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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e32835a0091
MYELOID BIOLOGY: Edited by David C. Dale

Lessons from rare maladies: leukocyte adhesion deficiency syndromes

Harris, Estelle S.a; Weyrich, Andrew S.a,b; Zimmerman, Guy A.a

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aDepartment of Internal Medicine

bProgram in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

Correspondence to Guy A. Zimmerman, MD, 15 North 2030 East, Room 4220, Salt Lake City, UT 84112, USA. Tel: +1 801 585 0950; fax: +1 801 585 0701; e-mail: guy.zimmerman@u2m2.utah.edu

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Abstract

Purpose of review: The leukocyte adhesion deficiency (LAD) syndromes are rare genetically determined conditions with challenging clinical features. These immunodeficiencies also provide insights that are broadly relevant to the biology of leukocytes, platelets, intercellular interactions, and intracellular signaling. Recent discoveries merit their review in the context of existing knowledge.

Recent findings: New activities of β2 integrins, which are deficient or absent in LAD-I, and new β2 integrin-dependent functions of neutrophils and other leukocytes have recently been identified. Genetic defects and mechanisms accounting for impaired fucosylation of selectin ligands and defective selectin binding and signaling in LAD-II are now apparent. LAD-III, which presents with bleeding similar to that in Glanzmann thrombasthenia and platelet dysfunction in addition to impaired leukocyte adhesion, is now known to be due to absence of KINDLIN-3, a cytoplasmic protein that acts cooperatively with TALIN-1 in activating β1, β2, and β3 integrins. Understanding of the leukocyte adhesion cascade and interactions of leukocytes with inflamed endothelium, which are impaired in each of the LAD syndromes, continues to be refined.

Summary: Although LAD syndromes are rare maladies, their investigation is generating new knowledge directly applicable to the diagnosis and care of patients and to fundamental paradigms in immunobiology and hemostasis.

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INTRODUCTION

The leukocyte adhesion deficiency (LAD) syndromes are primary immunodeficiency disorders that are classified as defects in adhesion-dependent functions of myeloid phagocytes, principally polymorphonuclear leukocytes (PMNs; neutrophils) and monocytes [1,2]. Although rare (≤1 : 1 000 000 births), their investigation has yielded fundamental insights relevant to inflammation, hemostasis, and regulation of cell–cell interactions, in addition to new knowledge applicable to clinical care. The LAD syndromes result from genetic alterations in the number or activation of integrins on leukocytes or in fucosylation of selectin ligands including P-selectin glycoprotein 1 (PSGL-1), a major leukocyte adhesion molecule that binds P-selectin, E-selectin, and L-selectin [3,4,5▪] (Fig. 1).

Figure 1
Figure 1
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Human and murine myeloid leukocytes express integrins – which are critical and widely distributed adhesion molecules [6,7] – of several subclasses in cell-specific patterns. Members of the β2 subclass of integrins (CD11/CD18; sometimes called the leukocyte, or leukocyte-specific, integrins because expression is restricted to these cells) are basally expressed by neutrophils, monocytes, and other circulating myeloid leukocytes (Fig. 1), and are essential for temporally and spatially regulated adhesion of these cells to endothelial cells of postcapillary venules and, under some conditions, other systemic vessels in response to inflammatory signals [3,4,8–11,12▪,13▪,14–18,19▪▪,20] (Fig. 2). In addition, β2 integrins are expressed by macrophages and on lymphocyte subsets, and mediate adhesion and signaling of these immune effector cells [21,22,23▪,24▪].

Figure 2
Figure 2
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P-selectin glycoprotein 1 and other selectin ligands are – like integrins – basally expressed on PMNs, monocytes, and other leukocytes including lymphocyte subclasses. PSGL-1 contributes to P-selectin-dependent interactions of leukocytes with activated platelets [25], in addition to their adhesion to activated endothelium (Fig. 2) and in leukocyte–leukocyte interactions [5▪].

