Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

II. Neutrophil Functions
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matrix with a dependence on divalent cations ( Fig. 11-2 ).
Integrins are noncovalent heterodimers ( α and β subunits)
of type I transmembrane glycoproteins, and are made up
of various subfamilies that are organized around a particular
subunit ( Harris et al. , 2000 ). For instance, the β 2 (CD18)
subfamily is expressed on all cells of hematopoietic origin
and plays a critical role in neutrophil transendothelial cell
migration ( Simon and Green, 2005 ) and other key effector
activities, such as phagocytosis and apoptosis ( Mayadas and
Cullere, 2005 ). CD18 integrins are present in an inactive
state on circulating leukocytes; however, upon cell stimulation
with various stimuli (e.g., chemoattractants) and ligand
interactions, they undergo rapid affinity and valency changes
required for optimal integrin function ( Carman and Springer,
2003 ). There are four known α (CD11) subunits that can
combine with the CD18 subunit to form unique receptors.
The α subunits are defined, in part, as CD11a, b, c, and d.
The α and β subunits are expressed from different genes and
can be independently expressed on different cell types.
CD11a/CD18 ( α L β 2 or lymphocyte function-associated
antigen [LFA-1]) is the most broadly expressed leukocyte
integrin. It is expressed on early hematopoietic progenitor
cells and on all mature leukocytes. LFA-1 interacts with
cell surface ligands known as intercellular adhesion molecules
(ICAMs). ICAMs are type I transmembrane glycoproteins
and belong to the immunoglobulin superfamily
( Kishimoto and Rothlein, 1994 ). ICAM-l is expressed on
resting endothelium and is induced on many cell types by
inflammatory cytokines. LFA-1 also binds to ICAM-2 or
ICAM-3, which are mainly expressed on endothelial cells
and leukocytes, respectively. ICAM-l is a more active
LFA-l ligand than ICAM-2 or ICAM-3.
CD11b/CD18 (α M β 2 or Mac-1) is constitutively expressed
by neutrophils, monocytes, and macrophages. Mac-l is stored
in endosome-like vesicles in neutrophils that are translocated
to the surface following certain types of activation, allowing
increased Mac-l surface expression ( Borregaard et al. ,
1987 ). Mac-1, like LFA-l, is less active on resting cells
than activated cells. Mac-l also interacts with ICAM-l, but
at a site distinct from LFA-l ( Diamond et al. , 1991 ). Both
of these CD18 subfamily members function as the primary
integrins that mediate arrest and transmigration at sites
of inflammation. Mac-1 interacts with a wider variety of
ligands compared to LFA-l, including fibronectin, fibrinogen,
vitronectin, laminin, collagen, ICAM-2, albumin, myeloperoxidase,
kininogen, elastase, heparin, and zymosan
( Kishimoto and Rothlein, 1994 ; Simon and Green, 2005 ).
Mac-l also participates in a number of adhesion reactions
where the nature of the ligand is not known, such as adhesion
of neutrophils to plastic or glass surfaces and binding to a
variety of denatured proteins, suggesting a scavenger receptor-like
function. Of particular importance is that Mac-1,
also referred to as complement receptor 3, binds to C3bi.
This complement fragment bonds to surfaces when triggered
by immunoglobulin or microbial surfaces, and particles
coated with C3bi (opsonization) are readily phagocytized by
neutrophils ( Mayadas and Cullere, 2005 ).
CD11c/CD18 (α X β 2 or P150,95) is highly homologous to
Mac-1, but it is expressed at lower levels on neutrophils and
not nearly as well studied. Like Mac-1, CD11c/CD18 binds
to some of the same ligands, including C3bi as well as binding
to many pathogens directly to promote their phagocytosis,
fibrinogen, and a variety of denatured proteins ( Kishimoto
and Rothlein, 1994 ; Mayadas and Cullere, 2005 ).
CD11d/CD18 (α D β 2 ) is the most recently defined member
of the leukocyte integrin family and is expressed on tissue
macrophages, dendritic cells, and eosinophils and binds
to ICAM-3 and vascular cell adhesion molecule-l (VCAM-l)
(Danilenko et al. , 1995 ; Grayson et al. , 1998 ; Van der Vieren
et al. , 1995 ). The later binding interaction may contribute
to recruitment of eosinophils to inflamed airways.
6 . Leukocyte Adhesion Defi ciency
Leukocyte adhesion deficiency (LAD) syndromes (LAD-1,
LAD-1 variants, and LAD-2) result in immunodeficiency
disorders caused by an impaired extravasation of neutrophils
into sites of inflammation because of dysfunctional selectinor
integrin-mediated adhesion events ( Fig. 11-2 ). The LAD
syndromes are relatively uncommon; however, the clinical
consequences are often severe and lethal and include recurrent
or unresolved localized infections, systemic sepsis, and
impaired wound surveillance and repair.
Classical leukocyte adhesion deficiency type I (LAD-1)
is an autosomal recessive disorder arising from germline
mutations in the gene encoding CD18 and thus affects all
CD18 subfamilies. LAD-1 has been described in humans,
Holstein cattle, and dogs ( Anderson and Springer, 1987 ; Gu
et al. , 2004 ; Nagahata, 2004 ). In humans, the CD18-integrin
subunit is either not synthesized or unable to associate with
the respective CD11 subunits, and the resulting LAD can be
characterized as severe to moderate. Children with severe
deficiency typically display less than 1% of normal levels
of CD11/CD18, and children with moderate deficiency typically
express 5% to 10% of normal levels of the integrin.
Bovine leukocyte adhesion deficiency (BLAD) has been
extensively investigated ( Nagahata, 2004 ; Shuster et al. ,
1992 ). The molecular basis of BLAD is a single point mutation
that results in an aspartic acid to glycine substitution
at amino acid 128 of the CD18 polypeptide. Interestingly,
expression of L-selectin on neutrophils from BLAD calves
appears to be reduced as well. Neutrophil adhesion is markedly
impaired and chemotactic responses are diminished.
The hallmark clinical findings in BLAD include recurrent
or chronic diarrhea, chronic pneumonia, ulcerative stomatitis,
gingivitis, chronic dermatitis, stunted growth, and
impaired wound healing. Persistent and severe neutrophilia
is the most prominent hematological finding; however, neutrophil
morphology is normal. Pathological lesions are primarily
located in the lungs and intestinal tract. Neutrophils