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 chromosomal abnormality. Although polygenic disorders ...

in humans.

Signs and symptoms

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

bacterial Bacteria (; singular: 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 ...

fungal A fungus ( : fungi 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 a kingdom, separately from th ...

soft tissue Soft tissue is all the tissue in the body that is not hardened by the processes of ossification or calcification such as bones and teeth. Soft tissue connects, surrounds or supports internal organs and bones, and includes muscle, tendons, ligam ...

infections. These infections are often apparent at birth and may spread throughout the body.

Omphalitis Omphalitis of newborn is the medical term for inflammation of the umbilical cord stump in the neonatal newborn period, most commonly attributed to a bacterial infection. Typically immediately after an infant is born, the umbilical cord is cut wi ...

(infection of the umbilical cord stump) is common shortly after birth. Other signs include delayed separation of the

umbilical cord In 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 is physiologic ...

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 caus ...

, 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. Structural Characteristics Basic structural characteristics, s ...

s or

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. 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 In molecular biology, CD18 (Integrin beta chain-2) is an integrin beta chain protein that is encoded by the ''ITGB2'' gene in humans. Upon binding with one of a number of alpha chains, CD18 is capable of forming multiple heterodimers, which play ...

, 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 integral m ...

complexes found on

white blood cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

,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 Integrin alphaXbeta2 (p150,95, CR4) is a complement receptor composed of CD11c and CD18 In molecular biology, CD18 (Integrin beta chain-2) is an integrin beta chain protein that is encoded by the ''ITGB2'' gene in humans. Upon binding with one o ...

(CR-4). The deficiency of LFA-1 causes

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

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 '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

phagocytosis Phagocytosis () is the process by which a 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 phagocytosis is ...

, 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 pla ...

Diagnosis

Flow cytometry Flow cytometry (FC) is a technique used to detect and measure 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 flo ...

with

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

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