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

Yufeng Peng,Jose C Crispin

doi:10.1371/journal.pone.0205172

Abstract

Defective clearance of apoptotic cells in MFG-E8 deficient mice results in lupus-like disease in the mixed B6x129, but not pure B6 background. The lack of overt autoimmunity in MFG-E8-/- B6 mice suggests that accumulation of apoptotic cells is not sufficient to break central tolerance. However, the delayed clearance of apoptotic cells in the follicles of MFG-E8-/- B6 mice provides an excellent opportunity to investigate how B cells respond to excessive apoptotic cells in the periphery under relatively non-inflammatory conditions. In MFG-E8-/- B6 mice, we found increased IgG2c production against apoptotic cells and oxidized LDL. Apoptotic cell induced antibody responses depended on MyD88 signal and T cell help. In addition, MFG-E8-/- B6 mice had enlarged MZ B cell compartments as well as an enhanced antibody response to NP-Ficoll. Moreover, a significant percentage of MZ B cells in aged MFG-E8-/- B6 mice migrated into follicles. Injecting apoptotic cells or oxidized LDL into wild type mice as well as physiological accumulation of LDL in ApoE-/- mice recapitulated the translocation of MZ B cells. To determine how MFG-E8 deficiency affects the functions of autoreactive B cells specific for nucleic acids in the periphery under non-inflammatory conditions, we utilized BCR transgenic mice to bypass central selection and compared the differentiation of TLR9 dependent anti-dsDNA 56R B cells and TLR7 dependent anti-ssRNA H564 B cells in MFG-E8-/- mice. In MFG-E8-/- 56R mice, anti-dsDNA specific 56R/Vκ38c B cells differentiated into MZ B cells but not AFCs. On the contrary, in MFG-E8-/-H564 mice, anti-ssRNA specific H564 B cells further differentiated into GC B cells and AFCs. Adoptive transfer of activated autoreactive B cells confirmed that H564 B cells were more sensitive to apoptotic cell antigens than 56R B cells. Our observations provide new insights about the MZ B cell translocation in lupus patients as well as the dichotomy of TLR9 and TLR7 signals in the pathogenesis of lupus.

Highlights

Both central and peripheral tolerance play critical roles in controlling autoreactive B cells [1]
When serum samples from 4 month old MFG-E8-/- females were incubated with apoptotic cells, we found a significant increase of IgG2c binding to dying cells (Fig 1C), suggesting accumulation of apoptotic cells was able to induce spontaneous B cell responses, including class switching
Since apoptotic cells may release endogenous TLR-like signals to promote MZ B cell migration, we examined the location of MZ B cells in 10–12 month old MFG-E8-/- mice

Summary

Introduction

Both central and peripheral tolerance play critical roles in controlling autoreactive B cells [1]. Autoreactive immature B cells are either deleted, forced to undergo receptor editing, or become anergic. Once they arrive in the periphery, mature B cells can re-acquire auto-reactivity through. Antigens deposited on FDCs (follicular dendritic cells) in the GC play an important role in selecting mutated B cells: B cells with the highest affinities differentiate into memory cells, whereas those with low affinities, including potentially autoreactive clones are deleted. Numerous animal models have demonstrated that defects in both central and peripheral B cell tolerance are required to develop overt lupus-like disease[2]

Methods

Results

Conclusion