Page 1042 - Williams Hematology ( PDFDrive )

1016 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1017

VAMP-2 is localized to the membranes of specific and gelatinase gran- components C1, C2, and C4; thus, disorders of these latter molecules
ule and secretory vesicles in resting human neutrophils, 105,106 and the result in less-severe clinical conditions. C3 deficiency is inherited as an
t-SNARE syntaxin 4 is associated with the plasma membrane as shown autosomal recessive disorder. Homozygotes have undetectable serum
by immunoelectron microscopy. Munc18–3 may interact with syntaxin levels of C3 and suffer from recurrent severe pyrogenic infections,
4 and regulate fusion of secondary and gelatinase granules. VAMP-7 is whereas asymptomatic heterozygotes have half the normal values.
associated with azurophil granule fusion and Munc18–2 may interact A functional deficiency of C3 protease resulting in severe pyro-
with syntaxin 3 and regulate azurophil granule fusion. 258,259 genic infections also is seen in patients with a deficiency in C3b inac-
tivator, a protein inhibitor of the alternative complement pathway.
Neutrophil Extracellular Traps Unchecked activation of this pathway leads to hypercatabolism of C3
272
What previously was considered pus was identified as a highly bacteri- and factor B. Properidin deficiency also results in a functional defi-
273
cidal structure composed of strands of chromatin and bactericidal neu- ciency in C3. Properidin is a serum protein that belongs to the alter-
trophil granule proteins attached. 260,261 These NETs (see Fig. 66–2) are native complement pathway; it is involved in the stabilization of the
extruded from neutrophils in a process called netosis and represent one enzyme complex C3bBb. The protein is a multimeric glycoprotein with
of three death programs of neutrophils: apoptosis, necrosis, and netosis. a subunit Mr of 56,000, the gene of which has been cloned. Absence
274
Neutrophils only undergo netosis if they have mounted a respiratory of properidin is associated with severe, often fatal, pyrogenic infections,
262
263
burst. Elastase and MPO are also required for netosis. The NADPH often with meningococci.
oxidase activity of stimulated neutrophils thus serves two purposes, Approximately 5 percent of the population have low serum levels
namely to generate reactive oxygen species for microbial killing and to of mannose-binding lectin (MBL), a serum lectin secreted by the liver
275
induce formation of the bactericidal NETs after the intact neutrophil that binds mannose sugars present and on the surface of bacteria, fungi,
has ceased to function. This, in turn, means that patients with defective and some viruses. MBL is one of the soluble collectin effector proteins
NADPH oxidase assembly (patients with chronic granulomatous dis- that contribute to the basic armamentarium of innate immunity. MBL
ease [CGD]) lack both the ability to generate microbicidal oxygen spe- can function as an opsonin when bound to the surfaces by activating
cies and the ability to form the NETs. Patients with the Papillon-Lefèvre the complement cascade. A deficiency of MBL has been reported in
syndrome (PLS) lack elastase and are incapable of generating NETs. PLS infants with frequent unexplained infection, chronic diarrhea, and oti-
patients do not have a major immune defect and their symptoms are tis media. Other studies have identified an increased susceptibility to
275
largely related to periodontal infections, in contrast to CGD patients. infection by specific pathogens in MBL-deficient individuals, including
Negative effects of NETs have been noted as NETs may induce throm- human immunodeficiency virus, Plasmodium falciparum, Cryptospo-
276
bosis. Neutrophils are able to generate NETs and maintain their ridium parvum, and Neisseria meningitidis. The deficiency in MBL
264
structural integrity as an anucleate cell still capable of migration and largely results from three relatively common single-point mutations in
phagocytosis. 265 exon 1 of the gene, which leads to the failure of MBL to activate com-
277
plement. In addition, the protein also modulates disease severity, at
CLINICAL DISORDERS OF least in part through complex, dose-dependent influences on cytokine
production.
NEUTROPHIL FUNCTION Phagocytes, including neutrophils, express a large number of cell
surface proteins that play crucial functional roles in their biology. Micro-
CLASSIFICATION bial PRRs are an essential component of innate immunity, in which they
Neutrophil dysfunction may arise from (1) the absence of antibodies recognize and detect PAMPs, resulting in activation of neutrophils and
or complement components required to opsonize microorganisms, an other phagocytes. The mammalian TLR family comprises an important
interaction that provides a chemotactic signal; (2) the abnormalities of class of PRRs, which recognize a wide range of microbial pathogens
cytoplasmic and granule movement that alter the chemotactic response and pathogen-related products. At least 12 different TLRs that can be
278
or that result in abnormalities of the plasma membrane affecting found on mononuclear phagocytes have been described. TLRs sig-
the cells in terms of capability to modulate movement; and (3) defective nal via MyD88, an adapter protein. MyD88 deficiency in humans can
microbicidal capability. Comprehensive reviews of these syndromes are lead to recurrent infections with both Gram-positive and Gram-nega-
available to the interested reader. 266–268 tive infections, thereby indicating a role for both mononuclear cells and
neutrophils in host defense in the MyD88-deficient state. 279
Because a large number of chemoattractants are generated dur-
ABNORMALITIES OF THE SIGNAL ing inflammation, it is difficult to establish the relative significance of
MECHANISM AS A RESULT OF ANTIBODY AND a given individual component. Furthermore, chemotactive factors and
COMPLEMENT DEFECTS OR IMPAIRMENT OF opsonins are involved in the activity of both neutrophils and mononu-
clear phagocytes. Therefore, it is not clear whether the clinical conse-
PATTERN RECEPTOR RECOGNITION quences of disorders involving these substances are unique to one or
Because the synergistic action of immunoglobulins and complement the other of these phagocytic cells. Patients with antibody- or
proteins creates the opsonins that coat microorganisms and stimulate complement-deficient syndromes suffer mainly from infections with
the development of chemotactic factors, a deficiency of either one may encapsulated pathogens such as Haemophilus influenzae, pneumococci,
280
result in impaired neutrophil function. The most profound disturbances streptococci, and meningococci. Furthermore, splenectomized indi-
arise from abnormalities in C3, because this protein is the focal point for viduals deprived of an organ rich in mononuclear phagocytes have a
generation of opsonins and chemotactic factors (Chap. 19). 269–271 Opson- small, but finite risk of sepsis because of the same microorganisms.
ins such as C3b, generated from cleavage of C3, serve to coat bacteria. Encapsulated pathogens characteristically are not associated with neu-
Opsonization in general refers to the coating of pathogens by serum tropenic states. Antibody coating of encapsulated organisms facilitates
proteins such that they are more likely to be ingested. Activation of C3 their ingestion by mononuclear phagocytes, but may be less important
can occur in the absence of an antibody or the classical complement for their ingestion by neutrophils.

Kaushansky_chapter 66_p1005-1042.indd 1017 9/21/15 10:48 AM