“It is in her moments of abnormalities that nature reveals its secrets.” (Goethe)

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 αV-integrins exhibited no deficit in angiogenesis or vasculogenesis,3 whereas αVβ3-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 and4).

Table 1.

LAD Syndromes

LAD I*LAD II
Clinical manifestations 
 Recurrent severe infections  Frequent  Not observed 
 Neutrophilia  
  Basal  +  ++  
  With infections  +++  ++  
 Periodontitis  Common  Marked 
 Skin infections  Common  Not observed  
 Delayed separation of the umbilical cord  Common  Not observed 
 Developmental abnormalities  None  Marked  
Laboratory findings  
 CD18 expression  Marked decrease or absent Normal  
 SLeX expression  Normal  Absent  
 Neutrophil rolling  Normal  Marked decrease  
 Neutrophil firm adherence Marked decrease  Normal  
 T- and B-cell function Decreased  Normal 
LAD I*LAD II
Clinical manifestations 
 Recurrent severe infections  Frequent  Not observed 
 Neutrophilia  
  Basal  +  ++  
  With infections  +++  ++  
 Periodontitis  Common  Marked 
 Skin infections  Common  Not observed  
 Delayed separation of the umbilical cord  Common  Not observed 
 Developmental abnormalities  None  Marked  
Laboratory findings  
 CD18 expression  Marked decrease or absent Normal  
 SLeX expression  Normal  Absent  
 Neutrophil rolling  Normal  Marked decrease  
 Neutrophil firm adherence Marked decrease  Normal  
 T- and B-cell function Decreased  Normal 

Adapted and reprinted from Etzioni et al8in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. New York, NY, Oxford, 1999.

*

Severe phenotype.

Table 2.

Adhesion Molecule-Deficient Mice

Integrins and IgSF Ligands Selectins
CD18 P-selectin (CD62P)  
LFA-1 (CD11a)  E-selectin (CD62E) 
Mac-1 (CD11b)  L-selectin (CD62L)  
ICAM-1 (CD54) E/P-selectin  
ICAM-2 (CD102)  Fuc-TVII  
VCAM-1 (CD106) C2 GlcNAcT  
VLA-4 (CD49d/CD29)  
ICAM-1 and P-selectin  
Integrins and IgSF Ligands Selectins
CD18 P-selectin (CD62P)  
LFA-1 (CD11a)  E-selectin (CD62E) 
Mac-1 (CD11b)  L-selectin (CD62L)  
ICAM-1 (CD54) E/P-selectin  
ICAM-2 (CD102)  Fuc-TVII  
VCAM-1 (CD106) C2 GlcNAcT  
VLA-4 (CD49d/CD29)  
ICAM-1 and P-selectin  

For reviews, see also Frenette and Wagner,72Hynes,73 and Hynes and Bader.74 

Table 3.

Phenotypes in Deficiencies of β2-Integrins and IgSF Ligands

LAD I CD18- Deficient CD11b- DeficientCD11a- Deficient ICAM-1– Deficient ICAM-2– Deficient
Spontaneous infections  Marked  Moderate-marked None  None  None  None  
Neutrophilia  Marked Marked  Minimal  Minimal  Moderate  None  
Neutrophil migration to  
 Skin  Absent  Absent  NR  NR  NR NR  
 Lung  Present  Present  NR  NR  Present NR  
 Peritoneum  Absent  Present  Present  Reduced Reduced  NR 
LAD I CD18- Deficient CD11b- DeficientCD11a- Deficient ICAM-1– Deficient ICAM-2– Deficient
Spontaneous infections  Marked  Moderate-marked None  None  None  None  
Neutrophilia  Marked Marked  Minimal  Minimal  Moderate  None  
Neutrophil migration to  
 Skin  Absent  Absent  NR  NR  NR NR  
 Lung  Present  Present  NR  NR  Present NR  
 Peritoneum  Absent  Present  Present  Reduced Reduced  NR 

Abbreviation: NR, not reported.

Table 4.

