X-linked agammaglobulinemia is characterized by a defect in the gene.
USMLE® Step 1 style questions USMLE
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A 27-year-old female comes to the clinic with an upper respiratory infection. She has had repeated respiratory and gastrointestinal infections over the last several months, including infection with organisms she has received vaccines for. She has a past history of sarcoidosis and alopecia. She does not take any medications. Serum laboratory studies show an absence of plasma cells and low levels of all immunoglobulins. Which of the following is the most likely diagnosis?
Content Reviewers:Rishi Desai, MD, MPH, Tanner Marshall, MS, Tanner Marshall, MS, Tanner Marshall, MS, Tanner Marshall, MS
With X-linked agammaglobulinemia, or XLA for short, gamma globulin is another name for immunoglobulin, which is another name for antibodies, a- means without, and -emia refers to the blood.
So this is a disease where there aren’t any antibodies in the blood, and X-linked means that it’s caused by a gene mutation on the X chromosome.
Way before that ever happens, though, those B cells start out in the bone marrow as pluripotent stem cells, pluripotent meaning that they can develop into a number of different types of cells.
But to become a B cell, first that pluripotent stem cell differentiates into a lymphoid precursor cell, then a pro-B cell, then a pre-B cell, then an immature B cell which migrates from the bone marrow to the spleen, where it becomes a mature or naive B cell, which after being exposed to the right antigen, moves into the blood or lymph and becomes an antibody-secreting plasma cell.
In XLA, this maturation process stops at the pre-B cell stage.
Why does it do that? Well, by the immature B cell stage, it has a B cell receptor, which is a membrane-bound antibody, specifically an immunoglobulin M or IgM.
But in the Pre- and Pro-B cell stages, this B cell receptor’s still being assembled, once it’s finished, it’s made up of heavy chain and light chain protein subunits, and the heavy chains are put together first.
Since it hasn’t been fully assembled yet, this IgM’s known as a pre-B cell receptor.
Now, an enzyme called bruton’s tyrosine kinase is super important for both the development and normal functioning of the B cell receptor.
With XLA, though, there’s a mutation in the BTK gene which makes the BTK enzyme ineffective.
And because of this ineffective BTK enzyme, the B cell maturation process gets stopped at this Pre-B cell stage, meaning no B cells leave the bone marrow, so ultimately people with XLA completely lack or have far fewer circulating B cells, and since B cells turn into plasma cells, which produce immunoglobulins or antibodies, they also lack circulating antibodies of all classes.
In the bone marrow, they might have normal or decreased levels of pre-B cells, with IgM heavy chains found in their cytoplasm.