LAD I is an autosomal recessive disorder caused by mutations in the common chain (CD18) of the p2 integrin family. Up to now, several hundreds of patients have been reported worldwide. The prominent clinical feature of these patients is recurrent bacterial infections, primarily localized to skin and mucosal surfaces. Sites of infection often progressively enlarge, and they may lead to systemic spread of the bacteria. Infections are usually apparent from birth onward, and a common presenting infection is omphalitis with delayed separation of the umbilical cord. The most frequently encountered bacteria are Staphylococcus aureus and gram-negative enteric organisms, but fungal infections are also common. The absence of pus formation at the sites of infection is one of the hallmarks of LAD I. Severe gingivitis and periodontitis are major features among all patients who survive infancy. Impaired healing of traumatic or surgical wounds is also characteristic of this syndrome (Anderson and Smith 2001).
The recurrent infections observed in affected patients result from a profound impairment of leukocyte mobilization into extravascular site of inflammation. Skin windows yield few, if any, leukocytes, and biopsies of infected tissues demonstrate inflammation totally devoid of neutrophils. These findings are particularly striking considering that marked peripheral blood leukocytosis (5 to 20 times normal values) is consistently observed during infections. In contrast to their difficulties in defense against bacterial and fungal microorganisms, LAD I patients do not exhibit a marked increase in susceptibility to viral infections (Etzioni 1996).
The severity of clinical infectious complications among patients with LAD I appear to be directly related to the degree of CD18 deficiency. Two phenotypes, designated severe deficiency and moderate deficiency, have been defined (Fischer et al. 1988). Patients with less than 1% of the normal surface expression exhibited a severe form of disease with earlier, frequent, and serious episodes of infection, often leading to death in infancy, whereas patients with some surface expression of CD18 (2.5-10%) manifested a moderate to mild phenotype with fewer serious infectious episodes and survival into adulthood.
The defective migration of neutrophils from patients with LAD I was observed in studies in vivo as well as in vitro. Neutrophils failed to mobilize to skin sites in the in vivo Rebuck skin-window test. In vitro studies demonstrated a marked defect in random migration as well as chemotaxis to various chemoattractant substances. Adhesion and transmigration through endothelial cells were found to be severely impaired. With the use of an intravital microscopy assay, it was found that fluorescein-labeled neutrophils from a LAD I boy rolled normally on inflamed rabbit venules, suggesting that they were capable of initiating adhesive interactions with inflamed endothelial cells (von Andrian et al. 1993). However, these cells failed to perform activation-dependent, p2-integrin-mediated adhesion steps and did not stick or emigrate when challenged with a chemotactic stimulus.
Patients with LAD I exhibit neutrophilia in the absence of overt infection with marked granulocytosis with neutrophils in peripheral blood reaching levels of up to 100,000/|l during acute infections. Early studies showed that patients with this disorder were uniformly deficient in the expression of all three leukocyte integrins (Mac-1, LFA-1, p150, and 95), suggesting that the primary defect was in the common p2-subunit, which is encoded by a gene located at the tip of the long arm of chromosome 21q22.3. Subsequently, several LAD I variants were reported in which there was a defect in p2-integrin adhesive functions despite normal surface expression of CD18. A child with classical LAD I features with normal surface expression of CD18 was reported (Hogg et al. 1999), in whom a mutation in CD18 was found to lead to a non-functional molecule.
The molecular basis for CD18 deficiency varies (Roos et al. 2002). In some cases, it is due to the lack or diminished expression of CD18 mRNA. In other cases, there is expression of mRNA or protein precursors of aberrant size with both larger and smaller CD18 subunits. Analysis at the gene level has revealed a degree of heterogeneity, which reflects this diversity. A number of point mutations have been reported, some of which lead to the biosynthesis of defective proteins with single amino acid substitutions, while others lead to splicing defects, resulting in the production of truncated and unstable proteins.
Notably, a high percentage of CD18 mutations identified in LAD I is contained in the extracellular domain of the CD18 (on exon 9), which is a highly conserved region. Domains within this segment are presumably required for association and biosynthesis of precursors and may represent critical contact sites between the a-subunit and p-subunit precursors. Thus, LAD I can be caused by a number of distinct mutational events, all resulting in the failure to produce a functional leukocyte p2-subunit. Recently, a case of somatic mosaicism due to in vivo reversion of the mutant CD18 was reported (Tone et al. 2007).
In any infant male or female with recurrent soft tissue infection and a very high leukocyte count, the diagnosis of LAD I should be considered. The diagnosis is even more suggestive if a history of delayed separation of the umbilical cord is present. To confirm the diagnosis, absence of the a- and p-subunits of the p2-integrin complex must be demonstrated. This can be accomplished with the use of the appropriate CD11 and CD18 monoclonal antibodies by flow cytometry. Sequence genetic analysis to define the exact molecular defect in the p2-subunit is a further option.
As leukocytes express CD 18 on their surface at 20 weeks of gestation, cordo-centesis performed at this age can establish a prenatal diagnosis. In families in whom the exact molecular defect has been previously identified, an earlier prenatal diagnosis is possible by chorionic biopsy and mutation analysis. Furthermore, recently, pre implantation diagnosis was also performed (Lorusso et al. 2006). Patients with the moderate LAD I phenotype usually respond to conservative therapy and the prompt use of antibiotics during acute infectious episodes. Prophylactic antibiotics may reduce the risk of infections. Although granulocyte transfusions may be life saving, their use is limited because of difficulties in supply of daily donors and immune reactions to the allogeneic leukocytes.
At present, the only corrective treatment that should be offered to all cases with the severe phenotype is bone marrow transplantation (Thomas et al. 1995). The absence of host LFA-1 may be advantageous in these transplants because graft rejection appears to be in part dependent upon the CD18 complex. The introduction of a normal p2-subunit gene (ITGB2) into hematopoietic stem cells has the potential to cure children with LAD I (Bauer and Hickstein 2000). Recently, successful gene therapy has been reported in canine model of LAD I (Bauer et al. 2006), applying this procedure may be beneficial also in humans.
Was this article helpful?