Human leukocyte antigen - AbsoluteAstronomy.com

The human leukocyte antigen (HLA) system is the name of the major histocompatibility complex

Major histocompatibility complex

Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

(MHC) in humans. The super locus

Locus (genetics)

In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

contains a large number of genes related to immune system

Immune system

An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen

Antigen

An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

-presenting proteins and many other genes. The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery

History and naming of human leukocyte antigens

Human leukocyte antigens began as a list of antigens identified as a result of transplant rejection. The list, HL-A1 to HL-A15. The antigens were identified based on serotypes that developed in transplant recipients, to donor antigens that could recognize one apparent antigen were found useful....

as factors in organ transplants. The major HLA antigens are essential elements for immune function. Different classes have different functions:

HLAs corresponding to MHC class I (A
HLA-A
HLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...

, B
HLA-B
HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...

, and C
HLA-C
HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane...

) present peptides from inside the cell (including viral peptides if present). These peptides are produced from digested proteins that are broken down in the proteasome

Proteasome

Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...

s. In general, the peptides are small polymer

Polymer

A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...

s, about 9 amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in length. Foreign antigens attract killer T-cells (also called CD8

CD8

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...

positive- or cytotoxic T-cells) that destroy cells.

HLAs corresponding to MHC class II (DP
HLA-DP
HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II region in the Human Leukocyte Antigen complex on human chromosome 6 .Less...

,DM
HLA-DM
HLA-DM is an intracellular protein involved in peptide presentation by MHC class II. It is encoded by the genes and .In the endosomes, HLA-DM functions by promoting the dissociation of the CLIP peptide from MHC class II which allows endosomal peptides to bind...

, DOA
HLA-DOA
HLA class II histocompatibility antigen, DO alpha chain is a protein that in humans is encoded by the HLA-DOA gene.-Further reading:...

,DOB
HLA-DOB
HLA class II histocompatibility antigen, DO beta chain is a protein that in humans is encoded by the HLA-DOB gene.-Further reading:...

,DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...

, and DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate the multiplication of T-helper cells, which in turn stimulate antibody

Antibody

An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

-producing B-cells

B cell

B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

to produce antibodies to that specific antigen. Self-antigens are suppressed by suppressor T-cells

Regulatory T cell

Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...

.

HLAs corresponding to MHC class III encode components of the complement system

Complement system

The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

.

HLAs have other roles. They are important in disease defense. They may be the cause of organ transplant rejections. They may protect against or fail to protect (if down regulated by an infection) against cancer

Cancer

Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

s. They may mediate autoimmune disease

Autoimmune disease

Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

(examples: type I diabetes, coeliac disease

Coeliac disease

Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...

). Also, in reproduction, HLA may be related to the individual smell of people and may be involved in mate selection.

Aside from the genes encoding the 6 major antigens, there are a large number of other genes, many involved in immune function, located on the HLA complex. Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci

Locus (genetics)

is very low. HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.

Functions

The protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s encoded by HLAs are those on the outer part of body cells that are (effectively) unique to that person. The immune system

Immune system

uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and therefore is not an invader.

In infectious disease

When a foreign pathogen

Pathogen

A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

enters the body, specific cells

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

called antigen-presenting cell

Antigen-presenting cell

An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...

s (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s) and loaded onto HLA antigens (to be specific, MHC class II

MHC class II

MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

). They are then displayed by the antigen-presenting cell

Antigen-presenting cell

s to T cell

T cell

T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s, which then produce a variety of effects to eliminate the pathogen.

Through a similar process, proteins (both native and foreign, such as the proteins of virus

Virus

A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

) produced inside most cells are displayed on HLAs (to be specific, MHC class I

MHC class I

MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...

) on the cell surface. Infected cells can be recognized and destroyed by CD8+ T cells.

The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule. In the illustration far below, a different view, one can see an entire DQ with a bound peptide in a similar cleft, as viewed from the side. Disease-related peptides fit into these "slots" much like a hand fits into a glove. When bound, peptides are presented to T cells. T cells require presentation via MHC molecules to recognize foreign antigens — a requirement known as MHC restriction

MHC restriction

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a given T cell will recognize a peptide antigen only when it is bound to a host bodies' own MHC molecule...

