Pathophysiology
Summary
Primary (inherited) immunodeficiencies can also involve dysfunction in neutrophils and macrophages, leading to impaired phagocytosis and an inherent defect in innate immunity.
Chronic granulomatous disease (CGD) is an X-linked recessive primary phagocytic disorder that manifests as a result of impaired degradation of ingested microbes within the phagolysosome due to a deficiency in NADPH oxidase, an electron carrier normally oxidized to produce NADP+ and reactive oxygen species. This deficiency means that NADPH is not converted into NADP+, leading to the absence of oxygen free radicals, superoxide ions (O2-), and consequently, minimal hydrogen peroxide. This results in a minimized respiratory burst within the phagolysosome.
Various types of bacteria and all fungal pathogens are catalase-positive, resulting in a predisposition to infections with these organisms, most commonly Staph aureus. Catalase breaks down the small amount of hydrogen peroxide present, thus further inhibiting the respiratory burst. Clinically, CGD presents with pneumonia and can feature granulomas in any organ, often containing multinucleated giant cells.
Diagnostic tests for CGD include dihydrorhodamine flow cytometry, which normally produces a green fluorescence due to the presence of superoxide. In CGD, minimal green fluorescence is observed. The nitroblue tetrazolium (NBT) test can also be used, which produces blue dye upon exposure to superoxide. In CGD, minimal blue dye is observed.
Myeloperoxidase (MPO) deficiency—an autosomal recessive primary phagocytic disorder—also leads to impairment in the degradation of ingested microbes in phagolysosomes. In MPO deficiency, the conversion of hydrogen peroxide into hypochlorous acid (bleach) within the phagolysosome is compromised. However, the respiratory burst—the production of superoxide and hydrogen peroxide—remains functional. MPO deficiency increases susceptibility to recurrent infections by Candida.
Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder characterized by impaired extravasation of leukocytes from blood into tissues. LAD is caused by CD18 deficiency, which disrupts the formation of integrins and subsequently impairs adhesion of leukocytes to endothelial walls. Clinically, LAD manifests with recurrent bacterial infections, particularly affecting skin and mucosal surfaces (e.g. skin abscesses & otitis media). LAD also presents with loss of adult teeth by adolescence due to periodontitis, absence of purulence in infections, and delayed separation of the umbilical cord. Lab findings show leukocytosis, predominantly composed of neutrophils, even in the absence of infection.
Hyper-IgE (Job) syndrome is an autosomal dominant disorder affecting neutrophil chemotaxis. It is caused by a mutation in the STAT3 gene, which leads to deficient Th17 helper T-cells and a consequent reduction in cytokine secretion for neutrophil chemotaxis. Clinical presentation includes cold skin abscesses, absence of fever during systemic infection, & recurrent skin infections that begin in newborns and coarse facies. Lab testing may show elevated eosinophil count.
Chediak Higashi syndrome is an autosomal recessive disorder characterized by defective fusion of phagosomes & lysosomes. This is due to disrupted lysosomal trafficking, which prevents the phagocytosed microbe from reaching the lysosome. Chediak Higashi syndrome is marked by the presence of giant azurophilic granules in neutrophils. Clinically, patients are prone to recurrent infections with Staph aureus and other pyogenic bacteria, and may also exhibit oculocutaneous albinism and peripheral neuropathy that affects both motor and sensory functions.
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FAQs
Chronic granulomatous disease (CGD) is a primary phagocytic disorder characterized by an impaired ability to degrade ingested microbes within phagolysosomes. The most common cause is an X-linked recessive deficiency in NADPH oxidase. This deficiency hinders the conversion of NADPH to NADP+, leading to a reduced production of oxygen free radicals essential for the respiratory burst in phagolysosomes. Patients with CGD often suffer from pneumonia due to infections with catalase positive organisms, notably Staph aureus. In CGD, granulomas can occur in various organs, often displaying multinucleated giant cells—a result of inflammatory mediators released by malfunctioning phagocytes.
Diagnosing CGD involves two key tests: the dihydrorhodamine test and the nitroblue tetrazolium (NBT) test. The dihydrorhodamine test measures superoxide production, which shows minimal green fluorescence due to the absence of superoxide in CGD. Similarly, the NBT test, which reacts with superoxide to produce a blue dye, will produce minimal blue dye in CGD patients.
Myeloperoxidase (MPO) deficiency is an autosomal recessive primary phagocytic disorder where the phagolysosome fails to produce hypochlorous acid, impairing the degradation of ingested microbes. As a result, individuals with MPO deficiency are more susceptible to recurrent Candida infections. Notably, respiratory burst mechanism, which produces superoxide and hydrogen peroxide, remains functional in MPO deficiency.
Leukocyte adhesion deficiency (LAD) is an autosomal recessive primary phagocytic disorder that prevents leukocytes from adhering to blood vessel walls, inhibiting their migration into tissues. This is due to a deficiency in the CD18 protein, which affects the formation of integrins. Patients with LAD frequently experience recurrent bacterial infections, especially on the skin and mucosal surfaces. They also exhibit leukocytosis, primarily of neutrophils, as these cells remain trapped in circulation due to their inability to adhere and migrate.
Chediak Higashi syndrome, an autosomal recessive primary phagocytic disorder, disrupts lysosomal trafficking, preventing the fusion of phagosomes with lysosomes. Consequently, ingested microbes aren't delivered to the lysosome and remain undestroyed. Patients with this syndrome have neutrophils containing large azurophilic granules. Clinically, they are prone to recurrent infections with Staph aureus and other pyogenic bacteria, and can also present with oculocutaneous albinism and peripheral neuropathy that affects both motor and sensory functions.
