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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3281-3288
REVIEW ARTICLE
By
From the Department of Pediatrics and Immunology, Rambam Medical
Center, B. Rappaport School of Medicine, Technion, Haifa, Israel; the
Physiology Program, Harvard School of Public Health, Boston, MA; and
the Division of Hematology, University of Washington, Seattle, WA.
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IMPORTANT INSIGHTS into a number of biological processes have come from studies of rare inherited diseases. Goethe's declaration is best exhibited by the leukocyte adhesion deficiency (LAD) syndromes, in which one of several molecules in the adhesion cascade is defective. Much has been learned from the study of LAD, yet the puzzle is far from being solved. Animal models have also been pivotal in understanding of biological events, and immunology has benefited tremendously from the investigation of various aspects of the immune response in mice. One of the most powerful techniques has been targeted gene deletion by homologous recombination.1 This approach allows comparison of animals of similar genetic backgrounds that differ only in the absence of a single gene. Phenotypic differences between the knockout and wild-type littermates are presumed then to be due to the targeted gene deletion. Furthermore, various knockout mice can be interbred to produce deletions of several genes, providing animal models for more complex genetic defects.
Although gene targeting has many advantages, it is important to
acknowledge that there are important differences in biology between the
mice and humans. Indeed, comparisons between rare human disease and
mice with deletion of the same gene have shown important differences as
well as similarities. For example, the defect in Bruton's tyrosine
kinase (BTK) in humans leads to severe hypogammaglobulinemia with
almost no B cells. In contrast, mice with targeted deletion of the BTK
gene produce some antibodies with up to 30% of normal B-cell
number.2 It is also important to recognize that comparisons
may be confounded by the recruitment of alternative pathways in the
human or mouse genetic deficiencies. In this regard, mice deficient in
V-integrins exhibited no deficit in angiogenesis or
vasculogenesis,3 whereas
V
3-integrin antagonists inhibit
angiogenic responses in wild-type animals.4 Whether such
differences result from alternative pathways in the deficient animals
or unexplained effects of the antagonists remains to be resolved.
In this brief review, we will compare 2 human LAD syndromes
(Table 1) with gene-targeted mice with
various adhesion molecule-deficiencies (Table 2), highlighting both disparities
and similarities (Tables 3 and
4).
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THE ADHESION CASCADE |
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 TOP
INTRODUCTION
 THE ADHESION CASCADE
  2-INTEGRINS AND IgSF LIGANDS
SELECTINS AND SELECTIN LIGANDS
CONCLUSION
REFERENCES
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Leukocytes must first adhere to the endothelium of blood vessels before they emigrate to tissue. The process of leukocyte emigration is a dynamic one involving multiple steps.5,6 Several families of adhesion molecules mediate the interactions of leukocytes with endothelial cells, each involved in a distinct phase of emigration. The initial, rapidly reversible, adhesion of leukocytes to the vessel wall under conditions of flow produces rolling. This phase is mediated largely by the interaction of selectin receptors (E [CD62E], P [CD62P], and L [CD62L]) and their glycoconjugate ligands. The precise nature of the carbohydrate counter-structures for the various selectins has not been fully defined, but fucosylated, sialylated glycans such as Sialyl Lewis x (SLeX; CD15s) are clearly involved.7
2-subfamily
comprises 4 -subunits (CD11a-d) with the common
2-integrins (CD18). CD11a/CD18 (L2) and CD11b/CD18
(M2) are the predominant
2-subunits involved in leukocyte adhesion to
endothelium. Other leukocyte integrins involved in emigration are VLA-4
(41; CD49d/CD29) and
47. The leukocyte integrins interact with
IgSF ligands on the endothelial cell. These include intercellular
adhesion molecule-1 (ICAM-1; CD54) and ICAM-2 (CD102) for the
2 integrins, vascular cell adhesion molecule-1 (VCAM-1;
CD106) for VLA-4, and mucosal addressin cell adhesion molecule-1
(MAdCAM-1) for 47.
2-integrin (LAD I and LAD I variant) or selectin ligands
(LAD II; Table 1).8 However, because LAD I and LAD II
affect different phases in the adhesion cascade, much can be learned
about leukocyte-endothelial interactions from these rare human diseases.
