X-Linked Agammaglobulinemia

- X-linked agammaglobulinemia is one of the more common forms of primary immunodeficiency.
- It is characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells.
- During normal B-cell maturation in the bone marrow, the Ig heavy-chain genes are rearranged first, in pre-B cells, and these are expressed on the cell surface in association with a "surrogate" light chain, where they deliver signals that induce rearrangement of the Ig light-chain genes and further maturation.
- This need for Ig-initiated signals is a quality control mechanism that ensures that maturation will proceed only if functional Ig proteins are expressed.
- X-linked agammaglobulinemia is caused by mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (Btk); the gene that encodes it is located on the long arm of the X chromosome at Xq21.22.
- Btk is a protein tyrosine kinase that is associated with the Ig receptor complex of pre-B and mature B cells and is needed to transduce signals from the receptor.
- When it is mutated, the pre-B cell receptor cannot deliver signals, and maturation stops at this stage.
- B/c light chains are not produced, the complete antigen receptor molecule (which contains Ig heavy and light chains) cannot be assembled and transported to the cell membrane.

- As an X-linked disease, this disorder is seen almost entirely in males, but sporadic cases have been described in females, possibly caused by mutations in some other gene that functions in the same pathway.
- The disease usually does not become apparent until about 6 months of age, as maternal immunoglobulins are depleted.
- In most cases, recurrent bacterial infections of the respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, call attention to the underlying immune defect.
- Almost always the causative organisms are Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus.
- These organisms are normally opsonized by antibodies and cleared by phagocytosis.
- B/c antibodies are important for neutralizing infectious viruses that are present in the bloodstream or mucosal secretions or being passed from cell to cell, individuals with this disease are also susceptible to certain viral infections, especially those caused by enteroviruses, such as echovirus, poliovirus, and coxsackievirus.
- These viruses infect the gastrointestinal tract, and from here they can disseminate to the nervous system via the blood.
- Thus, immunization with live poliovirus carries the risk of paralytic poliomyelitis, and echovirus can cause fatal encephalitis.
- For similar reasons, Giardia lamblia, an intestinal protozoan that is normally resisted by secreted IgA, causes persistent infections in persons with this disorder.
- In general, however, most intracellular viral, fungal, and protozoal infections are handled quite well by the intact T cell-mediated immunity.

- The classic form of this disease has the following characteristics:
   - B cells are absent or markedly decreased in the circulation, and the serum levels of all classes of immunoglobulins are depressed.  Pre-B cells, which express the B-lineage marker CD19 but not membrane Ig, are found in normal numbers in the bone marrow.
   - Germinal centers of lymph nodes, Peyer's pathces, the appendix, and tonsils are underdeveloped
   - Plasma cells are absent throughout the body
   - T cell-mediated reactions are normal

- Autoimmune diseases, such as arthritis and dermatocyositis, occur with increased frequency, in as many as 35% of individuals with this disease, which is paradoxical in the presence of an immune deficiency.
- It is likely that these autoimmune disorders are caused by a breakdown of self-tolerance resulting in autoimmunity, but chronic infections associated with the immune deficiency may play a role in inducing inflammatory reactions.
- The treatment of X-linked agammaglobulinemia is replacement therapy with immunoglobulins.
- In the past, most patients succombed to infection in infancy or early childhood.
- Prophylactic intravenous Ig therapy allows most individuals to reach childhood.


References:
1. Kumar, Raminder et al.  Robbins and Cotran Pathologic Basis of Disease 8th Ed.  Sander Elsevier. 2010.