Abstract
Lupus nephritis (LN) is a major organ complication and cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is an unmet medical need for developing more efficient and specific, mechanism-based therapies, which depends on improved understanding of the underlying LN pathogenesis. Here we present direct visual evidence from high-power intravital imaging of the local kidney tissue microenvironment in mouse models showing that activated memory T cells originated in immune organs and the LN-specific robust accumulation of the glomerular endothelial glycocalyx played central roles in LN development. The glomerular homing of T cells was mediated via the direct binding of their CD44 to the hyaluronic acid (HA) component of the endothelial glycocalyx, and glycocalyx-degrading enzymes efficiently disrupted homing. Short-course treatment with either hyaluronidase or heparinase III provided long-term organ protection as evidenced by vastly improved albuminuria and survival rate. This glycocalyx/HA/memory T cell interaction is present in multiple SLE-affected organs and may be therapeutically targeted for SLE complications, including LN.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs in millions of patients worldwide
Manipulation of NZM mice, such as deletion of IL-1 receptor-associated kinase 1 (IRAK1), type 1 IFN receptor A (IFNAR) [11], B cell activating factor (BAFF) [12], or STAT6 [8], that do not develop clinical Lupus nephritis (LN) show reduced levels of activated memory T cells at 8–9 months, to levels seen in WT at 5 months when there is no clinical disease
We present direct evidence for a mechanistically crucial interplay between cellular components of the immune system and local kidney tissue factors in the pathogenesis of LN
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs in millions of patients worldwide. The development of kidney disease (lupus nephritis, LN) is a major complication affecting 60% of people with SLE and is the most important predictor of morbidity and mortality [1,2,3]. Cellular effectors are more difficult to characterize and to study. Both the presence of effector T cells in lesions and their functional relevance in experimental models of glomerulonephritis imply a role for T cells in LN [1, 2]. In addition to the immune system, there is growing recognition that local tissue-resident cells play key roles in pathogenic events in target tissues that are affected by SLE. The role of the vascular endothelium has been unknown, even though endothelial cells and the endothelial cell surface layer ( known as the glycocalyx) are the first point of contact with circulating immune system components
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