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Leukocyte Extravasation

Introduction

Blood has three major cellular components; red blood cells which carry oxygen; white blood cells (leukocytes) fight infection; and platelets that cause blood clotting. Leukocytes, and their movements are the main area of scope for this report. The process by which Leukocytes are recruited to an area of infection and/or tissue injury, as part of acute and chronic inflammatory processes, is known as Leukocyte Extravasation. Leukocyte extravasation is a crucial step in all immune responses, and failures of it leave the host extremely vulnerable to opportunistic infections. More dramatic failures can result in shock and sepsis, often becoming fatal. Leukocyte extravasation can become a pathogenic process when it becomes excessive or targeted against the host tissue itself, a common occurrence and the cause of many autoimmune diseases. Thus, this process is very tightly regulated to prevent excessive function, whilst maintaining effectiveness.

Proteins

There are four families of cell adhesion receptors involved in leukocyte extravasation:

Integrins

Structure of the Integrin Beta3 (A711p,K716a) Transmembrane Segment

The integrins are a family of cell-to-surface glycoproteins that act as receptors for Extra-Cellular Matrix (ECM) proteins, or for membrane-bound counter-receptors on other cells. Focal contacts, or focal adhesions,[1] are sites where the cell adheres to the ECM via these integrins. Each integrin is a heterodimer (a protein composed of two differing poylpeptide chains) that contains an α and a β subunit. The α/β pairings specify the ligand-binding abilities of the integrin heterodimers. Although most of the ligands that bind with integrins are large ECM proteins such as collagen, vitronectin and fibronectin; some integrins have been found to be able to bind to short peptide sequences within these large proteins, thus allowing for opportunities to artificially create integrins that may be able to attach to shorter peptide chains within large ECM ligands. A known example of the shorter peptide chain found to allow integrin attachment is the RGD (Arg-Gly-Asp) sequence within fibronectin and vitronectin.

Both the α and β domains of integrins make important contributions to various aspects of overall integrin function including cytoskeletal organization, cell motility, signal transduction, and the connections between integrins and ligands.[2][3] α subunits influence cell motility and have been shown to limit certain functions of β domains while the integrin is not bound to its corresponding ligand. β subunits are the main functioning units and are involved in focal contact recruitment: mainly via FAK (focal adhesion kinase); endocytosis; communication between different integrins; assembly of fibronectin fibrils; and cell motility. Studies have shown that the β domain is sufficient for focal contact localization, but only while expressed as a fusion chimera with another membrane protein.[4][5][6]

Integrins are the link between the leukocytes and the large ECM proteins and transduce signals sent between these two groups. The signals from the ECM proteins cause drastic changes within the cell, including cell growth, cell differentiation and gene induction, after the integrin has integrated the extracellular environment with the cell interior. Integrins also have special inside-out properties, where changes inside the cell can lead to "activation" of the integrin. Integrins are the proteins used in the first step of leukocyte extravasation.


Immunoglobulin Cell-Adhesion Molecule Superfamily (ICAMs)

Structure of Engineered Single Domain Icam-1 D1 With High-Affinity Al Integrin I Domain of Native C-Terminal Helix Conformation

Proteins of this family are defined by the presence of one or more copies of the Immunoglobulin fold, a compact structure with two cysteine residues separated by 55 to 75 amino acids arranged as two antiparallel β sheets. Ig family adhesion receptors typically have a large amino-terminal extracellular domain, a single transmembrane helical segment, and a cytoplasmic tail.

Ig-CAM family adhesion receptors are found on vascular endothelial cells and, along with selectins and integrins, play an important role in leukocyte trafficking to inflamed tissue sites.[7][8] For example, vascular cell adhesion molecule-1 (VCAM-1) is an endothelial cell counter-receptor for the integrin α4β1 found on leukocytes. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an Ig-family cell-cell adhesion molecule that can engage in both homotypic and heterotypic interactions; one of its roles seems to be maintaining tight contacts between adjacent vascular endothelial cells.

