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

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Case Study0:00–1:14

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.

Pathology1:14–1:38

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.

X-linked (Bruton) agammaglobulinemia1:38–5:24

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.

Selective IgA deficiency5:24–7:04

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.

Common variable immunodeficiency7:04–8:51

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.

22q11.2 deletion syndrome (DiGeorge and velocardiofacial syndromes)8:51–12:50

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 musOn 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.
Now, in addition to affecting the thymus and parathyroid glands, you must know that deletion of the 22q11.2 region can also affect various other organs and tissues.
This includes the heart, resulting in congenital heart defects, in particular truncus arteriosus and tetralogy of Fallot, as well as the facial structures, resulting in abnormal facies, such as cleft palate, a long face, small teeth, or broad nose.
Finally, some individuals may also have speech or learning disabilities.As we said earlier, you must absolutely know that there are two main presentations of 22q11.2 deletion syndrome: DiGeorge and velocardiofacial syndromes.
These have overlapping features, however, DiGeorge syndrome mainly presents with thymic, parathyroid, and cardiac defects, whereas velocardiofacial syndrome is mostly characterized by facial, and again, cardiac defects.
And these are very high yield, especially DiGeorge syndrome!Diagnosis begins with blood tests revealing decreased T cell levels, low parathyroid hormone, and hypocalcemia.
It’s also important to know that a chest x-ray, in some cases, can reveal the absence of the thymic shadow, which indicates thymic hypoplasiaFinally, diagnosis can be confirmed with fluorescence in situ hybridization or FISH for short, which is a type of genetic testing able to detect the 22q11.2 deletion.There is no cure available for 22q11.2 deletion syndrome.
Infections can be treated with antibiotics, and hypocalcemia can be managed with vitamin D and calcium supplements. Severe cases may require surgery, like a thymus transplant for those with thymic hypoplasia, or heart surgery for children with congenital heart defects.
Another T cell disorder is IL-12 receptor deficiency. This is an autosomal recessive disease caused by mutations in the IL12RB1 gene that codes for the interleukin- or IL-12 receptor, which is normally involved in the activation of cell-mediated immunity against intracellular pathogens.

IL-12 receptor deficiency12:50–14:48

Long story short, here’s what you need to know. When an antigen-presenting cell comes in contact with an antigen, it produces IL-12, which interacts with IL-12 receptors found on the surface of T helper cells.
This makes the T helper cells differentiate into Th1 cells, which in turn produce IFN-gamma to activate macrophages and cytotoxic T-cells.
In addition, IL-12 activates natural killer or NK cells. And together, macrophages, cytotoxic T-cells, and NK cells are the main players in cell-mediated immunity.
Now, individuals with IL-12 receptor deficiency lack this cell-mediated immunity, which makes them more susceptible to develop disseminated infections from intracellular pathogens, meaning pathogens that are able to invade our cells and live inside them.
Intracellular pathogens include bacteria, such as salmonella or mycobacteria like tuberculosis, as well as some fungi like candida.
You should also know that these individuals may even develop an infection from getting the bacillus Calmette-Guérin or BCG vaccine, as it contains live attenuated mycobacteria that these individuals can’t fight.
These findings are collectively called Mendelian susceptibility to mycobacterial disease or MSMD for short.Diagnosis of IL-12 receptor deficiency involves laboratory tests showing decreased levels of IFN-gamma, and can be confirmed with genetic testing.
The only cure is hematopoietic stem cell transplantation. Up next we have autosomal dominant hyperimmunoglobulin E or hyper IgE syndrome, also known as Job syndrome.

Autosomal dominant hyper IgE syndrome (Job Syndrome)14:48–16:58

This is an autosomal dominant disease due to a mutation in the STAT3 gene, which codes for the transcription factor STAT3.
Normally, STAT3 is a key factor in the differentiation of T helper cells into Th17 cells, which produce interleukin- or IL-17 to recruit neutrophils to the infection site.
Once there, neutrophils trigger an acute inflammatory response to get rid of the infectious pathogen. Now, in hyper IgE syndrome, the mutated STAT3 affects the differentiation of Th17 cells.
As a consequence, neutrophil recruitment is impaired, thus infections occur without an acute inflammatory response. The most common symptoms of hyper IgE syndrome include eczematous skin rashes, meaning they’re red, weeping, and itchy, which most often involve the scalp and face; as well as bacterial lung infections, and recurrent cold or non-inflamed staphylococcal skin abscesses, which lack the typical signs of acute inflammation like warmth, redness, and tenderness.
In addition, many individuals have characteristic coarse facies, which can include a prominent forehead, flat nose, and large tongue; and they may also fail to lose and replace their primary or baby teeth with permanent teeth.Finally, these individuals may also have osteopenia or decreased bone mineral density, and what’s important is that this makes them more prone to frequent fractures even from minor trauma.
Now, diagnosis is based on blood tests. For unknown reasons, these individuals have abnormally increased levels of IgEs, which is where hyper IgE syndrome gets its name from.
Another high-yield finding is eosinophilia or increased eosinophils. There’s no cure for hyper IgE syndrome, but many individuals with hyper IgE syndrome are treated with long term antibiotics to help prevent infections.The final T cell disorder is chronic mucocutaneous candidiasis, which refers to a group of disorders that are characterized by chronic fungal infections caused by the candida species.

