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

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Case study0:00–1:01

Aurora, an 18 month old girl, is brought to the clinic because of frequent respiratory and ear infections. At first glance, you notice she has some small dilated blood vessels over the sclera of her eyes.
Upon physical examination, you also realize that she has a delay in speech, as well as frequent stumbling when walking. Laboratory studies are obtained, showing a low lymphocyte count, low immunoglobulin levels, and high alpha-fetoprotein or AFP.
Next comes Mathew, a 16 month old boy that’s brought to the clinic because of a skin rash that appeared on his back since infancy and won’t go away.
Mathew’s mother also tells you that he has frequent spontaneous nosebleeds, and has had recurrent respiratory tract infections over the last few months.
Laboratory studies are obtained, revealing that Mathew’s platelets are quite small in size and fewer than normal, while the immunoglobulins IgA and IgE are increased.Based on the initial presentation, both cases seem to have some form of combined B- and T-cell disorder causing immunodeficiency, meaning that their immune system's ability to fight pathogens is compromised.

Pathology1:01–1:37

Combined B- and T-cell disorders are characterized by defects in the development of both B and T cells, which respectively lead to impaired antibody and cellular immune responses.
For your exams, the most high yield combined B- and T-cell disorders include severe combined immunodeficiency, ataxia telangiectasia, hyper IgM syndrome, and Wiskott-Aldrich syndrome.Okay, then!

Severe Combined Immunodeficiency (SCID)1:37–6:03

Starting with severe combined immunodeficiency, or SCID for short, which is the most severe form of primary immunodeficiencies.
In fact, the immune system is so dysfunctional that it’s considered almost completely absent. Now, for your exams, remember that SCID can be caused by mutations in a variety of genes, the most common one codes for the gamma chain of the IL-2 receptor.
For your exams, remember that this mutation is X-linked recessive. Okay, now, this protein is a necessary component of the IL-2 receptor, which is involved in lymphocyte maturation and activation.
In SCID, the mutated gamma chain leads to the production of a defective IL-2 receptor, and thus a lack of functional mature lymphocytes.
Another high yield form of SCID is ADA deficiency or ADA-SCID, which is caused by an autosomal recessive mutation in the gene coding for adenosine deaminase, or ADA.
Now, normally, in the purine salvage pathway, ADA is required to degrade adenosine and deoxyadenosine. As a consequence there’s accumulation of adenosine and deoxyadenosine, and these can be toxic to B and T lymphocytes.
In addition, the excess deoxyadenosine gets converted into deoxyadenosine triphosphate or dATP. Accumulation of dATP leads to inhibition of the enzyme ribonucleotide reductase, which mediates the conversion of ribonucleotides to deoxynucleotides.
The end result is an impaired DNA synthesis in B and T cells, which leads to failure in their maturation and proliferation.
And a third type of SCID to keep in mind is caused by an autosomal recessive mutation in the recombination-activating genes, or RAG for short.
These enzymes are necessary for a process called VDJ recombination, where multiple V, D, and J gene segments in the DNA of T and B cells are randomly recombined to create variability in the T and B cell receptors.
So, mutations of the RAG genes prevent VDJ recombination, which means the B and T cell receptors lose their ability to recognize a wide variety of antigens.Now, regardless of the type of mutation, all forms of SCID typically present in infancy as an extreme susceptibility to all kinds of bacterial, viral, and fungal infections.
Most importantly, these include opportunistic pathogens, such as Candida albicans, nontuberculous Mycobacteria, or Pneumocystis jirovecii, which don’t usually cause serious infections in individuals with a healthy immune system.
For your exams, remember that oral candidiasis presents with a characteristic oral thrush that’s often described as “cottage cheese-like thrush”, isn’t painful, and can be scraped away with a tongue depressor, leaving behind a red mucosal base which sometimes bleeds.
In addition, individuals often present with chronic diarrhea, and a failure to thrive. If left untreated, SCID has a high mortality rate in the first year of life.
Diagnosis of SCID in many countries is based on newborn screening tests. These measure T-cell receptor excision circles, or TRECs, in blood.
The presence of TRECs is a biomarker for normal T-cell development, so remember that in SCID, TRECs are absent. Laboratory tests are also required, showing an absolute lymphocyte count lower than 2500 cells per cubic millimeter, with T cells making up less than 20 percent of the total lymphocytes in flow cytometry.
Additional findings can include absence of thymic shadow on chest X-rays, as T cell maturation normally takes place in the thymus.
A lymph node biopsy shows absence of germinal centers, which is where mature B cells would normally proliferate to fight infections.
Finally, to identify the specific form of SCID, genetic testing can be performed to look for the mutated gene.For treatment, hematopoietic stem cell transplantation is recommended before 3 month of age.
Until then, these infants are often kept in a sterile environment to prevent infections. In addition, intravenous IgG infusions can be given about once a month to help boost their immune system.
Next up, there’s ataxia telangiectasia, where ataxia refers to poor coordination and telangiectasia refers to dilated blood vessels, and these are the two key symptoms of this disease.

