Leukocyte Adhesion Deficiency

Updated: Oct 19, 2016
  • Author: Stephen J Nervi, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Overview

Background

Leukocyte adhesion deficiency (LAD) is a rare primary immunodeficiency. [1, 2] The clinical picture is characterized by marked leukocytosis and localized bacterial infections that are difficult to detect until they have progressed to an extensive level secondary to lack of leukocyte recruitment at the site of infection. Thus the infections in patients with leukocyte adhesion deficiency act similarly as those observed in patients with neutropenia. See the images below.

Labial ulceration from which Escherichia coli was Labial ulceration from which Escherichia coli was cultured in an 8-month-old girl with leukocyte adhesion deficiency type 1 (LAD I). Note the thin bluish scar at the superior aspect of the labia from an earlier cellulitis.
This 3-year-old girl had leukocyte adhesion defici This 3-year-old girl had leukocyte adhesion deficiency type I (LAD I) with complete absence of CD18 expression. Note the typical gingivostomatitis, which was culture-negative for any pathogen.
This 10-month-old patient with severe leukocyte ad This 10-month-old patient with severe leukocyte adhesion deficiency type I (LAD I) developed a cervical adenitis caused by Klebsiella pneumoniae. Following incision and drainage, wound healing took 4 months.

Leukocyte adhesion deficiency type I (LAD I) is a failure to express CD18, which composes the common ß2 subunit of LFA1 family (ß2 integrins). CD11a/CD18 (LFA-1) expressed on lymphocytes is known to play an important role in lymphocyte trafficking (adhesion to vascular endothelium), as well as interactions to antigen presenting cells (APC). LFA-1 also plays a role of cytotoxic killing by T cells. Another member of this family is CD11bCD18 (MacA or CR3) and CD11cCD18(CR4). These 2 members mediate leukocyte adhesions to endothelial cells but they also serve as receptors for iC3b (inactivated C3b). These patients succumb to life-threatening infection, usually within 2 years of life in severe cases of leukocyte adhesion deficiency I (< 1% expression of CD18). In milder forms of leukocyte adhesion deficiency I (1-30% expression of CD8), patients may survive to adulthood.

Leukocyte adhesion deficiency type II is extremely rare; only a handful cases have been reported and most of them are of Middle Eastern decent. It is a defect in the expression of ligands for selectins due to lack of enzymes required for expression of selectin ligands. Patients have leukocytosis, recurrent infections (more prominent in infants and toddlers), and severe growth and mental retardation. This disease is a defect in fucose metabolism (lack of fucosylation of the carbohydrate selectin ligands) that results in failure to express the ligand for E and P selectin, sialyl Lewis-X (CD15s) expressed on leukocytes and endothelial cells. The patients are unable to fucosylate other glycoproteins, including the H blood group polysaccharide.

Patients with leukocyte adhesion deficiency II manifest the Bombay phenotype (ie, negative for O and H blood group antigens with potential production of anti-H antibody). The immunoglobulin M (IgM) and immunoglobulin G (IgG) heavy chains are also not fucosylated. However, IgM and IgG serum levels are within the reference range in patients with leukocyte adhesion deficiency II.

Leukocyte adhesion deficiency II may be classified as one of the congenital disorders of glycosylation (CDG), a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. All stem from dysfunctional N -glycosylation of proteins. Currently, 18 subtypes have been reported: 12 are type I (dysfunctional lipid-linked oligosaccharide precursor synthesis), and 6 are type II (dysfunctional trimming/processing of the protein-bound oligosaccharide), including leukocyte adhesion deficiency II (CDG-IIc). [3]

Variants of leukocyte adhesion deficiency have also been reported, including fully expressed but nonfunctional CD18 and an E selectin that is expressed but rapidly cleaved from the cell surface (only present in soluble form). Another reported type of leukocyte adhesion deficiency involves dysfunction in platelet aggregation in addition to a defect in leukocyte adhesion. Thus, patients with this type of leukocyte adhesion deficiency manifest both severe bacterial infections and bleeding disorder. This leukocyte adhesion deficiency variant is associated with defective expression of the Rap-1 activator CalDAG-GEFI. Rap-1 is an essential protein involved in signaling mediated by integrins.

More than one leukocyte adhesion deficiency variant has been labeled leukocyte adhesion deficiency type III (LAD III), creating confusion in the literature.

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Pathophysiology

Peripheral blood leukocytes undergo a sequence of activation that leads to migration of cells into the site of inflammation. First, the cells roll along endothelial surfaces, a process that requires expression of P and E selectins on the endothelial cells and their ligands on leukocytes. Rolling is a reversible process, partly because E selectin is shed from the cell surface and P selectin is internalized in endothelial cells. Next, cells adhere to the endothelial surface and enter the tissues by diapedesis; this process requires the family of integrins. Most importantly, CD18 is the essential component of the ß2 integrins CD11a/CD18, CD11b/CD18, and CD11b/CD18. Ligands of ß2 integrins expressed on endothelial cells belong to the Ig supergene family.