Phenotypes in Deficiencies of Selectins and Selectin Ligands

LAD II E/P-Deficient Fuc-TVII–Deficient C2 GlcNAcT-Deficient
Developmental defects  Marked  Absent Absent  Absent  
Neutrophilia  Marked  Marked Moderate  Moderate  
Periodontitis  Marked  Present Absent  Absent  
Dermal ulcerations  Absent  Present Absent  Absent  
Hypergammaglobulinemia  Absent  Present NR  NR  
Lymphadenopathy  Absent  Present  Absent Absent  
Rolling defect  Marked  Marked  Marked Moderate  
Peritoneal emigration of neutrophils  Unknown Marked reduction  Marked reduction  Marked reduction 
Lymphocyte homing  Unknown  NR  Marked reduction Normal 
LAD II E/P-Deficient Fuc-TVII–Deficient C2 GlcNAcT-Deficient
Developmental defects  Marked  Absent Absent  Absent  
Neutrophilia  Marked  Marked Moderate  Moderate  
Periodontitis  Marked  Present Absent  Absent  
Dermal ulcerations  Absent  Present Absent  Absent  
Hypergammaglobulinemia  Absent  Present NR  NR  
Lymphadenopathy  Absent  Present  Absent Absent  
Rolling defect  Marked  Marked  Marked Moderate  
Peritoneal emigration of neutrophils  Unknown Marked reduction  Marked reduction  Marked reduction 
Lymphocyte homing  Unknown  NR  Marked reduction Normal 

Abbreviation: NR, not reported.

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 

In postcapillary venules of the systemic microcirculation, rolling is prerequisite for the subsequent steps in adhesion cascade of activation, firm adhesion, and transmigration. These latter events involve leukocyte integrins and their endothelial ligands of the Ig gene superfamily (IgSF). The β2-subfamily comprises 4 α-subunits (CD11a-d) with the common β2-integrins (CD18). CD11a/CD18 (αLβ2) and CD11b/CD18 (αMβ2) are the predominant β2-subunits involved in leukocyte adhesion to endothelium. Other leukocyte integrins involved in emigration are VLA-4 (α4β1; CD49d/CD29) and α4β7. 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 β2 integrins, vascular cell adhesion molecule-1 (VCAM-1; CD106) for VLA-4, and mucosal addressin cell adhesion molecule–1 (MAdCAM-1) for α4β7.

Although adhesion molecule-deficient mice have been generated for nearly all of the molecules involved in leukocyte emigration (Table 2), the best characterized human LAD syndromes are due to defects in β2-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.

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 β2-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 β2-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.

Recently, a murine model with complete absence of CD18 was reported.17,18 In these animals, as in LAD I, marked neutrophilia was found (11- to 30-fold increase over wild-type), and there was almost no emigration of neutrophils into the skin (Table 3). In contrast, when compared with wild-type, the CD18-deficient animals exhibited comparable neutrophil emigration into inflamed peritoneum and increased emigration into inflamed lung. The lack of neutrophil emigration to the skin with normal emigration to the lungs was also described in 1 patient with the severe phenotype of LAD I.19 The persistent emigration of neutrophils into inflamed peritoneum of the CD18-deficient mice contrasts with the nearly complete inhibition of peritoneal emigration by a CD18 monoclonal antibody (MoAb) in rabbits.20,21 This apparent disparity may reflect differences between species, but may also result in part from the marked increase in circulating neutrophils in the CD18-deficient animals. Compared with the antibody studies in normal animals, the number of circulating neutrophils in the CD18-deficient animals is many fold higher. Because the number of emigrating neutrophils is, in part, dependent on the number of circulating neutrophils, the observation that the same numbers of neutrophils emigrate in the CD18-deficient animals as in the wild-type mice may actually reflect a large inhibition. However, studies in an LAD I patient showed an absence of neutrophils in infected peritoneum.19 This discrepancy may reflect a true difference between mice and humans. Alternatively, it may be due to differences in sampling sites (peritoneal fluid in mice vtissue in humans) or to the duration of the inflammatory response (4 hours in mice v days in the patient).

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,22,23a 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 α-chain mutants versus the marked increase in circulating neutrophils in the CD18-deficient animals.

Based on studies in vitro and in vivo using blocking CD11a MoAbs, the CD11a/CD18 subunit has been implicated in a wide variety of immune functions, including delayed-type hypersensitivity (DTH) responses and cytolytic T-lymphocyte (CTL) effector functions. CD11a-deficient mice exhibited normal CTL responses to systemic virus infection25; LAD I patients also appear to mount adequate immune responses to viral challenge, because most infections and deaths have been due to bacterial and fungal infections rather than to viruses.10 However, CD11a-deficient mice failed to develop a DTH response to 2,4 dinitro-fluorobenzene sensitization and challenge,25 whereas LAD I patients mount normal skin reactions when challenged with antigen to which they have been sensitized.10 

These 2 mouse models have provided important insights into the role of the CD11a/CD18 and CD11b/CD18 subunits in leukocyte functions. It will be of interest to determine CD11c and CD11d functions in knockout models and to compare double knockouts for CD11a and CD11b with 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 β2-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 al29showed 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 

Comparisons of ICAM-1–deficient mice with CD18-deficient mice should provide insights into the contributions of the other ICAM molecules or other potential CD18 ligands in addition to this subfamily in various inflammatory and immune responses.

