Page 342 - Clinical Immunology_ Principles and Practice ( PDFDrive )

322 Part two Host Defense Mechanisms and Inflammation

After activation by chemotactic factors, such as the complement transmigration of neutrophils between endothelial cells out to
fragment C5a, IL-8, leukotriene B4 (LTB4), or the bacterial the extracellular matrix (ECM).
product formyl-methionyl-leucyl-phenylalanine (fMLF), leuko-
cytes rapidly become adhesive to the endothelium, other leuko- Leukocyte Adhesion Defect-1
cytes, or laboratory surfaces. The activation process involves In the 1970s, infants and children were recognized with severe,
translocation of subcellular granules containing adhesion recurrent life-threatening bacterial infections affecting the skin,
molecules (CD18/CD11b) to the polymorphonuclear leukocyte gingiva, and lungs. A common clinical feature was delayed separa-
(PMN) surface and qualitative alterations in the adhesion tion of the umbilical stump with severe omphalitis. These patients
molecules constitutively expressed on the plasma membrane. were shown to have defects in membrane expression of the
Adhesion and transmigration of leukocytes occur as a result of leukocyte adhesion glycoproteins of the integrin superfamily. 15,16
interactions between three groups of molecules: leukocyte Integrins are noncovalently associated, heterodimeric cell
integrins, endothelial intercellular adhesion molecules (ICAMs, surface receptors, comprising one α subunit (CD11a, CD11b,
members of the immunoglobulin supergene family), and gly- or CD11c) and a common β chain (CD18), which is required
cosaminoglycans or selectins (Fig. 22.1). The first step in targeting for surface expression of the CD11 chains. These proteins mediate
PMNs to inflamed tissues is the rolling or tethering of PMNs leukocyte adhesion to the endothelium and other leukocytes.
14
on the endothelium of postcapillary venules. This is attributed Leukocyte adhesion defect-1 (LAD-1) results from mutations
X
X
to the interactions between CD15s (sialyl Lewis or SLe ) in the CD18 gene (ITGB2), located on chromosome 21q22.
expressed on the leukocyte surface and P-selectin or E-selectin— Patients with LAD-1 have defective polymorphonuclear cell
members of the selectin family of adhesion molecules—expressed adherence, leading to defective chemotaxis and trafficking, as
on the vascular endothelium. In addition, l-selectin on the well as low natural killer (NK) and cytotoxic T-lymphocyte (CTL)
leukocyte surface interacts with its counterligands P-selectin, activity. The absence of CR3 leads to loss of complement-mediated
CD34, glyCAM-1, and other glycoproteins located on the phagocytosis and bacterial killing. LAD-1 is often manifested
endothelial surface. Rolling, a relatively low affinity interaction by delayed umbilical cord separation, omphalitis, persistent
mediated by selectins, is followed by firm adhesion, which is a leukocytosis, destructive periodontitis, and recurrent infections
high affinity interaction between integrins on the neutrophil with S. aureus, Pseudomonas aeruginosa, and Klebsiella spp. Patients
and ICAMs on the endothelium. Adhesion is followed by the with some residual CD18 expression and function (i.e., hypo-
morphic mutations) live beyond childhood with less frequent
or severe infections and do not typically have delayed umbilical
cord separation. Persistent neutrophil leukocytosis (usually
>15 000 cells/µL) in the absence of infection is common in all
patients, driven by both low-level ongoing infection and impaired
exit of neutrophils from the circulation. Oral ulcers, severe
Leukocyte L-selectin periodontitis, gingivitis with apical bone loss (Fig. 22.2), and
eventual loss of permanent teeth are major problems in LAD-1
(CD62L)
Mac-1 p150,95 and reflect excessive IL-17 expression by CD4 T cells as a result
LFA-1 (CR3) (CR4) of uninhibited IL-23 production by tissue macrophages.
17
SLe x
(CD62L) Necrotizing cutaneous ulcers with delayed wound healing and
Absent CD18 CD18 Absent in LAD-2 lingering eschar formation are common (Fig. 22.3). Defective
in LAD-1 CD11a CD18 chemotaxis and adhesion mean that leukocytes fail to migrate
CD11b CD11c
Fucose to sites of infection, accounting for the inability to form pus
ICAM-2 and erythema at the site of infection. Biopsies of the ulcers
ICAM-1 (CD54)
(CD54) E-selectin P-selectin
(CD62E)
(CD62E)
Endothelium
Tight adhesion Rolling
FIG 22.1 Leukocyte Adhesion to Nonlymphoid Endothelium.
Selectins (L-selectin/CD62L, P-selectin/CD62P, and E-selectin/
CD62E), integrins (CD18/CD11a or LFA-1, CD18/CD11b or Mac-1,
and CD18/CD11c or p150,95), and intercellular adhesion molecules
(ICAMs) are involved in leukocyte adhesion to the nonlymphoid
endothelium. Rolling, the initial step of leukocyte adhesion, is
mediated by the interactions of E-selectin and P-selectin on
endothelial surfaces with the sialyl Lewis (SLe or CD15s) of
x
x
leukocytes as well as L-selectin on the leukocyte surfaces with
its counterligands CD34 or glyCAM-1. This low-affinity tethering
or rolling facilitates tight adhesion as a result of the interactions
of leukocyte function–associated antigen-1 (LFA-1) with ICAM-1
or ICAM-2 and Mac-1 with ICAM-2. CD18 is the molecule that FIG 22.2 Oral Pathology in a Patient With Leukocyte Adhesion
is missing or dysfunctional in leukocyte adhesion defect-1 (LAD-1); Defect-1 (LAD-1). Gingivitis and severe periodontitis are hallmarks
x
SLe is the missing molecule in LAD-2. of LAD-1.