X-linked agammaglobulinemia
Encyclopedia
X-linked agammaglobulinemia (also called X-linked hypogammaglobulinemia, XLA, Bruton type agammaglobulinemia, Bruton syndrome, or Sex-linked agammaglobulinemia) is a rare X-linked genetic disorder that was discovered in 1952 which affects the body's ability to fight infection. XLA is an X-linked disorder, and therefore is more common in males. XLA patients do not generate mature B cell
s which manifests as a complete lack of antibodies in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (called immunoglobulins) which defends the body from infections by sustaining an immunological humoral antibody response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene which leads to a severe block in B cell development (at the pro-B to pre B cell stage) and a reduced Immunoglobulin (antibody) production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infection
s, particularly with extracellular, encapsulated bacteria
. It occurs in a frequency of about 1 in 100,000 male newborns, and has no ethnic predisposition
. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cell
s, but it is sufficient to reduce the severity and number of infections due to the passive immunity
granted by the exogenous antibodies.
XLA is caused by a mutation on the X chromosome
of a single gene
identified in 1993 and known as Bruton's tyrosine kinase
, or Btk. XLA was first characterized by Dr. Ogden Bruton
in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. Colonel Ogden C. Bruton first described the disease in 1952. It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system
, known as primary immunodeficiency
disorders.
s in the bone marrow
, and when mutated, immature pre-B lymphocytes are unable to develop into mature B cells that leave the bone marrow into the blood stream. The disorder is X-linked (it is on the X chromosome
), and is almost entirely limited to the sons of asymptomatic female carrier
s . This is because males have only one copy of the X chromosome, while females have two copies; one normal copy of an X chromosome can compensate for mutations in the other X chromosome, so they are less likely to be symptomatic. Females carriers have a 50% chance of giving birth to a male child with XLA.
An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient's daughters have a 50% chance of inheriting XLA. A female XLA patient can only arise as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus
of a non-carrier mother.
, through childhood. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19
and/or CD20
), as well as low levels of all antibody
classes, including IgG, IgA
, IgM
, IgE
and IgD
.
When XLA is suspected, it is possible to do a Western Blot
test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.
Surprisingly, though the symptoms of a XLA and other primary immune deceases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.
donations. IVIg does not cure XLA but increases the patient's lifespan and quality of life, by generating passive immunity
, and boosting the immune system
. With treatment, the number and severity of infections is reduced. With IVIg, XLA patients may live a relatively healthy life. A patient should attempt reaching a state where his IgG blood count exceeds 800 mg/kg. The dose is based on the patient's weight and IgG blood-count.
Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful, hence, IMIg is now uncommon.
Subcutaneous
treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.
Antibiotics are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long term treatment, if possible.
One of the future prospects of XLA treatment is gene therapy
, which could potentially cure XLA. Gene therapy technology is still in its infancy and may cause severe complications such as cancer and even death. Moreover, the long term success and complications of this treatment are, as yet, unknown.
(detection on antibodies to a specific pathogen or antigen
) is often used to diagnose viral diseases. Because XLA patients lack antibodies, these tests always give a negative result regardless of their real condition. This applies to standard HIV
tests. Special blood tests (such as the western blot
based test) are required for proper viral diagnosis in XLA patients.
It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio
, or the measles
, mumps
, rubella
(MMR vaccine
). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain immune memory.
XLA patients are specifically susceptible to viruses of the Enterovirus
family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echovirus
es. These may cause severe central nervous system
conditions as chronic encephalitis
, meningitis
and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus
(EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection.
It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE
antibodies.
There is no special hazard for XLA patients in dealing with pets or outdoor activities.
Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.
Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia
(CVID
), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.
XLA was also historically mistaken as Severe Combined Immunodeficiency
(SCID), a much more severe immune deficiency ("Bubble boys").
A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.
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...
s which manifests as a complete lack of antibodies in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (called immunoglobulins) which defends the body from infections by sustaining an immunological humoral antibody response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene which leads to a severe block in B cell development (at the pro-B to pre B cell stage) and a reduced Immunoglobulin (antibody) production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s, particularly with extracellular, encapsulated bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. It occurs in a frequency of about 1 in 100,000 male newborns, and has no ethnic predisposition
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cell
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...
s, but it is sufficient to reduce the severity and number of infections due to the passive immunity
Passive immunity
Passive immunity is the transfer of active humoral immunity in the form of readymade antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and can also be induced artificially, when high levels...
granted by the exogenous antibodies.
XLA is caused by a mutation on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
of a single gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
identified in 1993 and known as Bruton's tyrosine kinase
Bruton's tyrosine kinase
Bruton's tyrosine kinase is a type of kinase enzyme implicated in the primary immunodeficiency disease X-linked agammaglobulinemia . Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor...
, or Btk. XLA was first characterized by Dr. Ogden Bruton
Ogden Bruton
Ogden Carr Bruton was a pediatrician and chief of pediatrics at Walter Reed Army Hospital, where he organized the first pediatric residency at this hospital...
in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. Colonel Ogden C. Bruton first described the disease in 1952. It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the 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...