. These cells have receptors that are similar to B cell receptors, and each cell recognizes only a few class II-peptide combinations. Once a T cell recognizes a peptide within an MHC class II molecule, it can stimulate B-cells that also recognize the same molecule in their B cell receptors. Thus, T cells help B cells make antibodies to the same foreign antigens. Each HLA can bind many peptides, and each person has 3 HLA types and can have 4 isoforms of DP, 4 isoforms of DQ and 4 Isoforms of DR (2 of DRB1, and 2 of DRB3,DRB4, or DRB5) for a total of 12 isoforms. In such heterozygotes, it is difficult for disease-related proteins to escape detection.

In graft rejection

Any cell displaying some other HLA type is "non-self" and is seen as an invader by the body's immune system, resulting in the rejection of the tissue bearing those cells. This is particularly important in the case of transplanted tissue, because it could lead to transplant rejection

Transplant rejection

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...

. Because of the importance of HLA in transplantation, the HLA loci are some of the most frequently typed by serology and PCR.

HLA and autoimmune diseases
HLA allele	Diseases with increased risk	Relative risk Relative risk In statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....
HLA-B27 HLA-B27 Human Leukocyte Antigen B27 is a class I surface antigen encoded by the B locus in the major histocompatibility complex on chromosome 6 and presents antigenic peptides to T cells...	Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...	12
	Postgonococcal arthritis	14
	Acute anterior uveitis	15
HLA-B47 HLA-B47 HLA-B47 is an HLA-B serotype. The serotype identifies the HLA-B*47 gene products . Comparison of B47 nucleotide sequence with other HLA-B sequences shows a segment of 228 bp identical with B44 in the alpha 1 domain and a segment of 218 bp identical with B27 in the alpha 2 domain, but only a 91 bp...	21-hydroxylase deficiency Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Congenital adrenal hyperplasia due to 21-hydroxylase deficiency , in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia, and "CAH" in most contexts refers to 21-hydroxylase deficiency...	15
HLA-DR2 HLA-DR2 HLA-DR2 of the HLA-DR serotype system, is a broad antigen serotype that is now preferentially covered by HLA-DR15 and HLA-DR16 serotype group...	Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...	2 to 3
HLA-DR3 HLA-DR3 HLA-DR3 is composed to the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease....	Autoimmune hepatitis Autoimmune hepatitis Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...	14
	Primary Sjögren syndrome	10
	Diabetes mellitus type 1 Diabetes mellitus type 1 Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...	5
	Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...	2 to 3
HLA-DR4 HLA-DR4 HLA-DR4 is a HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number ofmoderate frequency alleles spread over large regions of the world.-Serology:The serological identification of DR4 is good...	Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...	4
	Diabetes mellitus type 1 Diabetes mellitus type 1 Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...	6
HLA-DR3 and -DR4 combined	Diabetes mellitus type 1 Diabetes mellitus type 1 Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...	15

In autoimmunity

HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, ankylosing spondylitis

Ankylosing spondylitis

Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...

, celiac disease

Coeliac disease

Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...

, SLE

Systemic lupus erythematosus

Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

(systemic lupus erythematosus), myasthenia gravis

Myasthenia gravis

Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...

, inclusion body myositis

Inclusion body myositis

Inclusion body myositis is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs...

, and Sjögren syndrome. HLA typing has led to some improvement and acceleration in the diagnosis of celiac disease and type 1 diabetes; however, for DQ2 typing to be useful, it requires either high-resolution B1*typing (resolving *02:01 from *02:02), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In celiac disease, it is the only effective means of discriminating between first-degree relatives that are at risk from those that are not at risk, prior to the appearance of sometimes-irreversible symptoms such as allergies and secondary autoimmune disease.

In cancer

Some HLA-mediated diseases are directly involved in the promotion of cancer. Gluten-sensitive enteropathy is associated with increased prevalence of enteropathy-associated T-cell lymphoma, and DR3-DQ2 homozygotes are within the highest risk group, with close to 80% of gluten-sensitive enteropathy-associated T-cell lymphoma cases. More often, however, HLA molecules play a protective role, recognizing increases in antigens that are not tolerated because of low levels in the normal state. Abnormal cells might be targeted for apoptosis, which is thought to mediate many cancers before diagnosis.

Classification

MHC class I proteins form a functional receptor on most nucleated cells of the body.

There are 3 major and 3 minor MHC class I genes in HLA:

HLA-A
HLA-A
HLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...
HLA-B
HLA-B
HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
HLA-C
HLA-C
HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane...
minor genes are HLA-E, HLA-F
HLA-F
HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.-Further reading:...

and HLA-G
HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G , is a protein that in humans is encoded by the HLA-G gene....
β₂-microglobulin
Beta-2 microglobulin
β2 microglobulin also known as B2M is a component of MHC class I molecules, which are present on all nucleated cells . In humans, the β2 microglobulin protein is encoded by the B2M gene.-Structure and function:...

binds with major and minor gene subunits to produce a heterodimer

There are 3 major and 2 minor MHC class II proteins encoded by the HLA.
The genes of the class II combine to form heterodimeric (αβ) protein
receptors that are typically expressed on the surface of antigen-presenting cells.

