Noninfectious Neutrophil-Mediated Inflammatory

Disease Although neutrophils provide the major means of defense against bacterial and fungal infections, they can also be destructive to host tissues. The same oxidative and nonoxidative processes that destroy microorganisms can affect adjacent host tissues. A number of disease states correspond to inappropriate phagocytosis (Box 1), as with prolonged activation of NADPH oxidase. This process occurs when phagocytes attempt to engulf particles that are too large. The phagocyte releases oxygen radicals and granule contents onto the particle, but these escape into the surrounding tissues, generating tissue damage. This is often observed in response to dust inhalation and smoking (e.g., nicotine) and in persistent infections such as cystic fibrosis. In addition, many autoimmune diseases are thought to be caused by inappropriate activation of the process of phagocytosis, whereby the body attacks its own cells and tis sues. Examples include rheumatoid arthritis, multiple sclerosis, and Graves’ disease.

Box1. Noninfectious Neutrophil-Mediated Diseases*

Abnormal Neutrophil Function

 Patients with quantitative or qualitative defects of neutrophils have a high rate of infection, which illustrates the importance of the neutrophil to body defenses. Individuals with a marked decrease of neutrophils (neutropenia) or severe defects in neutrophil function frequently have recurrent systemic bacterial infections (e.g., pneumonia), disseminated cutaneous pyogenic lesions, and other types of life-threatening bacterial and fungal infections.

Leukocyte mobility may be impaired in some diseases (e.g., rheumatoid arthritis, cirrhosis, CGD). Defective locomotion or leukocyte immobility can also be seen in patients receiving steroids and in those with lazy leukocyte syndrome. A marked defect in the cellular response to chemotaxis, an important step in phagocytosis, can be seen in patients with diabetes mellitus, Chédiak-Higashi anomaly (syndrome), or sepsis, as well as in those with high levels of antibody immunoglobulin E (IgE), as in Job’s syndrome.

Congenital Neutrophil Abnormalities

 A small number of patients have congenital abnormalities of neutrophil structure and function (Box 2).

Box2. Congenital Neutrophil Abnormalities

Chédiak-Higashi Syndrome

 T he Chédiak-Higashi syndrome represents a qualitative dis order of neutrophils. It is a rare familial disorder inherited as an autosomal recessive trait and expressed as an abnormal granulation of neutrophils. Neutrophils having giant granules display impaired chemotaxis and delayed killing of ingested bacteria.

 Chronic Granulomatous Disease

 The chronic granulomatous diseases (CGDs) are a genetically heterogeneous group of disorders of oxidative metabolism affecting the cascade of events required for H2O2 production by phagocytes. Patients with X-linked CGD (X-CGD) have a mutation in CYBB encoding the trans membrane gp91^phox subunit of phagocyte NADPH oxidase required for microbicidal ROS production by neutrophils and monocytes. As a result, patients have life-threatening infections and granulomatous complications. If a suitable hematopoietic stem cell donor is available, it can cure X-CGD, but graft-versus-host disease is a significant risk.

A number of types of inheritance of the disorder have been described, including sex-linked (X chromosome–linked) in 66%, autosomal recessive in 34%, and autosomal dominant in less than 1% of cases. Patients with the autosomal recessive form may have a less severe clinical course than patients with the X-linked form. CGD is a defect of neutrophil microbicidal ROS generation resulting from gp91phox deficiency. CGD is caused by a missense, nonsense, frameshift, splice, or deletion mutation in the genes for p22 phox, p40 phox, p47 phox, p67 phox (autosomal CGD), or gy91phox (X-linked CGD), which results in variable production of neutrophil derived ROIs.

The onset of CGD is during infancy, with one third of patients dying before the age of 7 years because of infections. It was observed that in the presence of normal or elevated leukocyte counts, the neutrophilic granulocytes in vitro ingested and destroyed only streptococci, not staphylococci. Subsequent testing revealed that cells from patients with CGD can phagocytize non–H2O2-producing bacteria such as Staphylococcus aureus and gram-negative rods (e.g., Enterobacteriaceae), but cannot destroy them. In the X-linked form, the defective leukocytes fail to exhibit increased anaerobic metabolism during phagocytosis because of a cytochrome b558 deficiency (which expresses itself as a defect in the 91,000-Da glycoprotein mem brane anchor of the cytochrome complex), or these defective leukocytes produce H2O2 because of a myeloperoxidase deficiency.