Chronic mucocutaneous candidiasis16:58–18:48

Most cases of chronic mucocutaneous candidiasis are caused by an autosomal recessive mutation in the AIRE gene, which codes for a protein called autoimmune regulator or AIRE for short.
Normally, AIRE is involved in the T cell selection process that takes place in the thymus, where self-reactive T cells are eliminated to prevent them from going around and attacking other cells throughout the body.
Now, with chronic mucocutaneous candidiasis, deficiency in AIRE ultimately results in T cell dysfunction and impaired cell-mediated immunity.
As a result, these individuals have a tendency to develop recurrent non invasive candida infections involving the skin, nails, and mucous membranes.
In addition, they can develop autoimmune manifestations that most often affect the thyroid, parathyroid, and adrenal glands, but can also lead to anemia, thrombocytopenia, neutropenia, and arthritis.Diagnosis of chronic mucocutaneous candidiasis involves assessing their response to candida antigens by doing in vitro T cell proliferation assays and in vivo cutaneous reaction testing.In chronic mucocutaneous candidiasis, both in vivo and in vitro tests fail to elicit a response to candida antigens.
Diagnosis can be confirmed via genetic testing, which reveals a mutation in the AIRE gene. Once again, no cure is available, so treatment involves antifungals and managing the associated autoimmune manifestations.
All right, as a quick recap… B cell disorders include X-linked agammaglobulinemia, selective IgA deficiency and common variable immunodeficiency.

Review18:48–21:06

X-linked agammaglobulinemia is caused by an X-linked recessive mutation in the BTK gene, which results in the absence of circulating mature B cells and immunoglobulins, leading to recurrent bacterial and enteroviral infections after six months of age and lymphoid hypoplasia.
Selective IgA deficiency is characterized by low levels of IgA, and is usually asymptomatic but may present with mucosal infections, autoimmune diseases, atopy, and anaphylactic reactions to IgA-containing blood products.
Common variable immunodeficiency is characterized by failure of mature B cells to differentiate into plasma cells, leading to recurrent infections, bronchiectasis, malignancies like lymphomas, or autoimmune manifestations.
Next, T cell disorders include 22q11.2 deletion syndrome, IL-12 receptor deficiency, autosomal dominant hyper IgE syndrome and chronic mucocutaneous candidiasis.
22q11.2 deletion can present as DiGeorge syndrome with thymic, parathyroid, and cardiac defects, or velocardiofacial syndrome with mainly facial and cardiac defects.
IL-12 receptor deficiency is an autosomal recessive disease that impairs the immune response to intracellular pathogens, which causes Mendelian susceptibility to mycobacterial disease.
Autosomal dominant hyper IgE syndrome or Job syndrome is due to a mutated STAT3, which impairs neutrophil recruitment and mainly presents as eczematous skin rashes, bacterial lung infections, and recurrent cold staphylococcal skin abscesses.
Individuals have characteristic coarse facies, fail to lose their primary teeth, and are more prone to bone fractures due to osteopenia.
Finally, chronic mucocutaneous candidiasis is most often caused by an autosomal recessive mutation of AIRE, leading to recurrent non invasive candida infections involving the skin and mucous membranes, as well as autoimmune manifestations.
Okay, back to our cases. Gaia is a 6 year old girl that has gastrointestinal issues, and her stool tests reveal that she had giardiasis.

Summary21:06–21:59

This is a very frequent infection among those with B cell deficiencies. Gaia also suffers from celiac disease, asthma, and allergic rhinitis, which combined should make you think of selective IgA deficiency.
The final clue is her immunoglobulin test, which shows low IgA and increased IgE levels. Joe is a 10 year old boy that presents with a fractured arm.
His immunoglobulin test also reveals increased IgE levels, but IgA levels are normal. The high IgEs are probably associated with the eczematous skin rash on his scalp.
Now, if you combine these findings with the history of recurrent cold abscesses, diagnosis of hyper IgE syndrome is highly likely.
This was confirmed with genetic testing that revealed a mutated