LECTURE: 16
Title
CELLULAR ADHESION MOLECULES
LEARNING OBJECTIVES:
The student should be able to:
•
Identify the receptor's families that the adhesion molecules belong
to.
• The location of adhesion molecules.
• Recognize the importance of role of adhesion molecules that perform
in immunological responses.
• Enumerate some of the important adhesion molecules, identify the
location (s) of each one, such as:
- Intercellular adhesion molecule (ICAM).
- Selectin ligand (SLIG).
- Selectin.
- Fas ligand (FasL).
- L-Selectin on virgin T-cells.
- Alpha 4 Beta 7.
- CD2.
- LFA-1.
- CD28.
- Know the role of adhesion molecules and cytokines production.
LECTURE REFRENCE:
1. TEXTBOOK: JONATHAN M. AUSTYN AND KATHRYN J. WOOD
Principles of Cellular and Molecular Immunology . Chapter 4. pg 218-27.
2. TEXTBOOK: ROITT, BROSTOFF, MALE
IMMUNOLOGY. 6th edition. pg. 21, 43, 47, 48, 51-54, 112-15, 372, 373, .
3. TEXTBOOK: ABUL K. ABBAS. ANDREW H. LICHTMAN. CELLULAR
AND MOLECULAR IMMUNOLOGY. 5TH EDITION. Chapter. 6 .pg 119-124.
4. ADVANCE IMMUNOLOGY. pg 1.12-14.4-10, 14.8-9. 14.10, 14.8-10, 14.8,
14.8-10.
5. TEXTBOOK: JANET M. DECLER. INTRODUCTION TO IMMUNOLOGY.
pg 111-113, 123-124, 126, 140, 154, 167.
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CELLULAR ADHESION MOLECUES
Adhesion molecules: Cell surface molecules involved in the binding of cells to extracellular matrix
or to neighboring cells, where the principal function is adhesion, rather than cell activation, e.g.,
integrins and selectins. One of the important functions of the adhesion molecules is to ensure that
cells are arrived to the required locations.
■ Extracellular matrix: The intercellular substance in a tissue.
-
The cell adhesion molecules on the endothelium (the lining of the blood vessels) which
interact with integrins (consist of Heterodimeric molecules containing α, and β chains. All
members of a particular subfamily share a common β chain, but each has a unique αchain. However, there are several exceptions to this rule, and it has more recently been
found that some α-chains can associate with more than one β-chain). Integrins are all
members of the immunoglobulin supergene family. Integrins are a major group of adhesion
molecules, present on many cells, including leucocytes. Each member of this large family of
molecules consists of two non-covalently bound polypeptides (α, and β), both of which traverse
the membrane. They fall into three major families depending on which β-chain they have,
because any β-chain can associate with several α-chains. The ability of integrins to bind to their
ligands depends on divalent cations. For example, LFA-1 (lymphocyte functional antigen-1
α1β2 integrin) has a mg2+ ion coordinated at the centre of a binding site which accommodates an
aspartate residue from the ligand. In addition Ca2+ ions another site causes it to dimerize at the
cell surface, thus increasing the effective affinity for its ligand intercellular adhesion molecule1 (ICAM-1).
■ The three integrin subfamilies are:
•
β1 integrins are involved in binding of cells to extracellular matrix.
♦ CD 29 "β-chain" + various polypeptides, and includes the VLA (very late activation) markers.
•
β2 integrins are involved in leucocyte adhesion to endothelium or to other immune cells. βchain uses CD18 in this subfamily:
♦ CD18 "β-chain" + CD11a "α -chain" yields → LFA-1.
♦ CD18 "β-chain" + CD11b "α -chain" yields → Mac-1 (CR3).
♦ CD18 "β-chain" + CD11c "α -chain" yields → p 150, 95 (CR4).
•
β3 integrins (cytoadhesions) are involved in the interactions of platelets and neutrophils at
inflammatory sites or sites of vascular damage.
