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Major Histocompatibility Complex (MHC)

Major histocompatibility complex (MHC)

In humans, the proteins coded by the genes of the major histocompatibility complex (MHC) include human leukocyte antigens (HLA ), as well as other proteins. HLA proteins are present on the surface of most of the body's cells and are important in helping the immune system distinguish "self" from "non-self" molecules, cells, and other objects.

The function and importance of MHC is best understood in the context of a basic understanding of the function of the immune system. The immune system is responsible for distinguishing foreign proteins and other antigens, primarily with the goal of eliminating foreign organisms and other invaders that can result in disease. There are several levels of defense characterized by the various stages and types of immune response.

Present on chromosome 6, the major histocompatibility complex consists of more than 70 genes, classified into class I, II, and III MHC. There are multiple alleles, or forms, of each HLA gene . These alleles are expressed as proteins on the surface of various cells in a co-dominant manner. This diversity is important in maintaining an effective system of specific immunity . Altogether, the MHC genes span a region that is four million base pairs in length. Although this is a large region, 99% of the time these closely linked genes are transmitted to the next generation as a unit of MHC alleles on each chromosome 6. This unit is called a haplotype.

Class I MHC genes include HLA-A, HLA-B, and HLA-C. Class I MHC are expressed on the surface of almost all cells. They are important for displaying antigen from viruses or parasites to killer T-cells in cellular immunity. Class I MHC is also particularly important in organ and tissue rejection following transplantation. In addition to the portion of class I MHC coded by the genes on chromosome 6, each class I MHC protein also contains a small, non-variable protein component called beta 2-microglobulin coded by a gene on chromosome 15. Class I HLA genes are highly polymorphic, meaning there are multiple forms, or alleles, of each gene. There are at least 57 HLA-A alleles, 111 HLA-B alleles, and 34 HLA-C alleles.

Class II MHC genes include HLA-DP, HLA-DQ, and HLA-DR. Class II MHC are particularly important in humoral immunity. They present foreign antigen to helper T-cells, which stimulate B-cells to elicit an antibody response. Class II MHC is only present on antigen presenting cells, including phagocytes and B-cells. Like Class I MHC, there are hundreds of alleles that make up the class II HLA gene pool.

Class III MHC genes include the complement system (i.e. C2, C4a, C4b, Bf). Complement proteins help to activate and maintain the inflammatory process of an immune response.

When a foreign organism enters the body, it is encountered by the components of the body's natural immunity. Natural immunity is the non-specific first-line of defense carried out by phagocytes, natural killer cells, and components of the complement system. Phagocytes are specialized white blood cells that are capable of engulfing and killing an organism. Natural killer cells are also specialized white blood cells that respond to cancer cells and certain viral infections. The complement system is a group of proteins called the class III MHC that attack antigens. Antigens consist of any molecule capable of triggering an immune response. Although this list is not exhaustive, antigens can be derived from toxins, protein, carbohydrates, DNA , or other molecules from viruses, bacteria , cellular parasites, or cancer cells.

The natural immune response will hold an infection at bay as the next line of defense mobilizes through acquired, or specific, immunity. This specialized type of immunity is usually what is needed to eliminate an infection and is dependent on the role of the proteins of the major histocompatibility complex. There are two types of acquired immunity. Humoral immunity is important in fighting infections outside the body's cells, such as those caused by bacteria and certain viruses. Other types of viruses and parasites that invade the cells are better fought by cellular immunity. The major players in acquired immunity are the antigen-presenting cells (APCs), B-cells, their secreted antibodies, and the T-cells. Their functions are described in detail below.

In humoral immunity, antigen-presenting cells, including some B-cells, engulf and break down foreign organisms. Antigens from these foreign organisms are then brought to the outside surface of the antigen-presenting cells and presented in conjunction with class II MHC proteins. The helper T-cells recognize the antigen presented in this way and release cytokines , proteins that signal B-cells to take further action. B-cells are specialized white blood cells that mature in the bone marrow. Through the process of maturation, each B-cell develops the ability to recognize and respond to a specific antigen. Helper T-cells aid in stimulating the few B-cells that can recognize a particular foreign antigen. B-cells that are stimulated in this way develop into plasma cells, which secrete antibodies specific to the recognized antigen. Antibodies are proteins that are present in the circulation, as well as being bound to the surface of B-cells. They can destroy the foreign organism from which the antigen came. Destruction occurs either directly, or by tagging the organism, which will then be more easily recognized and targeted by phagocytes and complement proteins. Some of the stimulated B-cells go on to become memory cells, which are able to mount an even faster response if the antigen is encountered a second time.

