The Importance of Adhesion Molecules in Health and Disease - Essay Example

They participate in the recruitment of neutrophils to the site of inflammation in a dynamic and multiple-step manner. Different families of adhesion molecules participate in leukocyte’s localization dynamics: selectin family and their ligand participate in the rolling phase; integrin family and their ligands mediate the activation and firm adhesion of leukocytes to the endothelium; both selectins and integrins participate in trans-endothelial migration. Inflammatory and immune responses are important in host defense but on the other hand, they can also generate pathological inflammation in a variety of conditions.

Several illnesses characterized by acute inflammation with infiltration of neutrophils are in most of the cases associated with augmented expression of selectins (E-selectin and P-selectin), while ICAM-1 and VCAM-1 expression prevails in chronic conditions (Etzioni, 1996). Furthermore, enhanced local expression and increased amount of serum-soluble adhesion molecules have been reported in atherosclerosis, ischemia-perfusion injury, acute lung injury, rheumatoid arthritis, and graft/organ rejection (Bevilacqua et al., 1994). Asthmatic symptoms have been linked to specific cytokines (IL-4 and IL-5) which are produced by CD4 T helper cells.

CD4 helper cells are not only the major lymphocyte responders in an allergic response but also the cells responsible for the memory of an allergen. Very Late Antigen 1 (VLA-1) and VLA-2 are two adhesion molecules (integrins) implicated in the attachment of CD4 T helper cells to the extra-cellular matrix of the lung during allergic asthma. The expression of these adhesion molecules is thought to be of vital importance in the capability of the immune system to react against allergens. Thus, in people without asthma normal adhesion of CD4 T helper cells will help the organism to react against a dangerous antigen, but in asthmatic patients, the inhalation of a harmless allergen will cause a lot of damage. 

Regardless of whether cell adhesion should be decreased or increased (to increase or decrease an immune response), the understanding of adhesion molecules functioning may demonstrate the importance of the reduction of respiratory diseases (Messenheimer, 2003).

Acute coronary syndromes are associated with sustained leukocyte activation. This intense inflammatory state has been linked to an unfavorable prognosis. It has been demonstrated that these syndromes are characterized by a coordinated pro-inflammatory increased regulation with activation of both leukocytes and endothelium. Indeed, monocyte receptor ligands and endothelial adhesion molecules were found in peripheral blood of patients with acute coronary syndromes (Murphy et al., 2003).  

Adhesion molecules and human brain development

Appropriate special and temporal control of cellular interactions is necessary for the development of neuronal connectivity. The neural adhesion molecule (NCAM) is crucial in neurogenesis, migration, axon outgrowth, and synaptic plasticity as it has been showing in animal models. Single nucleotide polymorphisms in the NCAM1 gene are significantly associated with both bipolar disorder and schizophrenia (Atz et al., 2007). On the other hand Mutation in the human genes encoding the proteins Po, L1, and merosin (laminin 2) cause inherited diseases in humans which are characterized by severe abnormalities in the nervous system.  This mutation leads to a loss of adhesive functions, disrupts intracellular signaling or interactions. Merosin and Po are key players in normal myelination and L1 is required for the development of major axon pathways (Kamiguchi et al., 1998).

Adhesion molecules and Cancer

In cancer progression and metastasis, adhesion molecules play a significant role. The metastatic spread is determined by cell-to-cell interactions of cancer cells with the endothelium in tissues. Cancer cells also interact with blood cells favoring cancer cell adhesion, extravasation, and the formation of metastasis.  Selectins and integrins participate actively in metastasis. While mechanisms of cancer cell adhesion differ from leukocyte recruitment, adhesion molecules involved in the cell-to-cell interaction of endothelium and cancer cells are potentially the same. Selectins and integrins have been linked in cancer progression of colon and lung carcinoma.

Therapeutic approaches

The description of molecular interactions that are the basis of leukocyte-endothelial interactions has led to the development of multiple anti-adhesion approaches including antibodies against adhesion molecules, soluble adhesion receptor proteins that compete for ligands, blockage of adhesion receptors, blocking of selectin-mediated rolling using saccharides, and blocking signaling pathways (Etzioni, 1996). For example, in ischemia-perfusion injury, reperfusion after a period of arrested blood flow is associated with tissue damage. Reperfusion activates leukocytes and endothelial cells inducing damage to blood vessels and surrounding tissue. L-selectin and adhesion molecule involved which mediates neutrophils rolling participates dynamically in the damage caused by reperfusion. An antibody that is directed to a functional epitope of L-selectin (MAb) ameliorates necrosis and edema after reperfusion in a rabbit model of ischemia-perfusion injury (Mihelcic et al., 1994). The late phase of asthma is induced by an inflammatory reaction with an accumulation of leukocytes resulting in airway hyper-reactivity and bronchoalveolar eosinophilia. These pathological responses to allergen challenges are effectively reduced by the administration of anti-ICAM -1 MAb.

Successful host response to stress (infection, tissue damage) needs a balanced immune response to promote the focal accumulation of leucocytes. Adhesion molecules participated actively in the recruitment of leucocytes, for that reason they have been implicated in human pathologies where immune responses are altered. Adhesion molecules also participate in physiological processes where migration or cell to cell interactions are necessary as in brain development. The same molecules that contribute to the immune defense of the host are also implicated in cancer metastasis.  The knowledge of how adhesion cell molecules interplay in organisms is an important requirement that will contribute to the development of new and very specific therapeutic approaches.