Hyaluronan in immune dysregulation and autoimmune diseases

The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity.