LFA-1

LFA-1 is the acronym for "Lymphocyte function-associated antigen 1", an integrin that is expressed by lymphocytes and other leukocytes. LFA-1 thus belongs to the integrin superfamily of adhesion molecules.

LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits. LFA-1 has two subunits, known as the alpha subunit and the beta subunit. The alpha subunit is called CD11a and the beta subunit, which is only found in leukocytes, is called beta-2 or CD18. The ICAM binding site is located on the alpha subunit.

LFA-1 plays a key role in the emigration of leukocytes from the bloodstream. It also mediates the adhesion of leukocytes (Faveeuw C et al. 2000). In addition, LFA-1 is involved in the process of cytotoxic T cell-mediated and antibody-mediated killing of microbial pathogens by granulocytes and monocytes. The ligands of LFA-1 are known: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5 and JAM-A. Recently, LFA-1/ICAM-1 interactions have been shown to stimulate signaling pathways that influence T cell differentiation.

It is now known that LFA-1 responds dynamically to a variety of biochemical signals and transmits molecular information through bidirectional signaling, i.e. information not only flows from extracellular stimuli to induce intracellular changes (outside-in signaling), but intracellular stimuli can also cause extracellular changes (inside-out signaling). Inside-out signaling, such as stimuli received from the cell surface receptors for cytokines and chemokines, and TCR activation by foreign antigens or phorbol esters, can trigger intracellular signaling cascades that act on the cytoplasmic domains of LFA-1 and lead to its activation. This activation increases the affinity and adhesion capacity of LFA-1 for extracellular ligands, which ultimately facilitates its clustering at the cell surface. In "outside-in" signaling, LFA-1 transmits a series of biochemical and molecular signals from its extracellular domains across the plasma membrane into the cytoplasm (Fig). Important kinases activated by LFA-1 stimulation in T cells include, for example, Syk-family tyrosine kinase ZAP-70, Src-family tyrosine kinase Lck, PKC isoforms, PLCγ1, Pyk-2, focal adhesion kinase, Rho-associated protein kinase (ROCK) and RAP1 17-19, 23-25, all of which are essential for lymphocyte homing.

LFA1 antibodies for the treatment of psoriasis: For example, efalizumab, a humanized antibody fragment that specifically blocks the α-subunit of LFA-1, was developed and approved in 2003 for the treatment of the moderate to severe chronic inflammatory disease psoriasis (Lebwohl M et al. 2003; Marecki S et al. 2004; Boehncke WH et al. 2007). Although effective, the drug was withdrawn from the market in July 2009 due to an increased risk of developing progressive multifocal leukoencephalopathy (PML), a fatal brain infection caused by the reactivation of a latent JC virus infection in patients receiving long-term treatment with efalizumab.

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