Leukocyte adhesion deficiency
Encyclopedia
Leukocyte adhesion deficiency (LAD), is a rare autosomal
recessive disorder characterized by immunodeficiency
resulting in recurrent infection
s. Leukocyte adhesion deficiency is divided into at least two subtypes: LAD1
and LAD2
.
l infection
s, defects in neutrophil adhesion
, and a delay in umbilical cord
sloughing. The defects in adhesion
result in poor neutrophil chemotaxis
and phagocytosis.
Individuals with LAD suffer from bacteria
l infection
s beginning in the neonatal period. Infections such as omphalitis
, pneumonia
, gingivitis
, abscess
es, and peritonitis
are common and often life-threatening due to the infant's inability to properly destroy the invading pathogen
s.
Types include:
The most common type is LAD1.
The inherited molecular defect
in patients with LAD is a deficiency of the β-2 integrin
subunit, also called CD18
, of the leukocyte cell adhesion
molecule
, which is found on chromosome 21
. This subunit is involved in making three other protein
s (LFA-1
, Integrin alphaXbeta2
, and Mac-1/CD3
) This basically means that the gene
creates a non-functioning protein. This results in the lack of important molecule
s which help neutrophils make their way from the blood
stream into the infected areas of the body (i.e. the lung
s in pneumonia
). Those neutrophils which do manage to make it to the infected areas have a difficult time phagocytosing (swallowing) the bacteria
. The bacteria can then proliferate, leading to symptomatic infection
. The infection can spread unimpeded and cause serious injury to important tissue
.
is made after several preliminary tests of immune function are made, including basic evaluation of the humoral immune system
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
s. Specific diagnosis is made through monoclonal antibody testing for CR3, one of the three complete proteins which fail to form properly as a result of β-2 integrin subunit deficiency.
ation is the current standard of care
. However, some progress has been made in gene therapy
, an active area of research.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive disorder characterized by immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
resulting in recurrent infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s. Leukocyte adhesion deficiency is divided into at least two subtypes: LAD1
Leukocyte adhesion deficiency-1
Leukocyte adhesion deficiency-1 is a rare and often fatal genetic disorder in humans.-Mechanism:LAD1 is caused by mutations in the ITGB2 gene which are inherited autorecessively...
and LAD2
Leukocyte adhesion deficiency-2
Congenital disorder of glycosylation type IIc or Leukocyte adhesion deficiency-2 is a type of leukocyte adhesion deficiency attributable to the absence of neutrophil sialyl-LewisX, a ligand of P- and E-selectin on vascular endothelium....
.
Characteristics
LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s, defects in neutrophil adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, and a delay in umbilical cord
Umbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
sloughing. The defects in adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
result in poor neutrophil chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
and phagocytosis.
Individuals with LAD suffer from bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s beginning in the neonatal period. Infections such as omphalitis
Omphalitis
Omphalitis is the medical term for infection of the umbilical cord stump in the neonatal newborn period. While currently an uncommon anatomical location for infection in the newborn in the United States, it has caused significant morbidity and mortality both historically and in areas where health...
, pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, gingivitis
Gingivitis
Gingivitis is a term used to describe non-destructive periodontal disease. The most common form of gingivitis is in response to bacterial biofilms adherent to tooth surfaces, termed plaque-induced gingivitis, and is the most common form of periodontal disease...
, abscess
Abscess
An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...
es, and peritonitis
Peritonitis
Peritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
are common and often life-threatening due to the infant's inability to properly destroy the invading pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s.
Cause and Genetics
| Type | OMIM | Gene |
|---|---|---|
| LAD1 | ITGB2 | |
| LAD2 or CDG2C | SLC35C1 SLC35C1 GDP-fucose transporter 1 is a protein that in humans is encoded by the SLC35C1 gene.Defects can be associated with Congenital disorder of glycosylation type IIc.-External links:*... |
|
| LAD3 | FERMT3 FERMT3 Fermitin family homolog 3) , also known as kindlin-3 , MIG2-like protein , or unc-112-related protein 2 is a protein that in humans is encoded by the FERMT3 gene.- Function :... |
The most common type is LAD1.
The inherited molecular defect
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
in patients with LAD is a deficiency of the β-2 integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
subunit, also called CD18
CD18
Integrin beta-2 is a protein that in humans is encoded by the ITGB2 gene.It is the beta subunit of four different structures:* LFA-1 * Macrophage-1 antigen * Integrin alphaXbeta2...
, of the leukocyte cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
, which is found on chromosome 21
Chromosome 21 (human)
Chromosome 21 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. The trisomy of the 21st chromosome causes Down Syndrome...
. This subunit is involved in making three other protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s (LFA-1
LFA-1
Lymphocyte function-associated antigen 1, also known as LFA-1 is found on all T-cells and also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule. LFA-1 is the first...
, Integrin alphaXbeta2
Integrin alphaXbeta2
Integrin alphaXbeta2 is a complement receptor composed of CD11c and CD18....
, and Mac-1/CD3
Macrophage-1 antigen
Macrophage-1 antigen is a complement receptor consisting of CD11b and CD18.It binds to C3b and C4b.-Function:...
) This basically means that the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
creates a non-functioning protein. This results in the lack of important molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s which help neutrophils make their way from the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream into the infected areas of the body (i.e. the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s in pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
). Those neutrophils which do manage to make it to the infected areas have a difficult time phagocytosing (swallowing) the bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. The bacteria can then proliferate, leading to symptomatic infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. The infection can spread unimpeded and cause serious injury to important tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
.
Diagnosis
Typically, diagnosisDiagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
is made after several preliminary tests of immune function are made, including basic evaluation of the humoral immune system
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
and the cell-mediated immune system
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
. A WBC
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
differential
Differential staining
Differential Staining is a general term that can refer to a number of specific processes. Generally, it is used to describe staining processes which use more than one chemical stain...
will reveal extremely elevated levels of neutrophils (on the order of 6-10x normal) because they are unable to leave the blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s. Specific diagnosis is made through monoclonal antibody testing for CR3, one of the three complete proteins which fail to form properly as a result of β-2 integrin subunit deficiency.
Treatment
Once the diagnosis of LAD is made, bone marrow transplantBone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
ation is the current standard of care
Standard of care
In tort law, the standard of care is the degree of prudence and caution required of an individual who is under a duty of care.The requirements of the standard are closely dependent on circumstances. Whether the standard of care has been breached is determined by the trier of fact, and is usually...
. However, some progress has been made in gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
, an active area of research.