T-lymphocytes express several Ig superfamily receptors including CD2, CD4, or CD8, ICAMs 1 and 2, and the T-cell receptor (TCR) itself. These receptors play important roles in antigen recognition, cytotoxic T-cell functions, and lymphocyte recirculation. In contrast to many of the neural Ig-CAMs, which are often homotypic receptors, Ig family proteins involved in the immune system primarily engage in heterotypic interactions. For example, CD2 on T cells interacts with LFA-3 (another Ig-CAM) expressed on target cells, the TCR interacts with major histocompatibility complex (MHC) class II proteins on antigen presenting cells (both Ig superfamily), whereas ICAMs on endothelial cells are recognized by β2 integrins on leukocytes.

The Ig-CAMs within the immune system are critically involved in the key signal transduction processes leading to activation of T cells and B cells by antigens. In essence, Ig-CAM and integrin-mediated contacts are established between the antigen-presenting cell and the T cell. This connection is such that the TCR recognizes antigen bound to an MHC protein on the presenting cell. This triggers the activation of intracellular tyrosine kinases associated with the TCR and with accessory receptors.[9] In B cells, the B-cell receptor (also an Ig-CAM) can recognize either soluble or particulate antigen, and it also can activate intracellular tyrosine kinases upon ligation.


Selectins

Diagram of the adhesion molecule variant of the selectin group; P-selectin. This example is attached to a sugar molecule, shown at the top in sticks.[10]

The selectins are a small family of lectin-like adhesion receptors composed of three members, L-, E-, and P-selectin.[11][12][13] The structure of a selectin includes an amino-terminal domain, followed by an epidermal growth factor (EGF)-type domain, two to nine complement regulatory protein repeats, a transmembrane helical segment, and a short cytoplasmic tail. The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells before their firm adhesion at sites of tissue injury and inflammation. Selectins mediate these heterotypic cell-cell interactions through calcium-dependent recognition of sialyated glycans.

The expression and function of selectins is tightly regulated so as to come into play only when leukocytes need to stick to the vessel wall as part of normal immune system cellular trafficking or during inflammation. Thus P-selectin is present in latent form in endothelial cells and platelets and it is rapidly translocated from secretory granules to the cell surface upon cell activation by thrombin or other agonists. E-selectin is synthesized and expressed on endothelial cells in response to inflammatory cytokines such as tumor necrosis factor (TNF) or Interleukin-1. L-selectin is expressed constitutively on leukocytes, but its presentation at the cell surface may be regulated. The best defined physiological role for selectins concerns leukocyte adherence to endothelial cells and platelets during inflammatory processes.

Cadherins

The computerised image of E-Cadherin Ec1-2 P5a P6a.

Cadherins are a family of transmembrane proteins formed from multiple repeats of cadherin-specific motif (a recurrent molecular sequence) and also share a large extracellular domain. Cadherins are classified into two groups: Classical Cadherins and Protocadherins. The main difference between the two groups of cadherins is the classical cadherins contain five cadherin repeats with the third (EC3) and the fifth (EC5) repeat having very specific features. The protocadherins do not share the same features of the EC3 and EC5 units; are longer than five repeats long; and the sequences are very similar to each other. As a result of these differences, the classical cadherins are very specific and do not adhere to a large number of different ECM proteins, whereas protocadherins are much more flexible in their attachments. Classical cadherins are known to only be found in vertebrates so far, while protocadherins are found in planaria, hydra, Drosophila, and various mammals.

Cadherins rely heavily on Calcium ions (Ca2+) for their adhesive capability. The Calcium ions play three signifacnt roles in classical cadherins: 1. Bringing rigidity to the ectodomain to give it a crescent shape[14], whilst still retaining its felxibility.[15][16] 2. Calcium ions are also involved in defining the structure of the X-dimer interface surfaces. The X-dimer binding intermediate of classical cadherins is centered around the EC1–EC2 Ca2+ binding region, which is unstructured in the absence of Ca2+.[17][18][19][20][21] Thus, in the absence of Ca2+, the mature adhesive strand-swap interface is likely to be kinetically unfavorable due to the slow exchange inherent in domain swap binding. 3. Lastly, Ca2+ ions are involved in direct energetic effects on strand swapping. Experiments have shown that Ca2+ ligation favours the opening of the A strand of the classical cadherin.

