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The GALE

ENCYCLOPEDIA of

Genetic

Disorders

The GALE

ENCYCLOPEDIA of

Genetic

Disorders

V O L U M E

2

M-Z

APPENDIX

GLOSSARY

INDEX

S T A C E Y L . B L A C H F O R D , E D I T O R

The GALE

ENCYCLOPEDIA

of GENETIC DISORDERS

STAFF

Stacey L. Blachford, Associate Editor

Christine B. Jeryan, Managing Editor

Melissa C. McDade, Associate Editor

Ellen Thackery, Associate Editor

Mark Springer, Technical Training Specialist

Andrea Lopeman, Programmer/Analyst

Barbara Yarrow, Manager, Imaging and Multimedia

Content

Robyn Young, Project Manager, Imaging and

Multimedia Content

Randy Bassett, Imaging Supervisor

Robert Duncan, Senior Imaging Specialist

Pamela A. Reed, Coordinator, Imaging and Multimedia

Content

Maria Franklin, Permissions Manager

Ryan Thomason, Permissions Associate

Lori Hines, Permissions Assistant

Kenn Zorn, Product Manager

Michelle DiMercurio, Senior Art Director

Mary Beth Trimper, Manager, Composition and

Electronic Prepress

Evi Seoud, Assistant Manager, Composition Purchasing

and Electronic Prepress

Dorothy Maki, Manufacturing Manager

Ronald D. Montgomery, Manager, Data Capture

Gwendolyn S. Tucker, Project Administrator Beverly Jendrowski, Data Capture Specialist

Indexing provided by: Synapse. Illustrations created by:

Argosy, West Newton, Massachusetts

Electronic Illustrators Group, Morgan Hill, California

Since this page cannot legibly accommodate all copyright notices, the acknowledgments constitute an extension of the copyright notice.

While every effort has been made to ensure the reliability of the information presented in this publication, the Gale Group neither guarantees the accuracy of the data contained herein nor assumes any responsibility for errors, omissions or discrepancies. The Gale Group accepts no payment for listing, and inclusion in the publication of any organization, agency, institution, publication, service, or individual does not imply endorsement of the editors or publisher. Errors brought to the attention of the publisher and verified to the satisfaction of the publisher will be corrected in future editions.

This book is printed on recycled paper that meets Environmental Protection Agency standards.

The paper used in this publication meets the minimum requirements of American National Standard for Information Sciences-Permanence Paper for Printed Library Materials, ANSI Z39.48-1984.

This publication is a creative work fully protected by all applicable copyright laws, as well as by misappropriation, trade secret, unfair competition, and other applicable laws. The authors and editors of this work have added value to the underlying factual material herein through one or more of the following: unique and original selection, coordination, expression, arrangement, and classification of the information.

Gale Group and design is a trademark used herein under license.

All rights to this publication will be vigorously defended.

Copyright © 2002

Gale Group

27500 Drake Road

Farmington Hills, MI 48331-3535

All rights reserved including the right of reproduction in whole or in part in any form.

ISBN 0-7876-5612-7 (set) 0-7876-5613-5 (Vol. 1) 0-7876-5614-3 (Vol. 2)

Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data

The Gale encyclopedia of genetic disorders / Stacey L. Blachford, associate editor.

p. cm.

Includes bibliographical references and index.

Summary: Presents nearly four hundred articles describing genetic disorders, conditions, tests, and treatments, including high-profile diseases such as Alzheimer’s, breast cancer, and heart disease.

ISBN 0-7876-5612-7 (set : hardcover : alk.paper

1. Genetic disorders—Encyclopedias, Juvenile. [1. Genetic disorders—Encyclopedias. 2. Diseases—Encyclopedias.]

I. Blachford, Stacey.

RB155.5 .G35 2001 616’.042’03—dc21

2001040100

M

Machado-Joseph disease see Azorean disease

I Macular degeneration— age-related

Definition

Macular degeneration age-related (AMD) is one of the most common causes of vision loss among adults over age 55 living in developed countries. It is caused by the breakdown of the macula, a small spot located in the back of the eye. The macula allows people to see objects directly in front of them (called central vision), as well as fine visual details. People with AMD usually have blurred central vision, difficulty seeing details and colors, and they may notice distortion of straight lines.