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-α, interleukin-1, and interferon-γ. 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.

Interestingly, during allergic lung inflammation, there was a delayed increase in eosinophils in the airway lumen and a prolonged presence of eosinophil infiltrates in lung tissue in the ICAM-2–deficient mice.32 Notably, there was no effect on lymphocyte or monocyte accumulation in airway lumen. Studies using bone marrow chimeras showed that the alterations in eosinophil trafficking in vivo resulted from deficiency of ICAM-2 on nonhematopoietic cells. Also, migration of normal eosinophils across ICAM-2–null endothelial monolayers in vitro was reduced compared with migration across normal endothelium. Together, these results suggested that ICAM-2 expressed on vascular endothelium, alveolar walls, or large airway epithelium participated in the traffic of eosinophils from the blood stream to the airway lumen.32 

β2-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 includeStreptococcus 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 byPseudomonas aeruginosa in rabbits, although CD11/CD18 mediated acute neutrophil emigration in response to this organism.39CD11/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 

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.

Clinically, LAD II is much a milder disease than LAD I. The 3 LAD II patients did not manifest delayed separation of the umbilical cord, a hallmark of LAD I. Although the children tended to suffer from an increased incidence of infections in early infancy,42compared with the severe form of LAD I, these episodes were quite mild, not requiring hospitalizations or intravenous antibiotics. Later in life, infections have been rare and the children are not on prophylactic antibiotics. The only persistent clinical symptom produced by neutrophil dysfunction is chronic, severe periodontitis, similar to that seen in LAD I.43 

In contrast to LAD I, in which all clinical symptoms relate to the leukocyte adhesion defect, multiple other organ systems are affected in LAD II. The children have a rare blood group type, the Bombay phenotype, and suffer from profound mental and severe growth retardation.44 The adhesion defect and other abnormalities result from a generalized defect in fucose metabolism.45Consequently, only 2% to 3% of normal fucosylated glycoproteins is expressed on the patients’ leukocytes. Because fucose is essential for the biosynthesis of E-, P-, and L-selectin ligands such as SLeX (CD15s),7 LAD II leukocytes are deficient in binding to endothelial E- and P-selectins.46 The endothelium in these patients likely also exhibits reduced expression of fucosylated L-selectin ligands.45 Thus, although the LAD II defect has no direct effect on the selectin genes themselves, the defect in fucose metabolism produces a deficiency of selectin ligands. With respect to leukocyte adhesion, the LAD II patients are therefore the human equivalent of mice with combined knockout of E- and P-selectin genes47,48 and mice with knockout of the fucosyltransferase gene that directs biosynthesis of fucose-containing selectin ligands49 (Table 4). The deficient selectin function accounts for the marked reduction of neutrophil rolling on inflamed mesenteric microvasculature observed by intravital microscopy.24 Interestingly, the children have not shown any defect in immune function and responded to intradermal antigen with normal numbers of T cells.50 In contrast, Th1 cells did not home to skin DTH sites in mice treated with anti–P- and anti–E-selectin antibody.51 

The growth and mental retardation are most probably also due to the defect in fucose metabolism, establishing a heretofore unknown role for fucose in human growth and development. It is unlikely that deficient selectin function accounts for these abnormalities as no such defects are observed in the selectin-deficient mice (vide infra). Recently, it was found that the primary defect in LAD II is in the biochemical activity of GDP-D-mannose-4, 6 dehydratase (GMD), the enzyme that converts mannose to fucose.45,52 However, cloning of GMD from an LAD II patient and a control showed normal amino acid sequence of patient GMD, suggesting that the LAD II defect results from a mutation(s) affecting some yet unidentified GMD-regulating protein(s).52 

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.