Ataxia telangiectasia6:03–10:03

Ataxia telangiectasia develops due to a genetic mutation in the ATM gene, which codes for a protein called ataxia telangiectasia mutated kinase, or ATM kinase for short.
Normally, the DNA of the cells in the body gets damaged throughout their lifespan. This can happen upon cell division, as well as from various environmental factors like ionizing radiation.
When there’s some kind of DNA damage, ATM kinase activates other proteins, which will either fix the DNA or kill the affected cell.
Now, for your exams, keep in mind that ATM is particularly important for the development of B- and T lymphocytes, since these cells are constantly dividing and rearranging their DNA to recognize a wide variety of antigens.
So this means they’re much more prone to DNA damage as a result! In ataxia telangiectasia, cells don't have sufficient ATM to properly repair the damaged DNA.
As a result, some of the defective cells might continue to grow and proliferate despite the mutations in their DNA. This leads to accumulation of mutations in future cells, which makes these individuals more prone to develop cancers, such as leukemias and lymphomas, especially after exposure to ionizing radiation, like X-rays.
And that’s a high yield fact! Now, some cells with damaged DNA will simply die.
This can especially impact the nervous system. When the cerebellum’s affected, which is the part of the brain that coordinates movement, it atrophies, leading to ataxia or difficulty with coordination and movement.
In terms of symptoms, ataxia can first manifest in infants or toddlers as a delay in reaching certain developmental milestones, such as sitting or walking.
As these children grow up, they can present with frequent stumbling or unsteady gait, and trouble with fine motor movements like those needed for writing or eye movement.
In addition, individuals can have difficulty with speech or swallowing, which can cause aspiration pneumonia. That’s where bits of food or liquids are able to enter the airways, and cause direct damage as well as infections in the lungs.
Now, a high yield fact is that these individuals may also develop recurrent infections, especially of the respiratory tract, because of the defects in B- and T-cell developmentLast but not least, for reasons we don't really know, most individuals affected by ataxia telangiectasia develop, well, telangiectasias, also called spider angiomas.
In a test question, look for a picture with dilated blood vessels visible especially on the sclera of the eyes. Diagnosis of ataxia telangiectasia can involve laboratory tests showing lymphopenia or low lymphocyte count, as well as a low level of serum immunoglobulins, especially IgA, although IgG and IgE levels may also be reduced.
In addition, for unknown reasons, these individuals may have a high level of a protein called alpha-fetoprotein or AFP for short.
Finally, diagnosis can be confirmed via genetic testing for mutations on the ATM gene. There’s no cure for ataxia telangiectasia, so treatment is aimed at managing symptoms and complications.
For reducing the risk of infections, immunoglobulin infusion and antibiotics can be used. For ataxia, in some cases, beta blockers can be used, as well as physical and speech therapy.
And finally, individuals should have increased surveillance for cancer.Moving on, there’s hyper IgM syndrome, which can be caused by a variety of genetic defects.
Now, the most common and high yield one is an X-linked recessive mutation of the CD40 ligand, which plays a major role in communication between B- and T- cells.
Normally, when a B cell comes in contact with an antigen from an invading pathogen, it will start producing IgM antibodies against that specific antigen, while also internalizing that antigen and presenting a piece of it to a T helper cell.

