Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of ... Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression.
Diagnosis of hereditary deficiency of CR3 is facilitated by commercial availability of monoclonal antibodies specific for the alpha-integrin chains of CR3 and p150,95.
Beginning in the 1970s, patients were recognized who had recurrent bacterial infections, defective neutrophil mobility, and delayed separation of the umbilical cord (e.g., Hayward et al., 1979). Before the elucidation by Springer et al. (1984, 1986) and Barclay ... Beginning in the 1970s, patients were recognized who had recurrent bacterial infections, defective neutrophil mobility, and delayed separation of the umbilical cord (e.g., Hayward et al., 1979). Before the elucidation by Springer et al. (1984, 1986) and Barclay et al. (1993), extraordinary confusion surrounded the group of patients with leukocyte dysfunction and deficiency of cell surface antigens (see, for example, Arnaout et al., 1982; Bowen et al., 1982; Dana et al., 1984). In the seventh edition of these catalogs (1986), one entry related to the ITGB2 locus (which is mutant in these patients), but 3 others described neutrophil dysfunction syndromes now known to be leukocyte adhesion deficiency. Confusion was created by different investigators looking at the different alpha subunits which share a common beta subunit. Van der Meer et al. (1975) described a 'new' defect in the intracellular killing of ingested microorganisms. A sister and probably 2 brothers were affected. During infections, the white blood count was as high as 55,000 per cu mm, mostly neutrophils, with a slight shift to the left. Other patients with recurring bacterial infections were reported who had defects in initiation of the neutrophil respiratory burst to particulate but not soluble stimuli (e.g., Weening et al., 1976; Harvath and Andersen, 1979), defects in neutrophil chemotaxis and phagocytosis (e.g., Niethammer et al., 1975), or both (Harvath and Andersen, 1979). Crowley et al. (1980) were the first to propose that the defects in neutrophil chemotaxis and phagocytosis were secondary to an abnormality in cell adhesion. Using specific monoclonal antibodies, Dana et al. (1984), Beatty et al. (1984), and others demonstrated deficiency of both the alpha and the beta subunits of Mac-1 (also designated Mo1, and as beta-2/alpha M in integrin terminology) in the neutrophils of patients of this type. Arnaout et al. (1984) and others demonstrated that the LFA-1 alpha-beta complex (beta-2/alpha-X) is also deficient on patients' neutrophils and lymphocytes. Springer et al. (1984, 1986) found that a third type of alpha-beta complex is also deficient on patients' neutrophils and lymphocytes. Springer et al. (1984, 1986) proposed that the primary defect in these patients resides in the beta subunit (which is shared by all 3 deficient proteins) and that the beta subunit is necessary for cell surface expression on the alpha subunit. Such neutrophils have a reduced phagocytic and respiratory burst response to bacteria and yeast as well as a reduced ability to adhere to various substances and migrate into sites of infection. Most of the clinical features are probably the result of neutrophil and monocyte deficiency of CR3 (beta-2/alpha-M). There have been reports of about 30 patients with recurrent bacterial infections due to deficiency of this family of cell membrane glycoproteins. Ross (1986) tabulated the findings in reported cases. Often the first manifestation is infection of the umbilical cord stump, occasionally progressing to omphalitis (Abramson et al., 1981; Bissenden et al., 1981). Gingivitis (periodontitis) may be noted with eruption of the primary teeth. Systemic bacterial infections such as pneumonia, peritonitis, and deep abscesses are more frequent during infancy and with complete deficiency. See review by Todd and Freyer (1988), who found reports of 41 patients in whom the clinical picture fitted that of CD18/CD11 (beta-2/alpha) glycoprotein deficiency. At least 4 patients suspected or documented to have a moderately severe variant (10% expression of CD18/CD11 glycoprotein) have survived to adulthood (Anderson et al., 1985; van der Meer et al., 1975; Weening et al., 1976) and 3 homozygous persons are known to have parented affected or presumably heterozygous offspring. Kobayashi et al. (1984) described a 3-month-old Japanese female infant with persistent navel infection due to Pseudomonas aeruginosa since birth and recurrent bacterial skin infections. They found a severe abnormality of neutrophil adhesion on a surface, leading to a lack of chemotaxis and mild impairment of phagocytosis. Neutrophil bactericidal activity and nitroblue tetrazolium reduction were unimpaired. By sodium dodecyl sulfate polyacrylamide gel electrophoresis of neutrophil membrane proteins, 2 glycoproteins were shown to be lacking. In both parents, both glycoproteins were reduced. Fujita et al. (1985) reported the subsequent birth of a male sib with the same defect. Fujita et al. (1988) described juvenile rheumatoid arthritis of systemic onset in these sibs, then aged 5 and 3 years, respectively, who had a severe form of congenital leukocyte adhesion deficiency. Etzioni and Harlan (1999) provided a comprehensive review of both type I (LAD1) and type II LAD (LAD2; 266265). While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1.
Dana et al. (1987) studied 4 unrelated patients with the family of 3 leukocyte adhesion molecules, which they called Leu-CAM. They called the 3 antigens Mo1, LFA-1, and Leu M5. In all 4 patients, they found that B ... Dana et al. (1987) studied 4 unrelated patients with the family of 3 leukocyte adhesion molecules, which they called Leu-CAM. They called the 3 antigens Mo1, LFA-1, and Leu M5. In all 4 patients, they found that B cells synthesized a normal-sized, beta-subunit precursor that either failed to 'mature' or matured only partially to the membrane-expressed form. Furthermore, B cells from all 4 patients had a single normal-sized, beta-subunit mRNA of about 3.4 kb. Thus, leukocyte adhesion deficiency in these 4 patients was not due to the absence of the beta chain gene or to aberrant splicing of its mRNA. The findings were consistent with a defective beta-subunit gene (ITGB2) resulting in abnormal posttranslational processing of the synthesized beta molecule. - Somatic Revertant Mosaicism Tone et al. (2007) reported an unusual case of somatic revertant mosaicism in a Japanese infant with LAD1 caused by compound heterozygosity for 2 truncating mutations in the ITGB2 gene, predicting complete loss of the CD18 antigen. However, flow cytometric analysis showed that a small proportion of the patient's memory/effector CD8+ T cells were CD18+. Sequencing of these CD18+ T cells indicated that they resulted from spontaneous site-specific single nucleotide reversion of the inherited paternal mutation. Although these T cells were functional in vitro, the patient did not show clinical improvement, likely because no reversion events had occurred in myeloid cells. Tone et al. (2007) concluded that somatic genetic reversion in a primary immunodeficiency can occur, but may be undetected in some cases if the changes do not result in modification of the clinical phenotype.