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 2-INTEGRINS AND IgSF LIGANDS |
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INTRODUCTION
THE ADHESION CASCADE
2-INTEGRINS AND IgSF LIGANDS
SELECTINS AND SELECTIN LIGANDS
CONCLUSION
REFERENCES
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LAD I.
LAD I is a rare disease, with only approximately 200 patients reported.
It results from heterogeneous mutations in the gene encoding the common
2-subunit, CD18.9,10 LAD I was described clinically in the late 1970s and early 1980s and is characterized by
delayed separation of the umbilical cord, marked neutrophilia, and
recurrent bacterial infections.11 Two phenotypes have been reported.9 In the severe form, there is no detectable
expression of CD11/CD18 on leukocytes and the patients have a turbulent
course, with death usually occurring from infection during the first
few years of life. Consequently, if feasible, bone marrow
transplantation is performed early in life. It is noteworthy that bone
marrow transplantation has a high success rate in LAD I due to
decreased graft rejection, even with haploidentical
donors.12 In the moderate phenotype, cells express 2% to
5% of the normal level of CD18, and the clinical course is much
milder.9 Recently, 2 LAD I variants have been described in
which the 2-subunits are expressed at adequate levels
but are dysfunctional. In 1 patient, the CD18 alleles are normal, but
may have an associated signaling defect.13 The other
patient has 2 mutated CD18 alleles, which are expressed but are
nonfunctional.14
CD18-deficient mice. Early studies by Wilson et al15 reported a mouse with partial CD18-deficiency, comparable to the mild-moderate LAD I phenotype. The CD18-hypomorphic mice were viable and fertile, without any gross anatomic or histologic abnormalities, and, in contrast to LAD I, exhibited only mild leukocytosis. Unlike LAD I patients,16 these mice did not develop any spontaneous infections in the skin or other organs. However, they did show an impaired inflammatory response to chemical peritonitis and delayed rejection of cardiac transplants. The tolerance to allograft is consistent with the good results obtained after bone marrow transplantation in LAD I.
CD11a- and CD11b-deficient mice.
The roles of the CD11a and CD11b subunits in several aspects of
neutrophil and lymphocyte function have also been examined in
genetically deficient mice. In contrast to LAD I or CD18-deficient mice, CD11b-deficient mice did not exhibit any leukocytosis or marked
increased incidence of bacterial infection.22 In vivo studies of CD11b-deficient mice showed normal rolling but defective firm adhesion,23 just as was observed with neutrophils from an LAD I patient.24 Furthermore, like LAD I, neutrophils of CD11b-deficient mice exhibited in vitro defects of adhesion,
iC3b-mediated phagocytosis, phagocytosis-induced respiratory burst, and
homotypic aggregation.22 However, in contrast to LAD I,
neutrophil accumulation in thioglycollate-induced peritonitis was
normal or even increased in the CD11b-deficient mice,22,23
a surprising result ascribed in part to impaired phagocytosis-induced
apoptosis.23 It is of interest that neutrophil emigration
into inflamed peritoneum was markedly reduced in these animals when an
anti-CD11a MoAb was administered, suggesting that CD11a/CD18 rather
than CD11b/CD18 was primarily responsible for transendothelial
migration of neutrophils.22 Consistent with this
observation, neutrophil accumulation in thioglycollate-induced peritonitis was modestly reduced in the CD11a-deficient
mice.25 The reduction in neutrophil emigration into
inflamed peritoneum in CD11a-deficient animals25 or
CD11b-deficient animals treated with CD11a MoAb,22 but not
in CD18-deficient mice,17 may reflect the relatively normal
circulating neutrophil counts in the -chain mutants versus the
marked increase in circulating neutrophils in the CD18-deficient animals.
ICAM-1-deficient mice.
ICAM-1 is a major ligand for both CD11a/CD18 and CD11b/CD18. Because
ICAM-2 and -3 are also 2-integrin ligands, it is
expected that the phenotype of ICAM-1-deficient mice might differ from those CD18-deficient mice or the LAD I patients in whom multiple ICAM
counter-receptors are deficient. Two groups reported ICAM-1-deficient mice.26,27 The mutant animals generated by Sligh et
al26 were found to express novel isoforms of ICAM-1 due to
alternative RNA splicing, although no in vivo function has yet been
established for these isoforms.28 Both ICAM-1-deficient
murine lines developed normally, were fertile, and had moderate
leukocytosis. The mice exhibited multiple abnormalities of inflammatory
response, including impaired neutrophil emigration in response to
chemical peritonitis, resistance to septic shock, and decreased contact
hypersensitivity reaction.26 Kumasaka et al29
showed that neutrophil emigration during endotoxin-induced pneumonia
was reduced substantially by anti-ICAM-1 MoAb or ICAM-1 antisense
oligonucleotide, but was not altered in ICAM-1-deficient mice.