Hyper IgM syndrome10:03–12:35

That T helper cell then expresses a protein called CD40 ligand on its surface, which attaches to a receptor on the B cell’s surface called CD40.
As a result, the B cell is stimulated to undergo antibody class-switching. This is when the B cells switch from producing IgMs to producing IgAs, IgEs, or IgGs, that will target the specific antigen.In hyper IgM syndrome, there’s a deficiency of CD40 ligand.
As a consequence, B cells are unable to undergo antibody class-switching, meaning that they can produce IgM, but struggle to produce other types of antibodies.
Now, because IgM isn’t as efficient as the other antibody classes in fighting off infections, individuals with hyper IgM syndrome are predisposed to infections by opportunistic pathogens, including fungi like Pneumocystis jirovecii, protozoa like cryptosporidium, viruses like cytomegalovirus, and encapsulated bacteria like Streptococcus pneumoniae.
Because of this, a high yield fact you should know is that the first symptoms that typically appear during infancy are recurrent episodes of pyogenic or pus-producing infections that most often involve the respiratory tract, causing sinusitis, pneumonia, and otitis.
The diagnosis of hyper IgM is based on laboratory studies, which show drastically low levels of IgG, IgA, and IgE antibodies, along with normal or elevated IgM levels.
In addition, a lymph node biopsy would show a lack of germinal centers, which is where CD40 activation of B- and T- cells normally takes place.
Finally, genetic testing can confirm that there’s a mutation in the gene coding for the CD40 ligand.Treatment includes prophylactic antibiotics to prevent infections, as well as immunoglobulin infusions, which provide passive immunity to help fight off pathogens.
In some instances, a bone marrow transplant can be done to establish a normal immune system.Last but not least, there’s Wiskott-Aldrich syndrome or WAS for short, which is an X-linked recessive disease caused by a mutation in the WAS gene.
This gene codes for the WAS protein or WASp, which normally is expressed by hematopoietic cells, like leukocytes, and it allows them to reorganize their cytoskeleton.
This is necessary for various cellular activities like cellular division, phagocytosis or swallowing up of foreign pathogens, and for communicating with other cells throughout the body.
So, individuals with Wiskott-Aldrich syndrome have an impaired immune response and are more prone to recurrent infections.

Wiskott-Aldrich Syndrome (WAS)12:35–16:02

The infections are classically due to encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, opportunistic fungi, such as Pneumocystis jirovecii and Candida albicans, and viruses, such as Molluscum contagiosum, Varicella zoster virus, and cytomegalovirus.
In addition, the impaired immune response can cause an inflammatory skin disorder called eczema, which is characterized by dry, itchy, red patches on the skin.
And finally, you must know that the impaired immune response in WAS can often lead to the development of autoimmune conditions, such as autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, as well as cancers, like leukemia and lymphoma.
Another type of blood cells that rely on the WAS protein are platelets, which originate from a large precursor cell called megakaryocyte.
Normally, the cytoskeleton of this megakaryocyte changes shape, so that small cellular fragments can detach, giving rise to platelets.
The platelets then go off to form clots at damaged sites to stop bleeding. In Wiskott-Aldrich syndrome, megakaryocytes are less able to form platelets, and the platelets that are made are small and fragile, so it’s called microthrombocytopenia.
In addition, these defective platelets are removed from circulation by the spleen, leading to even lower platelet counts.
Typically, the initial symptoms include easy bruising and petechiae, which are small red or purple spots caused by minor bleedings that leak into the skin.
Additional symptoms can include bleeding from the nose, mouth and gums, as well as bloody diarrhea. And that’s a high yield fact!To help you remember the classic triad of symptoms in Wiskott-Aldrich syndrome, think of WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, and Recurrent infections.For diagnosis, the initial workup includes a peripheral smear, which would show the microthrombocytopenia.
In addition, for unclear reasons, remember that laboratory studies can show an increase in IgA and IgE antibodies, and normal or decreased levels of IgM and IgG antibodies.
The diagnosis is then confirmed by genetic testing revealing the mutated WAS gene.Treatment of WAS includes prophylactic antibiotics, regular immunoglobulin infusions, platelet transfusions in the case of severe bleeding, and potentially surgery to remove the spleen, which can help to maintain platelet counts.
Finally, the only cure involves getting hematopoietic stem cell transplantation.All right, as a quick recap… SCID is the most severe form of primary immunodeficiencies.
Most cases are caused by an X-linked recessive mutation involving the gene coding for the IL-2 receptor gamma chain. However, some cases are autosomal recessive, including ADA deficiency, and RAG mutation.
SCID presents in infancy with various infections, and is diagnosed through screening tests showing decreased or absent TRECs in blood, or based on low total lymphocyte count on blood tests, and a low percentage of T- cells in flow cytometry.
For treatment, hematopoietic stem cell transplantation is recommended before the age of 3 months. Ataxia telangiectasia is an autosomal recessive disorder caused by a defective ATM kinase, resulting in an increased risk of developing cancers, especially after radiation exposure, atrophy of the cerebellum leading to ataxia, telangiectasias on the sclera of the eyes and immunodeficiency due to a decrease in T cells and immunoglobulins, which shows on laboratory tests.