Description

In order to understand how the macula normally functions and how it is affected by AMD, it is important to first understand how the eye works. The eye is made up of many different types of cells and tissues that all work together to send images from the environment to the brain, similar to the way a camera records images. When light enters the eye, it passes through the lens and lands on the retina, which is a very thin tissue that lines the inside of the eye. The retina is actually made up of 10 different layers of specialized cells, which allow the retina to function similarly to film in a camera, by recording images. The macula is a small, yellow-pigmented area located at the back of the eye, in the central part of the retina. The retina contains many specialized cells called photoreceptors that sense light coming into the eye and convert it into electrical messages that are then sent to the brain through the optic nerve. This allows the brain to “see” the environment.

The retina contains two types of photoreceptor cells: rod cells and cone cells. The rod cells are located primarily outside of the macula and they allow for peripheral (side) and night vision. Most of the photoreceptor cells inside of the macula, however, are the cone cells, which are responsible for perceiving color and for viewing objects directly in front of the eye (central vision). If the macula is diseased, as in AMD, color vision and central vision are altered. There are actually two different types of AMD: Dry AMD and Wet AMD.

Dry AMD

Approximately 90% of individuals with AMD have dry AMD. This condition is sometimes referred to as nonexudative, atrophic, or drusenoid macular degeneration. In this form of AMD, some of the layers of retinal cells (called retinal pigment epithelium, or RPE cells) near the macula begin to degenerate, or breakdown. These RPE cells normally help remove waste products from the cone and rod cells. When the RPE cells are no longer able to provide this “clean-up” function, fatty deposits called drusen begin to accumulate, enlarge and increase in number underneath the macula. The drusen formation can disrupt the cones and rods in the macula, causing them to degenerate or die (atrophy). This usually leads to central and color vision problems for people with dry AMD. However, some people with drusen deposits have minimal or no vision loss, and although they may never develop AMD, they should have regular eye examinations to check for this possibility. Dry AMD is sometimes called “nonexudative”, because even though fatty drusen deposits form in the eye, people do not have leakage of blood or other fluid (often called exudate) in the eye. In some cases, dry AMD symptoms remain stable or worsen slowly. In addition, approximately 10% of people with dry AMD eventually develop wet AMD.

Wet AMD

Around 10% of patients with AMD have wet AMD. This form of AMD is also called subretinal neovascular-

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K E Y T E R M S

Central vision—The ability to see objects located directly in front of the eye. Central vision is necessary for reading and other activities that require people to focus on objects directly in front of them.

Choroid—A vascular membrane that covers the back of the eye between the retina and the sclera and serves to nourish the retina and absorb scattered light.

Drusen—Fatty deposits that can accumulate underneath the retina and macula, and sometimes lead to age-related macular degeneration (AMD). Drusen formation can disrupt the photoreceptor cells, which causes central and color vision problems for people with dry AMD.

Genetic heterogeneity—The occurrence of the same or similar disease, caused by different genes among different families.

Macula—A small spot located in the back of the eye that provides central vision and allows people to see colors and fine visual details.

Multifactorial inheritance—A type of inheritance pattern where many factors, both genetic and environmental, contribute to the cause.

Optic nerve—A bundle of nerve fibers that carries visual messages from the retina in the form of electrical signals to the brain.

Peripheral vision—The ability to see objects that are not located directly in front of the eye. Peripheral vision allows people to see objects located on the side or edge of their field of vision.

Photoreceptors—Specialized cells lining the innermost layer of the eye that convert light into electrical messages so that the brain can perceive the environment. There are two types of photoreceptor cells: rod cells and cone cells. The rod cells allow for peripheral and night vision. Cone cells are responsible for perceiving color and for central vision.

Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve.

Visual acuity—The ability to distinguish details and shapes of objects.

ization, choroidal neovascularization, exudative form or disciform degeneration. Wet AMD is caused by leakage of fluid and the formation of abnormal blood vessels (called “neovascularization”) in a thin tissue layer of the eye called the choroid. The choroid is located underneath the retina and the macula, and it normally supplies them with nutrients and oxygen. When new, delicate blood vessels form, blood and fluid can leak underneath the macula, causing vision loss and distortion as the macula is pushed away from nearby retinal cells. Eventually a scar (called a disciform scar) can develop underneath the macula, resulting in severe and irreversible vision loss.