Similarly, Qin et al30 showed that Pseudomonas
aeruginosa-induced pneumonia did not require ICAM-1 when studied
using ICAM-1-deficient mice, whereas the blocking anti-ICAM-1 MoAb
inhibited neutrophil emigration by 70% in wild-type mice (but not in
the deficient mice). It is not clear whether these marked differences
result from compensation in the deficient mouse or from effects of MoAb
or antisense blockade apart from adhesion blockade (eg,
signaling).31
ICAM-2-deficient mice.
CD11a/CD18 binds to both ICAM-1 and ICAM-2. ICAM-2 is constitutively
expressed at high levels on all vascular endothelium, whereas ICAM-1
expression is strongly inducible by various cytokines, including tumor
necrosis factor-, interleukin-1, and interferon-
. These
expression patterns suggest that ICAM-2 may be important in leukocyte
trafficking into uninflamed tissues, as occurs during lymphocyte
recirculation, whereas ICAM-1 induction regulates leukocyte recruitment
at inflammatory sites. However, the biologic functions of ICAM-2 in
vivo have not been defined. Recently, ICAM-2-deficient mice were
described.32 Total leukocyte counts and leukocyte subset
numbers were unaltered compared with wild-type mice. Although platelet
counts were not reduced, there was a reduction in megakaryocyte progenitors in the bone marrow of the ICAM-2-deficient mice.
Lymphocyte homing to peripheral nodes, mesenteric nodes, and spleen was
unaffected by ICAM-2-deficiency.
2-integrin-independent neutrophil emigration.
The current multistep model of leukocyte-endothelial interactions was
developed primarily from studies in the systemic circulation in which
neutrophil emigration occurs predominantly in postcapillary venules. In
the lung, leukocytes emigrate largely within capillaries, raising the
possibility that adhesion pathways may differ in this organ. In studies
with a blocking CD18 MoAb in rabbits with acute pneumonia, Doerschuk et
al20 first reported that there was a CD18-independent
mechanism of neutrophil emigration in the lung during the acute
response to certain stimuli. Studies in an LAD I patient confirmed
neutrophil emigration into infected lung, whereas emigration to larynx,
peritoneum, and esophagus was absent.19 Stimuli that elicit
CD11/CD18-independent neutrophil emigration into the distal airspaces
of the lungs during the acute inflammatory process include
Streptococcus pneumoniae, group B Streptococcus, Staphylococcus aureus, hydrochloric acid, hyperoxia, and
complement protein C5a.20,30,33-38 CD11/CD18-independent
adhesion pathways were recruited during recurrent pneumonia induced by
Pseudomonas aeruginosa in rabbits, although CD11/CD18 mediated
acute neutrophil emigration in response to this organism.39
CD11/CD18-independent emigration was also noted in peritonitis induced
by glycogen or lipopolysaccharide at the 24-hour but not at the 4-hour
time point in rabbits21 and in the joints of rats after
induction of inflammatory arthritis.40 The molecular basis
of this pathway has not been defined, but it does not appear to involve
selectins.41
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SELECTINS AND SELECTIN LIGANDS |
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INTRODUCTION
THE ADHESION CASCADE
2-INTEGRINS AND IgSF LIGANDS
SELECTINS AND SELECTIN LIGANDS
CONCLUSION
REFERENCES
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LAD II. LAD II is a congenital defect in the selectin pathway that was first described in 1992.42 To date, there are 4 known patients: the 2 males originally reported and a female and another male recently identified (A. Etzioni, manuscript submitted). All 4 are of Arabic origin, and the parents of each child are related. Although there is no consanguinity among the families, they likely share a common genetic background.
