Bare lymphocyte syndrome type II (BLS II) is an inherited disorder of the immune system categorized as a form of combined immunodeficiency (CID). People with BLS II lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system.

BLS II is typically diagnosed in the first year of life. Most affected infants have persistent infections in the respiratory, gastrointestinal, and urinary tracts. Because of the infections, affected infants have difficulty absorbing nutrients (malabsorption), and they grow more slowly than their peers. Eventually, the persistent infections lead to organ failure. Without treatment, individuals with BLS II usually do not survive past early childhood.

In people with BLS II, infection-fighting white blood cells (lymphocytes) are missing specialized proteins on their surface called major histocompatibility complex (MHC) class II proteins, which is where the condition got its name. Because BLS II is the most common and best studied form of a group of related conditions, it is often referred to as simply bare lymphocyte syndrome (BLS).

BLS II is caused by mutations in the CIITA, RFX5, RFXANK, or RFXAP gene. Each of these genes provides instructions for making a protein that plays a role in controlling the activity (transcription) of genes called MHC class II genes. Transcription is the first step in the production of proteins, and the CIITA, RFX5, RFXANK, and RFXAP proteins are critical for the production of MHC class II proteins from these genes.

The RFX5, RFXANK, and RFXAP proteins come together to form the regulatory factor X (RFX) complex, which attaches (binds) to specific regions of DNA involved in the regulation of MHC class II gene activity. The CIITA protein interacts with the RFX complex and brings together other proteins that turn on gene transcription, leading to the production of MHC class II proteins.

MHC class II proteins play an important role in the body's immune response to foreign invaders, such as bacteria, viruses, and fungi. To help the body recognize and fight infections, MHC class II proteins on lymphocytes bind to fragments of proteins (peptides) from foreign invaders so that other specialized immune system cells can interact with them. When these immune system cells recognize the peptides as harmful, they trigger the lymphocytes to launch immune responses to get rid of the foreign invaders.

Mutations in the CIITA, RFX5, RFXANK, or RFXAP gene prevent transcription of MHC class II genes, which leads to an absence of MHC class II proteins on the surface of certain lymphocytes. Lack of these proteins on lymphocytes impairs the body's immune response to bacteria, viruses, and fungi, leading to persistent infections in individuals with BLS II syndrome.

Normal Function

The CIITA gene provides instructions for making a protein that primarily helps control the activity (transcription) of genes called major histocompatibility complex (MHC) class II genes. Transcription is the first step in the production of proteins, and CIITA is critical for the production of specialized immune proteins called MHC class II proteins from these genes. The CIITA protein coordinates various proteins to turn on MHC class II gene transcription and allow the production of MHC class II proteins.

MHC class II proteins are found on the surface of several types of immune cells, including white blood cells (lymphocytes) that are involved in immune reactions. These proteins play an important role in the body's immune response to foreign invaders, such as bacteria, viruses, and fungi. To help the body recognize and fight infections, MHC class II proteins bind to fragments of proteins (peptides) from foreign invaders so that other specialized immune system cells can interact with them. When these immune system cells recognize the peptides as harmful, they trigger the lymphocytes and other immune cells to launch immune responses to get rid of the foreign invaders.

The CIITA protein also appears to play a role in enhancing the transcription of MHC class I genes, which provide instructions for making immune system proteins called MHC class I proteins. Like MHC class II proteins, MHC class I proteins attach to peptides from foreign invaders and present them to specific immune system cells. These cells then attack the foreign invaders to rid them from the body. While the CIITA protein is able to help promote MHC class I gene activity, it is not the primary regulator of these genes. Other proteins play a more prominent role in their transcription.

Health Conditions Related to Genetic Changes

Bare lymphocyte syndrome type II

More than a dozen mutations in the CIITA gene have been found to cause an immune system disorder called bare lymphocyte syndrome type II (BLS II). BLS II is a type of combined immunodeficiency (CID), in which affected individuals have virtually no immune protection from foreign invaders. Consequently, individuals with BLS II have persistent infections in the respiratory, gastrointestinal, and urinary tracts, which can be life-threatening.

CIITA gene mutations involved in BLS II result in a lack of functioning CIITA protein. A shortage of CIITA to coordinate the factors that turn on MHC class II gene transcription prevents production of MHC class II proteins. Consequently, lymphocytes and other immune cells lack any MHC class II proteins on their surface, and the body has difficulty getting rid of bacteria, viruses, and fungi, leading to the persistent infections characteristic of BLS II.