Another type of acquired immunity involves killer T-cells and is termed cellular immunity. T-cells go through a process of maturation in the organ called the thymus, in which T-cells that recognized self-antigens are eliminated. Each remaining T-cell has the ability to recognize a single, specific, non-self antigen that the body may encounter. Although the names are similar, killer T-cells are unlike the non-specific natural killer cells in that they are specific in their action. Some viruses and parasites quickly invade the body's cells, where they are hidden from antibodies. Small pieces of proteins from these invading viruses or parasites are presented on the surface of infected cells in conjunction with class I MHC proteins, which are present on the surface of most all of the body's cells. Killer T-cells can recognize antigen bound to class I MHC in this way, and they are prompted to release chemicals that act directly to kill the infected cell. There is also a role for helper T-cells and antigen-presenting cells in cellular immunity. Helper T-cells release cytokines, as in the humoral response, and the cytokines stimulate killer T-cells to multiply. Antigen-presenting cells carry foreign antigen to places in the body where additional killer T-cells can be alerted and recruited.

The major histocompatibility complex clearly performs an important role in functioning of the immune system. Related to this role in disease immunity, MHC is also important in organ and tissue transplantation, as well as playing a role in susceptibility to certain diseases. HLA typing can also provide important information in parentage, forensic, and anthropologic studies.

There is significant variability of the frequencies of HLA alleles among ethnic groups. This is reflected in anthropologic studies attempting to use HLA-types to determine patterns of migration and evolutionary relationships of peoples of various ethnicity. Ethnic variation is also reflected in studies of HLA-associated diseases. Generally, populations that have been subject to significant patterns of migration and assimilation with other populations tend to have a more diverse HLA gene pool. For example, it is unlikely that two unrelated individuals of African ancestry would have matched HLA types. Conversely, populations that have been isolated due to geography, cultural practices, and other historical influences may display a less diverse pool of HLA types, making it more likely for two unrelated individuals to be HLA-matched.

There is a role for HLA typing of individuals in various settings. Most commonly, HLA typing is used to establish if an organ or tissue donor is appropriately matched to the recipient for key HLA types, so as not to elicit a rejection reaction in which the recipient's immune system attacks the donor tissue. In the special case of bone marrow transplantation, the risk is for graft-versus-host disease (GVHD), as opposed to tissue rejection. Because the bone marrow contains the cells of the immune system, the recipient effectively receives the donor's immune system. If the donor immune system recognizes the recipient's tissues as foreign, it may begin to attack, causing the inflammatory and other complications of GVHD. As advances occur in transplantation medicine, HLA typing for transplantation occurs with increasing frequency and in various settings.

There is an established relationship between the inheritance of certain HLA types and susceptibility to specific diseases. Most commonly, these are diseases that are thought to be autoimmune in nature. Autoimmune diseases are those characterized by inflammatory reactions that occur as a result of the immune system mistakenly attacking self tissues. The basis of the HLA association is not well understood, although there are some hypotheses. Most autoimmune diseases are characterized by the expression of class II MHC on cells of the body that do not normally express these proteins. This may confuse the killer T-cells, which respond inappropriately by attacking these cells. Molecular mimicry is another hypothesis. Certain HLA types may look like antigens from foreign organisms. If an individual is infected by such a foreign virus or bacteria, the immune system mounts a response against the invader. However, there may be a cross-reaction with cells displaying the HLA type that is mistaken for foreign antigen. Whatever the underlying mechanism, certain HLA-types are known factors that increase the relative risk for developing specific autoimmune diseases. For example, individuals who carry the HLA B-27 allele have a relative risk of 150 for developing ankylosing spondylitismeaning such an individual has a 150-fold chance of developing this form of spinal and pelvic arthritis, as compared to someone in the general population. Selected associations are listed below (disease name is first, followed by MHC allele and then the approximate corresponding relative risk of disease).

  • Type 1 diabetes, DR3, 5
  • Type 1 diabetes, DR4, 5
  • Type 1 diabetes, DR3 + DR4, 20-40
  • Narcolepsy, DR2, 260-360
  • Ankylosing spondylitis, B27, 80-150
  • Reiter's disease, B27, 37
  • Rheumatoid arthritis, DR4, 3-6
  • Myasthenia gravis, B8, 4
  • Lupus, DR3, 2
  • Graves disease, DR3, 5
  • Multiple sclerosis, DR2, 3
  • Celiac disease, DR3 and DR7, 5-10
  • Psoriasis vulgaris, Cw6, 8

In addition to autoimmune disease, HLA-type less commonly plays a role in susceptibility to other diseases, including cancer, certain infectious diseases, and metabolic diseases. Conversely, some HLA-types confer a protective advantage for certain types of infectious disease. In addition, there are rare immune deficiency diseases that result from inherited mutations of the genes of components of the major histocompatibility complex.

Among other tests, HLA typing can sometimes be used to determine parentage, most commonly paternity, of a child. This type of testing is not generally done for medical reasons, but rather for social or legal reasons.

HLA-typing can provide valuable DNA-based evidence contributing to the determination of identity in criminal cases. This technology has been used in domestic criminal trials. Additionally, it is a technology that has been applied internationally in the human-rights arena. For example, HLA-typing had an application in Argentina following a military dictatorship that ended in 1983. The period under the dictatorship was marked by the murder and disappearance of thousands who were known or suspected of opposing the regime's practices. Children of the disappeared were often adopted by military officials and others. HLA-typing was one tool used to determine non-parentage and return children of the disappeared to their biological families.

HLA-typing has proved to be an invaluable tool in the study of the evolutionary origins of human populations. This information, in turn, contributes to an understanding of cultural and linguistic relationships and practices among and within various ethnic groups.

See also Antibody and antigen; Immunity, cell mediated; Immunity, humoral regulation; Immunodeficiency disease syndromes; Immunodeficiency diseases; Immunogenetics; Immunological analysis techniques; Transplantation genetics and immunology

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major histocompatibility complex

major histocompatibility complex (MHC) A large multigene family that codes for histocompatibility antigens. Present on the surface of nucleated cells, histocompatibility antigens bind to and present foreign antigens to T cells which in turn may destroy infected cells or invading bodies, and use the histocompatibility antigens to recognize cells as self or foreign. The MHC tends to be highly polymorphic even within a single population, allowing a high level of discrimination between foreign and self, consequently organs transplanted from one member of a population to another are likely to be rejected by the new host unless the two members are very closely related. In different species different symbols are assigned to the MHC, e.g. in humans HLA is used, standing for human leucocyte antigen complex.

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major histocompatibility complex

major histocompatibility complex (MHC) A large gene cluster that encodes various components of the immune system, including the histocompatibility proteins and components of the complement system. In humans the MHC is located on chromosome 6 and includes the HLA system. Other vertebrate species have similar MHC regions. Certain MHC genes can have many variant alleles; this produces an enormous diversity of proteins in a population, each individual possessing a unique set.

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Major histocompatibility complex

Major histocompatibility complex

Definition

In humans, the proteins coded by the genes of the major histocompatibility complex (MHC) include human leukocyte antigens (HLA), as well as other proteins. HLA proteins are present on the surface of most of the body's cells and are important in helping the immune system distinguish 'self' from 'non-self'.

Description

The function and importance of MHC is best understood in the context of a basic understanding of the function of the immune system. The immune system is responsible for distinguishing 'self' from 'non-self', primarily with the goal of eliminating foreign organisms and other invaders that can result in disease. There are several levels of defense characterized by the various stages and types of immune response.

Natural immunity

When a foreign organism enters the body, it is encountered by the components of the body's natural immunity. Natural immunity is the non-specific first-line of defense carried out by phagocytes, natural killer cells, and components of the complement system. Phagocytes are specialized white blood cells capable of engulfing and killing an organism. Natural killer cells are also specialized white blood cells that respond to cancer cells and certain viral infections. The complement system is a group of proteins called the class III MHC that attack antigens. Antigens consist of any molecule capable of triggering an immune response. Although this list is not exhaustive, antigens can be derived from toxins, protein, carbohydrates, DNA , or other molecules from viruses, bacteria, cellular parasites, or cancer cells.

Acquired immunity

The natural immune response will hold an infection at bay as the next line of defense mobilizes through acquired, or specific immunity. This specialized type of immunity is usually needed to eliminate an infection and is dependent on the role of the proteins of the major histocompatibility complex. There are two types of acquired immunity. Humoral immunity is important in fighting infections outside the body's cells, such as those caused by bacteria and certain viruses. Other types of viruses and parasites that invade the cells are better fought by cellular immunity. The major players in acquired immunity are the antigen-presenting cells (APCs), B-cells, their secreted antibodies, and the T-cells. Their functions are described in detail below.