Intravital microscopy in the P-selectin–deficient mice showed a marked reduction in the initial rolling phase, confirming the crucial role of P-selectin in the initial interaction of the leukocyte with the blood vessel.53 Importantly, however, leukocyte rolling was observed at later time-points, despite the absence of P-selectin. Using neutrophils from an LAD II patient, a similar defect in neutrophil rolling was observed,24 but this defect persisted for a longer time, indicating that fucosylated glycoconjugates are also involved in later events. Extravasation of neutrophils to the skin was diminished for several hours after insult in the P-selectin–deficient mice.57 Using a skin chamber assay, neutrophil accumulation in an LAD II patient was markedly reduced over 24 hours.55 P-selectin–deficient mice were also reported to have a mild defect in hemostasis,58 but no bleeding tendency has been observed in the LAD II patients.

To determine the role of P-selectin in lymphocyte emigration, the contact hypersensitivity reaction was investigated in P-selectin–deficient mice. Accumulation of CD4+lymphocytes, monocytes, and neutrophils was reduced significantly, but there was no difference in vascular permeability or edema.59 In a similar study, a DTH reaction was investigated in an LAD II patient. In contrast to the findings in the P-selectin–deficient mouse, normal numbers of T cells were found, whereas the clinical signs of redness and swelling were severely depressed compared with normal.50 

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.50Recently, 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 β2-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-α.47 48 

To characterize the role of the endothelial selectins during bacterial sepsis in vivo, Streptococcus pneumoniae was inoculated into wild-type mice and mice with E-, P-, or E/P-selectin deficiency.66 When compared with wild-type mice, all of these selectin-deficient mice showed greater morbidity, a significantly higher mortality associated with persistent bacteremia, and a higher bacterial load. During the first 5 days, mortality was higher in the E-selectin–deficient, and only later did the double mutant approach the mortality rate observed in E-selectin–deficient mice. It is possible that the presence of persistently high numbers of circulating leukocytes and plasma cells and higher serum levels of Igs in the E/P-selectin–deficient mice provided an advantage in the initial response to pneumococcal sepsis. Ultimately, however, the defect in emigration was detrimental for prolonged survival after untreated infection.

As opposed to the E/P-deficient mice, the 2 older LAD II patients have had no increase in systemic infections, and the few episodes of localized infection have responded to conventional treatment as in any immunocompetent child. The phenotype of the E/P-deficient animals thus appears to be much more severe than observed in LAD II. This might simply reflect differences between humans and mice. Alternatively, it is possible that nonfucosylated ligands participate in selectin interactions in vivo; thus, the absence of fucosylated ligands in LAD II would not impact all E- and P-selectin–dependent functions, whereas the null mice would be severely affected. Also, selectin receptors may serve other functions important for host defense, eg, signaling molecules for endothelium.67 In this case, deficiency of the receptor proteins (in the deficient mice) would again have a greater impact than absence of their carbohydrate ligands (in the LAD II patients). In this regard, Ramos et al68 reported that an MoAb to the consensus repeat region of murine E-selectin blocked neutrophil recruitment to inflamed peritoneum of Balb/c mice in vivo without affecting rolling in vivo or adhesion to E-selectin transfectants in vitro.

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 α(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.48The 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 β1-6 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.

In contrast to the growth retardation and physical abnormalities observed in LAD II, C2 GlcNAcT–deficient mice, like Fuc-TVII–deficient mice, developed normally and lacked overt physical abnormalities.69 

Selectin-independent neutrophil emigration.

Just as with β2-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.24Selectin-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.

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:

What accounts for the discrepancies observed between deficient animals and wild-type animals treated with blocking MoAbs?

Does deficiency of the molecule create a milieu in which alternative pathways are recruited?

Do MoAbs produce effects other than adhesion blockade?

What is the CD18-independent pathway of neutrophil emigration?

What role does fucose play in somatic and neurological growth and development?

What accounts for the intact cell-mediated immune responses and skin DTH reaction in LAD II versus the defects observed in the selectin-deficient mice or with MoAb blockade of selectin receptors?

What accounts for the markedly reduced circulating half-life of LAD II neutrophils?

What accounts for the minimal infectious problems in LAD II versus E/P-selectin mutant mice or LAD I?

Are there nonfucosylated ligands for the selectins?

Do selectins serve functions apart from rolling?

Are there HEV-specific C2 GlcNAcT isozymes?