The paramount clinical feature common to the LAD syndromes is recurrent bacterial infection that is often severe, life-threatening, and difficult to treat [2,26▪▪]. Infection by other microorganisms also occurs. Recurrent infection is a consequence of defective leukocyte adhesion to activated endothelium that impairs migration of leukocytes into tissues at sites of microbial entry and injury [2–4,26▪▪,27▪] (Fig. 2). This prevents extravascular accumulation of PMNs and monocytes in many patients: a defect in formation of pus [26▪▪,27▪]. In addition, many patients with LAD syndromes have basal and persistent neutrophilia in the absence of obvious infection, and a dramatic increase in myeloid leukocyte counts when infected [26▪▪,27▪]. Each LAD syndrome also has other manifestations that are not uniformly shared [2,3,26▪▪,27▪,28▪▪,29]: delayed separation of the umbilical cord and dramatically impaired or dysregulated wound healing in LAD-I and LAD-III; mental retardation, short stature, and an abnormal erythrocyte phenotype (deficiency in H antigen; Bombay phenotype) in LAD-II; and ‘Glanzmann-type’ bleeding and, in some patients, hepatosplenomegaly and/or osteopetrosis in LAD-III. There can be substantial variations in phenotype in patients with the same LAD syndrome [27▪,30,31].

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After description of LAD-I (1970s and early 1980s) and LAD-II (1992) [32,33], characterization of a new syndrome in which leukocyte adhesion was defective but expression and sequence of leukocyte integrins was normal and defects in selectin ligands were excluded [3,34–37] (Table 1) generated controversy in the field, including controversial nomenclature [26▪▪,28▪▪,42,43]. The new syndrome, now identified as a defect in inside-out signaling of multiple integrin subtypes (Figs 1 and 3), was initially called LAD-I variant (LAD-Iv) [34] – a term that made sense because the defect involves leukocyte integrins, as does LAD-I, and many clinical features are similar [3,27▪,29]. Nevertheless, it is now commonly termed LAD-III [1,2,26▪▪,28▪▪,30], and we will use that designation here. Rare compound mutations and cases in which mutations in the β2 integrin subunit yields a nonfunctional but expressed αβ integrin heterodimer are also sometimes called LAD-I/variants [3,26▪▪].

Table 1
Table 1
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Figure 3
Figure 3
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LAD-I: ABSENT OR REDUCED EXPRESSION OF β2 INTEGRINS

Diverse mutations in ITGB2 at 21q22.3 cause absent or reduced expression of the β2 integrin subunit and, consequently, reduced expression of β2 integrin heterodimers [28▪▪,31], yielding the characteristic leukocyte phenotype (Fig. 1) and defect in tight adhesion (Fig. 2) in patients with LAD-I [3,26▪▪]. Over 80 mutations, many occurring in a 240-residue region encompassed by exons 5–9 in β2 that is common to all integrin β subunits, have been cataloged [28▪▪]. Severe (<2% expression of β2 integrins) and moderate (2–30% expression of β2 integrins) LAD-I phenotypes occur [31]. Very rarely, a mutation causes nonfunctional but normally expressed β2 integrins [28▪▪,31]. Compound heterozygous and somatic reverse mutations in humans, and spontaneous mutations in large animals, have been reported (reviewed in [26▪▪,31]).

Patients with moderate LAD-I can survive infancy with antibiotics and careful management, but usually are plagued by severe periodontitis, tooth loss, and impaired or dysplastic remodeling of infected sites and wounds [26▪▪]. Dysplastic wound healing may be due to dysregulated macrophage activities and macrophage–neutrophil interactions, with failure to clear apoptotic PMNs and generate molecular signals that modulate inflammation and repair [22,55,56], in addition to defects in tissue surveillance and defense by neutrophils and monocytes (Fig. 2). The efficacy, indications, and biologic strategies for hematopoietic stem cell transplantation in patients with severe and moderate LAD-I are under evaluation (reviewed in [26▪▪,31,57]). Mouse models of β2 integrin deficiency have provided useful insights and new approaches to explore the biology of LAD-I [22,29,55,56,58,59]. For example, murine models [56,60,61▪] may yield answers to outstanding questions regarding T cell and adaptive immune responses in LAD-I [29,32].

