Defective Lysosomal Degradation of Immune Complexes in Lupus-Prone Mice (171.30)

• Published in: The Journal of immunology (1950) Vol. 188; no. 1_Supplement; pp. 171 - 171.30
• Main Authors: Monteith, Andrew, Kang, Sun ah, Jacobson, Ken, Costello, M., Moorman, Nat, Vilen, Barbara
• Format: Journal Article
• Language: English
• Published: 01.05.2012
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.188.Supp.171.30

Abstract The production of autoantibody and subsequent tissue deposition of immune complexes (ICs) contributes to the end-organ disease associated with systemic lupus erythematosus. What role ICs play in the autoimmune disease process remains unclear. In this study we found that low levels of ICs were displayed on dendritic cells (DCs), macrophages (MFs) and B cells from C57BL/6 (B6) mice via Fc receptors (FcRs). In contrast, cells from lupus-prone (MRL/lpr) mice had a 30-50-fold increase in surface-bound ICs. MRL/lpr MFs internalized ICs at a rate comparable to B6 however, they failed to degrade the ICs and consequently recycled them back to the cell surface within 48 hours. The recycling defect was not due to the failure of endosomes to properly mature, as cryoelectron microscopy showed equal numbers of ICs in secondary lysosomes. Rather, it appeared that a defect occurred in the ability of MFs to properly acidify lysosomes. Ratiometric imaging revealed that vesicles found in B6 MFs consistently acidified to a pH of 4, while those within MRL/lpr MFs failed to attain a pH lower than 5. These findings suggest that the recycling of ICs to the surface of MRL/lpr MFs results from defects within the endocytic pathway that prevent degradation of internalized cargo. Studies are underway to define the molecular events preventing acidification, and to assess whether the accumulated ICs activate autoreactive B cells, or promote excessive cytokine secretion by DCs and MFs from lupus-prone mice.