HLA-G-mediated immunological tolerance and autoimmunity

Although detailed underlying mechanisms for the pathogenesis of autoimmune diseases remain largely unknown, multiple factors such genetic and epigenetic background, environmental inducers, and dysregulation of immune tolerance for self-antigens have been considered to be associated with a variety of autoimmune diseases. Human leukocyte antigen (HLA) system, the most polymorphic complex in human genome, functions fundamental roles in immune homeostasis by interaction with both immune activating and inhibitory receptors expressed on different types of immune cells. In line with this, an increasing evidence of genetic predisposition and molecular functions of the non-classical HLA class I antigen HLA-G has been revealed in the clinical significance of autoimmune diseases. Tissue HLA-G expression was firstly observed on the extravillous cytotrophoblasts, and later its immune suppressive features have become well documented. In contrast to its high polymorphic classical HLA class I (HLA-A, HLA-B, and HLA-C) counterparts, HLA-G is with very limited genetic variations, while at least four membrane-bound (HLA-G1–HLA-G4) and three soluble (HLA-G5–HLA-G7) isoforms have been identified, which differs either in extracellular domains or in intracellular cytoplasmic tails generated by HLA-G primary transcript alternative splicing. Functionally, HLA-G can induce profound immune inhibition by interacting with a panel of HLA-G-binding immune receptors such as immunoglobulin-like transcripts (ILT)-2, ILT-4, and killer inhibitory receptor (KIR) 2DL4 differentially expressed on autoimmune diseases related T cells, natural killer cells (NK), B cells, dendritic cells (DCs), or macrophages. In this context, induction of HLA-G expression could have a protective effect to diminish auto-reactive immune responses among autoimmunity. In this chapter, we focus on the genetic association, molecular function, and mechanisms of HLA-G-mediated immune tolerance in autoimmune diseases.