Neutrophil dysfunction may arise from (
- 1) the absence of antibodies or complement components required to opsonize microorganisms, an interaction that provides a chemotactic signal;
- (2) the abnormalities of cytoplasmic and granule movement that alter the chemotactic response or that result in abnormalities of the plasma membrane affecting the cells in terms of capability to modulate movement; and
- (3) defective microbicidal capability. Comprehensive reviews of these syndromes are available to the interested reader.223–225
Abnormalities of the Signal Mechanism as a Result of Antibody and Complement Defects or Impairment of Pattern Receptor Recognition
Because the synergistic action of immunoglobulins and complement proteins creates the opsonins that coat microorganisms and stimulate the development of chemotactic factors, a deficiency of either one may result in impaired neutrophil function. The most profound disturbances arise from abnormalities in C3, because this protein is the focal point for generation of opsonins and chemotactic factors (see Chap. 17).226–228 Opsonins such as C3b, generated from cleavage of C3, serve to coat bacteria. Opsonization in general refers to the coating of pathogens by serum proteins such that they are more likely to be ingested. Activation of C3 can occur in the absence of an antibody or the classical complement components C1, C2, and C4; thus, disorders of these latter molecules result in less-severe clinical conditions. C3 deficiency is inherited as an autosomal recessive disorder. Homozygotes have undetectable serum levels of C3 and suffer from recurrent severe pyrogenic infections, whereas asymptomatic heterozygotes have half the normal values.
A functional deficiency of C3 protease resulting in severe pyrogenic infections also is seen in patients with a deficiency in C3b inactivator, a protein inhibitor of the alternative complement pathway. Unchecked activation of this pathway leads to hypercatabolism of C3 and factor B.229 Properidin deficiency also results in a functional deficiency in C3.230 Properidin is a serum protein that belongs to the alternative complement pathway; it is involved in the stabilization of the enzyme complex C3bBb. The protein is a multimeric glycoprotein with a subunit Mr of 56,000, the gene of which has been cloned.231 Absence of properidin is associated with severe, often fatal, pyrogenic infections, often with meningococci.
Approximately 5 percent of the population have low serum levels of mannose-binding lectin (MBL),232 a serum lectin secreted by the liver that binds mannose sugars present and on the surface of bacteria, fungi, and some viruses. MBL is one of the collectin-soluble effector proteins that contribute to the basic armamentarium of innate immunity. MBL can function as an opsonin when bound to the surfaces by activating the complement cascade. A deficiency of MBL has been reported in infants with frequent unexplained infection, chronic diarrhea, and otitis media.232 Other studies have identified an increased susceptibility to infection by specific pathogens in MBL-deficient individuals, including human immunodeficiency virus, Plasmodium falciparum, Cryptosporidium parvum, and Neisseria. meningitides.233 The deficiency in MBL largely results from three relatively common single-point mutations in exon 1 of the gene, which leads to the failure of MBL to activate complement.234 In addition, the protein also modulates disease severity, at least in part through complex, dose-dependent influences on cytokine production.
Phagocytes, including neutrophils, express a large number of cell surface proteins that play crucial functional roles in their biology. Microbial pattern recognition receptors are an essential component of innate immunity, in which they recognize and detect pathogen-associated molecular patterns, resulting in activation of neutrophils and other phagocytes. The mammalian TLR family comprises an important class of pattern-recognition receptors, which recognize a wide range of microbial pathogens and pathogen-related products. At least 12 different TLRs that can be found on mononuclear phagocytes have been described.235 The neutrophil expresses both TLR2 and TLR4, which permit recognition of peptidoglycan and endotoxin, respectively, and TLR8, which allows recognition of RNA ligands.236 TLRs signal via MyD88, an adapter protein. MyD88 deficiency in humans can lead to recurrent infections with both Gram-positive and Gram-negative infections, thereby indicating a role for both mononuclear cells and neutrophils in host defense in the MyD88-deficient state.237
Because a large number of chemoattractants are generated during inflammation, it is difficult to establish the relative significance of a given individual component. Furthermore, chemotactive factors and opsonins are involved in the activity of both neutrophils and mononuclear phagocytes. Therefore, it is not clear whether the clinical consequences of disorders involving these substances are unique to one or the other of these phagocytic cells. Patients with antibody- or complement-deficient syndromes suffer mainly from infections with encapsulated pathogens such as Haemophilus influenzae, pneumococci, streptococci, and meningococci.238 Furthermore, splenectomized individuals deprived of an organ rich in mononuclear phagocytes have a small, but finite risk of sepsis because of the same microorganisms. Encapsulated pathogens characteristically are not associated with neutropenic states. Antibody coating of encapsulated organisms facilitates their ingestion by mononuclear phagocytes, but may be less important for their ingestion by neutrophils.