Humoral immunity

In humoral immunity, antigen-presenting cells, including some B-cells, engulf and break down foreign organisms. Antigens from these foreign organisms are then brought to the outside surface of the antigen-presenting cells and presented in conjunction with class II MHC proteins. The helper T-cells recognize the antigen presented in this way and release cytokines, proteins that signal B-cells to take further action. B-cells are specialized white blood cells that mature in the bone marrow. Through the process of maturation, each B-cell develops the ability to recognize and respond to a specific antigen. Helper T-cells aid in stimulating the few B-cells that can recognize a particular foreign antigen. B-cells that are stimulated in this way develop into plasma cells, which secrete antibodies specific to the recognized antigen. Antibodies are proteins that are present in the circulation, as well as being bound to the surface of B-cells. They can destroy the foreign organism from which the antigen came. Destruction occurs either directly, or by 'tagging' the organism, which will then be more easily recognized and targeted by phagocytes and complement proteins. Some of the stimulated B-cells go on to become memory cells, which are able to mount an even faster response if the antigen is encountered a second time.

Cellular immunity

Another type of acquired immunity involves killer T-cells and is termed celluar immunity. T-cells go through a process of maturation in the organ called the thymus, in which T-cells that recognize 'self' antigens are eliminated. Each remaining T-cell has the ability to recognize a single, specific, 'non-self' antigen that the body may encounter. Although the names are similar, killer T-cells are unlike the non-specific natural killer cells in that they are specific in their action. Some viruses and parasites quickly invade the body's cells, where they are 'hidden' from antibodies. Small pieces of proteins from these invading viruses or parasites are presented on the surface of infected cells in conjunction with class I MHC proteins, which are present on the surface of most all of the body's cells. Killer T-cells can recognize antigen bound to class I MHC in this way, and they are prompted to release chemicals that act directly to kill the infected cell. There is also a role for helper T-cells and antigen-presenting cells in cellular immunity. Helper T-cells release cytokines, as in the humoral response, and the cytokines stimulate killer T-cells to multiply. Antigen-presenting cells carry foreign antigen to places in the body where additional killer T-cells can be alerted and recruited.

The major histocompatibility complex clearly performs an important role in functioning of the immune system. Related to this role in disease immunity, MHC is important in organ and tissue transplantation, as well as playing a role in susceptibility to certain diseases. HLA typing can also provide important information in parentage, forensic, and anthropologic studies. These various roles and the practical applications of HLA typing are discussed in greater detail below.

Genetic profile

Present on chromosome 6, the major histocompatibility complex consists of more than 70 genes, classified into class I, II, and III MHC. There are multiple alleles, or forms, of each HLA gene . These alleles are expressed as proteins on the surface of various cells in a co-dominant manner. This diversity is important in maintaining an effective system of specific immunity. Altogether, the MHC genes span a region that is four million base pairs in length. Although this is a large region, 99% of the time these closely-linked genes are transmitted to the next generation as a unit of MHC alleles on each chromosome 6. This unit is called a haplotype.

Class I

Class I MHC genes include HLA-A, HLA-B, and HLA-C. Class I MHC are expressed on the surface of almost all cells. They are important for displaying antigen from viruses or parasites to killer T-cells in cellular immunity. Class I MHC is also particularly important in organ and tissue rejection following transplantation. In addition to the portion of class I MHC coded by the genes on chromosome 6, each class I MHC protein also contains a small, non-variable protein component called beta-2 microglobulin coded by a gene on chromosome 15. Class I HLA genes are highly polymorphic, meaning there are multiple forms, or alleles, of each gene. There are at least 57 HLAA alleles, 111 HLA-B alleles, and 34 HLA-C alleles.

Class II

Class II MHC genes include HLA-DP, HLA-DQ, and HLA-DR. Class II MHC are particularly important in humoral immunity. They present foreign antigen to helper T-cells, which stimulate B-cells to elicit an antibody response. Class II MHC is only present on antigen presenting cells, including phagocytes and B-cells. Like class I MHC, there are hundreds of alleles that make up the class II HLA gene pool .

Class III

Class III MHC genes include the complement system (i.e. C2, C4a, C4b, Bf). Complement proteins help to activate and maintain the inflammatory process of an immune response.

