Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disorder characterized by abundant immune complex (IC) deposition, with nephritis being a major cause of morbidity and mortality. Yet, IC deposition alone is not sufficient for disease development suggesting that additional factors dictate the propensity for developing target organ injury. Genome-wide association studies have identified polymorphisms in the leukocyte integrin Mac-1 (CD11b/CD18, ITGAM) that associate with lupus nephritis. Although Mac-1 promotes inflammation by triggering leukocyte recruitment and cytotoxic functions, there is emerging evidence that it may also serve protective roles under certain conditions. We demonstrate that Mac-1 deficiency in the context of the uniquely human FcgRIIA a receptor that binds IgG-IC, promotes susceptibility to lupus nephritis in two independent animal models. Analysis of renal tissue and intravital microscopy revealed that Mac-1 modulates neutrophil recruitment by FcgRIIA. The SLE-associated variant of Mac-1 rs1143679 (R77H), results in reduced Mac-1 functions, but the underlying mechanism remains undefined. CD18 integrin mediated adhesion is a multistep process that begins with affinity changes for ligand via transmission of allosteric signals. Moreover, mechanical forces (e.g. shear flow) paradoxically increase the lifetime of integrin-ligand bonds, referred to as "catch-bonds". Here, we show that expression of Mac-1 R77H on neutrophils, and blocking antibodies to the extracellular b-propeller domain in which it resides, markedly impairs Mac-1 adhesion to ligand under shear flow. R77H expressing cells exhibit a shift in equilibrium towards a bent conformation, a lower affinity and on- and off- rate for ligand and an inability to form catch-bonds. Additional mutants and activating antibodies reveal that R77H prevents allosteric signal transmission to the aI-domain required for productive ligand binding.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/12274121 |
| Date | 06 June 2014 |
| Creators | Rosetti Sciutto, Florencia |
| Contributors | Mayadas, Tanya |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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