P-selectin-deficient mice. P-selectin-deficient mice were found to be viable, fertile, and without any anatomic abnormalities.53 Whereas circulating neutrophil counts were 2 to 3 times higher than in wild-type animals, the numbers of progenitors in the bone marrow of the P-deficient mice were similar to the wild-type, suggesting a longer half-life of circulating neutrophils in the mutants. By injecting radiolabeled human neutrophils into the tail vein of mutant and wild-type animals, it was shown that neutrophils indeed survived longer in the P-selectin-deficient mice.54 These findings in the mouse contrast with results in LAD II. Price et al55 performed kinetic studies in 1 patient and showed a much reduced circulating half-life (<50% of normal), with a markedly increased marrow turnover rate. Although the increased turnover in the bone marrow could be explained in part by continuous stimulation (eg, the severe periodontitis), the reason for the markedly reduced half-life of the circulating neutrophils is not clear. In LAD I,56 as in the P-selectin mutant mice,54 the prolonged neutrophil half-life was ascribed to accumulation in the circulation due to the defect in emigration. It would be expected that this would also be the case in LAD II. It is possible that the defect in fucosylation of leukocyte membrane glycoproteins and glycolipids triggers their premature clearance by the reticulo-endothelial system.
E-selectin-deficient mice. The E-selectin mutant mouse was viable and exhibited no obvious developmental abnormalities. It displayed no significant change in trafficking of neutrophils in several models of inflammation.60 More direct studies showed that, whereas the percentage of rolling neutrophils was not reduced in this model, the cells rolled much faster,61 demonstrating a role for this selectin in the initial phase of the adhesion cascade. Blocking both endothelial selectins by treatment of the E-selectin-deficient mice with anti-P-selectin MoAb significantly inhibited neutrophil emigration to the skin and peritoneum, demonstrating that E- and P-selectin are functionally redundant in this regard.60
L-selectin-deficient mice.
L-selectin-deficient mice develop normally but exhibit defects in
lymphocyte homing and leukocyte rolling.62 Lymphocytes from
these mice did not bind to peripheral lymph node high endothelial venules (HEV), resulting in a marked reduction in the number of lymphocytes localized to peripheral lymph nodes. Other lymph nodes were
similarly affected. The DTH reaction was impaired in
L-selectin-deficient mice with 75% reduction in
swelling,63 similar to that seen in LAD II.50
Recently, it was shown that the defective DTH reaction in these
L-selectin knockout mice was restored by administration of activated
platelets into the systemic circulation.64 The activated
platelets expressing P-selectin formed a bridge between lymphocytes and
high endothelial venules, thereby enabling lymphocytes to undergo
subsequent 2-integrin--dependent firm adhesion.
Interestingly, as in LAD II,50 T-cell-dependent antibody
production to keyhole limpet hemocyanin was normal in the
L-selectin-deficient mice.65
E/P-selectin-deficient mice.
Whereas mice deficient in a single E- or P-selectin gene showed a
relatively mild phenotype, mice deficient in both endothelial selectins
(E/P-deficient) demonstrated extreme leukocytosis and elevated cytokine
levels.48 These mice developed a severe phenotype characterized by mucocutaneous infections, plasma cell proliferation, hypergammaglobulinemia, and severe deficiency of leukocyte rolling in
cremaster venules with or without addition of tumor necrosis factor-.47,48
Fuc-TVII-deficient mice.
The synthesis of the fucosylated glycans implicated in E-, P-, and
L-selectin ligand activity is catalyzed by several glycosylation reactions. The final reaction is controlled by (1,3)
fucosyltransferase Fuc-TVII and, thus, deletion of the gene for this
enzyme will result in a mouse deficient in SLeX and other fucosylated
selectin ligands.49 Consequently, the Fuc-TVII-deficient
mice are perhaps the best animal model to compare with LAD II.
Fuc-TVII-deficient mice yielded normal litter sizes, were vigorous,
and were free of microbial infections, including the spontaneous
bacterial dermatitis exhibited by the E/P-deficient mice.48
The Fuc-TVII-deficient mice exhibited a phenotype reminiscent of the
human LAD II, including marked leukocytosis, absent binding of
leukocytes to E- and P-selectins, and compromised neutrophil
trafficking to inflammatory sites. Absence of Fuc-TVII also yielded a
deficit in expression of L-selectin ligands by high endothelial venules
and a severe alteration in lymphocyte homing. However, the
Fuc-TVII-deficient mice did not show any gross anatomic abnormalities,
again implying that the growth and mental retardation in LAD II is due
to the general defect in fucose metabolism and not to the adhesion deficiency.