Demographics

There is significant variability of the frequencies of HLA alleles among ethnic groups. This is reflected in anthropologic studies attempting to use HLA-types to determine patterns of migration and evolutionary relationships of peoples of various ethnicity. Ethnic variation is also reflected in studies of HLA-associated diseases. Generally speaking, populations that have been subject to significant patterns of migration and assimilation with other populations tend to have a more diverse HLA gene pool. For example, it is unlikely that two unrelated individuals of African ancestry would have matched HLA types. Conversely, populations that have been isolated due to geography, cultural practices, and other historical influences may display a less diverse pool of HLA types, making it more likely for two unrelated individuals to be HLA-matched.

Testing

Organ and tissue transplantation

There is a role for HLA typing of individuals in various settings. Most commonly, HLA typing is used to establish if an organ or tissue donor is appropriately matched to the recipient for key HLA types, so as not to elicit a rejection reaction in which the recipient's immune system attacks the donor tissue. In the special case of bone marrow transplantation, the risk is for graft-versus-host disease (GVHD), as opposed to tissue rejection. Because the bone marrow contains the cells of the immune system, the recipient effectively receives the donor's immune system. If the donor immune system recognizes the recipient's tissues as foreign, it may begin to attack, causing the inflammation and other complications of GVHD. As advances occur in transplantation medicine, HLA typing for transplantation occurs with increasing frequency and in various settings.

Disease susceptibility

There is an established relationship between the inheritance of certain HLA types and susceptibility to specific diseases. Most commonly, these are diseases that are thought to be autoimmune in nature. Autoimmune diseases are those characterized by inflammatory reactions that occur as a result of the immune system mistakenly attacking 'self' tissues. The basis of the HLA association is not well understood, although there are some hypotheses. Most autoimmune diseases are characterized by the expression of class II MHC on cells of the body that do not normally express these proteins. This may confuse the killer T-cells, which respond inappropriately by attacking these cells. Molecular mimicry is another hypothesis. Certain HLA types may 'look like' antigen from foreign organisms. If an individual is infected by such a foreign virus or bacteria, the immune system mounts a response against the invader. However, there may be a 'cross-reaction' with cells displaying the HLA type that is mistaken for foreign antigen. Whatever the underlying mechanism, certain HLA-types are known factors that increase the relative risk for developing specific autoimmune diseases. For example, individuals who carry the HLA B-27 allele have a relative risk of 77–90 for developing ankylosing spondylitis—meaning such an individual has a 77- to 90-fold chance of developing this form of spinal and pelvic arthritis, as compared to someone in the general population. Selected associations are listed below, together with the approximate corresponding relative risk of disease.

In addition to autoimmune disease, HLA-type less commonly plays a role in susceptibility to other diseases, including cancer, certain infectious diseases, and metabolic diseases. Conversely, some HLA-types confer a protective advantage for certain types of infectious disease. In addition, there are rare immune deficiency diseases that result from inherited mutations of the genes of components of the major histocompatibility complex.

HLA disease associations
Disease MHC allele Approximate relative risk
Ankylosing spondylitis B27 77–90
Celiac disease DR3 + DR7 5–10
Diabetes, Type 1 DR3 5
Diabetes, Type 1 DR4 5–7
Diabetes, Type 1 DR3 + DR4 20–40
Graves disease DR3 5
Hemochromatosis A3 6–20
Lupus DR3 1–3
Multiple sclerosis DR2 2–4
Myasthenia gravis B8 2.5–4
Psoriasis vulgaris Cw6 8
Rheumatoid arthritis DR4 3–6
The relative risks indicated in this table refer to the increased chance of a patient with an MHC allele to develop a disorder as compared to an individual without one. For example, a patient with DR4 is three to six times more likely to have rheumatoid arthritis and five to seven times more likely to develop type 1 diabetes than an individual without the DR4 allele.

Parentage

Among other tests, HLA typing can sometimes be used to determine parentage, most commonly paternity, of a child. This type of testing is not generally done for medical reasons, but rather for social or legal reasons.

Forensics

HLA-typing can provide valuable DNA-based evidence contributing to the determination of identity in criminal cases. This technology has been used in domestic criminal trials. Additionally, it is a technology that has been applied internationally in the human-rights arena. For example, HLA-typing had an application in Argentina following a military dictatorship that ended in 1983. The period under the dictatorship was marked by the murder and disappearance of thousands who were known or suspected of opposing the regime's practices. Children of the disappeared were often 'adopted' by military officials and others. HLA-typing was one tool used to determine non-parentage and return children to their biological families.

Anthropologic studies

HLA-typing has proved to be an invaluable tool in the study of the evolutionary origins of human populations. This information, in turn, contributes to an understanding of cultural and linguistic relationships and practices among and within various ethnic groups.

