HLA-G Structure and Receptors
The Major Histocompatibility Complex (MHC), nestled on chromosome 6, encompasses a treasure trove of genes, over 200 of them dedicated to encoding HLA molecules. This genomic region orchestrates a symphony of immune responses and transplantation. Within the MHC, there are two recognized classes: MHC class I, responsible for presenting antigens to CD8+ T lymphocytes, and MHC class II, engaging in antigen presentation to CD4+ lymphocytes. However, HLA-G stands apart as a non-classical MHC molecule, distinctly different from its classical MHC I counterparts. Its expression is confined to specific tissues such as the thymus, cornea, nail matrix, stem cells, and the trophoblast. While HLA-G exhibits lower polymorphism in peptide-binding domains when compared to classical MHC genes, it boasts variations in regulatory regions that intricately influence its surface expression. The remarkable ability of HLA-G mRNA to undergo alternative splicing produces seven diverse protein isoforms with unique structures, capable of forming homodimers. These intricate forms find a receptive audience in various HLA-G receptors, including CD8, LILRB1, LILRB2, and KIR2DL4, which are expressed on an array of immune cells, ranging from monocytes and dendritic cells to B cells and natural killer cells.
HLA-G in Physiological Pregnancy
Placentation, a complex immunological process during pregnancy, emerges as a crucial juncture in maternal-fetal interactions. Fetal antigens and the maternal immune system converge, orchestrating a delicate balance between immunotolerance and trophoblastic invasion. HLA-G steps into the spotlight during this remarkable dance, playing an indispensable role in facilitating maternal acceptance of the fetus. It contributes significantly to the maintenance of an immunosuppressive environment and the remodeling of spiral arteries. Trophoblast cells, particularly extravillous cytotrophoblast cells (EVTs), serve as the champions of HLA-G expression. The interaction between HLA-G and natural killer (NK) cells and other immune sentinels is vital for the orchestration of immune tolerance during pregnancy. HLA-G in Recurrent Pregnancy Loss (RPL): Recurrent Pregnancy Loss (RPL), a condition defined by the heart-wrenching loss of two or more pregnancies, is marked by a web of intricate causative factors. HLA-G steps into the arena as a potential player in unexplained RPL. Researchers have ventured into the realms of soluble HLA-G (sHLA-G) levels and HLA-G gene polymorphisms, hoping to decipher their connection with RPL. However, the journey through these uncharted territories remains fraught with mixed results and elusive outcomes. The tantalizing prospect of employing HLA-G as a marker for adverse pregnancy outcomes, encompassing both RPL and recurrent implantation failure (RIF), remains an area of avid exploration.
HLA-G Polymorphisms
The realm of HLA-G is marked by its diverse polymorphisms, with certain variations wielding the power to alter HLA-G expression levels. Studies have diligently scrutinized the potential links between HLA-G polymorphisms, particularly within the 3' untranslated regions (3' UTRs) and the 5' upstream regulatory region (5' URR), and their association with RPL. However, this intricate labyrinth yields inconclusive results, leaving researchers yearning for clarity.
Therapeutic Implications
Amidst this scientific maze, there emerges a glimmer of hope through potential therapeutic interventions. Progesterone and the enigmatic preimplantation factor (PIF) have been unveiled as champions capable of inducing HLA-G expression, holding promise for RPL treatment. Additionally, the intriguing notion of extracellular vesicles (EVs) ferrying HLA-G offers a glimpse into the intriguing world of immune modulation during pregnancy, with potential implications for RPL.
In summation, HLA-G weaves a complex and intricate tale, from being a guardian of immunotolerance during physiological pregnancies to potentially contributing to the enigma of recurrent pregnancy loss. However, the true nature of this multifaceted protein and its therapeutic potential in RPL remain shrouded in the mists of further research and discovery.