Core 2 GlcNAcT-deficient mice.
The core 2 1-6 N-acetylglucosaminyltransferase (C2 GlcNAcT) is a key
branching enzyme in the synthesis of serine/threonine-linked oligosaccharides (O-glycans). The core 2 branch of the O-glycans provides a scaffold for the subsequent production of lactosamine disaccharide repeats and, hence, sialylated and fucosylated selectin ligands such as sialyl Lewis X (CD15s).7 As in LAD II and
Fuc-TVII deficiency, the C2 GlcNAcT-deficient mice developed moderate
neutrophilia. Moreover, like LAD II patients and Fuc-TVII-deficient
mice, blood leukocytes from mice lacking C2 GlcNAcT were deficient in
E- and P-selectin ligands.69 Furthermore, C2
GlcNAcT-deficient neutrophils exhibited decreased rolling on
immobilized E- and P-selectin Ig chimeras, although not as marked as
observed with Fuc-TVII-deficient cells. Notably, neutrophil rolling on
L-selectin appeared to be particularly dependent on core 2 oligosaccharide biosynthesis, because leukocytes from the deficient
mice were unable to bind to L-selectin except at the lowest shear
force. Neutrophil recruitment to inflamed peritoneum was markedly
reduced, comparable to Fuc-TVII-deficient mice,49 with
only 20% of control numbers recovered 4 hours after thioglycollate
instillation,69 thereby demonstrating a critical role for
C2 GlcNAcT in the biosynthesis of selectin ligands on myeloid cells.
Interestingly, although a defect in L-selectin binding to peripheral
lymph node HEV was observed in this model, lymphocyte homing to lymph
nodes and spleen was unaltered.69 Thus, in contrast to
Fuc-TVII,49 C2 GlcNAcT activity was not required for
lymphocyte homing, suggesting either that core 2 O-glycans such as
those expressed on CD34 and related mucins in HEV are not required for
L-selectin-dependent lymphocyte rolling or that a second gene encoding
a C2 GlcNAcT isozyme is expressed in HEV.
Selectin-independent neutrophil emigration.
Just as with 2-integrin, there are selectin-independent
pathways of neutrophil emigration. When flow is reduced in
postcapillary venules, shear force is diminished, and there is no
longer a requirement for selectin-mediated tethering and rolling. Under
these static conditions, integrin receptors can be directly engaged and
can support firm adhesion and transmigration. This phenomenon was demonstrated by intravital microscopy in the microvasculature of rabbit
mesentery using flourescein-labeled LAD II neutrophils.24 Selectin-independent neutrophil emigration has also been reported in
the microcirculation of the lung41,41 and
liver.70 These selectin-independent pathways of neutrophil
emigration may account for the relatively mild phenotype of LAD II
patients with respect to infections.
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CONCLUSION |
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INTRODUCTION
THE ADHESION CASCADE
2-INTEGRINS AND IgSF LIGANDS
SELECTINS AND SELECTIN LIGANDS
CONCLUSION
REFERENCES
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The careful investigation of the LAD syndromes in humans and the adhesion molecule-deficient mice has dramatically increased our understanding of the physiology and the cell and molecular biology of leukocyte emigration. As we have indicated, these experiments have also generated a number of questions:
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NOTE ADDED IN PROOF |
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Marquardt et al75 recently reported a fifth LAD II patient of Turkish descent. DeLisser et al76 described loss of endothelial E-selectin surface expression in a patient with recurrent infections, potentially representing the first inherited dysfunction of an endothelial adhesion molecule.
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FOOTNOTES |
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Submitted February 2, 1999; accepted July 2, 1999.
Address reprint requests to John M. Harlan, MD, Division of Hematology, Box 357710, 1959 NE Pacific St, University of Washington, Seattle, WA 98195.
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REFERENCES |
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INTRODUCTION
THE ADHESION CASCADE
2-INTEGRINS AND IgSF LIGANDS
SELECTINS AND SELECTIN LIGANDS
CONCLUSION
REFERENCES
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