Clearly, William Harvey’s observation of more than 300 years ago holds true even today: “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces other workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to discovery of the usual law of nature by careful investigation of cases of rarer forms of disease” (1657).71 

1
Majzoub
JA
Muglia
LJ
Knockout mice.
N Engl J Med
334
1996
904
2
Khan
WN
Alt
FW
Gerstein
RM
Malynn
BA
Larsson
I
Rathbun
G
Davidson
L
Muller
S
Kantor
AB
Herzenberg
LA
Rosen
FS
Sideras
P
Defective B cell development and function in Btk-deficient mice.
Immunity
3
1995
283
3
Bader
BL
Rayburn
H
Crowley
D
Hynes
RO
Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins.
Cell
95
1998
507
4
Eliceiri
BP
Cheresh
DA
The role of alpha v integrins during angiogenesis: insights into potential mechanisms of action and clinical development.
J Clin Invest
103
1999
1227
5
Carlos
TM
Harlan
JM
Leukocyte-endothelial adhesion molecules.
Blood
84
1994
2068
6
Springer
TA
Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm.
Cell
76
1994
301
7
Varki
A
Selectin ligands: Will the real ones please stand up?
J Clin Invest
99
1997
158
8
Etzioni
A
Harlan
JM
Leukocyte adhesion deficiency syndromes
Primary Immunodeficiency Diseases: A Molecular and Genetic Approach.
Ochs
HD
Smith
CIE
Puck
JM
1999
375
Oxford
New York, NY
9
Anderson
DC
Springer
TA
Leukocyte adhesion deficiency: An inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins.
Annu Rev Med
38
1987
175
10
Fischer
A
Lisowska
GB
Anderson
DC
Springer
TA
Leukocyte adhesion deficiency: Molecular basis and functional consequences.
Immunodefic Rev
1
1988
39
11
Harlan
JM
Leukocyte adhesion deficiency syndrome: Insights into the molecular basis of leukocyte emigration.
Clin Immunol Immunopathol
67
1993
S16
12
Thomas
C
Le
DF
Cavazzana
CM
Benkerrou
M
Haddad
E
Blanche
S
Hartmann
W
Friedrich
W
Fischer
A
Results of allogeneic bone marrow transplantation in patients with leukocyte adhesion deficiency.
Blood
86
1995
1629
13
Kuijpers
TW
Van-Lier
RA
Hamann
D
deBoer
M
Thung
LY
Weening
RS
Verhoeven
AJ
Roos
D
Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins.
J Clin Invest
100
1997
1725
14
Hogg
N
Stewart
MP
Scarth
SL
Newton
R
Shaw
JM
Law
S-KA
Klein
N
A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta 2 integrins Mac-1 and LFA-1.
J Clin Invest
103
1999
97
15
Wilson
RW
Ballantyne
CM
Smith
CW
Montgomery
C
Bradley
A
O’Brien
WE
Beaudet
AL
Gene targeting yields a CD18-mutant mouse for study of inflammation.
J Immunol
151
1993
1571
16
Etzioni
A
Adhesion molecules—Their role in health and disease.
Pediatr Res
39
1996
191
17
Mizgerd
JP
Kubo
H
Kutkoski
GJ
Bhagwan
SD
Scharffetter
KK
Beaudet
AL
Doerschuk
CM
Neutrophil emigration in the skin, lungs, and peritoneum: Different requirements for CD11/CD18 revealed by CD18-deficient mice.
J Exp Med
186
1997
1357
18
Scharffetter
KK
Lu
H
Norman
K
van Nood
N
Munoz
F
Grabbe
S
McArthur
M
Lorenzo
I
Kaplan
S
Ley
K
Smith
CW
Montgomery
CA
Rich
S
Beaudet
AL
Spontaneous skin ulceration and defective T cell function in CD18 null mice.
J Exp Med
188
1998
119
19
Hawkins
HK
Heffelfinger
SC
Anderson
DC
Leukocyte adhesion deficiency: Clinical and postmortem observations.
Pediatr Pathol
12
1992
119
20
Doerschuk
CM
Winn
RK
Coxson
HO
Harlan
JM
CD18-dependent and -independent mechanisms of neutrophil emigration in the pulmonary and systemic microcirculation of rabbits.
J Immunol
144
1990
2327
21
Winn
RK