Cadherins require another intracellular protein group, the catenins, to function normally. This is shown when the truncation of the cytoplasmic cadherin domain to delete the catenin binding sites instigates loss of cadherin-mediated adhesion. There are three catenin proteins: α-, β-, γ-catenin. β-Catenin binds directly to the cadherin cytoplasmic domain, with the α-catenin binding to it, connecting the cadherin protein to the actin cytoskeleton. Cadherins play an important role in signal transduction and regulating signaling cascades which are extremely important during inflammation.[22]

Pathway

Diagram of the major steps of Leukocyte Extravasation

Prior to the typical events of Leukocyte Extravasation some chemokines (e.g. Tumor Necrosis Factor and IL-1) and/or microbial products (e.g. Bacterial Lipopolysaccharides) are released into the bloodstream where they can recruit leukocytes towards the injured or infected tissue. However, its via Leukocyte Extravasation that the leukocytes finally leave circulation to enter the target tissue.[23]

1. Rolling

In response to chemokines released by injured tissue or to microbial products, endothelial cells express cell adhesion molecules called Selectins which bind leukocytes circulating in blood. The binding is weak and the leukocyte continues to move, rolling along the endothelium.

2. Activation

Not all chemokines enter circulation, and many are instead bound to and presented by the endothelial cell surface to chemokine receptors on the surface of leukocytes rolling along the endothelium. Chemokine receptors bound to their respective chemokine ligand set off a cascade of events within leukocytes that culminates in the conformation of another set of cell adhesion molecules expressed on the surface of leukocytes called Integrins (e.g. LFA-1 and VLA-1) changing from their normal, low-affinity state to a high-affinity state for ligands expressed on endothelial cells. [24] [25]

3. Adhesion

Activated leukocytes featuring high-affinity state Integrins bind tightly to ligands expressed on endothelial cells (e.g. ICAM-1 and VCAM-1), preventing further rolling of the leukocyte along the endothelium. The leukocyte also loses its spherical shape, becoming flattened against the endothelium.

4. Transmigration

The endothelial cell ligands bound by Integrins, by a currently unknown pathway, along with a cell-surface molecule present on endothelial and leukocyte cells called CD31, disrupt adherens junctions between endothelial cells allowing leukocytes to transmigrate between them and into the underlying tissue. The leukocyte then follows chemokine gradients to the appropriate region of tissue.[26]

History

1824: Leukocyte Extravasation first described by early pathologists [27]

1991: Early model of leukocyte adhesion suggested that the cascade achieved combinatorial specificity [28]

2002: Studies suggest additional steps occur during adhesion, however these are not yet fully understood [29]

2004: Molecular mechanisms of of leukocyte extravsation discovered [30]

Normal Function

An important role in Leukocyte function is during the inflammatory response. The inflammatory process occurs when the body detects a difference in normal antibody function. This can result from a break in the skin or an infection from a virus or bacteria. Leukocyte extravasation is the process by which leukocytes are delivered to the site of inflammation and then activated. Once leukocytes are at the site of inflammation, their role is to kill bacteria and dispose of other foreign objects. Leukocytes also carry out blood clotting and signal cell apoptosis. It is very important that leukocytes are only recruited at times when they are truly needed, because once activated they may destroy normal host tissues and cause tissue damage. [31]

Leukocyte recruitment to sites of inflammation

Leukocytes circulate in the blood and are recruited, when needed, into the extravascular tissue when foreign bodies or tissue damage has been discovered. They migrate to the site of injury and are activated to perform their role in aiding inflammation. In order for the recruitment process to take place, a few steps must be taken. It consists of various leukocytes binding to different types of attachments, such as loose and firm endothelium, as well as rolling on and migrating through the endothelium surfaces. The recruitment of leukocytes also involves various cytokines. These cytokines promote the expression of TNF and IL-1, which promote directional migration of leukocytes. [32]