, known as primary immunodeficiency
Primary immunodeficiency
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature...
disorders.
Genetics
The gene Bruton's tyrosine kinase (Btk) plays an essential role in the maturation of B cellB 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...
s in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, and when mutated, immature pre-B lymphocytes are unable to develop into mature B cells that leave the bone marrow into the blood stream. The disorder is X-linked (it is on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
), and is almost entirely limited to the sons of asymptomatic female carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
s . This is because males have only one copy of the X chromosome, while females have two copies; one normal copy of an X chromosome can compensate for mutations in the other X chromosome, so they are less likely to be symptomatic. Females carriers have a 50% chance of giving birth to a male child with XLA.
An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient's daughters have a 50% chance of inheriting XLA. A female XLA patient can only arise as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
of a non-carrier mother.
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Diagnosis
XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tractRespiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
, through childhood. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
and/or CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
), as well as low levels of all 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...
classes, including IgG, IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
, IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
, IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
and IgD
IGD
IGD can refer to:*Internet Gateway Device as defined in UPnP.*İGD, İlerici Gençler Derneği, Progressive Young Association of Turkey*Immunoglobulin D, an antibody protein involved in the maturation of B cells....
.
When XLA is suspected, it is possible to do a Western Blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...
test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.
Surprisingly, though the symptoms of a XLA and other primary immune deceases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.
Treatment
The most common treatment for XLA is an intravenous infusion of immunoglobulin (IVIg, human IgG antibodies) every 3–4 weeks, for life. IVIg is a human product extracted and pooled from thousands of bloodBlood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
donations. IVIg does not cure XLA but increases the patient's lifespan and quality of life, by generating passive immunity
Passive immunity
Passive immunity is the transfer of active humoral immunity in the form of readymade antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and can also be induced artificially, when high levels...
, and boosting the 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...
. With treatment, the number and severity of infections is reduced. With IVIg, XLA patients may live a relatively healthy life. A patient should attempt reaching a state where his IgG blood count exceeds 800 mg/kg. The dose is based on the patient's weight and IgG blood-count.
Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful, hence, IMIg is now uncommon.
Subcutaneous
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.
Antibiotics are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long term treatment, if possible.
One of the future prospects of XLA treatment is gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
, which could potentially cure XLA. Gene therapy technology is still in its infancy and may cause severe complications such as cancer and even death. Moreover, the long term success and complications of this treatment are, as yet, unknown.
Other considerations
SerologySerology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
(detection on antibodies to a specific pathogen or 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...
) is often used to diagnose viral diseases. Because XLA patients lack antibodies, these tests always give a negative result regardless of their real condition. This applies to standard HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
tests. Special blood tests (such as the western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...
based test) are required for proper viral diagnosis in XLA patients.
It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio
Polio vaccine
Two polio vaccines are used throughout the world to combat poliomyelitis . The first was developed by Jonas Salk and first tested in 1952. Announced to the world by Salk on April 12, 1955, it consists of an injected dose of inactivated poliovirus. An oral vaccine was developed by Albert Sabin...
, or the measles
Measles
Measles, also known as rubeola or morbilli, is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense RNA viruses...
, mumps
Mumps
Mumps is a viral disease of the human species, caused by the mumps virus. Before the development of vaccination and the introduction of a vaccine, it was a common childhood disease worldwide...
, rubella
Rubella
Rubella, commonly known as German measles, is a disease caused by the rubella virus. The name "rubella" is derived from the Latin, meaning little red. Rubella is also known as German measles because the disease was first described by German physicians in the mid-eighteenth century. This disease is...
(MMR vaccine
MMR vaccine
The MMR vaccine is an immunization shot against measles, mumps, and rubella . It was first developed by Maurice Hilleman while at Merck in the late 1960s....
). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain immune memory.
XLA patients are specifically susceptible to viruses of the Enterovirus
Enterovirus
Enteroviruses are a genus of ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the...
family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echovirus
Echovirus
An ECHO virus, is a type of RNA virus that belongs to the genus Enterovirus of the Picornaviridae family...
es. These may cause severe central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
conditions as chronic encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
(EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection.
It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
antibodies.
There is no special hazard for XLA patients in dealing with pets or outdoor activities.
Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.
Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia
Hypogammaglobulinemia
Hypogammaglobulinemia is a type of immune disorder characterized by a reduction in all types of gamma globulins.Hypogammaglobulinemia is a characteristic of common variable immunodeficiency.-Terminology:...
(CVID
Cvid
Cvid stands for*Common variable immunodeficiencyand is also used to refer to the video codec Compact Video or*Cinepak*Cvid also stands for Dollar...
), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.
XLA was also historically mistaken as Severe Combined Immunodeficiency
Severe combined immunodeficiency
Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...
(SCID), a much more severe immune deficiency ("Bubble boys").
A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.