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Autoimmunity: Altered self-N-glycans trigger innate-mediated autoimmunity

Steven J Van Dyken and Richard M Locksley

Correspondence: Dr SJ Van Dyken and Dr RM Locksley, Department of Medicine and Microbiology/Immunology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.

The ability to distinguish self from nonself is a central feature of the immune system. Without it, immune cells attack various tissues within the body that are mistakenly recognized as foreign, resulting in the development of autoimmune disorders. The initial events in this process have remained unclear, but disease is often accompanied by autoantibody production and involvement by T and B cells of the adaptive immune system. A new study by Green et al.1 however, reveals that autoimmune tissue destruction can develop in the absence of adaptive immunity, apparently triggered by innate recognition of malformed N-glycans produced by cells lacking alpha-mannosidase-II (alphaM-II). Intriguingly, the abnormal N-glycans mimic those commonly expressed by lower eukaryotes and prokaryotes, thereby providing an initiating signal for innate immune cell activation and subsequent pathologic autoimmunity.

Asparagine (N)-linked glycans are broadly categorized into three groups based on structural characteristics coinciding with distinct biosynthetic stages: high mannose, hybrid and complex (Figure 1). The initial events generating high mannose N-glycans are remarkably conserved among eukaryotic cells. A mannose-rich oligosaccharide precursor molecule is synthesized in the endoplasmic reticulum (ER), transferred en bloc to nascent polypeptides and modified to ensure proper protein folding and sorting.2,3 Upon transit through the Golgi, cell- and species-specific diversification is introduced as this N-linked oligosaccharide is subjected to trimming and extension by the sequential actions of various Golgi-resident glycosyltransferases and glycosidases. In vertebrates, these modifications produce primarily complex-typeN-glycans that decorate cell surface glycoproteins, in contrast to invertebrates, such as yeast, which express high-mannose and hybrid-type N-glycoforms.1

In normal cells, most membrane-bound and secreted glycoproteins are modified with complex-type N-glycans (simplified glycan structures indicated). In the absence ofalphaM-II, hybrid N-glycans are produced, mimicking structures expressed on lower eukaryotes and leading to engagement by lectin receptors, followed by chronic innate immune activation and autoimmune disease development, which is attenuated by the adaptive immune system.

Full figure and legend (158K)


The conversion of hybrid- into complex-type N-glycan structures in vertebrates requires the trimming of terminalalpha3- andalpha6-linked mannose residues on hybrid-N-glycan structures before further branching. In vivo mouse genetic studies have established that two isozymes,alphaM-II andalphaM-IIx, perform this critical mannose-trimming step, without which complex-type structures fail to be produced, and hybrid-type N-glycans accumulate.4,5,6,7 Deficiencies of bothalphaM-II andalphaM-IIx have severe consequences, as double-null mice die shortly after birth, a phenotype which supports observations made in other glycosyltransferase-deficient mice unable to synthesize complex N-glycans.7,8,9,10 In contrast, mice deficient in either isozyme alone display less drastic phenotypes, due to apparent compensation in specific cell types:alphaM-IIx-deficient mice, for instance, appear normal except for a defect in spermatogenesis, whereasalphaM-II-deficient mice display a complete absence of complex N-glycans on cells of the erythroid lineage (with variable compensation among other cell types) and develop dyserythropoietic anemia accompanied by an age-related autoimmune disease resembling systemic lupus erythematosus (SLE).

Green et al.1 exploited the cell- and tissue-specificity ofalphaM-II gene disruption to gain compelling insights about the initiation of autoimmunity. In this study, the authors performed bone marrow transplants amongalphaM-II null mice and wild-type littermates in an effort to identify the cellular origin of disease observed in the absence ofalphaM-II. Surprisingly, they found that increased autoantibody titers and kidney dysfunction were observed when the bone marrow recipient, not the donor, was deficient inalphaM-II, establishing that the disease pathogenesis arose from non-hematopoietic cells. The anemia due toalphaM-II deficiency was ameliorated by wild-type bone marrow transplantation, however, thereby uncoupling this phenotype from the development of autoimmunity, further highlighting the cell–type specific effects of defective complex N-glycan formation.

Given the non-hematopoietic origin of disease inalphaM-II deficiency and the well-documented adaptive component of autoimmune diseases, the authors examined the contribution of adaptive immune cells to disease using recombinase–activating gene-1 (RAG-1)-deficient mice, which lack mature lymphocytes and antibodies. In an unexpected twist, mice deficient in bothalphaM-II and RAG-1 failed to reduce markers of kidney disease, which instead were exacerbated in the double-deficient mice, accompanied by increased numbers of kidney-infiltrating macrophages and mesangial cells expressing activation markers. Suspecting that this attenuation of disease by the adaptive immune system was due to a lack of lymphocyte-derived immunoglobulin G (IgG), a molecule that can bind inhibitory Fc receptors on innate immune cells, Green et al.1 administered intravenous IgG (IVIG) to thealphaM-II/RAG-1 double-deficient mice over a period of several months. IVIG treatment led to a reduction in the autoimmune disease markers and improved kidney function, and lessened both glomerular expression of the chemokine MCP-1 and the magnitude of activated macrophage infiltration.1


The authors found that genetic absence of complement C3 did not reduce autoimmune disease markers inalphaM-II-deficient mice.1 Future experiments aimed at identifying the altered serum N-glycoproteins inalphaM-II deficiency, as well as their cellular source, are warranted. It might also be possible to target the mammalian mannose-binding lectin receptors or a specific cell type in the control of glomerulonephritis.