Immunodeficiencies: T-cell and B-cell disorders: Pathology review

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Immunodeficiencies: T-cell and B-cell disorders: Pathology review

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A 20-year-old woman presents to her primary care physician’s office for evaluation of a rash under her breasts. She first noticed the rash two days ago while bathing. The patient reports recurrent rashes of similar appearance affecting her face and limbs since the age of two. She was recently treated for oral thrush at a local clinic. Past medical history is significant for hypothyroidism managed with levothyroxine. Family history is significant for a brother who experienced similar cutaneous symptoms and died of fulminant hepatitis at the age of six. She does not use tobacco, alcohol, or illicit drugs. Vitals are within normal limits. Physical examination demonstrates red-brown, beefy, homogenous patches under the breasts and massive erythematous-desquamating dermatosis involving the face, limbs and nails. Genital examination shows multiple labial fissures. Intraepidermal injection of Candida antigens yields no reactogenicity. Which of the following is the most likely diagnosis?

Transcript

Content Reviewers:

Antonia Syrnioti, MD

Gaia, a 6 year old girl, is brought to the clinic by her parents because she’s been having diarrhea and abdominal cramps for the past few weeks.

When you ask about her clinical history, her parents tell you that Gaia was diagnosed with celiac disease a few years back; however, they point out that she's stopped consuming any food products that may contain gluten altogether.

You decide to first run stool tests, which reveal the presence of the parasite giardia lamblia.

In addition, Gaia’s parents tell you that she has a history of asthma and allergic rhinitis, so you also order an immunoglobulin test, which shows low IgA and increased IgE levels in her blood.

Next comes Joe, a 10 year old boy that’s brought to the clinic because he fell and broke his arm.

Upon physical examination, you notice a red, weeping rash on his scalp.

You also notice that there’s a skin abscess on his leg that lacks any surrounding warmth and redness.

Joe’s parents tell you that he develops abscesses like that all the time.

You order an immunoglobulin test for Joe too, which reveals increased IgE but normal IgA levels.

Based on the initial presentation, both cases seem to have some form of immunodeficiency, meaning that their immune system's ability to fight pathogens is compromised.

Immunodeficiencies can be classified according to the cell of the immune system that is defective, into B cell and T cell disorders, which respectively lead to a deficiency in humoral or antibody-mediated and cell-mediated immune responses.

Let’s begin with B cell disorders, starting with Bruton or X-linked agammaglobulinemia, or XLA for short.

This is caused by a mutation in the BTK gene, which is found on the X chromosome.

XLA is an X-linked recessive condition, so it almost exclusively manifests in biological males because they have only one X chromosome.

On the other hand, biological females have two X chromosomes, so even if they have a defective BTK gene on one chromosome, they still have another functional one.

Now, the BTK gene codes for an enzyme called Bruton’s tyrosine kinase or BTK, which has an important role in the maturation process of the B cells at the bone marrow.

Normally, once B cells are mature and ready, they can migrate from the bone marrow to the spleen, where they’re exposed to antigens, and finally move into the blood or lymph and become an antibody-secreting plasma cell.

With XLA, though, there’s a mutation in the BTK gene that makes the BTK enzyme ineffective.

As a result, the B cell maturation process stops at the bone marrow, so these B cells can't leave it to become plasma cells.

Ultimately, people with XLA completely lack or have far fewer circulating B cells, so they also lack circulating antibodies of all classes.

The end result is a deficiency of B cell and antibody-mediated immunity.

Symptoms of XLA are typically absent until after 6 months of age, which is when they run out of the mother’s supply of immunoglobulins that they received through the placenta during pregnancy.

And that’s a very high yield concept to keep in mind!

Now, after 6 months of age, children with XLA become very susceptible to recurrent infections.

For your exams, remember that these infections are typically caused by encapsulated bacteria, so Streptococcus pneumoniae, Neisseria meningitidis, Klebsiella, Haemophilus influenzae, and Pseudomonas aeruginosa.

Most often, these bacterial infections affect the respiratory tract, causing sinusitis, otitis media, pharyngitis, bronchitis, and pneumonia.

Less commonly, children with XLA may also get viral infections, especially from enteroviruses like polio and coxsackievirus, as well as protozoal infections from intestinal parasites like giardia lamblia.

Having said that, it’s important to remember that T-cell mediated immunity remains intact, and some viral, fungal, and protozoal infections can still be cleared.

Another high yield fact is that these individuals must avoid live attenuated vaccines, like the live polio vaccine, because the lack of antibodies makes even certain weakened pathogens tough to destroy.

Diagnosis typically begins with a physical examination, where lymph nodes and tonsils are diminished in size.