Leukocyte Activation

Once the leukocytes have reached the site of infection, they must then be activated. They are activated by different stimuli, including microbes and several other mediators. Leukocytes express on their surfaces different kinds of receptors that sense the presence of these microbes. When these receptors sense these microbes, different responses may occur; Phagocytosis of particles: this is when the leukocytes get rid of harmful bodies quickly and in its early stages. Another way is the production of substances: these substances destroy the phagocytosed objects and remove the dead tissues. A third way, the production of mediators: these mediators amplify the inflammation reaction.

-A brief explanation of the three steps of phagocytosis:

1) recognition and attachment of leukocyte to foreign body,

2) engulfment of phagocytic vacuole and

3) killing and degradation of the ingested material.

The way that this works is the leukocytes bind and ingest the foreign particles via certain surface receptors, which recognize microbes; dead particles; as well as proteins called opsonins(most import one is IgG). These proteins coat the microbes and target them for phagocytosis. The IgG class connects to the microbial surface antigens and then break down comnponents of the C3 protein. Plasma carbohydrate binding lectins called Collectins. Leukocytes express receptors for opsonins that implore a speedy phagocytosis of the coated microbes. Once the opsonized particles are bound, a process called engulfment occurs. In engulfment, pseudopods are extended on to the surroundings of the object at hand, which will form a phagocytic vacuole. This vacuole then fuses to the membrane of a lysosomal granule, this granule then results in discharge of its contents and finishes as a phagolysosome. [33]

Killing and Degradation of Microbes

The culmination of microbes going through phagocytosis is through ingested particles being killed and degraded. The key methods in this process is the production of microbicidal substances, the most important being Reactive Oxidative Species (ROS), within lysosomes and fusion of them both, creating phagolysosomes and exposing the ingested particles to the destructive components of the leukocytes. Phagocytosis stimulates an oxidative burst, which produces ROS as well as other substances. The production of the oxidation metabolites is due to rapid activation of leukocyte NADPH , called the phagocyte oxidase, which oxidises NADPH and in the pathway converts O2 to superoxide ion. This is then converted by spontaneous dismutation into H2O2. These ROS act as free radicals and destroy microbes. After the O2 burst, H2O2 is broken down to water and oxygen, this is done by catalysation. The other ROS are also degraded. The dead microorganisms are then degraded by the action of lysosomal acid hydrolases. [34]

Abnormal Function

Leukocyte Adhesion Deficiency (LAD)

Leukocyte adhesion deficiency is an autosomal recessive genetic disease in which there is a defect/deficiency with the adhesion molecules involved in the leukocyte extravasation process. This effects the normal functions of leukocytes including the adhesion and migration of leukocytes through the endothelium, typically resulting in a reduced immune response.[35]. There are several recognised forms of Leukocyte adhesion deficiency, referred to as LAD-1, LAD-2 and LAD-3

LAD-1

"(A) Gingivitis and (B) non-healing in a patient with leucocyte adhesion deficiency type 1 (LAD-1)" [36]

Leukocyte adhesion deficiency 1 (LAD-1) is the most common form of leukocyte adhesion deficiency, and occurs when there is a defect within the integrins involved in leukocyte adhesion, specifically the beta-2 integrins also referred to as CD18. This form results in a defective random chemotaxis as well as severely retarded leukocyte migration and adhesion.[35] [37]

Symptoms of LAD-1

As typical of a disease that affects the movement of leukocytes through the body, sufferers of LAD-1 suffer from defective/absent pus formation as well as defective wound healing. In addition to this, due to the impaired immune response, patients with LAD-1 also exhibit recurring bacterial infections, typically presenting on exposed surfaces. They will also often exhibit a raised leukocyte count (leukocytosis) during an infection due to the impaired movement of leukocytes towards sites of inflammation. Other symptoms concurrent with LAD-1 include "delayed separation of the umbilical cord" [37] which is due to an infection of the umbilical cord, also known as omphalitis. Those who survive the effects of LAD-1 into the later stages of life will then typically present with periodontitis. [35] [37] [38]

The severity of the symptoms are linked to the degree of CD18 deficiency, with a major defect in the expression of CD18 resulting in earlier, more frequent and stronger presenting symptoms, often resulting in infant fatality without proper treatment. A more moderate defect in CD18 expression leads to less severe presentation of symptoms and a higher chance of surviving infancy.