Major MHC class II

HLA-DP
HLA-DP
HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II region in the Human Leukocyte Antigen complex on human chromosome 6 .Less...
- α-chain encoded by HLA-DPA1 locus
- β-chain encoded by HLA-DPB1
  HLA-DPB1
  HLA class II histocompatibility antigen, DP beta chain is a protein that in humans is encoded by the HLA-DPB1 gene.-Further reading:...
  
  locus
HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
- α-chain encoded by HLA-DQA1
  HLA-DQA1
  Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 and also denotes the genetic locus which contains this gene...
  
  locus
- β-chain encoded by HLA-DQB1
  HLA-DQB1
  Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
  
  locus
HLA-DR
- α-chain encoded by HLA-DRA locus
- 4 β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci

The other MHC class II proteins, DM and DO, are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell

Antigen-presenting cell

Nomenclature

Modern HLA alleles are typically noted with a variety of levels of detail. Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA-prefix and locus notation.

Variability

MHC loci are some of the most genetically variable coding loci in mammals, and the human HLA loci are no exceptions. Despite the fact that the human population went through a constriction more than 150 000 years ago that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation. Of the 9 loci mentioned above, most retained a dozen or more allele-groups for each locus, far more preserved variation than the vast majority of human loci. This is consistent with a heterozygous or balancing selection

Balancing selection

Balancing selection refers to a number of selective processes by which multiple alleles are actively maintained in the gene pool of a population at frequencies above that of gene mutation. This usually happens when the heterozygotes for the alleles under consideration have a higher adaptive value...

coefficient for these loci. In addition, some HLA loci are among the fastest-evolving coding regions in the human genome. One mechanism of diversification has been noted in the study of Amazonian tribes of South America that appear to have undergone intense gene conversion

Gene conversion

Gene conversion is an event in DNA genetic recombination, which occurs at high frequencies during meiotic division but which also occurs in somatic cells. It is a process by which DNA sequence information is transferred from one DNA helix to another DNA helix, whose sequence is altered.It is one...

between variable
alleles and loci within each HLA gene class. Less frequently, longer-range productive recombinations through HLA genes have been noted producing chimeric genes.

Five loci have over 100 alleles that have been detected in the human population. Of these, the most variable are HLA B and HLA DRB1. As of 2004, the number of alleles that have been determined are listed in the table below. To interpret this table, it is necessary to consider that an allele is a variant of the nucleotide (DNA) sequence at a locus, such that each allele differs from all other alleles in at least one (single nucleotide polymorphism, SNP) position. Most of these changes result in a change in the amino acid sequences that result in slight to major functional differences in the protein.

There are issues that limit this variation. Certain alleles like DQA1*05:01 and DQA1*05:05 encode proteins with identically processed products. Other alleles like DQB1*0201 and DQB1*0202 produce proteins that are functionally similar. For class II (DR, DP and DQ), amino acid variants within the receptor's peptide-binding cleft tend to produce molecules with different binding capability.

Tables of variant alleles

Number of variant alleles at class I loci according to the IMGT-HLA database, last updated January 2009:

align="left" style = "font-size:90%" |
MHC class I
locus	#
Major Antigens
HLA A	767
HLA B	1,178
HLA C	439
Minor Antigens
HLA E	9
HLA F	21
HLA G	43

Number of variant alleles at class II loci (DM, DO, DP, DQ, and DR):

align="left" style = "font-size:90%" |
MHC class II
HLA	-A1	-B1	-B3 to -B5¹	Potential
locus	#	#	#	Combinations
DM-	4	7		28
DO-	12	9		72
DP-	27	133		3,591
DQ-	34	96		3,264
DR-	3	618	82	2,121
¹DRB3, DRB4, DRB5 have variable presence in humans

Sequence Feature Variant Type (SFVT)

The large extent of variability in HLA genes poses significant challenges in investigating the role of HLA genetic variations in diseases. Disease association studies typically treat each HLA allele as a single complete unit, which does not illuminate the parts of the molecule associated with disease. Karp D. R. et al. describes a novel Sequence Feature Variant Type

Sequence feature variant type

The Sequence Feature Variant Type refers to the defined mutation of a given sequence feature in a protein. Consider a protein, its amino acid sequence determines the its structure and function...

