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

Summary

This video explains various immune deficiencies in children, focusing on both B-cell and T-cell disorders. It covers conditions like X-linked agammaglobulinemia (XLA), selective IgA deficiency, and common variable immunodeficiency (CVID), highlighting their causes, symptoms, and diagnostic features. T-cell disorders such as 22q11.2 deletion syndrome (DiGeorge syndrome), IL-12 receptor deficiency, and hyper IgE syndrome (Job syndrome) are also explored. Real-life cases of children, including a girl with celiac disease and Giardia infection, and a boy with recurrent skin abscesses, are discussed to demonstrate how these conditions manifest and how they are diagnosed and treated.

Takeaways

• 😀 B cell immunodeficiencies, like X-linked agammaglobulinemia (XLA), result from a mutation in the BTK gene, leading to a lack of B cells and antibodies, making individuals highly susceptible to infections.
• 😀 Selective IgA deficiency is the most common and least severe immunodeficiency, characterized by low IgA levels, often leading to recurrent respiratory or gastrointestinal infections and a higher risk of autoimmune diseases.
• 😀 Common Variable Immunodeficiency (CVID) is caused by mutations preventing B cells from maturing into plasma cells, leading to recurrent infections and increased risk of malignancies, especially lymphomas.
• 😀 22q 11.2 Deletion Syndrome (including DiGeorge Syndrome) is an autosomal dominant disorder causing thymic and parathyroid hypoplasia, leading to T-cell deficiency, recurrent infections, hypocalcemia, and congenital heart defects.
• 😀 IL-12 receptor deficiency impairs the activation of T-helper cells, leading to susceptibility to intracellular infections like tuberculosis, salmonella, and fungi, commonly known as Mendelian susceptibility to mycobacterial disease (MSMD).
• 😀 Hyper IgE syndrome (Job syndrome) is an autosomal dominant disease caused by mutations in the STAT3 gene, leading to defective neutrophil recruitment and increased susceptibility to eczema, recurrent lung infections, and cold skin abscesses.
• 😀 Chronic mucocutaneous candidiasis is often due to mutations in the AIRE gene, leading to defective T-cell selection and increased susceptibility to non-invasive candida infections and autoimmune conditions.
• 😀 Individuals with XLA are highly susceptible to infections caused by encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae, and viral infections such as polio.
• 😀 Diagnosis of immune deficiencies often involves genetic testing, immunoglobulin levels, and a physical examination that may reveal lymphoid hypoplasia (in B-cell disorders) or diminished T-cell function.
• 😀 Treatment for many immunodeficiencies includes lifelong immunoglobulin infusions and antibiotics for bacterial infections, with some requiring additional therapies like corticosteroids or stem cell transplants depending on the condition.

Q & A

What are the key features of X-linked Agammaglobulinemia (XLA)?

XLA is caused by a mutation in the BTK gene, which is crucial for B cell maturation. It primarily affects males due to its X-linked recessive inheritance. Individuals with XLA have few or no circulating B cells and antibodies, leading to recurrent bacterial and viral infections, particularly those caused by encapsulated bacteria.

Why are individuals with Selective IgA deficiency at an increased risk of infections?

Selective IgA deficiency results in low levels of IgA, the antibody responsible for protecting mucosal surfaces like the gastrointestinal and respiratory tracts. Although other antibody levels (IgM and IgG) remain normal, individuals are more prone to infections caused by pathogens like Giardia lamblia, which targets the gastrointestinal system.

What is the most common pathogen associated with gastrointestinal issues in individuals with Selective IgA deficiency?

The most common gastrointestinal pathogen in individuals with Selective IgA deficiency is Giardia lamblia, which can cause a diarrheal condition known as giardiasis.

How is the diagnosis of X-linked Agammaglobulinemia (XLA) confirmed?

The diagnosis of XLA is confirmed through blood tests showing a complete absence of B cells and a decrease in immunoglobulin levels of all classes. Genetic testing for the mutated BTK gene can also confirm the diagnosis.

What are the clinical presentations of Common Variable Immunodeficiency (CVID)?

CVID typically presents with recurrent infections, especially in the respiratory tract, and can lead to conditions like bronchiectasis. Individuals with CVID may also develop autoimmune diseases, such as autoimmune anemia or arthritis, and are at an increased risk of malignancies like lymphomas.

What is the main cause of 22q 11.2 deletion syndrome (DiGeorge syndrome)?

22q 11.2 deletion syndrome is caused by the deletion of a portion of chromosome 22, which includes the TBX1 gene. This gene is essential for the development of the thymus and parathyroid glands. The deletion results in thymic hypoplasia, leading to a T-cell deficiency, and parathyroid hypoplasia, causing hypocalcemia.

What are the characteristic facial features seen in individuals with 22q 11.2 deletion syndrome?

Individuals with 22q 11.2 deletion syndrome, particularly those with Velocardiofacial syndrome, may have characteristic facial features such as a long face, small teeth, a broad nose, and a cleft palate.

What is the primary immune deficiency associated with Hyper IgE syndrome (Job syndrome)?

Hyper IgE syndrome is caused by a mutation in the STAT3 gene, which impairs the differentiation of T-helper cells into Th17 cells. This results in impaired neutrophil recruitment and an inability to mount an acute inflammatory response, leading to recurrent skin abscesses, eczema, and bacterial lung infections.

What is the relationship between IL-12 receptor deficiency and susceptibility to infections?

IL-12 receptor deficiency leads to a lack of cell-mediated immunity, making individuals more susceptible to disseminated infections from intracellular pathogens such as Salmonella, Mycobacterium, and fungi like Candida. These individuals also have an increased risk of developing infections from the BCG vaccine, which contains live attenuated Mycobacterium.

How is Chronic Mucocutaneous Candidiasis (CMC) diagnosed?

Chronic Mucocutaneous Candidiasis is diagnosed through in vivo cutaneous reaction testing and in vitro T-cell proliferation assays, which fail to elicit a response to Candida antigens. Genetic testing can confirm the diagnosis by identifying mutations in the AIRE gene, which is involved in T-cell selection in the thymus.