Treatment of LAD-1

Patients suffering with a milder form of LAD-1 often respond well to antibiotic therapy, however the only current treatment for those suffering from the more profound effects of LAD-1 is "hematopoietic cell transplantation" [39]. Typically this procedure shows good patient response, with an average 75% survival rate, although this could be improved if the "degree of matching" [39] is improved, with those that matched having a 82% survival rate. If the cell transplantation is not undergone, it will often result in infant fatality, however the outlook of patients who undergo the procedure before developing serious complications is often vastly improved. [39] [40]

LAD-2

Leukocyte adhesion deficiency 2 (LAD-2) is one of the rarer forms of leukocyte adhesion deficiency, as stated by a review article published in 2006, only 7 patients have thus far been diagnosed with LAD-2 [41]. LAD-2 occurs when there is a defect with the 'rolling' stage of leukocyte extravasion, this being a result of the lack of ligands found on the surface of neutrophils that typically interact with selectins found on the epithelial surface during this stage of the adhesion cascade.[41] [42] [43]

Symptoms of LAD-2

Sufferers of LAD-2 appear to fare better than their LAD-1 counterparts in terms of the severity of their immunodeficient symptoms. At birth, there is no delayed separation of the umbilical cord as there is in LAD-1. While pus formation is impaired in those with LAD-2, both the strength and frequency of infections is not as severe as it is in LAD-1. These infections often do not prove to be fatal, with the possibility of reduced severity as time passes. The other symptoms unrelated to the immunodeficient side include both mental and physical retardation with impaired psychomotor skills. [41] [42] [43]

Treatment of LAD-2

Patients with LAD-2, as with those with milder presentations of LAD-1 responded well to antibiotic therapy. In dealing with the psychomotor retardation, fructose supplementation is advised as it has in one case improved the psychomotor function of a patient [44]

LAD-3

Leukocyte adhesion deficiency 3 (LAD-3), also know as LAD-1 variant is similar to LAD-1 in that the problem occurs with the leukocyte integrins. In LAD-1 integrins of the beta-2 family are affected in that their expression is defective. In contrast to this, LAD-3 affects all the integrin families, beta-1, beta-2 and beta-3, and while the expression of these integrins may be normal, their defect is that the integrin activation is dysfunctional. [45] [46] [47]

Symptoms of LAD-3

As expected, the symptoms of LAD-3 are typical of the immunodeficiency problems that those with LAD-1 suffer from. Patients with LAD-3 present with impaired wound healing, defective/absent pus formation, suffer from recurring bacterial infections. LAD-3 patients will also have a delayed separation of the umbilical cord and show signs of leukocytosis. Survivors of LAD-3 will also present with the same complications in later life as those with LAD-1, namely, periodontitis. [45] [46] [47]

As well as these symptoms in common with LAD-1, sufferers of LAD-3 will also experience abnormal platelet aggregation that results in several bleeding complications such as cerebral hemorrhaging and blood in the urine and stool of a patient, similar to the bleeding disorder Glanzmann's thrombasthenia. [45] [48] [49]

Treatment of LAD-3

Thus far, the only treatment available to patients with LAD-3 is bone marrow/hematopoietic cell transplantation, with the survival chance raised if the transplantation is performed earlier in infancy. [50]

