X-linked agammaglobulinemia

Definitions & Key takeaways

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.

Chapters:

Watch video only

Introduction0:00–0:24

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.

Physiology0:24–1:12

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.

Pathology1:12–2:35

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.

Causes2:35–3:13

The BTK gene is found on the X chromosome, therefore XLA’s considered an X-linked recessive genetic condition, and it almost exclusively manifests as a disease in men, since they have one X and one Y chromosome, so if the one and only chromosome has the mutation, then they have the disorder.
Women on the other hand have two X chromosomes, so those with an X chromosome that has the mutation, still have another X chromosome with a normal copy of the gene, so they’re considered carriers and don’t have any immune system issues.
Finally, the mutation can sometimes develop sporadically rather than being inherited from a parent. Newborns with XLA don’t typically have symptoms until after 6 months of age, at which point the mother’s supply of immunoglobulins that they receive through the placenta runs out.

Signs and symptoms3:13–4:16

Without immunoglobulins, children with XLA are at high risk of developing infections. Often patients with XLA develop bacterial infections like acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, as well as viral infections such as enteroviruses like polio and coxsackievirus, and finally protozoal intestinal parasites like giardia lamblia, which is usually neutralized by IgA in the gut.
Even live but attenuated vaccines have to be avoided, like the live polio vaccine, because the lack of antibodies makes even certain weakened pathogens tough to destroy.
Having said that, it’s important to remember that even though the B-cell and antibody-mediated immunity’s been compromised, T-cell mediated immunity remains intact, so some viral, fungal, and protozoal infections can still be cleared.

Treatment4:16–4:41

Treatment for XLA includes lifelong intravenous infusion of immunoglobulin, given about once a month. This immunoglobulin is typically pooled across a lot of individuals and therefore provides a nice diverse set of antibodies, which gives people with XLA passive immunity and helps boost their immune system.
If there is an infection that has already begun, patients are usually started on antibiotics right away. Alright, as a quick recap, X-linked agammaglobulinemia is an X-linked recessive genetic condition where there’s a mutation in the Bruton’s tyrosine kinase, or the BTK gene, causing a dysfunctional BTK enzyme, which causes B cell maturation process to stop, resulting in the absence of B cells and immunoglobulins in the circulation, which can lead to various infections.

Review4:41–5:16