Alternative titles; symbols
SNOMEDCT: 234582006; ORPHA: 2968, 99842; DO: 0110910;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 21q22.3 | Leukocyte adhesion deficiency | 116920 | Autosomal recessive | 3 | ITGB2 | 600065 |
A number sign (#) is used with this entry because of evidence that leukocyte adhesion deficiency-1 (LAD1) is caused by homozygous or compound heterozygous mutation in the CD18 gene (ITGB2; 600065) on chromosome 21q22.
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.
Genetic Heterogeneity of Leukocyte Adhesion Deficiency
Also see LAD2 (266265), caused by mutation in the SLC35C1 gene (605881), and LAD3 (612840), caused by mutation in the FERMT3 gene (607901).
ITGB2 encodes the beta subunit common to 3 cell adhesion molecules: CD11A (ITGAL; 153370), CD11B (ITGAM; 120980), and CD11C (ITGAX; 151510).
The 3 alpha-integrin chains that each heterodimerize with the beta-2 chain (ITGAL, ITGAM, and ITGAX) have leukocyte antigen designations of (1) CD18/CD11A: also referred to as LFA-1, Leu CAMa, and integrin beta-2/alpha-L; (2) CD18/CD11B: also referred to as CR3, Leu CAMb, Mac-1, Mo1, OKM-1 and integrin beta-2/alpha-M; (3) CD18/CD11C: also referred to as p150 (p150, 95) Leu CAMc, and integrin beta-2/alpha-X (Barclay et al., 1993).
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., 1976), 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.
Kishimoto et al. (1987) identified 5 distinct beta-subunit phenotypes among LAD patients: an undetectable beta-subunit mRNA and protein precursor; low levels of beta-subunit mRNA and precursor; an aberrantly large beta-subunit precursor, probably due to an extra glycosylation site; an aberrantly small precursor; and a grossly normal precursor. Mutant beta-subunit precursors from LAD patients failed to associate with the LFA-1 alpha subunit (alpha-L). Family studies with aberrant precursors correlated with recessive inheritance of leukocyte adhesion deficiency.
Marlin et al. (1986) showed that the genetic defect in leukocyte adhesion deficiency (also known as LFA-1 immunodeficiency and by several other designations) resides in the beta subunit that is common to 3 cell adhesion molecules. Boucheix (1987) indicated that a tentative designation for the beta chain of these 3 proteins is CD18. The 3, each with a unique alpha chain, are CD11A (153370), CD11B (120980), and CD11C (151510).
The neutrophils from parents and sibs of patients often show half-normal amounts of CR3/LFA1/p150,95 antigens (CD18/CD11B, CD18/CD11A and CD18/CD11C, respectively) (Arnaout et al., 1984; Springer et al., 1984). In other cases, both parents have normal amounts of antigen or only 1 parent has half-normal amounts (Ross et al., 1985; Arnaout et al., 1984). The only suggestion of a mode of inheritance other than autosomal recessive came from Crowley et al. (1980), who first proposed that an adhesion defect exists in this condition. X-linked recessive inheritance was suggested because only the mother and sister of the affected male showed evidence of the carrier state; the cells of the father and brother were functionally normal and had a normal content of the relevant glycoprotein.
Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is located on chromosome 21.
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.
In a patient with LAD deficiency, Arnaout et al. (1990) identified compound heterozygous mutations in the CD18 gene (600065.0001-600065.0002).
In 2 patients with LAD deficiency, Wardlaw et al. (1990) identified mutations in the CD18 gene (600065.0003; 600065.0004).
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.
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.
In a retrospective survey of 162 patients in whom bone marrow transplantation was performed in 14 European centers between 1969 and 1985, Fischer et al. (1986) found 4 patients with leukocyte adhesion deficiency. Bone marrow transplantation was successful; engraftment of donor cells resulted in complete restoration of leukocyte function and the absence of need for any further treatment in some of these patients.
Wilson et al. (1990) corrected the genetic and functional abnormalities in a lymphocyte cell line from a patient with LAD by retrovirus-mediated transduction of a functional ITGB2 (CD18) gene. Yorifuji et al. (1993) extended this work by reporting the introduction of human CD18 cDNA into the bone marrow progenitor cells of patients with LAD.
Vedder et al. (1988) showed that use of a monoclonal antibody against CD18 reduced organ injury and improved survival from hemorrhagic shock in rabbits. Krauss et al. (1991) developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human ITGB2 (CD18) gene into murine bone marrow cells which were then transplanted into lethally irradiated syngeneic recipients. Since they had human-specific CD18 monoclonal antibodies and since human CD18 can form chimeric heterodimers with murine CD11A on the cell surface, Krauss et al. (1991) were able to do a reliable flow cytometric assay for human CD18 in transplant recipients. Human CD18 was detected in leukocytes in a substantial number of transplant recipients for at least 6 months, suggesting that the gene had been transduced into stem cells. There were no apparent untoward effects. Expression was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C with PMA.
Kehrli et al. (1992) described beta-2 integrin deficiency in Holstein cattle. The disorder was characterized by recurrent pneumonia, ulcerative and granulomatous stomatitis, enteritis with bacterial overgrowth, periodontitis, delayed wound healing, persistent neutrophilia, and death at an early age. The underlying genetic defect was identified as a D128G (asp128-to-gly) amino acid substitution in the 26-amino acid sequence that is completely homologous with human and murine CD18 protein sequences. In a Holstein calf afflicted with leukocyte adhesion deficiency, Shuster et al. (1992) found 2 point mutations: one caused a D128G substitution in a highly conserved extracellular region where several mutations have been found to cause human LAD, and the other mutation was silent. All 20 calves tested were homozygous for the D128G allele. The carrier frequency among Holstein cattle in the United States was approximately 15% among bulls and 6% among cows. All cattle with a mutant allele are related to 1 bull, who through the use of artificial insemination sired many calves in the 1950s and 1960s. It was suggested that the organization of the dairy industry and the diagnostic test described by Shuster et al. (1992) would enable nearly complete eradication of bovine LAD within 1 year.
Using homologous recombination, Scharffetter-Kochanek et al. (1998) created and characterized mice with a CD18 null mutation. These mice have a phenotype closely resembling type I LAD in humans and cattle, including leukocytosis, chronic dermatitis, alopecia, and mucocutaneous infections. Intravital microscopy in these mice revealed a lack of firm neutrophil attachment to venules in the cremaster muscle in response to FMLP (see 136537). Scharffetter-Kochanek et al. (1998) also observed defective T-cell proliferation after stimulation with alloantigen or staphylococcal enterotoxin A.
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