(SFVT) approach for HLA genetic analysis that categorizes HLA proteins into biologically relevant smaller sequence features (SFs), and their variant types (VTs). Sequence features are combinations of amino acid sites defined based on structural information (e.g., beta-sheet 1), functional information (e.g., peptide antigen-binding), and polymorphism. These sequence features can be overlapping and continuous or discontinuous in the linear sequence. Variant types for each sequence feature are defined based upon all known polymorphisms in the HLA locus being described. SFVT categorization of HLA is applied in genetic association analysis so that the effects and roles of the epitopes shared by several HLA alleles can be identified. Sequence features and their variant types have been described for all classical HLA proteins; the international repository of HLA SFVTs will be maintained at IMGT/HLA database. A tool to convert HLA alleles into their component SFVTs can be found on the Immunology Database and Analysis Portal (ImmPort) website.

Serotype and allele names

There are two parallel systems of nomenclature that are applied to HLA. The, first, and oldest system is based on serological (antibody based) recognition. In this system, antigens were eventually assigned letters and numbers (e.g., HLA-B27

HLA-B27

Human Leukocyte Antigen B27 is a class I surface antigen encoded by the B locus in the major histocompatibility complex on chromosome 6 and presents antigenic peptides to T cells...

or, shortened, B27). A parallel system that allowed more refined definition of alleles was developed. In this system, a
"HLA" is used in conjunction with a letter * and four-or-more-digit number (e.g., HLA-B*08:01, A*68:01, A*24:02:01N N=Null) to designate a specific allele

Allele

An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

at a given HLA locus

Locus (genetics)

. HLA loci can be further classified into MHC class I

MHC class I

MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...

and MHC class II

MHC class II

MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

(or rarely, D locus). Every two years, a nomenclature is put forth to aid researchers in interpreting
serotypes to alleles.

Serotyping

In order to create a typing reagent, blood from animals or humans would be taken, the blood cells allowed to separate from the serum, and the serum diluted to its optimal sensitivity and used to type cells from other individuals or animals. Thus, serotyping became a way of crudely identifying HLA receptors and receptor isoforms. Over the years, serotyping antibodies became more refined as techniques for increasing sensitivity improved and new serotyping antibodies continue to appear. One of the goals of serotype analysis is to fill gaps in the analysis. It is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles. These studies using serotyping techniques frequently revealed, in particular for non-European or north East Asian populations a large number of null or blank serotypes. This was particularly problematic for the Cw locus until recently, and almost half of the Cw serotypes went untyped in the 1991 survey of the human population.

There are several types of serotypes. A broad antigen serotype is a crude measure of identity of cells. For example, HLA A9 serotype recognizes cells of A23- and A24-bearing individuals. It may also recognize cells that A23 and A24 miss because of small variations. A23 and A24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens.

Cellular typing

A representative cellular assay is the mixed lymphocyte culture (MLC) and used to determine the HLA class II types. The cellular assay is more sensitive in detecting HLA differences than serotyping. This is because minor differences unrecognized by alloantisera can stimulate T cells. This typing is designated as Dw types. Serotyped DR1 has cellularly defined as either of Dw1 or of Dw20 and so on for other serotyped DRs. Table shows associated cellular specificities for DR alleles. However, cellular typing has inconsistence in the reaction between cellular-type individuals, sometimes resulting differently from predicted. Together with difficulty of cellular assay in generating and maintaining cellular typing reagents, cellular assay is being replaced by DNA-based typing method.

Gene sequencing

Minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group. The sequence of the antigens determines the antibody reactivities, and so having a good sequencing capability (or sequence-based typing) obviates the need for serological reactions. Therefore, different serotype reactions may indicate the need to sequence a person's HLA to determine a new gene sequence.
Broad antigen types are still useful, such as typing very diverse populations with many unidentified HLA alleles (Africa, Arabia, Southeastern Iran and Pakistan, India). Africa, Southern Iran, and Arabia show the difficulty in typing areas that were settled earlier. Allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques.

In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or by reactivity. Once the sequence is verified, it is assigned a number. For example, a new allele of B44 may get a serotype B*44:65, as it is the 65th B44 allele discovered. Marsh et al. (2005) can be considered a code book for HLA serotypes and genotypes, and a new book biannually with monthly updates in Tissue Antigens.