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Other Names for This Gene

• C2TA
• CIITAIV
• MHC class II transactivator
• MHC2TA
• NLR family, acid domain containing
• NLRA
• nucleotide-binding oligomerization domain, leucine rich repeat and acid domain containing

Genomic Location

Normal Function

The RFX5 gene provides instructions for making a protein that primarily helps control the activity (transcription) of genes called major histocompatibility complex (MHC) class II genes. Transcription is the first step in the production of proteins, and RFX5 is critical for the production of specialized immune proteins called MHC class II proteins from these genes.

The RFX5 protein is part of a group of proteins called the regulatory factor X (RFX) complex. This complex attaches to a specific region of DNA involved in the regulation of MHC class II gene activity. The RFX5 protein helps the complex attach to the correct region of DNA. The RFX complex attracts other necessary proteins to this region and helps turn on MHC class II gene transcription, allowing production of MHC class II proteins.

MHC class II proteins are found on the surface of several types of immune cells, including white blood cells (lymphocytes) that are involved in immune reactions. These proteins play an important role in the body's immune response to foreign invaders, such as bacteria, viruses, and fungi. To help the body recognize and fight infections, MHC class II proteins bind to fragments of proteins (peptides) from foreign invaders so that other specialized immune system cells can interact with them. When these immune system cells recognize the peptides as harmful, they trigger the lymphocytes and other immune cells to launch immune responses to get rid of the foreign invaders.

The RFX complex also appears to play a role in the transcription of MHC class I genes, which provide instructions for making immune system proteins called MHC class I proteins. Like MHC class II proteins, MHC class I proteins attach to peptides from foreign invaders and present them to specific immune system cells. These cells then attack the foreign invaders to rid them from the body. While the RFX complex is able to help control MHC class I gene activity, it is not the primary regulator of these genes. Other proteins play a more prominent role in their transcription.

Health Conditions Related to Genetic Changes

Bare lymphocyte syndrome type II

At least seven mutations in the RFX5 gene have been found to cause an immune system disorder called bare lymphocyte syndrome type II (BLS II). BLS II is a type of combined immunodeficiency (CID), in which affected individuals have virtually no immune protection from foreign invaders. Consequently, individuals with BLS II have persistent infections in the respiratory, gastrointestinal, and urinary tracts, which can be life-threatening.

Mutations in the RFX5 gene lead to production of an abnormally short RFX5 protein that likely does not function properly. These changes impair binding of the RFX complex to DNA, which prevents transcription of MHC class II proteins. Consequently, lymphocytes lack any MHC class II proteins on their surface, and the body has difficulty getting rid of bacteria, viruses, and fungi, leading to the persistent infections characteristic of BLS II.

Other Names for This Gene

• DNA-binding protein RFX5
• regulatory factor X 5
• regulatory factor X, 5 (influences HLA class II expression)

Genomic Location

Normal Function

The RFXANK gene provides instructions for making a protein that primarily helps control the activity (transcription) of genes called major histocompatibility complex (MHC) class II genes. Transcription is the first step in the production of proteins, and RFXANK is critical for the production of specialized immune proteins called MHC class II proteins from these genes.

The RFXANK protein is part of a group of proteins called the regulatory factor X (RFX) complex. This complex attaches to a specific region of DNA involved in the regulation of MHC class II gene activity. RFXANK helps the complex attach to the correct region of DNA. The RFX complex attracts other necessary proteins to this region and helps turn on MHC class II gene transcription, allowing production of MHC class II proteins.

MHC class II proteins are found on the surface of several types of immune cells, including white blood cells (lymphocytes) that are involved in immune reactions. These proteins play an important role in the body's immune response to foreign invaders, such as bacteria, viruses, and fungi. To help the body recognize and fight infections, MHC class II proteins bind to fragments of proteins (peptides) from foreign invaders so that other specialized immune system cells can interact with them. When these immune system cells recognize the peptides as harmful, they trigger the lymphocytes and other immune cells to launch immune responses to get rid of the foreign invaders.

The RFX complex also appears to play a role in the transcription of MHC class I genes, which provide instructions for making immune system proteins called MHC class I proteins. Like MHC class II proteins, MHC class I proteins attach to peptides from foreign invaders and present them to specific immune system cells. These cells then attack the foreign invaders to rid them from the body. While the RFX complex is able to help control MHC class I gene activity, it is not the primary regulator of these genes. Other proteins play a more prominent role in their transcription.

