Leading Edge Previews Innate Immune Response Triggers Lupus like Autoimmune Disease James C Paulson1 Departments of Chemical Physiology and Molecular Biology The Scripps Research Institute 10550 N Torrey Pines Road La Jolla CA 92014 USA Correspondence jpaulson scripps edu DOI 10 1016 j cell 2007 08 009 1 Autoimmune 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 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 Autoimmune diseases including systemic lupus erythematosus SLE juvenile type 1 diabetes rheumatoid 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 initiation and progression of autoimmune diseases are still poorly understood In work recently published in Immunity Green et al 2007 report on a mouse model of an autoimmune disease 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 diabetes and rheumatoid arthritis respectively 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 important 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 Mensah 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 glycan specific C type lectin receptors CLRs that recognize pathogen 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 homeostasis Geijtenbeek et al 2004 Marshak Rothstein and Rifkin 2007 Robinson et al 2006 In light of the roles of myeloid cells as effector cells in disease progression can autoimmune disease occur in the absence of adaptive immunity The case of the motheaten mouse mutant suggests that it can Yu et al 1996 Motheaten mice are deficient in hematopoietic cell phosphatase They exhibit a severe autoimmune like disease characterized by alopecia hence the motheaten appearance inflamed paws high titers of autoimmune antibodies deposition of immune complexes in kidney and other tissues and shortened 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 deficient in the hematopoietic cell phosphatase with mice lacking recombinase 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 antibodies and deposition of immune complexes in tissues they exhibited all of the other symptoms of the disease including shortened lifespan Although the detailed mechanism of the initiation and progression of the disease was not defined it was concluded that the autoimmune disease of motheaten mice was mediated by an aggressive response of macrophages and other myeloid cells Now Green et al 2007 describe an SLE like disease in mice deficient in the enzyme mannosidase II M II that appears to be driven solely by a mechanism involving an innate immune response Green et al 2007 Aging M II null mice acquire symptoms characteristic of SLE and lupus nephritis including high titers of anti DNA antibody immunoglobulin deposition in the kidney and other tissues glomerulonephritis renal dysfunction and kidney failure To assess the Cell 130 August 24 2007 2007 Elsevier Inc 589 Figure 1 Self Glycans Trigger an Innate Immune Response in Mice Lacking M II A mannosidase II M II participates in the normal processing of N linked glycans from the high mannose type left to complex type top right In M II null mice most cell types process glycans normally due to a compensating enzyme M IIx However M IIx is not expressed by erythroid cells or kidney mesangial cells resulting in hybrid type glycans with terminal mannose residues bottom right B Recognition of hybrid type glycans by macrophage mannose receptor MMR on mesangial cells and binding of mannose binding lectins MBL to hybrid type glycans on membrane glycoproteins is proposed to induce expression of monocyte chemoattractant protein 1 MCP 1 This results in recruitment of activated macrophage effector cells which then mediate tissue damage that leads to an automimmune like disease with features similar to systemic lupus erythematosus role of antibodies and the adaptive immune system in the pathology of the disease mice lacking M II were crossed with RAG 1 deficient mice which are incapable of producing T and B lymphocytes Surprisingly the absence of an adaptive immune system exacerbated and accelerated the onset of the SLE like disease demonstrating that the initiation and propagation of the disease was independent 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 conclusion that the disease is mediated by an innate immune response resulting from M II deficiency So what is the link between MII deficiency and induction of an autoimmune like disease The MII enzyme carries out a key step in the biosynthesis of N linked glycans of glycoproteins and is constitutively expressed in most cell