For your exams, remember that this is known as lymphoid hypoplasia, and is due to the lack of primary follicles and germinal centers, which are normally the B cell compartments in healthy lymphoid tissues.

The next step for diagnosis involves blood tests revealing the complete absence of B cells, as well as decreased levels of all immunoglobulin classes.

Finally, diagnosis can be confirmed through genetic tests looking for the mutated BTK gene.

Treatment for XLA includes lifelong intravenous infusion of immunoglobulins, and if there is a bacterial infection, these individuals should be started on antibiotics right away.

Next up, selective IgA deficiency is the most common and least serious immunodeficiency.

Though the exact mutation is unknown, the end result is a failure of IgA-producing B cells to mature into plasma cells.

As a result, these individuals have low levels of IgA, which is normally the main antibody protecting the mucous membranes lining the respiratory and gastrointestinal tracts.

However, what's important to keep in mind is that the production of other antibodies isn’t affected.

For that reason, most children with selective IgA deficiency have no symptoms, but some of them may have an increased tendency to develop recurrent infections involving the respiratory or gastrointestinal tracts.

A high yield gastrointestinal pathogen is the parasite giardia lamblia, which is responsible for a diarrheal condition known as giardiasis.

In addition, there’s an increased frequency of atopy, mainly manifesting as asthma, rhinitis, and dermatitis, as well as autoimmune diseases like rheumatoid arthritis and celiac disease, although the link between them is not fully understood.

Finally, some individuals develop severe anaphylactic reactions when they’re transfused with blood containing IgA, because the IgA is recognized like a foreign antigen and attacked by the immune system.

Diagnosis is based on blood tests showing low IgA levels, normal levels of IgM and IgG, and sometimes, increased IgE.

There’s no specific treatment for selective IgA deficiency.

The last B cell disorder you should know for your exams is common variable immunodeficiency, or CVID for short.

Now, the exact mutation that causes CVID remains largely unknown, but it is thought to result from a combination of several mutations that ultimately make mature B cells unable to differentiate into antibody-producing plasma cells.

For your exams, it’s important not to confuse this with X-linked agammaglobulinemia, where there’s an absence of mature B cells altogether.

As the name suggests, symptoms tend to vary a lot.

Most often, they first appear during puberty or early adulthood, and include recurrent infections, mainly of the respiratory tract.

Over time, if these infections are not properly treated, they can lead to the development of bronchiectasis, meaning their bronchi become abnormally enlarged.

And that’s a high yield fact!

In addition, for unknown reasons, individuals with CVID are at an increased risk of developing malignancies, especially lymphomas, as well as autoimmune conditions like autoimmune anemia, thrombocytopenia, or arthritis.

For diagnosis, what you must know is that laboratory tests demonstrate an overall decrease in plasma cells and immunoglobulins.

Also, it’s important to note that genetic testing can’t confirm the diagnosis of CVID, but it can be useful to rule out similar conditions, such as X-linked agammaglobulinemia.

Treatment for CVID includes lifelong intravenous infusion of immunoglobulins.

In addition, individuals with autoimmune conditions may require immunosuppressive treatment with corticosteroids, while recurrent bacterial infections can be treated with antibiotics.

Okay, next are T cell disorders.

Let’s start from a very high yield disease, which is 22q11.2 deletion syndrome, also called thymic aplasia.

If these names don’t ring a bell, you probably know it as DiGeorge syndrome, which is in fact one presentation of 22q11.2 deletion syndrome along with velocardiofacial syndrome.

Now, 22q11.2 deletion syndrome is an autosomal dominant condition where the q11.2 portion of DNA on chromosome 22 is deleted, and this region encodes for some really important genes, one of which is the TBX1 gene.

Now, TBX1 gene is involved in normal embryonic development of the pharyngeal pouches, which are fetal structures that develop into parts of the head and neck.

More specifically, for your exams you should know that the ones affected are the third pharyngeal pouch, which goes on to develop into the thymus and the inferior parathyroid glands, as well as the fourth pouch, which goes on to develop into the superior parathyroid glands.

So with a 22q11.2 deletion and therefore no TBX1 gene, the thymus and parathyroid gland both end up hypoplastic, meaning that they are underdeveloped.

And that’s a high yield fact!

Now, parathyroid gland hypoplasia leads to low levels of parathyroid hormone, which causes hypocalcemia or low levels of calcium in blood, and this can manifest as osteoporosis and tetany, or involuntary contraction of mus

On the other hand, thymic hypoplasia results in a T cell disorder, since the thymus is where T cells mature.

As a result, these individuals are more susceptible to recurrent infections.

Often within 6 months of age, infants begin having recurrent or severe infections from common viruses like Varicella zoster virus, or opportunistic fungi like Candida albicans and Pneumocystis jiroveci, and bacteria like nontuberculous Mycobacteria.