■ Examples of some common adhesion molecules involved in cellular transportation from the
vascular system into the body tissues.
-
Intercellular adhesion molecule (ICAM) is found on endothelial cells (in human there are about
100 billion endothelial cells), and another adhesion molecule is called selectin ligand (SLIG) is
expressed on neutrophils (neutrophils represent about 70% of blood cells). These two adhesion
molecules are "not" partners, so they don't bind to each other, and the neutrophil is free to zip
along with the flowing blood.
-
When some one get infected bacteria for example, these bacteria activated the macrophages
which secrete the cytokines IL-1, and TNF (TNF activate neutrophils as they travel to the site
of inflammation) to "alarm" the body that infection has begun. As soon as these two alarm
signals arrive to the endothelial cell that line nearby blood vessels, the endothelial begin to
express a new protein called selectin (SEL) on their surfaces (it takes about 6 hours for selectin
to be made and transported to the surface of the endothelial cells). This selectin is the adhesion
partner for selectin ligand that is usually expressed on the cell surface of the neutrophils.
Selectins grab neutrophils and cause neutrophil to reduce their speed and start roll along the
inner surface of the blood vessels.
2
-
Neutrophils recognize two inflammatory signals, these are the complement protein fragment
C5a, and the bacterial cell wall component lipopoly saccharide (LPS). As soon as neutrophils
recognize these two inflammatory signals, they express a new surface protein called Integrin
(INT). This protein is made by neutrophils in advance and stored in the cell until needed.
Integrin binds to its partner ICAM which cause the neutrophils to stop rolling.
-
As soon as neutrophils stop rolling, chemoattractants (e.g., C5a and fragment of bacterial
proteins called formyl methionine "f-met" peptides "all bacterial proteins begin with a special
initiator which is this "f-met", which less than .01% of human proteins contain, so f-met
peptides are relatively unique to bacteria) influence the endothelial cells to move apart to allow
neutrophils exit into the tissues, and migrate to the site of inflammation for performing their
functions (phagocytosis).
-
All the cells (e.g., eosinophil, mast cell, and monocytes) of the immune system use the same
migration mechanism as neutrophils (roll, and stop).
-
Immune cells vary in the types of molecules that cause them to roll and stop.
-
Molecules that monitor and control the immune cells to roll and stop are variables form one
cell type to another, and also destination to destination is also different.
-
By providing the immune cells with different adhesion molecules and by providing their
corresponding destinations with their appropriate adhesion partners ALLAH ensures that these
immune cells will be transported in to the exact position where they are needed.
■ Examples of some common adhesion molecules on NK-cells
-
Fas ligand (FasL) is expressed on the NK cell
Fas is a protein found on the surface of the target.
■ Examples of some common adhesion molecules on T, B-lymphocytes, antigen presenting
cells (APCs), and high endothelial venules in lymph node and Peyer's patches to control
lymphocyte trafficking
Virgin T and B-lymphocytes express adhesion molecules allow them to get into the secondary
lymphoid organs (e.g., Peyer's patches, and lymph nodes), but not the inflamed areas.
The experienced (previously activated) T-lymphocytes express adhesion molecules to encourage
them to re-enter the secondary lymphoid organs.
-
L-Selectin on virgin T-cells binds to GlyCAM-1 on the high endothelial venules.
-
Virgin T-cell express alpha 4 Beta 7 (α4β7: the gut specific integrin), and they will express
high level α4β7 when they were activated in the Peyer's patches and down regulate the
expression of L-selectin. These T cells will bind to its partner Mad CAM-1 that found on the
high endothelial venules of Peyer's patches and the lymph node.
-
CD2 on T-cells binds to LFA-3 on APCs.
-
LFA-1 on T-cells binds to ICAM-1 on APCs.
-
CD28 binds to CD80, and CD86 (B7-1, and B7-2) on APCs.
-
CD 40 on B-Lymphocytes binds CD 40 L (ligand) expressed on T-lymphocytes.
DR. MUSTAFA HASAN LINJAWI
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