Patients with CGD have infections with catalase-positive bacteria and fungi affecting the skin, lungs, liver, and bones. T hey also develop granulomas, resulting from a lack of resolution of inflammatory foci, even after the infection has been eliminated. This leads to extensive granuloma formation and, in some circumstances, impairment of physiologic processes (e.g., obstruction of the esophagus or urinary tract).

Laboratory evaluation of CGD begins with non-specific testing to rule out other disorders. These assays include serum quantitative immunoglobulin, complement activity enzyme immunoassay, CBC with differential, myeloperoxidase stain and a neutrophil receptor profile. The evaluation of neutrophil phagocytic function is best determined by the neutrophil oxidative burst assay (DHR) via flow cytometry (see Appendix C) that can indicate CGD by the absence or significant alteration of activity. Other, less-reliable tests include measurement of superoxide production, ferrocytochrome reduction, and the classic nitroblue tetrazolium test (NBT).

 Complement Receptor 3 Deficiency

 The complement receptor 3 (CR3) deficiency is a rare condition inherited as an autosomal recessive trait. A deficiency of CR3 on phagocytic cells presents as a leukocyte adhesion deficiency. Leukocyte adhesion deficiency type 1 (LAD-1) is caused by a deficiency of CD18. LAD-2 is caused by the absence of sialyl–Lewis X (CD15s) blood group antigen.

A CR3 deficiency in neutrophils is associated with marked abnormalities of adherence-related functions, including decreased aggregation of neutrophils to each other after activation, decreased adherence of neutrophils to endothelial cells, poor adherence and phagocytosis of opsonized microorganisms, defective spreading, and decreased diapedesis and chemotaxis. Patients may also lack an intravascular marginating pool of neutrophils. Defects in T lymphocytes are characterized by faulty lymphocyte-mediated cytotoxicity, with poor adherence to target cells. Abnormalities of B lymphocytes have also been observed.

Clinically, a deficiency can manifest as delayed separation of the umbilical cord. Other signs and symptoms include early onset of bacterial infections, including skin infections, mucositis, otitis, gingivitis, and periodontitis. A depressed inflammatory response and neutrophilia can be observed.

Myeloperoxidase Deficiency

A deficiency of myeloperoxidase is inherited as an autosomal recessive trait on chromosome 17. Myeloperoxidase is an iron-containing heme protein responsible for the peroxidase activity characteristic of azurophilic granules; it accounts for the greenish color of pus. Human neutrophils contain many granules of various sizes that are morphologically, biochemically, and functionally distinct. The azurophilic granules normally contain myeloperoxidase. In this disorder, azurophilic granules are present, but myeloperoxidase is decreased or absent. If phagocytes are deficient in myeloperoxidase, the patient’s phagocytes manifest a mild to moderate defect in bacterial killing and a marked defect in fungal killing in vitro.

Persons with a myeloperoxidase deficiency are generally healthy and do not have an increased frequency of infection, probably because of other microbicidal mechanisms compensating for the deficiency. Patients with diabetes and myeloperoxidase deficiency, however, may have deep fungal infections caused by Candida spp.

 Specific Granule Deficiency

 Specific granule deficiency is believed to be an autosomal recessive disease. It is caused by a failure to synthesize specific granules and some contents of other granules during differentiation of neutrophils in the bone marrow. Patients with specific granule deficiency have recurrent, severe bacterial infections of the skin and deep tissues, with a depressed inflammatory response.

مواضيع ذات صلة

Congenital Immunodeficiencies: Defects in Lymphocyte Maturation

Congenital Immunodeficiencies: Defects in Innate Immunity

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Cell Surface Receptors

Sepsis

Acute Inflammation

Diseases Caused by T Lymphocytes

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases

Examples and Treatment of Diseases Caused by Cell- or Tissue-Specific Antibodies

Mechanisms of Antibody-Mediated Tissue Injury and Disease

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy