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 (eg, bacterial lipo-oligosaccharides) or glycan-based polymers (eg, 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 …