Harlan
JM
CD18-independent neutrophil and mononuclear leukocyte emigration into the peritoneum of rabbits.
J Clin Invest
92
1993
1168
22
Lu
H
Smith
CW
Perrard
J
Bullard
D
Tang
L
Shappell
SB
Entman
ML
Beaudet
AL
Ballantyne
CM
LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice.
J Clin Invest
99
1997
1340
23
Coxon
A
Rieu
P
Barkalow
FJ
Askari
S
Sharpe
AH
von-Andrian
UH
Arnaout
MA
Mayadas
TN
A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: A homeostatic mechanism in inflammation.
Immunity
5
1996
653
24
von-Andrian
UH
Berger
EM
Ramezani
L
Chambers
JD
Ochs
HD
Harlan
JM
Paulson
JC
Etzioni
A
Arfors
KE
In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes.
J Clin Invest
91
1993
2893
25
Schmits
R
Kundig
TM
Baker
DM
Shumaker
G
Simard
JJ
Duncan
G
Wakeham
A
Shahinian
A
vander-Heiden
A
Bachmann
MF
Ohashi
PS
Mak
TW
Hickstein
DD
LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor.
J Exp Med
183
1996
1415
26
Sligh
JEJ
Ballantyne
CM
Rich
SS
Hawkins
HK
Smith
CW
Bradley
A
Beaudet
AL
Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1.
Proc Natl Acad Sci USA
90
1993
8529
27
Xu
H
Gonzalo
JA
St
PY
Williams
IR
Kupper
TS
Cotran
RS
Springer
TA
Gutierrez-Ramos
JC
Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice.
J Exp Med
180
1994
95
28
King
PD
Sandberg
ET
Selvakumar
A
Fang
P
Beaudet
AL
Dupont
B
Novel isoforms of murine intercellular adhesion molecule-1 generated by alternative RNA splicing.
J Immunol
154
1995
6080
29
Kumasaka
T
Quinlan
WM
Doyle
NA
Condon
TP
Sligh
J
Takei
F
Beaudet
A
Bennett
CF
Doerschuk
CM
Role of the intercellular adhesion molecule-1 (ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice.
J Clin Invest
97
1996
2362
30
Qin
L
Quinlan
WM
Doyle
NA
Graham
L
Sligh
JE
Takei
F
Beaudet
AL
Doerschuk
CM
The roles of CD11/CD18 and ICAM-1 in acute Pseudomonas aeruginosa-induced pneumonia in mice.
J Immunol
157
1996
5016
31
Ward
PA
Adhesion molecule knockouts: One step forward and one step backward.
J Clin Invest
95
1995
1425
32
Gerwin
N
Gonzalo
JA
Lloyd
C
Coyle
AJ
Reiss
Y
Banu
N
Wang
BP
Xu
H
Avraham
H
Engelhardt
B
Springer
TA
Gutierrez-Ramos
JC
Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2-deficient mice results in extended hyperresponsiveness.
Immunity
10
1999
9
33
Hellewell
PG
Young
SK
Henson
PM
Worthen
GS
Disparate role of the beta 2-integrin CD18 in the local accumulation of neutrophils in pulmonary and cutaneous inflammation in the rabbit.
Am J Respir Cell Mol Biol
10
1994
391
34
Keeney
SE
Mathews
MJ
Haque
AK
Rudloff
HE
Schmalstieg
FC
Oxygen-induced lung injury in the guinea pig proceeds through CD18-independent mechanisms.
Am J Respir Crit Care Med
149
1994
311
35
Motosugi
H
Quinlan
WM
Bree
M
Doerschuk
CM
Role of CD11b in focal acid-induced pneumonia and contralateral lung injury in rats.
Am J Respir Crit Care Med
157
1998
192
36
Mulligan
MS
Wilson
GP
Todd
RF
Smith
CW
Anderson
DC
Varani
J
Issekutz
TB
Myasaka
M
Tamatani
T
Rusche
JR
Vaporciyan
AA
Ward
PA
Role of beta 1, beta 2 integrins and ICAM-1 in lung injury after deposition of IgG and IgA immune complexes.
J Immunol
150
1993
2407
37
Ramamoorthy
C
Sasaki
SS
Su
DL
Sharar
SR
Harlan
JM
Winn
RK
CD18 adhesion blockade decreases bacterial clearance and neutrophil recruitment after intrapulmonary E. coli, but not after S. aureus.
J Leukoc Biol
61
1997
167
38
Sherman
MP
Johnson
JT
Rothlein
R
Hughes
BJ
Smith
CW
Anderson
DC
Role of pulmonary phagocytes in host defense against group B streptococci in preterm versus term rabbit lung.