Genetic profile

AMD is considered to be a complex disorder, likely caused by a combination of genetic and environmental factors. This type of disorder is caused by multifactorial inheritance, which means that many factors likely interact with one another and cause the condition to occur. As implied by the words “age-related”, the aging process is one of the strongest risk factors for developing AMD. A number of studies have suggested that genetic susceptibility also plays an important role in the development of AMD, and it has been estimated that the brothers and sisters of people with AMD are four times more likely to also develop AMD, compared to other individuals.

Genetic factors

Determining the role that genetic factors play in the development of AMD is a complicated task for scientists. Since AMD is not diagnosed until late in life, it is difficult to locate and study large numbers of affected people in the same family. In addition, although AMD seems to run in families, there is no clear inheritance pattern (such as dominant or recessive) observed when examining families. However, many studies have supported the observation that inheritance plays some role in the development of AMD.

One method scientists use to locate genes that may increase a person’s chance to develop multifactorial conditions like AMD is to study genes that cause similar conditions. In 1997, this approach helped researchers identify changes (mutations) in the ATP-binding cassette transporter, retina-specific (ABCR) gene in people diagnosed with AMD. The process began after genetic research identified changes in the ABCR gene among people with an autosomal recessive macular disease called Stargardt macular dystrophy. This condition is phenotypically similar to AMD, which means that people with Stargardt macular dystrophy and AMD have similar symptoms, such as yellow deposits in the retina and decreased central vision.

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The ABCR gene maps to chromosome 1p22, and people who have Stargardt macular dystrophy have mutations in each of their two alleles (gene copies). However, the researchers who found mutations in the ABCR gene among people with AMD located only one allele with a mutation, which likely created an increased susceptibility to AMD. They concluded that people with an ABCR gene mutation in one allele could have an increased chance to develop AMD during their lifetime if they also had inherited other susceptibility genes, and/or had contact with environmental risk factors. Other scientists tried to repeat this type of genetic research among people with AMD in 1999, and were not able to confirm that the ABCR gene is a strong genetic risk factor for this condition. However, it is possible that the differing research results may have been caused by different research methods, and further studies will be necessary to understand the importance of ABCR gene mutations in the development of susceptibility to AMD.

In 1998, another genetic researcher reported a family in which a unique form of AMD was passed from one generation to the next. Although most families with AMD who are studied do not show an obvious inheritance pattern in their family tree, this particular family’s pedigree showed an apparently autosomal dominant form of AMD. Autosomal dominant refers to a specific type of inheritance in which only one copy of a person’s gene pair (i.e. one allele) needs to have a mutation in order for it to cause the disease. An affected person with an autosomal dominant condition thus has one allele with a mutation and one allele that functions properly. There is a 50% chance for this individual to pass on the allele with the mutation, and a 50% chance to pass on the working allele, to each of his or her children.

Genetic testing done on the family reported in 1998 showed that the dominant gene causing AMD in affected family members was likely located on chromosome 1q25-q31. Although the gene linked to AMD in this family and the ABCR gene are both on chromosome 1, they are located in different regions of the chromosome. This indicates that there is genetic heterogeneity among different families with AMD, meaning that different genes can lead to the same or similar disease among different families. It is also possible that although one particular gene may be the main cause of susceptibility for AMD, other genes and/or environmental factors may help alter the age of onset of symptoms or types of physical changes seen by examining the eye. Some studies have shown that other medical conditions or certain physical characteristics may be associated with an increased risk for AMD. Some of these include:

Heart disease

High blood pressure

Cataracts

Farsightedness

Light skin and eye color

However, not all studies have found a strong relationship between these factors and AMD. Further research is needed to decipher the role that both genetic and environmental factors play in the development of this complex condition.

Environmental factors

Determining the role that environmental factors play in the development of AMD is an important goal for researchers. Unlike genetic factors that cannot be controlled, people can often find motivation to change their behaviors if they are informed about environmental risk factors that may be within their control. Unfortunately, identifying environmental factors that clearly increase (or decrease) the risk for AMD is a challenging task. Several potential risk factors have been studied. These include:

Smoking

High fat/high cholesterol diet

Ultraviolet (UV) exposure (sunlight)

Low levels of dietary antioxidant vitamins and minerals

Although research has identified these possible risk factors, many of the studies have not consistently shown strong associations between these factors and the development of AMD. This makes it difficult to know the true significance of any of these risk factors. One exception, however, is the relationship between smoking and AMD. As of 1999, at least seven studies consistently found that smoking is strongly associated with AMD. This is one more important reason for people to avoid and/or quit smoking, especially if they have a family history of AMD. Further research is needed to clarify the significance of the factors listed above so people may be informed about lifestyle changes that may help decrease their risk for AMD.

