular level, preliminary IP data show that Cbl-b forms a complex with Bcl-6 in human TFH cells
Conclusion: The association of Cbl-b and Blc-6 suggests that Cbl-b could be the E3 ubiquitin ligase for Bcl-6. Down regulation of Cbl-b in the TFH cells of patients with SLE may be the primary cause of heightened TFH and germinal center B cells in lupus and the decreased expression of Cbl-b could serve as a biomarker for lupus flares. Ongoing studies examine Cbl-b expression prospectively in SLE patients who have a remitting relapsing disease course and the functional implication of down regulation of Cbl-b on human TFH cells.
To cite this abstract in AMA style:Hampton J, Valiente GR, Munir A, Tsuzuki Wada T, Willis W, Young NA, Wu LC, Zhang J, Jarjour W. Cbl-b Associates with Bcl-6 and Is Differentially Expressed in Circulating Follicular T Helper Cells of Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/cbl-b-associates-with-bcl-6-and-is-differentially-expressed-in-circulating-follicular-t-helper-cells-of-patients-with-systemic-lupus-erythematosus/. Accessed July 14, 2020.
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