LAD-I causes deficient expression of each of the four members of the β2 integrin subfamily: αLβ2 (CD11a/CD18, LFA-I), αMβ2 (CD11b/CD18, MAC-I, CR3), αXβ2 (CD11c/CD18, p150/95), and αDβ2 (CD11d/CD18) [3,28▪▪]. New facets of the biology of β2 integrins continue to be discovered. Differential activities of αLβ2 and αMβ2 in PMN adhesion and transmigration (Fig. 2) have recently been identified, based in part on intensive study of αLβ2[62], which is a prototype integrin [24▪]. The most recently identified member of the β2 subfamily is αDβ2[63]. Its biology is less well defined than that of the other β2 integrins. Experiments in mice with targeted deletions of the αD subunit and, consequently, absent expression of αDβ2, indicate that it has intricate activities in host defense, immune regulation, and inflammatory injury [21,64]. Expression of αDβ2 is said to be restricted to subsets of macrophages [28▪▪,62], but this is based on the pattern of basal expression in mice [21,64], which is different from the pattern of expression in humans ([63]; our unpublished studies). Nevertheless, αDβ2 on macrophages appears to be important in both experimental animals and humans [21,65].

New activities of PMNs and monocytes involving β2 integrin-mediated adhesion and signaling also continue to be discovered [22,23▪,66–69]. It is possible that some of these functions, or β2 integrin activities yet to be identified, are altered in LAD-I. Because integrins are also molecular effectors in inflammatory tissue injury [11], identification of new β2-dependent activities of myeloid leukocytes may have relevance beyond LAD syndromes.

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LAD-II: A DEFECT IN FUCOSYLATION OF SELECTIN LIGANDS LEADING TO IMPAIRED SELECTIN BINDING AND SIGNALING

Defects in fucosylation of oligosaccharides including sialyl Lewis X, which is present on PSGL-1 and other key leukocyte glycoconjugates, were previously identified as the molecular basis of LAD-II (reviewed in [3,31]). A human gene encoding a guanosine diphosphate (GDP)-fucose-specific transporter present in the Golgi membrane, SLC35C1, was subsequently cloned and is mutated in LAD-II (also termed congenital disorder of gylcosylation IIc), which is much less common than LAD-I [26▪▪,28▪▪,31,70–75]. Mutations resulting in defective function, or dual defects in function and subcellular localization, have been identified [74]. Decreased fucosylation of selectin ligands on leukocytes resulting from mutations in SLC35C1 (Fig. 1) leads to their impaired tethering and rolling on activated endothelial cells in LAD-II (Fig. 2) [3,26▪▪,28▪▪,31]. Impaired signaling through defective PSGL-I and other selectin ligands may also cripple β2 integrin-mediated slow rolling [5▪,8,9] and, possibly, other functional responses of leukocytes [29] in LAD-II.

Targeted deletion of slc35c1 in mice resulted in loss of GDP-fucose import into the Golgi lumen and yielded a complex phenotype with features similar to LAD-II, including neutrophilia, monocytosis, and leukocyte adhesion defects [76]. A second slc35c1−/− mouse model also demonstrated phenotypic features consistent with LAD-II, and provided information on differential effects on myeloid leukocyte and T-lymphocyte targeting in vivo[77]. Treatment of cultured cells from slc35c1−/− animals with fucose resulted in partial rescue of fucosylation of glycoconjugates [76]. Orally administered fucose has corrected features of LAD-II in some, but not all, humans in which this approach has been studied (reviewed in [26▪▪]), and resulted in appearance of the fucosylated erythrocyte H antigen and autoimmune neutropenia in one individual [73].

The cellular defects and molecular mechanisms causing growth impairment and psychomotor retardation in LAD-II are yet to be defined [26▪▪]. These features may be more severe than immunodeficiency in older patients [26▪▪,75].