Phenotyping

Gene typing is different from gene sequencing and serotyping.
With this strategy, PCR primers specific to a variant region of DNA are used (called SSP-PCR), if a product of the right size is found. The assumption is that the HLA allele has been identified. New gene sequences often result in an increasing appearance of ambiguity. Because gene typing is based on SSP-PCR, it is possible that new variants, in particular in the class I and DRB1 loci, may be missed.

For example, SSP-PCR within the clinical situation is often used for identifying HLA phenotypes. An example of an extended phenotype for a person might be:

A*01:01/*03:01, C*07:01/*07:02, B*07:02/*08:01, DRB1*03:01/*15:01,
DQA1*05:01/*01:02, DQB1*02:01/*06:02

In general, this is identical to the extended serotype:
A1,A3,B7,B8,DR3,DR15(2), DQ2,DQ6(1)

For many populations, such as the Japanese or European populations, so many patients have been typed that new alleles are relatively rare, and thus SSP-PCR is more than adequate for allele resolution. Haplotypes can be obtained by typing family members in areas of the world where SSP-PCR is unable to recognize alleles and typing requires the sequencing of new alleles. Areas of the world were SSP-PCR or serotyping may be inadequate include Central Africa, Eastern Africa, parts of southern Africa, Arabia, S. Iran, Pakistan, and India.

Haplotypes

An HLA haplotype is a series of HLA "genes" (loci-alleles) by chromosome, one passed from the mother and one from the father.

The phenotype exampled above is one of the more common in Ireland and is the result of two common genetic haplotypes:

A*01:01 ; C*07:01 ; B*08:01 ; DRB1*03:01 ; DQA1*05:01 ; DQB1*02:01
(By serotyping A1-Cw7-B8-DR3-DQ2

HLA A1-B8-DR3-DQ2

HLA A1-B8-DR3-DQ2 haplotype is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6...

)

which is called ' 'super B8' ' or ' 'ancestral haplotype' ' and

A*03:01 ; C*07:02 ; B*07:02 ; DRB1*15:01 ; DQA1*01:02 ; DQB1*06:02
(By serotyping A3-Cw7-B7-DR15-DQ6 or the older version "A3-B7-DR2-DQ1")

These haplotypes can be used to trace migrations in the human population
because they are often much like a fingerprint of an event that has occurred
in evolution. The Super-B8 haplotype is enriched in the Western Irish, declines along gradients away from that region, and is found only in areas of the world where Western Europeans have migrated. The "A3-B7-DR2-DQ1" is more widely spread, from Eastern Asia to Iberia. The Super-B8 haplotype is associated with a number of diet-associated autoimmune diseases. There are 100,000s of extended haplotypes, but only a few show a visible and nodal character in the human population.

Role of allelic variation

Studies of humans and other animals imply a heterozygous selection mechanism operating on these loci as an explanation for this exceptional variability. One credible mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type. While the DQ and DP encoding loci have fewer alleles, combinations of A1:B1 can produce a theoretical potential of 1586 DQ and 2552 DP αβ heterodimers, respectively. While nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable DQ and DP isoforms, increasing the potential number of antigens that these receptors can present to the immune system in individual immune system. Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on class II molecules are most frequently the site of variation in the protein primary structure. Therefore, through a combination of intense allelic variation and/or subunit pairing, the class II 'peptide' receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. Individuals in a population frequently have different haplotypes, and this results in many combinations, even in small groups. This diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system.

Antibodies

HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally-inherited antigens), or organ or tissue transplant.

Antibodies against disease-associated HLA haplotypes have been proposed as a treatment
for severe autoimmune diseases.

Donor-specific HLA antibodies have been found to be associated with graft failure in kidney, heart, lung, and liver transplantation.

HLA matching for sick siblings

In some diseases requiring hematopoietic stem cell transplantation, preimplantation genetic diagnosis

Preimplantation genetic diagnosis

In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...

may be used to give rise to a sibling with matching HLA, although there are ethical considerations.

External links

IMGT/HLA Sequence Database at European Bioinformatics Institute
European Bioinformatics Institute
The European Bioinformatics Institute is a centre for research and services in bioinformatics, and is part of European Molecular Biology Laboratory...
hla.alleles.org
HLA Informatics Group at The Anthony Nolan Trust
British Society for Histocompatibility and Immunogenetics
American Society for Histocompatibility and Immunogenetics
European Federation for Immunogenetics
HistoCheck HLA matching tool for organ and stem cell transplantation
Allele Frequencies at Variable Immune related loci

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.