Human Leukocyte Antigen-C (HLA-C) is a gene that produces a protein for the immune system. As part of the Human Leukocyte Antigen (HLA) family, it helps the body distinguish its own healthy cells from foreign invaders like viruses. The HLA-C gene and its protein have specific functions distinct from other HLA family members, influencing both viral defense and the biological processes of pregnancy.
What is HLA-C?
The HLA gene complex, also known as the Major Histocompatibility Complex (MHC) in other species, is divided into several classes. HLA-C is a Class I gene, and the protein it codes for is displayed on the surface of nearly every cell in the body with a nucleus. This presence functions like a cellular identification card. Immune cells check these HLA-C proteins to determine if a cell is healthy or has been compromised by a pathogen.
The HLA-C protein on the cell surface holds a small piece of protein, called a peptide, from inside the cell. In a healthy cell, this peptide is a normal self-protein that the immune system ignores. If a cell becomes infected or cancerous, the HLA-C molecule will display a piece of the foreign protein instead. This change alerts the immune system that the cell needs to be eliminated.
The HLA-C gene is highly polymorphic, meaning there are many different versions, or alleles, in the population. This diversity helps the human species mount an immune response against a wide array of pathogens. Each person inherits one set of HLA genes from each parent, resulting in a unique HLA profile that shapes their individual immune responses.
The Role of HLA-C in the Immune System
The HLA-C protein engages with the immune system through two primary pathways. The first is the presentation of antigens to cytotoxic T-cells, a type of white blood cell designed to kill infected cells. When a cell is invaded by a virus, it breaks down viral proteins into peptides. These peptides are then loaded onto HLA-C molecules and transported to the cell surface.
Once displayed, the HLA-C-peptide complex acts as a beacon. A passing cytotoxic T-cell with a matching receptor can bind to this complex, confirming the cell is infected. This activates the T-cell to release factors that induce programmed cell death in the compromised cell, helping to control the infection.
A second function involves interaction with Natural Killer (NK) cells, which operate differently than T-cells. HLA-C molecules serve as ligands for Killer-cell Immunoglobulin-like Receptors (KIRs) on NK cells. This interaction is often inhibitory; when a KIR binds to HLA-C on a healthy cell, it sends a “do not attack” signal. This ensures NK cells target only cells that have lost HLA-C expression, a tactic some viruses and cancers use to evade T-cells.
HLA-C in Pregnancy and Reproduction
The role of HLA-C is complex during pregnancy, when the mother’s immune system must tolerate the semi-foreign fetus. The fetus inherits half of its HLA genes from the father, so its placental cells express HLA-C proteins different from the mother’s. Fetal placental cells that invade the uterine wall, known as extravillous trophoblasts, uniquely express HLA-C. This makes the interaction between fetal HLA-C and the mother’s uterine NK (uNK) cells a central event in establishing a healthy pregnancy.
Maternal uNK cells are abundant in the uterine lining during early pregnancy and are equipped with KIR receptors that recognize the fetal HLA-C. This dialogue is less about immunity and more about regulating placental development. It specifically remodels the mother’s spiral arteries to provide adequate blood flow to the growing fetus.
HLA-C alleles are divided into two groups, HLA-C1 and HLA-C2. The C2 group binds more strongly to its corresponding KIR receptors on NK cells, sending a more potent inhibitory signal. The mother’s KIR genes are also variable, with some individuals having a KIR AA genotype, which is dominated by inhibitory receptors, and others having a KIR Bx genotype, which includes additional activating receptors.
Research has shown that certain combinations of maternal KIR and fetal HLA-C are associated with a higher risk of pregnancy complications. For example, a mother with a KIR AA genotype who is carrying a fetus with an HLA-C2 gene is at an increased risk for conditions like preeclampsia and fetal growth restriction. The theory is that the strong inhibitory signal from the fetal C2 molecule leads to insufficient artery remodeling and an inadequate blood supply for the fetus.
HLA-C and Disease Association
Specific variants of the HLA-C gene are linked to the risk of developing certain diseases. One of the most well-documented associations is between the HLA-Cw6 allele and psoriasis, an autoimmune condition causing chronic skin inflammation. Individuals carrying the HLA-Cw06:02 allele have a significantly higher likelihood of developing psoriasis, often with an earlier onset and more severe form. The mechanism is thought to involve the HLA-C protein presenting a self-antigen to T-cells, triggering an autoimmune attack on skin cells.
Variations in HLA-C also affect the body’s ability to manage viral infections. In the context of HIV, certain HLA-C alleles are associated with better control of the virus and slower progression to AIDS. These protective alleles tend to be expressed at higher levels on the cell surface, leading to a more robust presentation of HIV peptides to cytotoxic T-cells. This allows for a more effective attack against infected cells.
This dual role in autoimmunity and viral defense highlights a delicate balance. The same high-expression HLA-C variants that are beneficial for controlling viruses may also increase the risk for autoimmune conditions. This shows that HLA-C is a central molecule in regulating immune responses and influencing health outcomes.
Testing for HLA-C Variants
Determining an individual’s specific HLA-C type is accomplished through genetic testing from a blood sample. In a laboratory, DNA is extracted and analyzed using methods like Polymerase Chain Reaction (PCR). This technology amplifies the HLA-C gene to identify the particular alleles present.
This type of testing is ordered in several clinical contexts. For couples experiencing recurrent pregnancy loss or implantation failure after IVF, KIR and HLA-C genotyping of both partners may be performed. Identifying high-risk combinations can inform treatment decisions.
HLA-C typing is also a standard procedure in transplantation medicine, such as for bone marrow transplants, to ensure the best possible match between donor and recipient. It is also used in research to better understand disease associations and may aid in the diagnosis of conditions like psoriasis. The results help clarify an individual’s genetic predisposition and can guide medical strategies.