105P- What is X-Linked Agammaglobulinemia, XLA, or Bruton Disease?

Summary

X-linked agammaglobulinemia (XLA), also known as Bruton's disease, is a genetic disorder characterized by a failure of pre-B cells to differentiate into mature B cells, resulting in the absence of gamma globulin in the blood. This impairs immune function, as the body cannot produce immunoglobulins, which are crucial for fighting infections. The condition affects males exclusively and is marked by recurrent bacterial and viral infections. Treatment often involves immunoglobulin replacement therapy. While T-cell responses remain intact, autoimmune diseases can also develop in some XLA patients. The disorder typically manifests after six months of age.

Takeaways

• 😀 X-linked agammaglobulinemia (XLA), also known as Bruton's disease, is a genetic disorder that impairs the maturation of B cells, leading to a lack of gamma globulin in the blood.
• 😀 In XLA, pre-B cells fail to differentiate into mature B cells, preventing the production of immunoglobulins (Ig).
• 😀 The mutation in XLA affects Bruton's tyrosine kinase (BTK), which is essential for the recombination process of immunoglobulin genes in B cells.
• 😀 In healthy B cells, heavy chain rearrangement occurs first, followed by light chain rearrangement. However, in XLA, light chain recombination does not occur due to the lack of BTK.
• 😀 The failure of light chain recombination leads to an excess of unpaired heavy chains in the cytoplasm but no complete immunoglobulins.
• 😀 XLA is an X-linked recessive disorder, meaning it primarily affects males, as males have only one X chromosome.
• 😀 XLA results in a marked decrease or complete absence of B cells and low levels of all classes of immunoglobulins in the blood.
• 😀 The bone marrow may show normal or reduced numbers of pre-B cells, but these cells cannot mature or activate to become plasma cells.
• 😀 XLA manifests around six months of age when maternal immunoglobulins are no longer present to provide immunity, leading to recurrent bacterial infections like otitis media, pneumonia, and sinusitis.
• 😀 Treatment for XLA involves intravenous immunoglobulin (IVIG) therapy, which provides patients with immunoglobulins from other people's blood to help fight bacterial infections.

Q & A

What is X-linked agammaglobulinemia (XLA)?

X-linked agammaglobulinemia (XLA), also known as Bruton's disease, is a genetic disorder that causes the failure of pre-B cells to mature into B cells, leading to a severe lack of immunoglobulins (gamma globulins) in the blood, making individuals more vulnerable to infections.

What role does Bruton's tyrosine kinase (BTK) play in B cell maturation?

Bruton's tyrosine kinase (BTK) is an enzyme that is essential for B cell maturation. In XLA, a mutation in the BTK gene prevents the proper recombination of light chains in B cells, halting their maturation and leading to a lack of functional antibodies.

How do B cells mature under normal circumstances?

In normal B cell maturation, heavy chain genes in the pre-B cell undergo recombination, followed by light chain recombination, which results in the formation of functional immunoglobulins (antibodies) that can be expressed on the surface of B cells or secreted.

What happens to B cells in individuals with XLA?

In individuals with XLA, the mutation in BTK halts B cell maturation after the heavy chain recombination step, preventing the light chain recombination, which leads to the accumulation of unpaired heavy chains and a lack of functional antibodies.

Why do individuals with XLA experience immune deficiencies?

Individuals with XLA lack functional B cells and immunoglobulins (antibodies), which are crucial for fighting infections. As a result, they are susceptible to bacterial and certain viral infections due to the absence of antibody-mediated immunity.

At what age do symptoms of XLA typically manifest?

Symptoms of XLA typically manifest around six months of age, when maternal antibodies that were passed to the baby begin to deplete, and the child's own immune system fails to produce sufficient antibodies.

What are common infections in individuals with XLA?

Individuals with XLA commonly experience bacterial infections, such as acute and chronic pharyngitis, sinusitis, ear infections (otitis media), bronchitis, and pneumonia, due to the lack of antibodies to clear these pathogens.

Which bacterial pathogens are often problematic for individuals with XLA?

Common bacterial pathogens in XLA patients include *Haemophilus influenzae*, *Streptococcus pneumoniae*, and *Staphylococcus aureus*, which are typically cleared by antibodies but persist due to the lack of immunoglobulins in XLA.

What is the role of antibodies in the immune response, and why is their absence a problem in XLA?

Antibodies are crucial for neutralizing pathogens and facilitating opsonization, which flags pathogens for destruction by phagocytes. In XLA, the lack of antibodies impairs the body's ability to clear infections, especially bacterial ones.

How is XLA treated, and what role does immunoglobulin replacement therapy play?

XLA is treated with immunoglobulin replacement therapy, where patients receive intravenous immunoglobulins (IVIG) derived from healthy donors. This helps to boost their immune response, particularly against bacterial infections, though it doesn't fully compensate for the lack of antibodies.