Integrin knockouts in mouse and human

Many integrins have now been the target of gene deletion or 'knockout' (KO) experiments in mice. The majority of KOs are either embryonic or perinatal lethal, which indicates the importance of integrins in development. For example, the lethal KO characterized by the Hynes laboratory has confirmed a role for a4-integrins in muscle and neural crest development. Other approaches, such as inducible KOs or 'integrin null' chimeric mice, will allow exploration of the role of this integrin, which is of

Hölting

Arrest

Firm adhesion

Transmigration

Hölting

Arrest

Firm adhesion

Transmigration

L-selectin Ë-se lectin P-se lectin <tißi/VCAM-1 CuJVMAdCAM-1 /VCAM-1

Figure 2 Sequential interactions of a leukocyte with endothelium under the guidance of the 'adhesion cascade'. ICAM-1, intercellular adhesion molecule-1 ; LFA-1, lymphocyte function-associated molecule-1 ; MAdCAM-1, mucosal addressin cell adhesion molecule-1 ; VCAM-1, vascular cell adhesion molecule-1. (Reproduced with permission from Hogg N and Berlin C (1990) Immunology Today 16: 327-330.)

L-selectin Ë-se lectin P-se lectin <tißi/VCAM-1 CuJVMAdCAM-1 /VCAM-1

Figure 2 Sequential interactions of a leukocyte with endothelium under the guidance of the 'adhesion cascade'. ICAM-1, intercellular adhesion molecule-1 ; LFA-1, lymphocyte function-associated molecule-1 ; MAdCAM-1, mucosal addressin cell adhesion molecule-1 ; VCAM-1, vascular cell adhesion molecule-1. (Reproduced with permission from Hogg N and Berlin C (1990) Immunology Today 16: 327-330.)

such importance in the adhesion cascade. On the other hand (32 (CD18) KO mice have a normal phenotype but have severely depressed immune responses, e.g. reduced response to chemically induced peritonitis and also delay in transplant rejection. This analysis has become more specific with the characterization of the LFA-1 KO. These mice show the expected deficiencies when challenged in in vitro adhesion assays and also fail to mount an antitumor response in vivo, suggesting cell trafficking problems. Surprisingly, cytotoxic T lymphocyte responses toward common viruses are normal, indicating that LFA-1 may not always be necessary in the interaction between leukocytes and their targets.

The human 'KO' of the (32 subunit or CD18, termed leukocyte adhesion deficiency (LAD), is a rare condition recognized in some 60 patients worldwide. Patients suffer from severe bacterial and fungal infections which arise from the inability of myeloid cells to perform phagocytosis and chemotaxis. In LAD, expression of three leukocyte integrins LFA-1, Mac-I and pi50,95, is reduced or absent owing to five types of genetic defect in the p2 subunit, which prevents membrane expression of the a(3 complex. Another recognized integrin defect occurs in the equally rare Glanzmann's thrombasthenia, in which the expression of gpIIb/IIIa on platelets is reduced or absent due to mutations in the a subunit gpllb.

See also: Adhesion molecules; CD2; Complement receptors; Fibronectin; Intercellular adhesion molecules: ICAM-1, ICAM-2 and ICAM-3; Lymphocyte function-associated antigen 1 (LFA-1); Lymphocyte function-associated antigen 3 (LFA-3).

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