Letter to the Glyco-Forum: Since there are PAMPs and DAMPs, there must be SAMPs? Glycan "self-associated molecular patterns" dampen innate immunity, but pathogens can mimic them
Open accessAbstract
The ∼500-million-year-old adaptive immune system detects foreign (“non-self”) epitopes via B cell-derived antibodies and/or T cell receptor interactions with major histocompatibility complex (MHC)/peptide complexes (Hedrick 2004). Cells of the more ancient innate immune system display receptors that detect foreign glycans, for example, fungal glycan recognition by the macrophage mannose receptor (Stahl and Ezekowitz 1998) or by circulating collectins and pentraxins (Bottazzi et al. 2010). The latter field was revolutionized by definition of “pathogen-associated molecular patterns” (PAMPs; Medzhitov and Janeway 1997), microbial products that can be detected by pattern recognition receptors (PRRs), particularly the Toll-like receptors (TLRs; Beutler 2009), Nod-like receptors (Davis et al. 2011) and dendritic cell receptors such as C-type lectins (Geijtenbeek et al. 2004). Many PAMPs are glycoconjugates (e.g., bacterial lipo-oligosaccharides) or glycan-based polymers (e.g., bacterial peptidoglycans), including bacterial DNA or viral RNA (which are (deoxy)ribose-based polymers). The innate immune system also recognizes “danger-associated molecular patterns” (DAMPs; Matzinger 2002; Chen and Nunez 2010), molecules released during tissue damage, such as heat-shock proteins, high mobility group box 1 (Lotze and Tracey 2005), hyaluronan (HA) fragments (Taylor and Gallo 2006), glycosaminoglycan (GAG)-bearing matrix proteoglycans (Moreth et al. 2010) and certain crystals (Martinon et al. 2009), all of which originate from damaged host cells or matrices. Signals initiated by DAMPs and PAMPs are transduced via similar pathways, activating innate immune inflammatory responses. Since the innate immune system recognizes invaders via PAMPs and endogenous damage via DAMPs, it is reasonable to suggest a class of “self-associated molecular patterns” (SAMPs), which would be recognized by intrinsic inhibitory receptors, to maintain the baseline non-activated state of innate immune cells and dampen their reactivity following an immune response. In this regard, note that circulating cells of the innate immune system (neutrophils, monocytes etc.) remain quiescent in the bloodstream under normal conditions, and only become activated as they routinely enter into extravascular spaces and encounter PAMPs or DAMPs, and/or are subjected to experimental manipulations in vitro. The term “SAMP” was suggested once before, but referred not to patterns, but to proteins such as complement regulatory protein CD200 (Elward and Gasque 2003). Such defined molecules mediating protein:protein interactions are not really “patterns”, but more akin to how MHC molecules are recognized as “self” by natural killer cells (Parham 2008). What might be the true SAMPs for inhibitory feedback on innate immunity? Given their dominance on cell surfaces and extracellular matrices, the likely candidates are “self” glycans, of the kind not easily confused with PAMPs and DAMPs. Glycans that best fit this criterion are sialic acids, which are found primarily on cells of the deuterostome lineage of animals (Varki and Schauer 2009). Other candidates are GAGs such as sulfated heparan and dermatan sulfate (Esko et al. 2009); glycans that evolved only in multicellular animal forms (Varki et al. 2009). To detect such SAMPs, there must be cognate Self-PRRs (SPPRs). The first-studied example was factor H, a serum protein which restricts alternate complement pathway activation on host cell surfaces by recognizing “self” in the form of sialic acid-containing patterns on cell surfaces. Factor H also recognizes heparan/heparin sulfate GAGs as “self”, apparently via the same anion binding domains that recognize sialic acids (Pangburn et al. 2000; Kajander et al. 2011). Indeed, naturally occurring mutations of these anion-binding domains of factor H are associated with unwanted innate immune reactivity (Herbert et al. 2007). Interestingly, efforts to identify structurally defined glycan ligands of factor H have failed. Rather, recognition involves certain polyanionic “self” patterns on cell surfaces. And factor H is evolving to best recognize such patterns (Granoff et al. 2009). The second class of SPPRs are the Siglecs (sialic acid recognizing Ig-like lectins), which have N-terminal V-set Ig-like domains that recognize sialic acids and often have tyrosine-based inhibitory signaling motifs within their cytosolic tails (Varki and Crocker 2009; Cao and Crocker 2011). Ongoing work on the CD33-related subset of inhibitory Siglecs indicates that they recognize sialic acid patterns as “self” and deliver inhibitory signals to innate immune cells. Consistent with this notion, deletion of Siglec-F from mouse eosinophils gives a hyperactive response (Zhang et al. 2007); mouse Siglec-G deletion results in over-reactive response to DAMPs and PAMPs (Chen et al. 2009, 2011) and Siglec-8 polymorphisms are associated with asthma risk (Gao et al. 2010). Again, rather than being highly specific sialo
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- Authors
- Varki, A.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Varki, A.
- ORCID
- Varki, A.
- Venue
- Glycobiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08-04
- Volume
- 21
- Issue
- 9
- Pages
- 1121-1124
- ISSN
- 0959-6658 (ISSN-L)
- 1460-2423
- PMC
- PMC3150115
- OpenAlex
- W2144971524
- Cited by
- 263
- References
- 48
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 19 · 2023: 15 · 2022: 22 · 2021: 17 · 2020: 25 · 2019: 19 · 2018: 20 · 2017: 20 · 2016: 13 · 2015: 19 · 2014: 19 · 2013: 8 · 2012: 8
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Glycobiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM032373, R01-GM-32373)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- innate immunity, pattern recognition receptors, damage-associated molecular patterns, pathogen-associated molecular patterns, carbohydrate recognition, glycosaminoglycans, hyaluronic acid, innate immune tolerance, Toll-like receptors, NOD-like receptors, C-type lectin, CD206, collectins, pentraxins
- MeSH terms
- Animals, Antigens, Bacterial, Antigens, Fungal, Antigens, Viral, Glycosaminoglycans, Humans, Immunity, Innate, Sialic Acids, Molecular Mimicry, Lectins, Receptors, Pattern Recognition, Adaptive Immunity, Sialic Acid Binding Immunoglobulin-like Lectins
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