Agammaglobulinemia: X-linked (XLA) and autosomal recessive (ARA)

Some people with primary immunodeficiency (PI) lack the cells that are responsible for producing antibodies (immunoglobulins). They have very low or absent levels of all types of antibodies and an increased risk of infection. People with genetic causes of low or absent antibodies (agammaglobulinemia) have a severe form of antibody deficiency with absent B cells. This results from the failure of precursor B cells to develop into mature B cells and plasma cells.

Definition

The basic defect in agammaglobulinemia is the inability of the patient to produce antibodies. Antibodies are an integral part of the body's defense mechanism against germs. When a germ, such as bacteria, lands on a mucous membrane or enters the body, antibody molecules that recognize the germ stick to its surface. 

Antibodies bound to the surface of a germ can have one or more effects that are beneficial. For example, some germs must attach to body cells before they can cause an infection and antibodies prevent the germs from sticking to the body's cells. Antibody on the surface of some germs will also activate other body defenses, such as a group of blood proteins called serum complement, which can directly kill the bacteria or viruses. Finally, antibody-coated bacteria are much easier for white blood cells (phagocytes) to ingest and kill than bacteria that are not coated with antibody. 

All of these actions prevent germs from invading body tissues where they may cause serious infections. Antibodies are also important in the recovery from infections and to protect against getting certain infections more than once. 

Antibodies are produced by specialized cells in the body, called plasma cells. Plasma cells are derived from B lymphocytes (a type of white cell) that develop in an orderly sequence of steps beginning with stem cells located in the bone marrow. The stem cells give rise to immature lymphocytes that eventually develop into mature lymphocytes including T cells, B cells, or NK cells. A subset of these immature lymphocytes called pro-B lymphocytes next develop into pre-B lymphocytes, which then give rise to mature B lymphocytes (Figure 2:1). 

Each B lymphocyte has antibodies on its cell surface. Each B cell makes a slightly different antibody, or immunoglobulin, to allow the body to respond to millions of different foreign substances (also known as antigens), like vaccines or parts of bacteria or viruses. There are specific antibodies designed to recognize each unique antigen. When the B lymphocyte comes into contact with its antigen, it is triggered to mature into a plasma cell. Plasma cells specialize in making and secreting large amounts of specific antibodies.

The first form of agammaglobulinemia to be recognized, X-Linked agammaglobulinemia (XLA), was described in 1952 by Colonel Ogden Bruton, MD. This disease, sometimes called Bruton’s agammaglobulinemia or congenital agammaglobulinemia, typically affecting boys, was the first type of PI to be identified. Most individuals with XLA have normal numbers of B cell precursors, but very few of these are able to go on to become mature B cells. People with XLA have variants, or changes, in a gene that is necessary for the normal development of B cells. This gene, discovered in 1993, is named Bruton’s tyrosine kinase (BTK) in honor of Dr. Bruton.

After BTK variants were identified as the cause of XLA, it became clear that only about 85% of children with agammaglobulinemia and absent B cells had variants in BTK. In addition, it had been known for several years that there were girls who had an immunodeficiency that looked just like XLA, with agammaglobulinemia and absent B cells, but which could not be explained by X-linked inheritance of BTK variants.

Since 1996, several genes that can cause agammaglobulinemia with autosomal recessive inheritance (ARA) have been identified. The following genes (and their official gene symbol) have been reported to cause ARA:

• μ heavy chain (IGHM).
• λ5 (IGLL1).
• Igα (CD79A).
• Igß (CD79B).
• BLNK (BLNK).
• PI3K p85α (PIK3R1).

In addition, more recently, autosomal dominant forms of agammaglobulinemia have been described due to variants in LRRC8 (LRRC8A) and E2A (TCF3).

All of these genes code for proteins involved in the maturation of B cells. Individuals with variants in any of these genes have clinical and laboratory findings that are very similar to those seen in those with variants in BTK.

Treatment

At this time, the only treatment for individuals with agammaglobulinemia is immunoglobulin (Ig) replacement therapy. There currently is no cure for XLA, but there has been promising research regarding gene therapy for XLA, which is still in the pre-clinical stage. Ig replacement therapy for those with agammaglobulinemia replenishes some of the antibodies that they are lacking. The antibodies are supplied in the form of Ig, also known as gamma globulins or IgG. This Ig replacement therapy can be given directly into the bloodstream (intravenously) or under the skin (subcutaneously).

The varying types of Ig replacement therapy contain antibodies that substitute for the antibodies that the individual cannot make themselves. These products contain antibodies to a wide variety of germs and are purified from the blood of healthy donors. Ig is particularly effective in preventing the spread of infections into the bloodstream and to deep body tissues or organs. Some people may also need daily oral antibiotics to protect them from infection or to treat chronic sinusitis or chronic bronchitis.

People with antibody deficiency with absent B cells should not receive any live viral vaccines, such as live polio, the measles, mumps, rubella (MMR) vaccine, the chicken pox vaccine, the rotavirus vaccine, yellow fever, live typhoid, or the live shingles vaccine. Although uncommon, it is possible that live vaccines, particularly the oral polio vaccine, in people with agammaglobulinemia can transmit the diseases that they were designed to prevent.

Individuals with antibody deficiency with absent B cells should receive the yearly influenza (flu) vaccine. Ig replacement therapy may interfere with the response to a vaccine; therefore, individuals should contact their healthcare provider prior to receiving any vaccination. It is also important for family members and close contacts of people with antibody deficiency with absent B cells to be vaccinated in order to provide them with a level of protection called herd immunity or community immunity.