Resources

BOOKS

Abbas, A.K., et al. Cellular and Molecular Immunology. Philadelphia: W.B. Saunders, 1991.

Doherty, D.G., and G.T. Nepom. "The human major histocompatibility complex and disease susceptibility." In Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Ed. D.L. Rimoin, J.M. Connor, and R.E. Pyeritz, 479–504. New York: Churchill Livingston, 1997.

Jorde L.B., et al. "Immunogenetics." In Medical Genetics. 2nd ed. St. Louis: Moseby, 1999.

PERIODICALS

Diamond, J.M. "Abducted orphans identified by grandpaternity testing." Nature 327 (1987): 552–53.

Svejgaard, A., et al. "Associations between HLA and disease with notes on additional associations between a 'new' immunogenetic marker and rheumatoid arthritis." HLA and Disease—The Molecular Basis. Alfred Benzon Symposium. 40 (1997): 301–13.

Trachtenberg, E.A., and H.A. Erlich. "DNA-based HLA typing for cord blood stem cell transplantation." Journal of Hematotherapy 5 (1996): 295–300.

WEBSITES

"Biology of the immune system." The Merck Manual<http://www.merck.com/pubs/mmanual_home/sec16/176.htm>.

Jennifer Denise Bojanowski, MS, CGC

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Major Histocompatibility Complex

Major histocompatibility complex

Definition

In humans, the proteins coded by the genes of the major histocompatibility complex (MHC) include human leukocyte antigens (HLA), as well as other proteins. HLA proteins are present on the surface of most of the body's cells and are important in helping the immune system distinguish "self" from "non-self."

Description

The function and importance of MHC is best understood in the context of a basic understanding of the function of the immune system. The immune system is responsible for distinguishing "self" from "non-self," primarily with the goal of eliminating foreign organisms and other invaders that can result in disease. There are several levels of defense characterized by the various stages and types of immune response.

Natural immunity

When a foreign organism enters the body, it is encountered by the components of the body's natural immunity. Natural immunity is the non-specific first-line of defense carried out by phagocytes, natural killer cells, and components of the complement system. Phagocytes are specialized white blood cells capable of engulfing and killing an organism. Natural killer cells are also specialized white blood cells that respond to cancer cells and certain viral infections. The complement system is a group of proteins called the class III MHC that attack antigens. Antigens consist of any molecule capable of triggering an immune response. Although this list is not exhaustive, antigens can be derived from toxins, protein, carbohydrates, DNA , or other molecules from viruses, bacteria, cellular parasites, or cancer cells.

Acquired immunity

The natural immune response will hold an infection at bay as the next line of defense mobilizes through acquired, or specific immunity. This specialized type of immunity is usually needed to eliminate an infection and is dependent on the role of the proteins of the major histocompatibility complex. There are two types of acquired immunity. Humoral immunity is important in fighting infections outside the body's cells, such as those caused by bacteria and certain viruses. Other types of viruses and parasites that invade the cells are better fought by cellular immunity. The major players in acquired immunity are the antigen-presenting cells (APCs), B-cells, their secreted antibodies, and the T-cells. Their functions are described in detail below.

Humoral immunity

In humoral immunity, antigen-presenting cells, including some B-cells, engulf and break down foreign organisms. Antigens from these foreign organisms are then brought to the outside surface of the antigen-presenting cells and presented in conjunction with class II MHC proteins. The helper T-cells recognize the antigen presented in this way and release cytokines, proteins that signal B-cells to take further action. B-cells are specialized white blood cells that mature in the bone marrow. Through the process of maturation, each B-cell develops the ability to recognize and respond to a specific antigen. Helper T-cells aid in stimulating the few B-cells that can recognize a particular foreign antigen. B-cells that are stimulated in this way develop into plasma cells, which secrete antibodies specific to the recognized antigen. Antibodies are proteins that are present in the circulation, as well as being bound to the surface of B-cells. They can destroy the foreign organism from which the antigen came. Destruction occurs either directly, or by "tagging" the organism, which will then be more easily recognized and targeted by phagocytes and complement proteins. Some of the stimulated B-cells go on to become memory cells, which are able to mount an even faster response if the antigen is encountered a second time.