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LAD-III: DEFECTIVE INSIDE-OUT SIGNALING OF MULTIPLE INTEGRINS

Patients with LAD-III have clinical features similar to those in LAD-I and a defect in tight adhesion of activated PMNs to endothelial cells and to purified β2 integrin ligands in vitro and/or in vivo[3,26▪▪,27▪,29] (Figs 1–3). In contrast to LAD-I, β2 integrins are expressed at expected or near-normal levels (Fig. 1). In addition, they are functional, indicating a defect in inside-out signaling [3,29]. Inside-out signaling of integrins induces transition from an inactive, or low-affinity, state to one that allows avid binding of ligands, and is sometimes termed activation [44]. Furthermore, there is a defect in inside-out signaling of β1 integrins on activated leukocytes from patients with LAD-III ([3,31]; also see below). In striking contrast to other LAD syndromes [3,26▪▪,27▪,29], patients with LAD-III also have a bleeding tendency similar to that in Glanzmann thrombasthenia [78] and defective inside-out signaling of integrin αIIbβ3, which is the major integrin mediating aggregation and adhesion of platelets [79] (Tables 1 and 2; Fig. 3). There is variability in severity of bleeding and in other phenotypic features of LAD-III [27▪,30,39,40,48–52,80]. Bone marrow or hematopoietic stem cell transplantation has been effective in some patients [26▪▪,30,39,48,51].

Table 2
Table 2
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Clinical presentation and characterization of cells from four index patients originally defined the LAD-III syndrome [27▪,34–38] (Table 1). Reports of affected siblings and new patients also yielded important clinical, genetic, and molecular insights [27▪,39,40,48–52,80]. Analysis of defects in function of primary leukocytes and platelets from patients with LAD-III has been a critical feature of these investigations (Table 2).

Independently, studies in genetically altered mice demonstrated that kindlin-3, a cytoplasmic protein, is required for activation of β1, β2, and β3 integrins and that its targeted deletion yields leukocyte and platelet adhesion defects that phenocopy those in LAD-III [83▪,84] – a breakthrough in the field. Prior to these observations, the molecular defect(s) in inside-out signaling [44] that causes LAD-III was an unsolved mystery [3,27▪,29]. After reports of kindlin-3−/− mice [83▪], genotyping of patients with LAD-III rapidly identified mutations in FERMT3 and deficiency of its protein product, KINDLIN-3, in cells from LAD-III patients [30,40,48,50]. FERMT3 mutations have now been found in all patients with LAD-III in whom genotyping has been reported [30,39,40,48–53,80] (Fig. 3c).

On the basis of studies of genetically altered mice [85,86] and patients with LAD-III [87], it was proposed that mutations in CALDAGGEF1 (RASGRP2) leading to impaired RAP-1 signaling are a molecular cause of LAD-III (reviewed in [4,44,88]). Genotyping of patients with LAD-III from seven Turkish families, the most common background of patients with this syndrome [31], yielded three sequence variations, including alterations in CALDAGGEF1 and FERMT3, but unequivocal evidence that mutations in FERMT3 and deficiency of KINDLIN-3 are sufficient to cause LAD-III [30]. Furthermore, patients with LAD-III and mutations in FERMT3 but without variations in CALDAGGEF1 have been identified [30,38–40,48], and engineered expression of KINDLIN-3, but not CALDAGGEF1, has rescued adhesion deficiency in cells derived from LAD-III patients [39,40,48,88]. The impact of variations in CALDAGGEF1 on functions of leukocytes and platelets in patients who also have mutations in FERMT3 remains controversial [26▪▪,28▪▪,41,49,54,87], although it is possible that isolated mutations in the CALDAGGEF1-regulated pathway – or in other inside-out signaling intermediates yet to be identified – could cause LAD-III [4,88]. The functional impact of mutations in FERMT3 and deficiency of KINDLIN-3 is, however, clear.

KINDLIN-3 deficiency also likely contributes to impaired outside-in signaling by leukocyte and platelet integrins [46,83▪], a key feature of their biology [6,79], in LAD-III. Further, deficiency of KINDLIN-3 likely contributes to features of LAD-III apart from impaired leukocyte interaction with endothelium and platelet functional defects. In kindlin-3−/− mice, defective inside-out signaling of β1, β2, and β3 integrins on monocyte-lineage osteoclasts impairs podosome formation and bone resorption, culminating in osteopetrosis [89▪▪] as occurs in some patients with LAD-III [45,48,50,51,80,87]. Recently, KINDLIN-3 was reported to be present in human erythrocytes, as the ortholog is in mice [90], and its deficiency proposed to be a cause of poikilocytosis and anemia in LAD-III [49]. Anemia was reported in three of the four index patients (Table 1), although the contributions of bleeding and other causes were not determined.

