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B cell responses to apoptotic cells in MFG-E8-/- mice

¹Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.

|October 5, 2018

Summary

Defective clearance of apoptotic cells in MFG-E8 deficient mice leads to lupus-like disease. This study reveals how B cells respond to apoptotic cells, impacting autoimmunity and highlighting TLR9 and TLR7 signaling roles in lupus pathogenesis.

Area of Science:

Immunology
Autoimmunity
Cellular Biology

Background:

MFG-E8 deficiency impairs apoptotic cell clearance, leading to lupus-like disease in certain mouse models.
The accumulation of apoptotic cells is a key factor in breaking immune tolerance.
MFG-E8-/- B6 mice offer a model to study peripheral B cell responses to apoptotic cells under non-inflammatory conditions.

Purpose of the Study:

To investigate B cell responses to accumulated apoptotic cells in MFG-E8 deficient mice.
To explore the role of MyD88 signaling and T cell help in antibody production against apoptotic cells.
To examine the differentiation of autoreactive B cells in response to apoptotic cell antigens and Toll-like receptor (TLR) signaling.

Main Methods:

Analysis of antibody production (IgG2c) against apoptotic cells and oxidized LDL in MFG-E8-/- B6 mice.
Assessment of marginal zone (MZ) B cell compartment size and function, including translocation into follicles.
Utilized BCR transgenic mice to study the differentiation of TLR9-dependent anti-dsDNA (56R) and TLR7-dependent anti-ssRNA (H564) B cells in MFG-E8-/- backgrounds.

Main Results:

MFG-E8-/- B6 mice showed increased IgG2c production against apoptotic cells and oxidized LDL, dependent on MyD88 and T cell help.
Enlarged MZ B cell compartments and enhanced antibody response to NP-Ficoll were observed in MFG-E8-/- B6 mice, with MZ B cells migrating into follicles.
TLR7-dependent H564 B cells differentiated into germinal center (GC) B cells and antibody-forming cells (AFCs) in MFG-E8-/- mice, while TLR9-dependent 56R B cells differentiated into MZ B cells but not AFCs.

Conclusions:

Delayed apoptotic cell clearance in MFG-E8 deficiency promotes specific B cell responses and MZ B cell translocation, contributing to autoimmunity.
TLR7 signaling is more critical than TLR9 signaling for the differentiation of autoreactive B cells into antibody-forming cells in this model.
These findings provide insights into MZ B cell dynamics in lupus and the differential roles of TLR7 and TLR9 in disease pathogenesis.

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