J Infect Dis
166
1992
818
39
Kumasaka
T
Doyle
NA
Quinlan
WM
Graham
L
Doerschuk
CM
Role of CD 11/CD 18 in neutrophil emigration during acute and recurrent Pseudomonas aeruginosa-induced pneumonia in rabbits.
Am J Pathol
148
1996
1297
40
Issekutz
TB
Miyasaka
M
Issekutz
AC
Rat blood neutrophils express very late antigen 4 and it mediates migration to arthritic joint and dermal inflammation.
J Exp Med
183
1996
2175
41
Mizgerd
JP
Meek
BB
Kutkoski
GJ
Bullard
DC
Beaudet
AL
Doerschuk
CM
Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs.
J Exp Med
184
1996
639
42
Etzioni
A
Frydman
M
Pollack
S
Avidor
I
Phillips
ML
Paulson
JC
Gershoni
BR
Brief report: Recurrent severe infections caused by a novel leukocyte adhesion deficiency.
N Engl J Med
327
1992
1789
43
Etzioni
A
Gershoni
BR
Pollack
S
Shehadeh
N
Leukocyte adhesion deficiency type II: long-term follow-up.
J Allergy Clin Immunol
102
1998
323
44
Frydman
M
Etzioni
A
Eidlitz
MT
Avidor
I
Varsano
I
Shechter
Y
Orlin
JB
Gershoni
BR
Rambam-Hasharon syndrome of psychomotor retardation, short stature, defective neutrophil motility, and Bombay phenotype.
Am J Med Genet
44
1992
297
45
Karsan
A
Cornejo
CJ
Winn
RK
Schwartz
BR
Way
W
Lannir
N
Gershoni
BR
Etzioni
A
Ochs
HD
Harlan
JM
Leukocyte adhesion deficiency type II is a generalized defect of de novo GDP-fucose biosynthesis. Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium.
J Clin Invest
101
1998
2438
46
Phillips
ML
Schwartz
BR
Etzioni
A
Bayer
R
Ochs
HD
Paulson
JC
Harlan
JM
Neutrophil adhesion in leukocyte adhesion deficiency syndrome type 2.
J Clin Invest
96
1995
2898
47
Bullard
DC
Kunkel
EJ
Kubo
H
Hicks
MJ
Lorenzo
I
Doyle
NA
Doerschuk
CM
Ley
K
Beaudet
AL
Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice.
J Exp Med
183
1996
2329
48
Frenette
PS
Mayadas
TN
Rayburn
H
Hynes
RO
Wagner
DD
Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins.
Cell
84
1996
563
49
Maly
P
Thall
AD
Petryniak
B
Rogers
GE
Smith
PL
Marks
RM
Kelly
RJ
Gersten
KM
Cheng
G
Saunders
TL
Camper
SA
Camphausen
RT
Sullivan
FX
Isogai
Y
Hindsgaul
O
von-Andrian
UH
Lowe
JB
The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis.
Cell
86
1996
643
50
Kuijpers
TW
Etzioni
A
Pollack
S
Pals
ST
Antigen-specific immune responsiveness and lymphocyte recruitment in leukocyte adhesion deficiency type II.
Int Immunol
9
1997
607
51
Austrup
F
Vestweber
D
Borges
E
Lohning
M
Brauer
R
Herz
U
Renz
H
Hallmann
R
Scheffold
A
Radbruch
A
Hamann
A
P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues.
Nature
385
1997
81
52
Sturla
L
Etzioni
A
Bisso
A
Zanardi
D
DeFlora
G
Silengo
L
DeFlora
A
Tonetti
M
Defective intracellular activity of GDP-D-mannose-4,6-dehydratase in leukocyte adhesion deficiency type II syndrome.
FEBS Lett
429
1998
274
53
Mayadas
TN
Johnson
RC
Rayburn
H
Hynes
RO
Wagner
DD
Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice.
Cell
74
1993
541
54
Wagner
DD
P-selectin knockout: A mouse model for various human diseases.
Ciba Found Symp
189
1995
2
55
Price
TH
Ochs
HD
Gershoni
BR
Harlan
JM
Etzioni
A
In vivo neutrophil and lymphocyte function studies in a patient with leukocyte adhesion deficiency type II.
Blood
84
1994
1635
56
Davies
KA
Toothill
VJ
Savill
J
Hotchin
N
Peters
AM
Pearson
JD
Haslett
C
Burke
M
Law
SK
Mercer
NFG
Walport
MJ
Webster
ADB
A 19-year-old man with leucocyte adhesion deficiency. In vitro and in vivo studies of leucocyte function.
Clin Exp Immunol
