Role of CD45 Dependent Signaling in B-cell Subsets in Atherosclerosis
Poster #: 086
Session/Time: A
Author:
Aravindan Balaguru, BS
Mentor:
Elena Galkina, PhD
Research Type: Clinical Research
Abstract
INTRODUCTION:
Atherosclerosis is an inflammatory disease characterized by the deposition of oxidized lipids within medium and large-sized arteries. A chronic inflammatory environment is indispensable in the progression of atherosclerosis. The existence of antibodies against LDL, oxLDL, and ApoB suggests a spectrum of different antigens that can activate the immune system in atherosclerosis. B cells play a subset specific role in atherosclerosis with marginal zone (MZ) cells and B1 B cells playing an atheroprtective role and follicular (FO) and innate response activator (IRA) B cells playing an atherogenic role. While the role of B cell subsets in atherosclerosis is well-established, the mechanisms by which B cell subsets are activated are unclear. B cell activation can occur through antigen binding and signaling through the B cell receptor (BCR) along with activation of toll-like receptors (TLR). CD45 is a protein tyrosine phosphatase that supports BCR signaling. Currently, it is not well understood how CD45 functions in TLR induced B cell in atherosclerosis.
METHODS:
We utilized a transgenic mouse model that express low levels of CD45 (CD45 L/L) and examined B cell subset specific activation in response to BCR and TLR stimulation. Flow cytometry was used to analyze Ca2+ flux responses after stimulation. To test the effects of low expression of CD45 in CD45L/L B cells in atherosclerosis, we performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient atherosclerotic prone mice (uM-/-Apoe-/-) and fed a high fat diet for 23-28 weeks. Hearts were collected and MOVAT stainig was performed to assess lesion formation.
RESULTS AND CONCLUSION:
We demonstrate that LPS stimulated TLR activation of B cells occurs in a subset specific manner and is affected by expression of CD45. MZ and B1 B cells are the most sensitive to LPS stimulation as indicated by increased Ca2+ flux. Reduced CD45 expression attenuates TLR induced B cell activation in all B cell subsets. In atherosclerosis, CD45 L/L recipients had increased lesion formation. This suggests that CD45 impacts TLR induced B cell activation in a subset specific manner. Attenuated MZ and B1 B cell activation expressing low CD45 levels suggest an atheroprotective role of TLR signaling.
Atherosclerosis is an inflammatory disease characterized by the deposition of oxidized lipids within medium and large-sized arteries. A chronic inflammatory environment is indispensable in the progression of atherosclerosis. The existence of antibodies against LDL, oxLDL, and ApoB suggests a spectrum of different antigens that can activate the immune system in atherosclerosis. B cells play a subset specific role in atherosclerosis with marginal zone (MZ) cells and B1 B cells playing an atheroprtective role and follicular (FO) and innate response activator (IRA) B cells playing an atherogenic role. While the role of B cell subsets in atherosclerosis is well-established, the mechanisms by which B cell subsets are activated are unclear. B cell activation can occur through antigen binding and signaling through the B cell receptor (BCR) along with activation of toll-like receptors (TLR). CD45 is a protein tyrosine phosphatase that supports BCR signaling. Currently, it is not well understood how CD45 functions in TLR induced B cell in atherosclerosis.
METHODS:
We utilized a transgenic mouse model that express low levels of CD45 (CD45 L/L) and examined B cell subset specific activation in response to BCR and TLR stimulation. Flow cytometry was used to analyze Ca2+ flux responses after stimulation. To test the effects of low expression of CD45 in CD45L/L B cells in atherosclerosis, we performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient atherosclerotic prone mice (uM-/-Apoe-/-) and fed a high fat diet for 23-28 weeks. Hearts were collected and MOVAT stainig was performed to assess lesion formation.
RESULTS AND CONCLUSION:
We demonstrate that LPS stimulated TLR activation of B cells occurs in a subset specific manner and is affected by expression of CD45. MZ and B1 B cells are the most sensitive to LPS stimulation as indicated by increased Ca2+ flux. Reduced CD45 expression attenuates TLR induced B cell activation in all B cell subsets. In atherosclerosis, CD45 L/L recipients had increased lesion formation. This suggests that CD45 impacts TLR induced B cell activation in a subset specific manner. Attenuated MZ and B1 B cell activation expressing low CD45 levels suggest an atheroprotective role of TLR signaling.