Leukocyte adhesion deficiency-1 (LAD1) is a rare and often fatal

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

in humans.

Signs and symptoms

The main sign of the disease is life-threatening, recurrent

bacterial Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

fungal A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as one of the tradit ...

soft tissue Soft tissue connective tissue, connects and surrounds or supports internal organs and bones, and includes muscle, tendons, ligaments, Adipose tissue, fat, fibrous tissue, Lymphatic vessel, lymph and blood vessels, fasciae, and synovial membranes.� ...

infections. These infections are often apparent at birth and may spread throughout the body. Omphalitis (infection of the umbilical cord stump) is common shortly after birth. Other signs include delayed separation of the

umbilical cord In Placentalia, placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord i ...

periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...

, elevated neutrophils, and impaired

wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...

, but not increased vulnerability to

viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Examples include the common cold, gastroenteritis, COVID-19, t ...

s or

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. Such patients have fever as the manifestation of infection, inflammatory responses are indolent.

Mechanism

LAD1 is caused by mutations in the ITGB2 gene which are inherited autorecessively. This gene encodes CD18, a protein present in several

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...

complexes found on

white blood cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

,Etzioni A, Harlan JM. Cell adhesion and leukocyte adhesion defects. In: Ochs HD, Smith CIE, Puck JM, eds. Primary immunodeficiency diseases: a molecular and genetic approach. Oxford: Oxford University Press, 2007:550–564. including

lymphocyte function-associated antigen 1 Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates ...

(LFA-1), complement receptor 3 (CR-3), and complement receptor 4 (CR-4). The deficiency of LFA-1 causes

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s to be unable to adhere to and migrate out of blood vessels, so their counts can be high. It also impairs immune cell interaction, immune recognition, and cell-killing lymphocyte functions. The lack of CR3 interferes with

chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

, and

respiratory burst Respiratory burst (or oxidative burst) is the rapid release of the reactive oxygen species (ROS), superoxide anion () and hydrogen peroxide (), from different cell types. This is usually utilised for mammalian immunological defence, but also pl ...

Diagnosis

Flow cytometry Flow cytometry (FC) is a technique used to detect and measure the physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the ...

with

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...

is used to screen for deficiencies of CD18.

Treatment

Because the CD18 gene has been cloned and sequenced, this disorder is a potential candidate for gene therapy.

Epidemiology

, LAD1 has been observed in several hundred children worldwide.

References

External links

Autosomal recessive disorders Congenital defects of phagocyte number, function, or both Rare diseases {{Cell surface receptor deficiencies