Cellular immunity

Another type of acquired immunity involves killer T-cells and is termed celluar immunity. T-cells go through a process of maturation in the organ called the thymus, in which T-cells that recognize "self" antigens are eliminated. Each remaining T-cell has the ability to recognize a single, specific, "non-self" antigen that the body may encounter. Although the names are similar, killer T-cells are unlike the non-specific natural killer cells in that they are specific in their action. Some viruses and parasites quickly invade the body's cells, where they are "hidden" from antibodies. Small pieces of proteins from these invading viruses or parasites are presented on the surface of infected cells in conjunction with class I MHC proteins, which are present on the surface of most all of the body's cells. Killer T-cells can recognize antigen bound to class I MHC in this way, and they are prompted to release chemicals that act directly to kill the infected cell. There is also a role for helper T-cells and antigen-presenting cells in cellular immunity. Helper T-cells release cytokines, as in the humoral response, and the cytokines stimulate killer T-cells to multiply. Antigen-presenting cells carry foreign antigen to places in the body where additional killer T-cells can be alerted and recruited.

The major histocompatibility complex clearly performs an important role in functioning of the immune system. Related to this role in disease immunity, MHC is also important in organ and tissue transplantation, as well as playing a role in susceptibility to certain diseases. HLA typing can also provide important information in parentage, forensic, and anthropologic studies. These various roles and the practical applications of HLA typing are discussed in greater detail below.

Genetic profile

Present on chromosome 6, the major histocompatibility complex consists of more than 70 genes, classified into class I, II, and III MHC. There are multiple alleles, or forms, of each HLA gene . These alleles are expressed as proteins on the surface of various cells in a co-dominant manner. This diversity is important in maintaining an effective system of specific immunity. Altogether, the MHC genes span a region that is four million base pairs in length. Although this is a large region, 99% of the time these closely linked genes are transmitted to the next generation as a unit of MHC alleles on each chromosome 6. This unit is called a haplotype.

Class I

Class I MHC genes include HLA-A, HLA-B, and HLA-C. Class I MHC are expressed on the surface of almost all cells. They are important for displaying antigen from viruses or parasites to killer T-cells in cellular immunity. Class I MHC is also particularly important in organ and tissue rejection following transplantation. In addition to the portion of class I MHC coded by the genes on chromosome 6, each class I MHC protein also contains a small, non-variable protein component called beta-2 microglobulin coded by a gene on chromosome 15. Class I HLA genes are highly polymorphic, meaning there are multiple forms, or alleles, of each gene. There are at least 57 HLA-A alleles, 111 HLA-B alleles, and 34 HLA-C alleles.

Class II

Class II MHC genes include HLA-DP, HLA-DQ, and HLA-DR. Class II MHC are particularly important in humoral immunity. They present foreign antigen to helper T-cells, which stimulate B-cells to elicit an antibody response. Class II MHC is only present on antigen presenting cells, including phagocytes and B-cells. Like class I MHC, there are hundreds of alleles that make up the class II HLA gene pool .

Class III

Class III MHC genes include the complement system (i.e. C2, C4a, C4b, Bf). Complement proteins help to activate and maintain the inflammatory process of an immune response.

Demographics

There is significant variability of the frequencies of HLA alleles among ethnic groups. This is reflected in anthropologic studies attempting to use HLA-types to determine patterns of migration and evolutionary relationships of peoples of various ethnicity. Ethnic variation is also reflected in studies of HLA-associated diseases. Generally speaking, populations that have been subject to significant patterns of migration and assimilation with other populations tend to have a more diverse HLA gene pool. For example, it is unlikely that two unrelated individuals of African ancestry would have matched HLA types. Conversely, populations that have been isolated due to geography, cultural practices, and other historical influences may display a less diverse pool of HLA types, making it more likely for two unrelated individuals to be HLA-matched.

Testing

Organ and tissue transplantation

There is a role for HLA typing of individuals in various settings. Most commonly, HLA typing is used to establish if an organ or tissue donor is appropriately matched to the recipient for key HLA types, so as not to elicit a rejection reaction in which the recipient's immune system attacks the donor tissue. In the special case of bone marrow transplantation, the risk is for graft-versus-host disease (GVHD), as opposed to tissue rejection. Because the bone marrow contains the cells of the immune system, the recipient effectively receives the donor's immune system. If the donor immune system recognizes the recipient's tissues as foreign, it may begin to attack, causing the inflammation and other complications of GVHD. As advances occur in transplantation medicine, HLA typing for transplantation occurs with increasing frequency and in various settings.

