Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology
Leukocyte Extravasation. This video describes how a leukocyte moves out of the endothelium of a blood vessel. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
CD18 is the beta subunit of 3 different structures (paired with CD11 a, b, c):
- LFA-1 (paired with CD11a)
- Macrophage-1 antigen, MAC-1 (paired with CD11b)
- Integrin alphaXbeta2 (paired with CD11c)
CD11a - Subunit of LFA-1, a membrane glycoprotein that provides cell-cell adhesion by interaction with ICAM-1. Lymphocyte function-associated antigen 1 (LFA-1) consists of an alpha-chain (CD11a) and beta-chain (CD18).
CD11b - Subunit of MAC-1, a complement receptor (CR3). MAC-1 consists of an alpha-chain (CD11b) and beta-chain (CD18).
CD11c - Integrin alphaXbeta2 is a subunit of the complement receptor CR4. CR4 consists of an alpha-chain (CD11c) and beta-chain (CD18). CD11c is expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell CLL. CD11c is one of the defining markers for dendritic cells.
CD11a. Image source: Wikipedia, public domain.
Lymphocyte function-associated antigen 1 (LFA-1) is found on leukocytes 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 part of the family of leukocyte integrins which are recognised by their common β-chains (CD18). LFA-1 also has a distinct α-chain (CD11a).
Integrin, alpha L (antigen CD11A, lymphocyte function-associated antigen 1) is also known as ITGAL or CD11a. CD11a is one of the two components, along with CD18, which form lymphocyte function-associated antigen-1. Efalizumab (Raptiva), used to treat psoriasis, is a recombinant humanized monoclonal antibody that binds to CD11a and acts as an immunosuppressant. Due to risk for progressive multifocal leukoencephalopathy (PML), Efalizumab (Raptiva) was withdrawn from the market in 2009.
CD11b. Image source: Wikipedia, public domain.
Macrophage-1 antigen, MAC-1 (integrin alphaMbeta2) is a complement receptor (CR3) consisting of CD11b and CD18. It binds to C3b and C4b. Integrin alpha M (ITGAM) is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3) ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B).
CD11b. Image source: Wikipedia, public domain.
Integrin alphaXbeta2 (CR4) is a complement receptor composed of CD11c and CD18. CD11c is also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX).
Complement receptors (click to enlarge the image).
CD18 helps neutrophils make their way from the blood stream into the infected areas of the body.
Neutrophils extravasate from blood vessels to the site of tissue injury or infection during the innate immune response. Image source: Wikipedia, GNU Free Documentation License.
CD18 is integrin, beta 2 (ITGB2) (complement component 3 receptor 3 and 4 subunit). Integrins are surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. For example, beta 2 combines with the alpha L chain to form the integrin LFA-1, and combines with the alpha M chain to form the integrin Mac-1.
The integrin superfamily consists of 30 proteins that promote cell-cell or cell-matrix interactions. The name integrins derives from the idea that they coordinate (i.e., "integrate") signals.
All integrins are cell surface proteins composed of 2 polypeptide chains, α and β.
Integrins are classified into several subfamilies based on the β chains.
The β1-containing integrins are also called VLA molecules. VLA ("very late antigens") received their name because α1β1 and α2β1 were expressed on T cells 2 to 4 weeks after repetitive stimulation in vitro in the early experiments.
The β1 integrins are also called CD49a-fCD29. CD49a-f refers to different α chains (α1 to α6). CD29 refers to the common β1 subunit.
The β2 integrins are also known as the LFA-1 family or CD11a-cCD18. CD11 refers to different α chains and CD18 to the common β2 subunit. LFA-1 is also called CD11aCD18.
Other members of the LFA-1 family include CD11bCD18 (Mac-1 or CR3) and CD11cCD18 (p150,95 or CR4), both of which have the same β subunit as LFA-1.
LAD type 1
First recognized as a distinct clinical entity in the 1970s. The inherited molecular defect in patients with LAD type 1 is a defect in CD18. CD18 is the β2 chain (β-2 integrin subunit) common to LFA-1 and MAC-1.
LAD type 2
There is inability to put sialyl-LewisX cap on leukocytes. Sialyl LewisX (SLeX, CD15) is a tetrasaccharide carbohydrate attached to O-glycans on the surface of the cells that plays a vital role in cell-cell recognition processes. Sialyl Lewis X is also a blood group antigen.
Sialyl LewisX. Image source: Wikipedia, public domain.
Sialyl Lewis X determinant, E-selectin ligand carbohydrate structure, is expressed on granulocytes and monocytes and mediates extravasation. Defective synthesis of Sialyl Lewis X can be caused by defects in fucose metabolsims.
Fucose is a hexose deoxy sugar. Image source: Wikipedia, GNU Free Documentation License.
LAD type 2
Fucose, Sialyl LewisX (SLeX)
Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS.
Neutrophils (PMN) are the most numerous among peripheral leukocytes (70%) and are the first line of defense against pathogens. PMN circulate in the blood for only 6 hours. PMN migration is regulated via adhesion molecules.
Recruitment of Leukocytes to Sites of Infection
SIP of wine:
Penetration of BM by PMN
Selectins are first in the chain of events. They upregulate TNF and IL-1.
Integrins cause release of VCAM and VLA.
Adhesion molecules, 3 groups = SIS
The name selectin comes from the words "selected" and "lectins." Selectins are a type of carbohydrate-recognizing proteins.
There are 3 groups of selectins = LEP
Selectin E (endothelial adhesion molecule 1). Image source: Wikipedia.
CD62E - E-selectin is a cell adhesion molecule expressed only on endothelial cells activated by cytokines.
CD62L - L-selectin is a cell adhesion molecule found on leukocytes.
CD62P - P-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells (cells lining blood vessels) and activated platelets.
LAD type 1 is a problem of PMNs binding to integrins (LAF-1). Integration (tight adhesion) is the second phase of the PMN recruitment (see the "SIP" mnemonic above). LAD type 2 is a problem of PMNs binding to selectins. Selection ("rolling") is the first phase of the PMN recruitment (see the "SIP" mnemonic above).
LFA (leukocyte function Ag), VLA (very late Ag). For example, LFA 1-3 bind to CD (cluster of differentiation) cell adhesion molecules on the surface of T cells.
Ig Superfamily = cell adhesion molecules (CAM)
VCAM (vascular cell adhesion molecule)
ICAM (intercellular adhesion molecule)
PECAM (platelet-endothelial cell adhesion molecule)
Intercellular adhesion molecule 2 (ICAM 2). Image source: Wikipedia.
Leukocyte adhesion deficiency. Wikipedia.
Sialyl Lewis X. Wikipedia.