Pathophysiology
Summary
Primary (inherited) immunodeficiencies can also arising from combined B-cell and T-cell deficiency, and includes syndromes such as Wiskott-Aldrich syndrome, hyper-IgM syndrome, severe combined immunodeficiency (SCID), and ataxia-telangiectasia.
Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by eczema and thrombocytopenia. A mutation in the Wiskott-Aldrich syndrome protein disrupts actin cytoskeleton reorganization, resulting in impaired B-cell and T-cell function. Patients are particularly susceptible to encapsulated bacterial infections (e.g. Strep pneumo, H. influenzae, & N. meningitidis), viral infections (e.g CMV & varicella zoster), and fungal infections (e.g. candida & PJP). Serum IgG & IgM levels are low to normal, while IgA & IgE levels are increased.
Hyper-IgM syndrome is an X-linked recessive disorder arising from mutations in the gene encoding CD40 ligand on helper T-cells, preventing B-cells from binding to helper T-cells and inhibiting B-cell isotype switching. This results in lymphoid tissue lacking germinal centers, sites normally involved in B cell proliferation and differentiation. The disease manifests as increased susceptibility to viral, fungal, & encapsulated bacterial infections.
Severe combined immunodeficiency (SCID) encompasses a range of syndromes leading to severe B-cell and T cell deficiencies. SCID can arise from an X-linked recessive mutation affecting cytokine receptors like IL-7, or from an autosomal recessive mutation in the adenosine deaminase (ADA) gene. These mutations hinder the maturation of B-cells and T-cells, resulting in reduction of all immunoglobulin types due to the lack of mature B-cells and scarce T-cells. Clinically, SCID is marked by thymic hypoplasia and an absence of germinal centers in lymphoid tissues.
Ataxia-telangiectasia results from an autosomal recessive mutation in the ataxia telangiectasia mutated (ATM) gene, leading to impaired DNA damage surveillance. Clinical features include ataxia due to cerebellar atrophy and telangiectasias in the skin. Ataxia-telangiectasia primarily increases susceptibility to encapsulated bacteria, resulting in recurrent sinopulmonary infections. Lab findings include low T-cells, low serum IgA, & elevated serum alpha-fetoprotein (AFP).
Lesson Outline
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FAQs
Wiskott-Aldrich syndrome is a combined B-cell and T-cell primary immunodeficiency disorder caused by mutations in the Wiskott-Aldrich syndrome protein (WASP). This mutation disrupts the actin cytoskeleton reorganization, leading to impaired T-cell function and abnormal B-cell regulation. Patients with this syndrome often exhibit eczema and thrombocytopenia. Serum IgG & IgM levels are typically low to normal, while IgA & IgE levels are elevated. This imbalance increases their vulnerability to encapsulated bacteria, certain viruses, and fungal infections, including Candida.
Hyper-IgM syndrome is a combined B-cell and T-cells primary immunodeficiency where B-cells predominantly produce IgM, but not IgA, IgG, or IgE. The root cause is a mutation in the gene encoding the CD40 ligand on helper T-cells, preventing B-cells from binding to helper T-cells and inhibiting B-cell isotype switching. Hyper-IgM syndrome is usually X-linked recessive. Affected individuals lack germinal centers in their lymphoid tissue, which are essential sites for mature B cell activities.
Severe combined immunodeficiency (SCID) encompasses a group of syndromes that result in a profound deficiency in both B-cells and T-cells. SCID can arise from an X-linked recessive mutation affecting cytokine receptors, such as IL-7, or from an autosomal recessive mutation in the adenosine deaminase (ADA) gene. These mutations hinder the maturation of B-cells and T-cells, resulting in reduction of all immunoglobulin types due to the lack of mature B-cells and absent or scarce T-cells. Clinically, SCID is marked by thymic hypoplasia and an absence of germinal centers in lymphoid tissues.
Ataxia-telangiectasia results from an autosomal recessive mutation in the ataxia telangiectasia mutated (ATM) gene. This mutation impairs DNA damage surveillance, leading to deficiencies in both B-cell and T-cell. This manifests clinically as telangiectasias and ataxia due to cerebellar atrophy. In ataxia-telangiectasia, T-cell count and serum IgA levels are decreased, while serum alpha-fetoprotein (AFP) levels are increased.
Combined B-cell and T-cell deficiencies such as Wiskott-Aldrich syndrome, hyper-IgM syndrome, SCID, and ataxia-telangiectasia, increase the risk of infections. The compromised function of both B-cells and T-cells weakens the body's immune response, especially against encapsulated bacteria, viruses, and fungi. For example, patients with Wiskott-Aldrich syndrome are more prone to infections from encapsulated bacteria such as Strep pneumo, H. influenzae, and N. meningitidis, as well as from viruses like CMV and varicella zoster, and fungi like Candida and PJP.
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