Relapse of lupus after B cell depletion therapy is associated with loss of apoptotic debris clearing marginal zone macrophages in BXD2 mice (THER5P.911)

Abstract

Abstract B-cell depletion therapy (BCDT) is used to treat autoimmune diseases but development of autoreactive B cells can occur during repopulation. Marginal zone macrophages (MZMs) are essential for tolerogenic clearance of apoptotic debris. Maintenance of MZMs requires MZ B cells. To determine if BCDT using anti-CD20 depletes MZ B cells and promote the loss of MZMs, lupus prone BXD2 mice were administered α-CD20 or isotype control (250 µg/single dose i.v.). This resulted in depletion of >80% B cells in the spleen at week 2 in BCDT group. This was associated with increased uncleared apoptotic debris in the spleen MZ and a dramatic decline in MZMs. By 5 weeks of BCDT, the B-cell repopulation rate was >50%. However, there was a significantly elevated expression of type I IFN signature genes Usp18 and Oasl in repopulated MZ precursor B cells in anti-CD20 group. There was a 2.8-fold increase in PNA+Fas+ CD19+ germinal center B cells in the spleens of anti-CD20-treated BXD2 mice, compared to isotype-treated mice. At week 9, the serum titers of IgG autoantibodies against DNA, histone, and malondialdehyde, a lipid peroxidation product associated with apoptotic blebs, were markedly increased in the α-CD20-treated BXD2 mice than control group. These results indicate that BCDT in BXD2 mice promotes an environment with excessive uncleared apoptotic debris which enhanced the effects of type I IFNs on repopulating B cells, leading to the return of autoreactive B cells.