A substantial body of evidence indicates that integrin cytoplasmic domains – particularly the β subunit cytoplasmic tail – regulate conformational changes that result in ligand binding, and are key ‘trigger’ regions in inside-out signaling (reviewed in [44]). KINDLIN-3, which is one of three kindlin orthologs in mammals, binds to cytoplasmic domains of β1, β2, and β3 integrins [46,83▪,84] and works in cooperation with TALIN 1, a cytoplasmic protein that links integrin β tails to the actin cytoskeleton (reviewed in [44,47▪▪]). The actin cytoskeleton is critical for stabilization of integrin bonds and platelet and leukocyte adhesiveness [91], but early experiments indicated that impaired actin polymerization does not underlie defective adhesion of neutrophils in LAD-III [34–36]. TALIN 1 has an N-terminal head domain (THD) with a FERM (4.1, ezrin, radixin, moesin) motif and four subdomains in its structure; overexpression of the THD is sufficient to activate β1, β2, and β3 integrins [44]. This and other observations demonstrate that TALIN 1 is critical in inside-out signaling of integrins on leukocytes and platelets (reviewed in [44,47▪▪]). Nevertheless, TALIN 1 is widely expressed, and its mutation or deletion is unlikely to account for the unique cellular defects in LAD-III; global deletion of talin 1 in mice is embryonic lethal [47▪▪]. KINDLIN-3, on the contrary, is largely restricted to blood cells [46,54], although it is also found in endothelial cells [92]. KINDLIN-3 and other kindlins contain a FERM domain similar in sequence to that in TALIN but in which the F2 subdomain is split by an embedded pleckstrin homology domain [46,54]. The interrupted kindlin FERM domain and, particularly, the F3 subdomain mediate binding to integrin β tails at a motif that is distinct, and distal to, the THD-binding region (reviewed in [44,46,47▪▪]). The mechanisms by which KINDLIN-3 and TALIN cooperatively modify integrin conformation, affinity, and avidity, and interact in inside-out signaling and activation of β1, β2, and β3 integrins on platelets and leukocytes are not yet precisely defined [44,46,47▪▪] and are being aggressively explored [93–99] – an explosion of work triggered, in part, by recognition that KINDLIN-3 deficiency is the molecular basis for LAD-III.

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CONCLUSION

Rare maladies of humans teach observant physicians and translational biologists much, as was recognized by Harvey and Garrod [3]. There have been many such lessons from the LAD syndromes. Ongoing investigations of the intricate nature of integrins, selectin binding and signaling, and inside-out and outside-in signal transduction mechanisms suggest that other such lessons are in the offing, and that the molecular mechanisms that underlie LAD-I, LAD-II, and LAD-III will be further illuminated.

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Acknowledgements

The authors thank Alex Greer for skillful preparation of the manuscript and Diana Lim for her creative contributions and drafting of the figures. They also thank Tammy Smith for help in evaluating information on gene sequence and variations and contributions to reference[39], and other members of their research group and collaborators for contributions to work cited. The authors’ work, including observations mentioned in this article, is funded by awards R37HL44525, R01HL066277, RC1HL100121, R01HL092746, and U54HLH2311 from the National Institutes of Health.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 67–68).

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Interesting observations in a mouse model of LAD-I that address unresolved issues in adaptive immune function in this syndrome. Also see references [60] and [64] and clinical correlates in references [29] and [32].

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This study suggests a molecular mechanism that accounts for bleeding that is clinically more severe in LAD-III than in Glanzmann thrombasthenia. Deficiency of KINDLIN-3 in LAD-III likely impairs function of β1 and β3 integrins on platelets, including α2β1, whereas integrin αIIbβ3-dependent hemostatic functions alone are impaired in Glanzmann thrombasthenia. Deficiency of KINDLIN-3 and defects in function of multiple integrins may also impair antimicrobial activities of platelets in LAD-III [25].

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Important observations demonstrating that kindlin-3-deficient mice have major defects in adhesion and spreading of osteoclasts and severe osteopetrosis, which is also seen in some patients with LAD-III.

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Keywords:

immunodeficiency; infection; monocyte; neutrophil; platelet

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