Review16:02–19:16

There’s no cure for ataxia telangiectasia, so treatment is aimed at managing symptoms and complications. Hyper IgM syndrome is characterized by a defect in the ability of B cells to undergo antibody class-switching.
The most common cause is an X-linked recessive genetic defect of the CD40 ligand. Affected individuals experience recurrent infections with opportunistic pathogens and encapsulated bacteria, and may require treatment with antibiotics and immunoglobulin infusions.
Finally, Wiskott-Aldrich syndrome is an X-linked recessive disease caused by a mutation in the gene coding for WAS protein, which is produced by hematopoietic cells.
The classic triad of symptoms includes microthrombocytopenia, repeated infections, and eczema. Treatment can include antibiotics and immunoglobulin infusions, as well as platelet transfusions, surgery to remove the spleen, or hematopoietic stem cell transplantation.Okay, back to our cases.
Aurora is an 18 months old girl that has frequent respiratory and ear infections, and her laboratory results reveal low lymphocytes and immunoglobulins.
These findings should make you think she has some form of immunodeficiency. Aurora also presents with scleral telangiectasias, milestone delays of speech and walking, and high alpha-fetoprotein levels, so diagnosis of ataxia telangiectasia is likely.
On the other hand, Mathew is a 16 month old boy that also has frequent respiratory tract infections. Unike Aurora though, Mathew’s laboratory results revealed high levels of IgA and IgE immunoglobulins.
In addition, he has macrothrombocytopenia, which is probably associated with his frequent nosebleeds. This already should make you suspect of Wiskott-Aldrich syndrome.
The final clue is the eczema, which completes the classic triad of symptoms. In both cases, genetic testing confirmed the suspected diagnosis, revealing a mutation in the ATM and WAS gene, respectively.
is an 18 month old girl that has frequent respiratory and ear infection and a laboratory results, reveal low lymphocytes and immunoglobulins.
These findings should make you think that she has some form of immunodeficiency. Aurora, also presents with scleral.
Telangiectasia is Milestone delays of speech and walking in high alpha, fetoprotein level, is a diagnosis of a taxi at Atlantic Station, is very likely.
On the other hand, Matthew is a 16 month old boy who also has frequent respiratory tract. Infections.
Unlike Aurora. However, Matthews the laboratory results, revealed high levels of IGA in igee.
Immunoglobulins, in addition. He has micro thrombocytopenia, which is probably associated with his frequent nosebleeds.
This already should make you suspect this. Scott Aldridge syndrome.
The final clue is the eggs, which completes the classic tryout of symptoms. In both cases, genetic testing confirmed the suspect, a diagnosis revealing mutations in the ATM and was Gene
Immunodeficiencies: Combined T-cell and B-cell disorders | Osmosis