Diagram highlighting which stages of leukocyte extravasation the differing LAD types affect
Leukocyte Adhesion Deficiency Summary
Type Mutation Effects Treatment
Lad-1 Defect in/absence of the beta-2 integrins [35] [37]
  • defective pus formation
  • defective wound healing
  • recurring bacterial infections
  • leukocytosis
  • omphalitis
  • periodontitis [35] [37]
  • anti-biotic therapy for milder presentations
  • bone marrow transplants for more severe presentations [39]
Lad-2 Defect in/absence of the ligands involved in leukocyte extravasation [41] [42] [43]
  • defective pus formation
  • recurring bacterial infections - though less frequent than LAD-1 counterpart
  • mental/physical retardation
  • impaired psychomotor function [41] [42] [43]
  • anti-biotic therapy in dealing with the immunodeficiency presentations
  • fructose supplementation in dealing with the psychomotor problems [44]
Lad-3 Defect in/absence of the beta-1, beta-2 and beta-3 integrins [45] [46] [47]
  • defective wound healing
  • defective pus formation
  • recurring bacterial infections
  • leukocytosis
  • omphalitis
  • the above symptoms generally present more severely in LAD-3 than they do in LAD-1
  • cerebral hemorrhaging
  • blood in urine and stool [45] [48]
  • Bone marrow transplant [50]

Other

Leukocyte extravasation can be a pathogenic process when signaling goes wrong, such as in cases of multiple sclerosis where there is a recruitment of leukocytes into the CNS where they should not be normally present [51]

The presence of excess leukocytes in the CNS blood supply is thought to linked to Disseminated Intravascular Coagulation, or Sepsis[52]

Furthermore, some pathogenic organisms can manipulate or counter the usual signaling processes involved in Leukocyte extravasion an example of which includes Bacilus anthracis more commonly known as Anthrax by which the organism reduces the recruitment of leukocytes to an infection[53]





New or Current Research

As an alternative to hematopoietic cell transplantation, gene therapy is also being looked at in order to deal with leukocyte adhesion deficiency. Ex vivo studies on canines presenting with LAD-1 appear to show promise, however clinical trials have thus far been unsuccessful. Bauer et al (2006) looked at transplanting the gene-corrected CD34+ cells, which resulted in a marked increase in the percentage of CD18 leukocytes. [54]

External Links

[Leukocyte Extravasation] Video explaining the process of leukocyte extravasation. Around the 6:40 mark the video will start explaining the process that occurs once inflammation is detected.

Glossary of Terms

  • CD31 - A cell-adhesion molecule found on leukocytes and endothelial cells thought to play a role in the transmigration of leukocytes through endothelium (PCAM)
  • Cell-adhesion molecules - Proteins found on the surfaces of cells that mediate the binding to cells to each other or to extracellular matrix proteins
  • Chemokines - Cytokines which recruit and stimulate leukocytes
  • Cytokine - Small proteins secreted by a cell which affect the behaviour of surrounding cells
  • Diapedesis - The movement of blood cells out of blood vessels and into the surrounding tissue.
  • Endothelial activation - Changes shown by endothelium as part of inflammation which include increased permeability, expression and activation of cell-adhesion molecules and the secretion of cytokines and chemokines.
  • Endothelial cell - Cell type that forms the epithelium of blood vessels
  • Endothelium - The epithelium of all blood vessels, formed by endothelial cells
  • Intercellular adhesion molecules (ICAM) - Cell- adhesion molecules of the immunoglobin family that can bind to leukocyte integrins
  • Integrins - Heterodimeric cell-adhesion molecule
  • Leukocyte - A white blood cell
  • Leukocyte adhesion deficiency – A type of immunodeficiency disease, in which leukocytes are unable to reach sites of infection, typically due to defects in the leukocyte integrins
  • Omphalitis - An infection of the umbilical cord
  • Periodontitis - Inflammatory disease regulated to the tissues surrounding the teeth
  • Selectin - Found on both leukocytes and endothelial cells, their main purpose is to mediate cellular rolling

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  41. 42.0 42.1 42.2 42.3 OMIM 266265
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  44. 45.0 45.1 45.2 45.3 45.4 OMIM 612840
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