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UGA BCMB 8020 - N-Glycan-Paper3Preview

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Innate Immune Response Triggers Lupus-like Autoimmune DiseaseReferencesLeading EdgePreviewsCell 130, August 24, 2007 ©2007 Elsevier Inc. 589Autoimmune diseases, including systemic lupus erythematosus (SLE), juvenile (type 1) diabetes, rheuma-toid arthritis, Crohn’s disease, and over 80 others, are generally thought to be triggered by aggressive responses of the adaptive immune system to self antigens, resulting in tissue damage and pathological sequelae (Davidson and Diamond, 2001). Yet, the molecular and cellular mechanisms that underlie the initia-tion and progression of autoimmune diseases are still poorly understood. In work recently published in Immu-nity, Green et al. (2007) report on a mouse model of an autoimmune dis-ease similar to lupus that does not require the adaptive immune system but is instead triggered by the innate immune response.For many autoimmune diseases, the key roles of T cells and B cells are well documented and are evident in the success of T cell (anti-CD3) and B cell (anti-CD20) depletion strategies for the treatment of diabe-tes and rheumatoid arthritis, respec-tively. Research continues to reveal new insights into the respective roles of the humoral and cell-mediated arms of adaptive immunity and the distinct roles of T cell subsets, for example Th17 cells, in autoimmunity (Bettelli et al., 2007).Dendritic cells, macrophages, and other myeloid cells also play impor-tant roles in autoimmune diseases, both as antigen presenting cells and as effector cells that mediate tissue damage (Davidson and Diamond, 2001; Geijtenbeek et al., 2004; Men-sah-Brown et al., 2006; Ohtsubo and Marth, 2006). Because these cells are also major mediators of innate immunity, interest has surfaced in the potential for innate immune responses to contribute to disease pathology. Receptors that mediate innate immune responses such as Toll-like receptors (TLRs) and gly-can-specific C-type lectin recep-tors (CLRs) that recognize patho-gen-associated molecular patterns (PAMPs) have been implicated in autoimmune disease mechanisms, both directly through recognition of self ligands and indirectly through the regulation of immune homeosta-sis (Geijtenbeek et al., 2004; Mar-shak-Rothstein and Rifkin, 2007; Robinson et al., 2006).In light of the roles of myeloid cells as effector cells in disease progres-sion, can “autoimmune” disease occur in the absence of adaptive immunity? The case of the moth-eaten mouse mutant suggests that it can (Yu et al., 1996). Mo theaten mice are deficient in hematopoietic cell phosphatase. They exhibit a severe autoimmune-like disease character-ized by alopecia (hence the “moth-eaten” appearance) inflamed paws, high titers of autoimmune antibodies, deposition of immune complexes in kidney and other tissues, and short-ened lifespan resulting from pneu-monia associated with accumulation of leukocytes in the lungs. Although this mouse was considered a model of classic autoimmune disease, Yu et al. (1996) crossed the mice defi-cient in the hematopoietic cell phos-phatase with mice lacking recombi-nase-activating gene-1 (RAG-1) that are deficient in production of T and B cells. They found that the disease progressed normally in the absence of an adaptive immune response (Yu et al., 1996). Although the mice lacked the high titers of antibod-ies and deposition of immune com-plexes in tissues, they exhibited all of the other symptoms of the dis-ease, including shortened lifespan. Although the detailed mechanism of the initiation and progression of the disease was not defined, it was con-cluded that the autoimmune disease of mothea ten mice was mediated by an aggressive response of macro-phages and other myeloid cells.Now, Green et al. (2007) describe an SLE-like disease in mice defi-cient in the enzyme α-mannosidase II (αM-II) that appears to be driven solely by a mechanism involving an innate immune response (Green et al., 2007). Aging αM-II null mice acquire symptoms characteristic of SLE and lupus nephritis includ-ing high titers of anti-DNA anti-body, immunoglobulin deposition in the kidney and other tissues, glo-merulonephritis, renal dysfunction, and kidney failure. To assess the Innate Immune Response Triggers Lupus-like Autoimmune DiseaseJames C. Paulson1,*1Departments of Chemical Physiology and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92014, USA*Correspondence: [email protected] 10.1016/j.cell.2007.08.009Autoimmune disease is typically defined as an aberrant response of lymphocytes to self antigens that ultimately leads to tissue damage. Reporting in Immunity, Green et al. (2007) now show that mice lacking α-mannosidase II develop an autoimmune disease similar to lupus. Remarkably, this illness is precipitated by an innate immune response to altered self glycans that mimic molecular patterns found on pathogens.590 Cell 130, August 24, 2007 ©2007 Elsevier Inc.role of antibodies and the adaptive immune system in the pathology of the disease, mice lacking αM-II were crossed with RAG-1-deficient mice, which are incapable of producing T and B lymphocytes. Surprisingly, the absence of an adaptive immune sys-tem exacerbated and accelerated the onset of the SLE-like disease, demonstrating that the initiation and propagation of the disease was inde-pendent of an immune response to self antigen. High dose intravenous immunoglobulin actually reduced the disease pathology, suggesting that the adaptive immune system had a moderating effect. These and supporting results led to the conclu-sion that the disease is mediated by an innate immune response resulting from αM-II deficiency.So, what is the link between αM-II deficiency and induction of an autoimmune-like disease? The αM-II enzyme carries out a key step in the biosynthesis of N-linked glycans of glycoproteins and is constitu-tively expressed in most cell types. Its function is to complete the trim-ming of mannose residues from the high-mannose type N-linked glycans of newly synthesized glycoproteins, prior to addition of terminal “com-plex”


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