B-Cell Disorders & DiGeorge Syndrome

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B-cell disorders primarily concern the immune system's capacity to fend off infections, autoimmunity, and malignancies. Common B-cell disorders include primary immunodeficiency and specific disorders like Bruton disease and Common Variable Immunodeficiency (CVID).

Primary immunodeficiency typically presents with an increased risk of bacterial, viral, fungal, and protozoal infections, autoimmune disorders, and malignancies like non-Hodgkin lymphoma. Presentation often occurs between 6 months and 2 years of age, after the passive immunity conveyed through maternal IgG and IgA has waned. Live vaccines are contraindicated in these individuals due to their compromised immune state.

X-linked agammaglobulinemia (XLA) arises from a failure of pre-B cells to differentiate into mature B-cells, resulting in diminished B-cells and all classes of immunoglobulins in the peripheral blood. XLA is caused by mutations in the Bruton tyrosine kinase (BTK) gene. Clinically, this increases susceptibility to encapsulated bacteria like Strep pyogenes and H. influenzae, as well as viral infections like enteroviruses and the protozoan Giardia lamblia. Diagnosis can be confirmed by the absence of germinal centers in lymphoid tissue, which are also abnormally small. Skin testing with candida antigens can help pinpoint isolated B-cell defects.

Common variable immunodeficiency (CVID) is heterogenous group of B-cell primary immunodeficiency disorders. CVID is characterized by hypogammaglobulinemia with a normal number of mature B-cells in peripheral blood, as the deficiency lies in the transformation of mature B-cells into plasma cells. CVID typically presents in early adulthood because some antibody production is preserved, delaying the onset of clinical symptoms.

Selective IgA deficiency is the most common primary immunodeficiency and is often asymptomatic. It occurs when B-cells fail to differentiate into IgA-secreting plasma cells. The deficiency primarily increases susceptibility to sinopulmonary infections and the intestinal protozoa Giardia lamblia due to the protective role of IgA immunoglobulins in mucosal secretions. Patients with selective IgA may experience anaphylaxis during blood transfusions due to the presence of anti-IgA antibodies, as the immune system perceives IgA as a foreign protein, which can trigger mast cell degranulation and subsequent anaphylaxis.

DiGeorge syndrome is a congenital disorder caused by the defective migration of neural crest cells, leading to abnormal development of the 3rd & 4th pharyngeal pouches, impairing the development of the thymus. This results in a T-cell primary immunodeficiency disorder that manifests as thymus hypoplasia/aplasia and absent mature (CD3+) T-cells. DiGeorge syndrome significantly increases susceptibility to viral, fungal, and intracellular bacterial infections, all of which require T-cell mediated immunity for effective clearance. An absent thymic shadow on X-ray and poorly developed paracortex in lymph nodes confirm the diagnosis.

Clinical manifestations of DiGeorge syndrome includes low PTH, hypocalcemia, abnormal facies, & cleft palate, as well as cyanotic congenital heart diseases like truncus arteriosus and tetralogy of Fallot. DiGeorge syndrome is caused by a 22q11 microdeletion. A 22q11 microdeletion can also cause velocardiofacial syndrome, which presents similarly to DiGeorge syndrome but with a normal thymus.

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How does X-linked agammaglobulinemia (XLA) impact B-cell development and function?

X-linked agammaglobulinemia (XLA), also known as Bruton disease, is a B-cell primary immunodeficiency disorder. In individuals with XLA, a mutation in the Bruton tyrosine kinase gene prevents pre B-cells from maturing into mature B cells. This leads to a near absence of all immunoglobulin classes as the differentiation into plasma cells is hindered. As a result, patients become susceptible to infections by encapsulated bacteria and certain viruses. Lymphoid tissue in XLA is abnormally small due to the absence of germinal centers, where B cells typically aggregate.

What characterizes common variable immunodeficiency (CVID) and its effect on B-cells?

Common variable immunodeficiency (CVID) is marked by reduced (but not absent) immunoglobulin levels, indicating a failure in B-cells to differentiate into plasma cells. However, the number of mature B-cells in the peripheral blood remains normal. CVID typically manifests in early adulthood because antibodies are not completely absent, leading to a delayed presentation of symptoms.

How does selective IgA deficiency present and what implications does it have on B-cell function?

Selective IgA deficiency is the most prevalent primary immunodeficiency, where B-cells cannot differentiate into IgA-producing plasma cells. While often asymptomatic, it can increase susceptibility to sinopulmonary infections and certain intestinal protozoa like Giardia lamblia. Additionally, individuals with IgA deficiency may experience anaphylactic reactions during blood transfusions due to the formation of anti-IgA antibodies, as their immune system recognizes IgA as a foreign protein.

What are the primary features of DiGeorge syndrome and how does it influence T-cell maturation?

DiGeorge syndrome is a congenital disorder characterized by an underdeveloped or absent thymus, leading to impaired T-cell maturation. As a result, mature T cells are absent, increasing vulnerability to viral, fungal, and intracellular bacterial infections. The syndrome manifests with various symptoms, including low parathyroid hormone levels, abnormal facial features, cleft palate, and specific congenital heart diseases, all stemming from the abnormal development of the 3rd and 4th pharyngeal pouches.

How do primary immunodeficiency disorders, such as B-cell disorders and DiGeorge syndrome, impact infants and children?

Primary immunodeficiency disorders typically manifest between 6 months to 2 years of age with recurrent infections. Infants initially receive passive immunity from maternal IgG during the third trimester and IgA during breastfeeding, providing protection for the first 4-6 months of life. Once this passive immunity wanes, children with primary immunodeficiency start exhibiting symptoms. It's crucial to note that live vaccines should be avoided in these children due to the risk posed by attenuated pathogens.