ß2 integrins are heterodimeric glycoproteins that are expressed as transmembrane proteins that transmit signals from the extracellular surface to cytoskeletal proteins. As such, CD18 is an integral part of other phagocytic functions. CD11b/CD18 (Mac-1) on myeloid cells is a receptor for iC3b and, thus, is important for recognizing bacteria and other microorganisms opsonized with iC3b. This recognition leads to phagocytosis and efficient microbicidal activity by the neutrophil, monocyte, or macrophage. Lymphocyte function antigen-1 (LFA-1) or CD11a/CD18, promotes adhesion by its expression on lymphocytes, monocytes, and neutrophils but also plays a role as one of the costimulatory molecules between lymphocyte and APC interactions. The third β2 integrin is CD11c/CD18 (p150/95) and is expressed on myeloid cells and some natural killer cells.

Binding of CD11/CD18 to ligands induces intracellular signaling that activates multiple cellular functions including cytokine production, cytotoxicity, apoptosis, and proliferation.

The major selectin ligand, sialylated Lewis X (SleX), is absent in leukocyte adhesion deficiency II. SleX, or CD15s, is a blood group tetrasaccharide. Both the sialic acid and the fucose moieties of SleX are needed for binding to the selectins; a primary defect in fucosylation in leukocyte adhesion deficiency II results in absence of fucosylated glycans in the cell surface including SleX.

Two other integrins are known to induce adhesion to extracellular proteins such as fibronectin, collagen, and laminin. These are members of the ß1 integrin subfamily, α4ß1, and the α4ß7. Both are expressed on lymphocytes, eosinophils, and natural killer cells.

Irish setter dogs and Holstein cattle have a disorder similar to human leukocyte adhesion deficiency I with leukocytosis and increased infections. This is secondary to a mutation in the gene homologous to human CD18. Both strains serve as promising large-animal models for leukocyte adhesion deficiency.

Knockout mice have been developed with the genes deleted for many of the adhesion-related molecules, (eg, CD18, CD11a, CD11b, ICAM1, ICAM2; E, P, and L selectins; fucosyl transferase; acetylglucosaminyltransferase). The murine models have milder disease than LAD I in humans, and no growth or mental defects as observed in murine leukocyte adhesion deficiency II models; most knockout mice strains revealed mild-to-moderate neutrophilia, but infections are absent except for CD18 knockout mice.

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Epidemiology

Frequency

United States

Leukocyte adhesion deficiency I has been reported in fewer than 400 individuals; 75% have the severe form, expressing less than 1% CD18. Only a handful of children have been described with leukocyte adhesion deficiency II. Three cases of with variant leukocyte adhesion deficiency I or decreased cell-expressed E selectin have been reported in the literature.

International

Although leukocyte adhesion deficiency I is rare, it is reported worldwide, indicating a lack of ethnic predisposition. Patients with leukocyte adhesion deficiency II are mainly reported in the Middle East and Brazil.

Mortality/Morbidity

Most patients with severe leukocyte adhesion deficiency I succumb to death within the first year of life. Bacterial infections not treated with stem cell transplantation are responsible for most deaths. Life-threatening viral infections are less frequently reported; however, aseptic meningitis and croup-like syndromes are well known complications as described in a 1985 review by Anderson et al. [4]

Patients with leukocyte adhesion deficiency II usually do not succumb to death with infections but develop severe mental retardation and developmental delay, neurologic impairment, and short stature. Periodontitis and colitis in rare occasions may be found in older individuals with leukocyte adhesion deficiency II.

Race

Leukocyte adhesion deficiency I can affect people of all racial groups. Leukocyte adhesion deficiency II has been reported only in people from the Middle East and Brazil.

Sex

Approximately equal numbers of males and females are affected, which is consistent with the autosomal recessive inheritance in both leukocyte adhesion deficiency I and leukocyte adhesion deficiency II.

Age

Most patients present within the first several months of life. Delayed umbilical cord separation beyond the normal range of 3-45 days is the classic presentation for leukocyte adhesion deficiency I. Patients who are less severely affected may not be identified until periodontitis develops with tooth eruption; oral ulcerations may be present at the same age. Patients who survive into childhood without hematopoietic stem cell transplantation (HSCT) express some CD18 on leukocytes and have less severe infections.

Patients with leukocyte adhesion deficiency II do not have delayed umbilical cord separation. They may be identified by their characteristic facial appearance and growth failure and, in some cases, by prenatal ultrasonography.

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