84
1991
223
57
Yamada
S
Mayadas
TN
Yuan
F
Wagner
DD
Hynes
RO
Melder
RJ
Jain
RK
Rolling in P-selectin-deficient mice is reduced but not eliminated in the dorsal skin.
Blood
86
1995
3487
58
Subramaniam
M
Frenette
PS
Saffaripour
S
Johnson
RC
Hynes
RO
Wagner
DD
Defects in hemostasis in P-selectin-deficient mice.
Blood
87
1996
1238
59
Subramaniam
M
Saffaripour
S
Watson
SR
Mayadas
TN
Hynes
RO
Wagner
DD
Reduced recruitment of inflammatory cells in a contact hypersensitivity response in P-selectin-deficient mice.
J Exp Med
181
1995
2277
60
Labow
MA
Norton
CR
Rumberger
JM
Lombard-Gillooly
KM
Shuster
DJ
Hubbard
J
Bertko
R
Knaack
PA
Terry
RW
Harbison
ML
Kontgen
F
Stewart
CL
McIntyre
KW
Will
PC
Burns
DK
Wolitzky
BA
Characterization of E-selectin-deficient mice: Demonstration of overlapping function of the endothelial selectins.
Immunity
1
1994
709
61
Kunkel
EJ
Ley
K
Distinct phenotype of E-selectin-deficient mice. E-selectin is required for slow leukocyte rolling in vivo.
Circ Res
79
1996
1196
62
Arbon
Ord
DC
Ley
K
Ratech
H
Maynard
CC
Otten
G
Capon
DJ
Tedder
TF
Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice.
Immunity
1
1994
247
63
Tedder
TF
Steeber
DA
Pizcueta
P
L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.
J Exp Med
181
1995
2259
64
Diacovo
TG
Catalina
MD
Siegelman
MH
von-Andrian
UH
Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin-deficient mice.
J Exp Med
187
1998
197
65
Xu
J
Grewal
IS
Geba
GP
Flavell
RA
Impaired primary T cell responses in L-selectin-deficient mice.
J Exp Med
183
1996
589
66
Munoz
FM
Hawkins
EP
Bullard
DC
Beaudet
AL
Kaplan
SL
Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice.
J Clin Invest
100
1997
2099
67
Lorenzon
P
Vecile
E
Nardon
E
Ferrero
E
Harlan
JM
Tedesco
F
Dobrina
A
Endothelial cell E- and P-selectin and vascular cell adhesion molecule-1 function as signaling receptors.
J Cell Biol
142
1998
1381
68
Ramos
CL
Kunkel
EJ
Lawrence
MB
Jung
U
Vestweber
D
Bosse
R
McIntyre
KW
Gillooly
KM
Norton
CR
Wolitzky
BA
Ley
K
Differential effect of E-selectin antibodies on neutrophil rolling and recruitment to inflammatory sites.
Blood
89
1997
3009
69
Ellies
LG
Tsuboi
S
Petryniak
B
Lowe
JB
Fukuda
M
Marth
JD
Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation.
Immunity
9
1998
881
70
Wong
J
Johnston
B
Lee
SS
Bullard
DC
Smith
CW
Beaudet
AL
Kubes
P
A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.
J Clin Invest
99
1997
2782
71
Garrod
A
The lessons of rare maladies.
Lancet
1
1928
1055
72
Frenette
PS
Wagner
DD
Insights into selectin function from knockout mice.
Thromb Haemost
78
1997
60
73
Hynes
RO
Targeted mutations in cell adhesion genes: What have we learned from them?
Dev Biol
180
1996
402
74
Hynes
RO
Bader
BL
Targeted mutations in integrins and their ligands: Their implications for vascular biology.
Thromb Haemost
78
1997
83
75
Marquardt
T
Burne
T
Luhn
K
Zimmer
KP
Korner
C
Fabritz
L
van der Werft
N
Vormoor
J
Freeze
HH
Louwen
F
Biermann
B
Harms
E
von Figura
K
Vestweber
D
Koch
HG
Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism.
J Pediatr
134
1999
681
76
DeLisser
HM
Christofidou-Solomidou
M
Sun
J
Nakada MT, Sullivan KE: Loss of endothelial surface expression of E-selectin in a patient with recurrent infections.
Blood
94
1999
884

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.

Author notes

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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