The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE), often known simply as lupus, is a severe chronic autoimmune disease that is characterized by multi-organ and tissue damage and high levels of autoantibodies in serum. We have recently investigated, using animal models, the role of organ-deposited IgG autoantibodies in the pathogenesis of organ and tissue damage in SLE. We found that intra-organ injection of serum from mice with lupus (i.e., lupus mice) into healthy mice triggered inflammation in tissue and organs but that serum from other healthy mice did not, and that the severity of inflammation was related to the dose of serum injected. Immunohistochemistry showed that a large number of IgG molecules are deposited at the site of organ and tissue damage in lupus mice, and that IgG is a major contributor to the development of tissue inflammation triggered by serum from lupus mice or patients. The development of tissue inflammation induced by IgG in serum from lupus mice requires the presence of monocytes/macrophages, but not of lymphocytes or neutrophils; tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) and interleukin 1 (IL-1) also play essential roles in the development of tissue inflammation triggered by IgG. In addition, it has been found that TNFR1 inhibitors can suppress skin injury in lupus mice and that spleen tyrosine kinase (Syk) inhibitors, which can block the signaling transduction of IgG/Fc gamma receptors (FcγRs), can prevent and treat skin injury and kidney damage in lupus mice. We have also observed that lupus IgG might protect against bone erosion. Based on these results, we conclude that IgG plays a crucial role in the development of organ and tissue damage in SLE and in protecting bone erosion and arthritis, and we suggest that the IgG/FcγR signaling pathway is an important therapeutic target in SLE.

A Novel Human Interleukin‐23A Overexpressing Mouse Model of Systemic Lupus Erythematosus

“…These data suggest that the pathology is driven by an IL‐23 dimer, composed of a human IL‐23A and a mouse IL‐12B subunit. The simultaneous manifestation of inflammation in the skin, the impaired renal function, and anemia together with the presence of antinuclear antibodies and the dependency of the pathology on T cells and B cells as well as on the expression of the IL‐12B subunit support that TghIL‐23A mice reproduce key features of systemic lupus autoimmunity 15,31–33 that are IL‐23 dependent.…”

A Novel human IL-23A Overexpressing Mouse Model of Systemic Lupus Erythematosus

“…The simultaneous manifestation of inflammation in the skin, the impaired renal function and anemia together with the presence of antinuclear antibodies and the dependency of the pathology on T and B cells as well as on the expression of IL12B subunit, support that TghIL23A mice reproduce key features of systemic lupus autoimmunity (13,(28)(29)(30) that are IL23-dependent.…”

Microvascular Density Analysis of Patients with Inactive Systemic Lupus Erythematosus—A Two-Year Follow-Up Optical Coherence Tomography Angiography Study

“…Systemic lupus erythematosus (SLE) is a multisystemic inflammatory autoimmune disease of the connective tissue. SLE patients suffer from significant morbidity and carry a high mortality risk due to multiple organ and tissue damage [1]. Due to the severe consequences of the disease, research providing new insights into vascular changes in SLE is important, and new insights into SLE pathophysiology and disease activity are desirable.…”