Disease susceptibility

There is an established relationship between the inheritance of certain HLA types and susceptibility to specific diseases. Most commonly, these are diseases that are thought to be autoimmune in nature. Autoimmune diseases are those characterized by inflammatory reactions that occur as a result of the immune system mistakenly attacking "self" tissues. The basis of the HLA association is not well understood, although there are some hypotheses. Most autoimmune diseases are characterized by the expression of class II MHC on cells of the body that do not normally express these proteins. This may confuse the killer T-cells, which respond inappropriately by attacking these cells. Molecular mimicry is another hypothesis. Certain HLA types may "look like" antigen from foreign organisms. If an individual is infected by such a foreign virus or bacteria, the immune system mounts a response against the invader. However, there may be a "cross-reaction" with cells displaying the HLA type that is mistaken for foreign antigen. Whatever the underlying mechanism, certain HLA-types are known factors that increase the relative risk for developing specific autoimmune diseases. For example, individuals who carry the HLA B-27 allele have a relative risk of 77–90 for developing ankylosing spondylitis—meaning such an individual has a 77–90-fold chance of developing this form of spinal and pelvic arthritis, as compared to someone in the general population. Selected associations are listed below, together with the approximate corresponding relative risk of disease.

In addition to autoimmune disease, HLA-type less commonly plays a role in susceptibility to other diseases, including cancer, certain infectious diseases, and metabolic diseases. Conversely, some HLA-types confer a protective advantage for certain types of infectious disease. In addition, there are rare immune deficiency diseases that result from inherited mutations of the genes of components of the major histocompatibility complex.

Parentage

Among other tests, HLA typing can sometimes be used to determine parentage, most commonly paternity, of a child. This type of testing is not generally done for medical reasons, but rather for social or legal reasons.

HLA disease associations

Disease MHC allele Approximate relative risk
The relative risks indicated in this table refer to the increased chance of a patient with an MHC allele to develop a disorder as compared to an individual without one. For example, a patient with DR4 is three to six times more likely to have rheumatoid arthritis and five to seven times more likely to develop type 1 diabetes than an individual without the DR4 allele.
Ankylosing spondylitisB2777–90
Celiac diseaseDR3 + DR75–10
Diabetes, Type 1DR35
Diabetes, Type 1DR45–7
Diabetes, Type 1DR3 + DR420–40
Graves diseaseDR35
HemochromatosisA36–20
LupusDR31–3
Multiple sclerosisDR22–4
Myasthenia gravisB82.5–4
Psoriasis vulgarisCw68
Rheumatoid arthritisDR43–6

Forensics

HLA-typing can provide valuable DNA-based evidence contributing to the determination of identity in criminal cases. This technology has been used in domestic criminal trials. Additionally, it is a technology that has been applied internationally in the human-rights arena. For example, HLA-typing had an application in Argentina following a military dictatorship that ended in 1983. The period under the dictatorship was marked by the murder and disappearance of thousands who were known or suspected of opposing the regime's practices. Children of the disappeared were often "adopted" by military officials and others. HLA-typing was one tool used to determine non-parentage and return children to their biological families.

Anthropologic studies

HLA-typing has proved to be an invaluable tool in the study of the evolutionary origins of human populations. This information, in turn, contributes to an understanding of cultural and linguistic relationships and practices among and within various ethnic groups.

Resources

BOOKS

Abbas, A. K., et al. Cellular and Molecular Immunology. Philadelphia: W. B. Saunders, 1991.

Doherty, D. G., and G. T. Nepom. "The human major histocompatibility complex and disease susceptibility." In Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Ed. D. L. Rimoin, J. M. Connor, and R. E. Pyeritz, 479–504. New York: Churchill Livingston, 1997.

Jorde L. B., et al. "Immunogenetics." In Medical Genetics. 2nd ed. St. Louis: Moseby, 1999.

PERIODICALS

Diamond, J. M. "Abducted orphans identified by grandpaternity testing." Nature 327 (1987): 552–53.

Svejgaard, A., et al. "Associations between HLA and disease with notes on additional associations between a 'new' immunogenetic marker and rheumatoid arthritis." HLA and Disease—The Molecular Basis. Alfred Benzon Symposium. 40 (1997): 301–13.

Trachtenberg, E. A., and H. A. Erlich. "DNA-based HLA typing for cord blood stem cell transplantation." Journal of Hematotherapy 5 (1996): 295–300.

WEBSITES

"Biology of the immune system." The Merck Manual<http://www.merck.com/pubs/mmanual_home/sec16/176.htm>.

Jennifer Denise Bojanowski, MS, CGC

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