X-linked agammaglobulinemia

A 2 year-old boy is brought to the emergency department for evaluation of fever, cough, and shortness of breath. The patient has a history of recurrent infections including otitis media, pneumonia, and erysipelas. He recently recovered from a prolonged course of diarrhea due to infection with Giardia. Temperature is 38.7 C° (101.7 F°), pulse is 140/min, respirations are 55/min and blood pressure is 100/50 mmHg. Physical examination shows small bilateral tonsils and rales in the right lower lobe of the lung. The patient is at 25th percentile for height and 10th percentile for weight. Intraepidermal injection of Candida antigens results in the appearance of a large indurated nodule within 48 hours. Flow cytometry of the patient’s peripheral blood smear demonstrates absence of CD19+ cells. Impairment of which of the following immunoprotective mechanisms is most likely contributing to this patient’s disease process?

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Agammaglobulinemia

chromosome affected p. 62

Bruton agammaglobulinemia p. 59, 114

Hypogammaglobulinemia p. 219

Tonsils

agammaglobulinemia p. 114

X-linked agammaglobulinemia p. 114

X-linked recessive disorders

agammaglobulinemia p. 114

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.

Now, normally, immunoglobulins are secreted into the blood by plasma cells, which are fully matured or differentiated B cells, a type of immune cell.

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.

Summary

X-linked agammaglobulinemia (XLA) is an x-linked genetic disorder of the immune system caused by mutations in the BTK (Bruton's tyrosine kinase) gene. XLA primarily affects males, as they only have one X chromosome, while females have two and are typically carriers of the mutated gene. Individuals with XLA have a deficiency in B cells. This results in an inability to mount an effective immune response against bacterial infections, leading to recurrent and often severe infections, especially of the respiratory tract and ears. The symptoms of XLA typically appear in early childhood, and affected individuals may experience recurrent bacterial infections, chronic diarrhea, and failure to thrive.

Sources

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X-linked agammaglobulinemia

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