Loss of LFA-1, but not Mac-1, Protects MRL/MpJ-Faslpr Mice from Autoimmune Disease

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.

Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

“…Despite a dominant role for ICAM-1 and a codominant requirement for Mac-1 and LFA-1 in the cutaneous reverse Arthus reaction (36), the K/B ϫ N serum transfer model of autoantibody-induced synovial inflammation displays only partial dependence on ICAM-1 and no dependence on Mac-1 for disease induction. Indeed, the dependence on LFA-1 in the K/B ϫ N serum transfer model is more similar to that reported in the MRL/MpJ-Fas lpr immune complex-dependent model of lupus, which demonstrates attenuated nephritis with decreased renal neutrophil accumulation in LFA-1 null mice (37). These differences highlight the anatomic specificity for ␤ 2 integrins and their ligands in distinct immune complex-mediated diseases.…”

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…We have recently reported that the loss of CD11b in the MRL/ MpJ-Fas lpr mouse lupus model results in enhanced lymphadenopathy with focal accumulation of plasma and Mott cells. 15 A recent study has also shown that CD11b may also govern T-cell development and function, in that the loss of CD11b decreased CD3 and CD28 expression and CD4/CD8 ratios. 60 Early reports dismissed a role for T cells in DSS colitis; however, recent reports suggest that this cell population may participate in a regulatory manner through influencing recruitment of specific leukocyte populations (ie monocytes vs granulocytes) or by providing growth factors necessary for epithelial cell survival and regeneration during DSS colitis.…”

“…[12][13][14][15][16] The b 2 integrins are heterodimeric proteins that consist of a common beta subunit (CD18) noncovalently attached to different alpha subunits (CD11a-d). 17 The b 2 integrin family, or CD18 integrins, consists of four different adhesion proteins LFA-1 (CD11a/CD18), Mac-1 (CD11b/ CD18), p150/95 (CD11c/CD18), and CD11d/CD18.…”

“…Data from our lab and others using mouse models of arthritis, SLE, psoriasis, and autoimmune diabetes show that the b 2 integrins serve as the dominant adhesion molecules involved in chronic immune cell recruitment and activation, despite prominent expression of other known leukocyte adhesion proteins (eg VLA-4). 12,13,15,20 However, the pathological importance of b 2 integrin regulation of leukocyte recruitment and function during experimental colitis is not known.…”

Epigenetics, aging, and autoimmunity

“…Additionally, inhibiting T cell DNA methylation with the DNA methyltransferase inhibitor 5-azacytidine increases LFA-1 overexpression. Furthermore, Kevil et al reported that in MRL/MpJ-Fas lpr mice which develop a systemic autoimmune disease with similarities to SLE, loss of LFA-1 significantly protected mice from the development of murine lupus, as measured by attenuated autoantibody formation, and inhibited development of glomerulonephritis, and increased survival compared to control MRL/MpJ-Fas Lpr mice (63). Dr Richardson's group demonstrated that regions flanking the promoter of the ITGAL gene, which encodes for the CD11a chain of LFA-1, demethylate during aging, providing evidence that age-dependent decreases in T cell DNA methylation may contribute to the changes in T cell function and gene expression that occur in aging (64).…”