IMMUNOLOGY TEXTBOOK - Mercury Podillya 2013

IMMUNOLOGICAL RESEARCH METHODS

HLA Typing

Virtually all Cells in the body feature molecules (Proteins) on their surface known as the Major Histocompatibility Complex Antigens (HLA antigens). HLA stands for human leucocyte antigens, also referred to as MHC (major histocompatibility complex). Every individual possesses a unique set of HLA antigens.

HLA molecules act as specific "antennas" on The Cell surface, enabling the body to distinguish between self and non-self cells (such as Bacteria, Viruses, and Cancer cells) and, when necessary, trigger an Immune Response to produce specific Antibodies and eliminate the foreign agent.

The composition of each HLA antigen is encoded by the corresponding HLA Gene on chromosome 6. In other words, an individual's specific combination of HLA antigens is determined by their unique combination of HLA genes. The set of HLA genes inherited from parents is as unique as a fingerprint. HLA genes are inherited in a codominant manner, meaning a child inherits one chromosome from the mother and the other from the father. Consequently, an individual has two haplotypes, and every somatic cell carries a diploid set of antigens—one maternal and one paternal. The only exception is Germ Cells (oocytes and spermatozoa), each containing just a single haplotype in its Nucleus.

The Histocompatibility Antigens expressed on a person's cells constitute their HLA phenotype. Determining this phenotype requires phenotyping the individual's cells. Typically, peripheral Blood lymphocytes are "typed." To establish the subject's haplotypes and, by extension, their genotype—the sequential arrangement of genes on the chromosome—parental typing must be performed.

The genes encoding HLA are located in 7 regions (loci) on chromosome 6: HLA-A, B, C, D (which actually comprises 4 loci: HLA-D proper and HLA-DP), DQ, and DR.

Each gene can have dozens of variants (alleles), and their diverse combinations form a multitude of gene configurations. It is the specific alleles identified during the test that are listed in the HLA typing report.

There are 2 classes of HLA antigens. Class I comprises antigens of the A, B, and C loci, whereas Class II comprises antigens of the DR, DP, and DQ loci. Class I antigens are present On the surface of all nucleated cells (as well as platelets), while Class II antigens are found on The surface of cells involved in immune responses (B lymphocytes, activated T lymphocytes, monocytes, macrophages, and dendritic cells).

HLA genes are designated by the same letters as the HLA antigens they encode. The names of HLA genes and antigens consist of one or more letters and numbers, such as A3, B45, DR15, and DQ4. The letter denotes the gene (region and locus), while the numbers indicate the specific allele of that gene, assigned sequentially as new alleles are discovered.

Outside of Pregnancy, circulating immune cells continuously scan the protein code on cell surfaces—specifically, the histocompatibility proteins. If cells with an altered Structure are detected (whether foreign microbes or mutated Cells of the body itself), The Immune System mounts an immediate response to destroy the atypical cells.

During the inheritance of histocompatibility antigens, a child receives one gene for each locus from both parents; thus, half of the histocompatibility antigens are inherited from the mother and half from the father. Consequently, the fetus is half-foreign to the mother's Organism. Parental mismatch in HLA antigens and the distinction between fetal and maternal cells are normal physiological phenomena necessary for the preservation and successful progression of pregnancy. This "foreignness" triggers the immunological reactions required to maintain the pregnancy.

Upon the establishment of pregnancy, endometrial lymphocytes form a clone of immune cells that produce specialized "protective" (blocking) antibodies against the paternal HLA antigens. These antibodies shield the father's HLA antigens from the effector cells of the mother's immune system, protecting the fetus from maternal natural killer cells that might otherwise promote embryo rejection. These "blocking" antibodies directed against paternal HLA antigens are known as APLA (anti-paternal leukocyte antibodies) and are expressed by endometrial lymphocytes. APLA can be detected as early as the 5th week of pregnancy. APLA antibodies are produced in response to antigenic differences between the parents within the HLA Class II system. As a result, during pregnancy, the fetus and its cellular structures remain unrecognizable to the maternal immune system.