Demographics

Among adults aged 55 and older, AMD is the leading cause of vision loss in developed countries. The chance to develop AMD increases with age, and although it usually affects adults during their sixth and seventh decades of life, it has been seen in some people in their forties. It is estimated that among people living in developed countries, approximately one in 2,000 are affected by AMD. By age 75, approximately 30% of people have early or mild forms of AMD, and roughly 7% have an advanced form of AMD. Since the number of people in the United States aged 65 years or older will likely dou-

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Macular degeneration—age-related

A retinal photograph showing macular degeneration.

(Custom Medical Stock Photo, Inc.)

ble between 1999 and 2024, the number of people affected also should increase. Although AMD occurs in both sexes, it is slightly more common in women.

The number of people affected with AMD is different in various parts of the world and it varies between different ethnic groups. Some studies suggest that AMD is more common in Caucasians than in African Americans; however, other reports suggest the numbers of people affected in these two groups are similar. Some studies of AMD among Japanese and other Asian ethnic groups have shown an increasing number of affected individuals. Further studies are needed to examine how often AMD occurs in other ethnic groups as well.

Signs and symptoms

During eye examinations, eye care specialists may notice physical changes in the retina and macula that make them suspect the diagnosis of AMD. However, affected individuals may notice:

Decreased visual acuity (ability to see details) of both up-close and distant objects

Blurred central vision

Decreased color vision

Distorted view of lines and shapes

A blind spot in the visual field

The majority of people with AMD maintain their peripheral vision. The severity of symptoms depends

upon whether a person has dry or wet AMD. In addition, the degree of vision loss and physical symptoms that can be seen by an eye exam change over time. For example, people with dry AMD usually develop vision loss very slowly over a period of many years. Their vision may change very little from one year to the next, and they usually do not lose central vision completely. However, individuals with wet AMD usually have symptoms that worsen more quickly and they have a greater risk to develop severe central vision loss, sometimes in as little as a two-month period. Since people diagnosed with dry AMD may go on to develop wet AMD, it is important for them to take note of any changes in their symptoms and to report them to their eye care specialist.

The physical symptoms of AMD eventually impact people emotionally. One study published in 1998 reported that people with advanced stages of AMD feel they have a significantly decreased quality of life. In addition, they may have a limited ability to perform basic daily activities due to poor vision, and as a result, they often suffer psychological distress. Hopefully, improved treatment and management will eventually change this trend for affected individuals in the future.

Diagnosis

Eye care specialists use a variety of tests and examination techniques to determine if a person has AMD. Some of these include:

Acuity testing—Involves testing vision by determining a person’s ability to read letters or symbols of various sizes on an “eye chart” from a precise distance away with specific lighting present.

Color testing—Assesses the ability of the cone cells to recognize colors by using special pictures made up of dots of colors that are arranged in specific patterns.

Amsler grid testing—Involves the use of a grid printed on a piece of paper that helps determine the health of the macula, by allowing people to notice whether they have decreased central vision, distorted vision, or blind spots.

Fluorescein angiography—Involves the use of a fluorescent dye, injected into the bloodstream, in order to look closely at the blood supply and blood vessels near the macula. The dye allows the eye specialist to examine and photograph the retina and macula to check for signs of wet AMD (i.e. abnormal blood vessel formation or blood leakage).

As of 2001, there are no genetic tests readily available to help diagnose AMD. Genetic research in the coming years will hopefully help scientists determine the genetic basis of AMD. This could help diagnose people

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with increased susceptibility before they have symptoms, so they may benefit from early diagnosis, management and/or treatment. This knowledge may also allow people who are at a genetically increased risk for AMD to avoid environmental risk factors and thus preserve or prolong healthy vision.

Treatment and management

Treatment

There is no universal treatment available to cure either wet or dry forms of AMD. However, some people with wet AMD can benefit from laser photocoagulation therapy. This treatment involves the use of light rays from a laser to destroy the abnormal blood vessels that form beneath the retina and macula and prevent further leakage of blood and fluid. Previously lost vision cannot be restored with this treatment, and the laser can unfortunately damage healthy tissue as well, causing further loss of vision.

