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| Leukocyte-adhesion deficiency | |
|---|---|
| Specialty | Immunology  |
Leukocyte adhesion deficiency (LAD) is a rareautosomalrecessive disorder characterized byimmunodeficiency resulting in recurrentinfections.[1] LAD is currently divided into three subtypes:LAD1,LAD2, and the recently describedLAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by aGlanzmann thrombasthenia-like bleeding tendency.[2][3]
LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrentbacterialinfections, defects inneutrophil adhesion, and a delay inumbilical cord sloughing. The adhesion defects result in poorleukocytechemotaxis, particularly neutrophil, inability to form pus andneutrophilia.[3]
Individuals with LAD suffer from bacterial infections beginning in theneonatal period. Infections such asomphalitis,pneumonia,gingivitis, andperitonitis are common and often life-threatening due to the infant's inability to properly destroy the invadingpathogens. These individuals do not formabscesses becausegranulocytes cannot migrate to the sites ofinfection.
Types of leukocyte adhesion deficiency include LAD1, LAD2, and LAD3. LAD1 is the most common.[4]
| Type | OMIM | Gene |
|---|---|---|
| LAD1 | 116920 | ITGB2 |
| LAD2 orCDG2C | 266265 | SLC35C1 |
| LAD3 | 612840 | FERMT3 |
Patients with LAD1 have aninheritedmolecular defect that causes a deficiency of the β-2integrin subunit,[5] also calledCD18, which is encoded by the ITGB2 gene found onchromosome 21. This subunit is involved in the formation of the β-2 integrins (LFA-1,integrin alphaXbeta2/CR4/p150,95, andMac-1/CR3) by dimerization with different CD11 subunits.[6][7]
Mutations in the ITGB2 gene lead to absent, reduced, or aberrantCD18protein expression, causing a lack of expression in the leukocyte membrane of the β-2 integrins. The main function of these proteins is to allowneutrophils to make their way out of the blood stream and into the infected tissues by adhering to differentligands expressed by theendothelium, e.g.ICAM-1. In LAD-I patients, neutrophils cannotextravasate and fight against bacteria in tissues. The bacteria can then proliferate, leading tosymptomatic infection, which can spread unimpeded and cause serious injury to importanttissues.[citation needed]
Typically,diagnosis involves several preliminary tests ofimmune function, including basic evaluation of thehumoral immune system and thecell-mediated immune system. AWBCdifferential will reveal extremely elevated levels of neutrophils (on the order of 6–10x normal) because they are unable to leave theblood vessels.In the case of LAD-I, specific diagnosis is done byflow cytometry. This technique will reveal absent or reducedCD18 expression in the leukocyte membrane. Recently, prenatal diagnosis systems has been established, allowing an early detection of the disease.LAD-II diagnosis includes the study of different glycosylated forms of thetransferrin protein. In LAD-III, asplatelet function is also affected, this could be used to differentiate it from the other types.[citation needed]
Although patients can receive intensive antibiotherapy and evengranulocyte transfusions from healthy donors, the only current curative therapy is thehematopoietic stem cell transplant.[8] However, progress has been made ingene therapy, an active area of research. Bothfoamyviral andlentiviral vectors expressing the humanITGB2 gene under the control of different promoters have been developed and have been tested so far in preclinical LAD-I models (such as CD18-deficient mice and canine leukocyte adhesion deficiency-affected dogs).[citation needed]
A 2009 study reported results from 36 children who had received a stem cell transplant. At the time of follow-up (median time 62 months), the survival rate was 75%.[9]
LAD is a rare disease, with an estimated prevalence of one in 100,000 births, with no described racial or ethnic predilection. The most common type is LAD1.