Leukocyte adhesion deficiency (LAD) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

disorder characterized by

immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

resulting in recurrent

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

s. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a Glanzmann thrombasthenia-like bleeding tendency.

Signs and symptoms

LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent

bacteria 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 am ...

s, defects in

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 ...

adhesion, and a delay in

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 physiologi ...

sloughing. The adhesion defects result in poor

leukocyte 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 ...

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 ...

, particularly neutrophil, inability to form pus and

neutrophilia Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophils in the blood. Because neutrophils are the main type of granulocytes, mentions of granulocytos ...

. Individuals with LAD suffer from bacterial infections beginning in the neonatal period. Infections such as

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 ...

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...

gingivitis Gingivitis is a non-destructive disease that causes inflammation of the gums. The most common form of gingivitis, and the most common form of periodontal disease overall, is in response to bacterial biofilms (also called plaque) that is attac ...

, and

peritonitis Peritonitis is inflammation of the localized or generalized peritoneum, the lining of the inner wall of the abdomen and cover of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One part o ...

are common and often life-threatening due to the infant's inability to properly destroy the invading

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...

s. These individuals do not form

abscess An abscess is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pressed. The area of redness often extends ...

es because

granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...

s cannot migrate to the sites of

Cause

Types of leukocyte adhesion deficiency include LAD1, LAD2, and LAD3. LAD1 is the most common. Patients with LAD1 have an inherited molecular defect that causes a deficiency of the β-2

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...

subunit, also called

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 ...

, which is encoded by the ITGB2 gene found on chromosome 21. This subunit is involved in the formation of the β-2 integrins ( LFA-1, Integrin alphaXbeta2, and Mac-1/CR3) by dimerization with different CD11 subunits. Mutations in the ITGB2 gene lead to absent, reduced, or aberrant

protein expression, causing a lack of expression in the leukocyte membrane of the β-2 integrins. The main function of these proteins is to allow

s to make their way out of the blood stream and into the infected tissues by adhering to different

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s expressed by the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...

, e.g.

ICAM-1 ICAM-1 ( Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...

. In LAD-I patients, neutrophils cannot

extravasate __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to th ...

and fight against bacteria in tissues. The bacteria can then proliferate, leading to

symptomatic Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

infection, which can spread unimpeded and cause serious injury to important tissues.

Diagnosis

Typically,

diagnosis Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine "cause and effect". In systems engin ...

involves several preliminary tests of immune function, including basic evaluation of the

humoral immune system Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it inv ...

and the cell-mediated immune system. A WBC differential will reveal extremely elevated levels of neutrophils (on the order of 6-10x normal) because they are unable to leave the

blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide awa ...

s. In the case of LAD-I, specific diagnosis is done by

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 flow ...

. This technique will reveal absent or reduced

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 the

transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encod ...

protein. In LAD-III, as

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

function is also affected, this could be used to differentiate it from the other types.

Treatment

Although patients can receive intensive antibiotherapy and even granulocyte transfusions from healthy donors, the only current curative therapy is the

hematopoietic stem cell transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to prod ...

. However, progress has been made in

gene therapy Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...

, an active area of research. Both foamyviral and lentiviral vectors expressing the human ITGB2 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).

Prognosis

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%.

Epidemiology

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.

References

External links

{{DEFAULTSORT:Leukocyte Adhesion Deficiency Autosomal recessive disorders Congenital defects of phagocyte number, function, or both Rare diseases Hematology de:Leukozyt#Adhäsionsdefizit