In April 2000, the FDA approved the use of a lightactivated drug called Visudyne to help treat people with wet AMD. Visudyne is a medication that is injected into the bloodstream, and it specifically attaches to the abnormal blood vessels present under the macula in people with AMD. When light rays from a laser land on the blood vessels, the Visudyne is activated and can destroy the abnormal vessels, while causing very little damage to nearby healthy tissues. Although long term studies are needed to determine the safety and usefulness of this medication beyond two years, early reports find it an effective way to reduce further vision loss.

Researchers have been trying to identify useful treatments for dry AMD as well. Laser photocoagulation treatments are not effective for dry AMD since people with this form do not have abnormal blood or fluid leakage. Although many drugs have been tested, most have not improved visual acuity. However, one study published in October 2000, reported that people with dry AMD who received a medication called Iloprost over a six-month period noted improvements in visual acuity, daily living activities and overall quality of life. Followup studies will be needed to determine how safe and useful this medication will be over time.

Management

Although no treatments can cure AMD, a number of special devices can help people make the most of their remaining vision. Some of these include:

Walking canes

Guide dogs

Audiotapes

Magnifying lenses

Telescopes

Specialized prisms

Large print books

Reading machines

Computer programs that talk or enlarge printed information

People with AMD may also find it useful to meet with low-vision specialists who can help them adapt to new lifestyle changes that may assist with daily living. Eye care specialists can help people locate low-vision specialists. There are also a number of nationwide and international support groups available that provide education and support for individuals and families affected by AMD.

Prognosis

People can live many years with AMD, although the physical symptoms and emotional side effects often change over time. The vision problems caused by dry AMD typically worsen slowly over a period of years, and people often retain the ability to read. However, for people who develop wet AMD, the chance to suddenly develop severe loss of central vision is much greater. Regular monitoring of vision by people with AMD (using an Amsler grid) and by their eye care specialists, may allow for early treatment of leaky blood vessels, therefore reducing the chance for severe vision loss. As physical symptoms worsen, people are more likely to suffer emotionally due to decreasing quality of life and independence. However, many low-vision devices and various support groups can often provide much needed assistance to help maintain and/or improve quality of life.

Resources

BOOKS

D’Amato, Robert, and Joan Snyder. Macular Degeneration: The Latest Scientific Discoveries and Treatments for Preserving Your Sight. New York: Walker & Co., 2000.

Solomon, Yale, and Jonathan D. Solomon. Overcoming Macular Degeneration: A Guide to Seeing Beyond the Clouds. New York: Morrow/Avon, 2000.

PERIODICALS

Bressler, Neil M., and James P. Gills. “Age related macular degeneration.” British Medical Journal 321, no. 7274 (December 2000): 1425–1427.

Fong, Donald S. “Age-Related Macular Degeneration: Update for Primary Care.” American Family Physician 61, no. 10 (May 2000): 3035–3042.

“Macular degeneration.” Harvard Women’s Health Watch 6, no. 2 (October 1998): 2–3.

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“Researchers set sights on vision disease.” Harvard Health Letter 23, no.10 (August 1998):4–5.

“Self-test for macular degeneration.” Consumer Reports on Health 12, no.12 (December 2000): 2.

ORGANIZATIONS

AMD Alliance International. PO Box 550385, Atlanta, GA 30355. (877) 263-7171. http://www.amdalliance.org .

American Macular Degeneration Foundation. PO Box 515, Northampton, MA 01061-0515. (413) 268-7660.http://www.macular.org .

Foundation Fighting Blindness Executive Plaza 1, Suite 800, 11350 McCormick Rd., Hunt Valley, MD 21031. (888) 394-3937. http://www.blindness.org .

Macular Degeneration Foundation. PO Box 9752, San Jose, CA 95157. (888) 633-3937. http://www.eyesight.org .

Retina International. Ausstellungsstrasse 36, Zürich, CH-8005. Switzerland ( 41 1 444 10 77). http://www.retinainternational.org .

Pamela J. Nutting, MS, CGC

Madelung deformity see Leri-Weill dyschondrosteosis

Maffuci disease see Chondrosarcoma

I 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-pre- senting 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

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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-pre- senting 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-domi- nant 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

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