Health Conditions Related to Genetic Changes

Bare lymphocyte syndrome type II

Mutations in the RFXANK gene are the most common genetic cause of an immune system disorder known as bare lymphocyte syndrome type II (BLS II). More than 40 mutations in this gene have been identified in affected individuals. BLS II is a type of combined immunodeficiency (CID), in which affected individuals have virtually no immune protection from foreign invaders. Consequently, individuals with BLS II have persistent infections in the respiratory, gastrointestinal, and urinary tracts, which can be life-threatening.

Mutations in the RFXANK gene lead to production of an altered protein that likely does not function properly. These changes impair binding of the RFX complex to DNA, which prevents transcription of MHC class II proteins. Consequently, lymphocytes lack any MHC class II proteins on their surface, and the body has difficulty getting rid of bacteria, viruses, and fungi, leading to the persistent infections characteristic of BLS II.

Other Names for This Gene

• ANKRA1
• ankyrin repeat family A protein 1
• ankyrin repeat-containing regulatory factor X-associated protein
• F14150_1
• MGC138628
• regulatory factor X subunit B
• RFX-B
• RFX-Bdelta4

Genomic Location

Normal Function

The RFXAP gene provides instructions for making a protein called RFX associated protein (RFXAP). It primarily helps control the activity (transcription) of genes called major histocompatibility complex (MHC) class II genes. Transcription is the first step in the production of proteins, and RFXAP is critical for the production of specialized immune proteins called MHC class II proteins from these genes.

The RFXAP protein is part of a group of proteins called the regulatory factor X (RFX) complex. This complex attaches to a specific region of DNA involved in the regulation of MHC class II gene activity. The RFXAP protein helps the complex attach to the correct region of DNA. The RFX complex attracts other necessary proteins to this region and helps turn on MHC class II gene transcription, allowing production of MHC class II proteins.

MHC class II proteins are found on the surface of several types of immune cells, including white blood cells (lymphocytes) that are involved in immune reactions. These proteins play an important role in the body's immune response to foreign invaders, such as bacteria, viruses, and fungi. To help the body recognize and fight infections, MHC class II proteins bind to fragments of proteins (peptides) from foreign invaders so that other specialized immune system cells can interact with them. When these immune system cells recognize the peptides as harmful, they trigger the lymphocytes and other immune cells to launch immune responses to get rid of the foreign invaders.

The RFX complex also appears to play a role in the transcription of MHC class I genes, which provide instructions for making immune system proteins called MHC class I proteins. Like MHC class II proteins, MHC class I proteins attach to peptides from foreign invaders and present them to specific immune system cells. These cells then attack the foreign invaders to rid them from the body. While the RFX complex is able to help control MHC class I gene activity, it is not the primary regulator of these genes. Other proteins play a more prominent role in their transcription.

Health Conditions Related to Genetic Changes

Bare lymphocyte syndrome type II

At least seven mutations in the RFXAP gene have been found to cause an immune system disorder called bare lymphocyte syndrome type II (BLS II). BLS II is a type of combined immunodeficiency (CID), in which affected individuals have virtually no immune protection from foreign invaders. Consequently, individuals with BLS II have persistent infections in the respiratory, gastrointestinal, and urinary tracts, which can be life-threatening.

Mutations in the RFXAP gene lead to production of an abnormally short RFXAP protein that likely does not function properly, if any protein is produced at all. These changes impair binding of the RFX complex to DNA, which prevents transcription of MHC class II proteins. Consequently, lymphocytes lack any MHC class II proteins on their surface, and the body has difficulty getting rid of bacteria, viruses, and fungi, leading to the persistent infections characteristic of BLS II.

Other disorders

At least one mutation in the RFXAP gene has been found to cause bare lymphocyte syndrome type III (BLS III). This type of bare lymphocyte syndrome is characterized by absence of MHC class II proteins and a reduced amount of MHC class I proteins on the surface of lymphocytes. However, it is unclear if BLS III is a distinct diagnosis. Some doctors consider such cases to be BLS II (described above). Both types of BLS cause persistent, life-threatening infections.

The RFXAP gene mutation involved in BLS III likely impairs the function of the RFX complex, preventing transcription of MHC class II genes and reducing the activity of MHC class I genes. Without the important immune system proteins produced from these genes, the body is less able to fight infections. It is unclear why certain RFXAP gene mutations impair production of MHC class I proteins and others do not.

Other Names for This Gene

• regulatory factor X-associated protein
• RFX DNA-binding complex 36 kDa subunit
• RFX-associated protein

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

BLS II is a rare condition. At least 100 cases have been reported in the medical literature. While BLS II has been found in several populations throughout the world, it appears to be especially prevalent in the Mediterranean region and North Africa.