Background/Purpose:

Hyaluronic acid (HA) is a component of the extracellular matrix and is known to be involved in cancer biology. Although evidence suggests that HA plays a role in the expression of kidney pathology in patients with SLE, its function is not fully understood. T cells from patients with SLE express increased amounts of CD44 to which HA binds inducing T cell polarization, adhesion, and migration (J Immunol. 2007, 178:1938-47). In this study, we asked how HA contributes to the expression of lupus pathology and whether it can be targeted therapeutically.

Methods: We analyzed HA expression in kidneys from patients with SLE and a lupus-prone MRL/lpr mice, by using immunohistochemistry. Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated with anti-CD3/CD28 in the presence or not of HA. 4-Methylumbelliferone (4-MU), an HA synthase inhibitor, was orally administrated to male MRL/lpr starting at the age of 3 months (prevention) or 5 months of age (treatment). In addition, in a third group, 4-MU was administered at the age of 3 months and discontinued at the age of 5 months. At the end of the treatment tissues (kidney and skin) were evaluated by immunohistochemestry, spleen, lymph node and kidney cells were evaluated by flow cytometry.

Results: Kidneys from MRL/lpr and patients with SLE displayed increased accumulation of HA compared to control tissues coinciding with the accumulation of immune cells. MRL/lpr mice which received 4-MU at 3 months of age did not develop any organ inflammation, but discontinuation of treatment resulted in late disease (proteinuria, kidney and skin inflammation) development. Treatment of 5 months old mice that already developed disease halted further progression of the disease with minimal reversal of tissue pathology. Treatment with 4-MU led to increased proportions of Tregs and reduced double negative (DN)T cells, Th17, and Th1 cells both in the spleen and the kidney. Exposure of PBMC from healthy donors to low molecular weight HA in vitro while stimulated with anti-CD3/CD28 led to the expansion of DNT cells.

Conclusion:

HA expression is increased in tissues in patients with SLE and lupus-prone mice and probably enable the homing and activation of CD44 positive T cells. Inhibition of HA synthesis prevents disease development but fails to reverse established pathology. In addition, HA promotes the generation of CD4^–CD8^–CD3⁺ cells which are known to contribute to lupus immunopathology. The development of drugs which prevent the entrance and activation of T cells to tissues should represent novel approaches to prevent relapses in patients with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hyaluronic-acid-synthesis-inhibition-blocks-nephritis-and-extends-lifespan-in-mice-prone-to-lupus/