Integrins

Integrins are a large family of heterodimeric transmembranc glycoproteins that attach cells to extracellular matrix proteins of the basement membrane or to ligands on other cells. Integrins contain large ($\alpha$) and small ($\beta$) subunits of sizes 120-170 kDa and 90-100 kDa, respectively. Some integrins mediate direct cell-cell recognition and interactions. Integrins contain binding sites for divalent cations Mg and Ca , which are necessary for their adhesive function. Mammalian integrins form several subfamilies sharing common ($\beta$ subunits that associate with different $\alpha$ subunits.

$\beta_2$ integrins are exclusively expressed on leukocytes and undergo a conformational change encompassing the phosphorylation of the $\beta$ subunit upon activation. ($\beta_2$ integrins include 4 different heterodimers CD11a/CD18 [Lymphocyte Function-Associated Antigen-1 ] (LFA-1) the predominant ($\beta_2$ integrin, CD11b/CD18 (Mac-1) exclusive to granulocytes and monocytes, CD11c/CD18 (P150), and CD11d/CD18. A mutation in the gene encoding the $\beta_2$ (CD18) molecule results in a genetic disorder, LAD, Leukocyte Adhesion Deficiency. LAD patients have recurrent bacterial infections due to the inability to effectively recruit granulocytes in response to infections.

CD11a/CD18 (LFA-1) (Lymphocyte Function-Associated Antigen-1) is critical in neutrophil transmigration, and important in transmigration of other leukocyte subtypes. CD11b (Mac-1) antibodies alone are not as potent an inhibitor of neutrophil transmigration in vitro, but add significantly to the effect of CD11a antibodies in vitro. In vivo, both CD11a and CD11b monoclonal antibodies can reduce inflammation, suggesting both redundancy and a dependence on the inflammatory stimulus and organ involved. Antibodies to CD11b are not particularly effective in inhibiting transmigration in vitro, nor do CD11b knockout mice show defective transmigration [LSP$^+$97]. CD11b monoclonal antibodies can inhibit inflammation in vivo, but in contrast to CD11a antibodies, CD11b antibodies reduce IgG immune-complex glomerulonephritis, but not IgG immune-complex lung injury [ASW94].

Mac-1, also called CD11b/CD18, is stored in specific granules that are shuttled to the granulocyte surface. It exists as a chemoattractant activation-dependent molecule that undergoes a conformational change upon stimulation. Expression of new epitopes on Mac-1 can be detected after activation by specific receptor monoclonal antibodies.

Until stimulation occurs, Mac-1 remains in a resting, non-adhesive state. Activation of Mac-1 may play a role during neutrophil recruitment to the inflamed site. Interestingly, Mac-1 knockout mice have no inflammatory defect.