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How can the structure-function relationship explain

immunological “recognition”?

 

Gregor Greslehner

CNRS & University of Bordeaux

The structure-function relationship plays a central explanatory role in the life sciences, frequently under the slogan “structure determines function”. Both terms, ‘structure’ and ‘function’, however, are highly ambiguous and denote conceptionally different things at various levels of organization. Among philosophers of biology, the discussion has traditionally focused on two central notions of function: a selected effect (Wright, 1973) and a causal role (Cummins, 1975) account. Much philosophical attention has been devoted to dealing with these two notions of function, e.g. (Godfrey-Smith, 1993). The notion of structure, on the other hand, has not received much philosophical attention in its biological context. In the biological sciences, especially since the emergence of molecular biology, the three-dimensional structure of individual molecules has played an important explanatory role. With the rise of systems biology, organizational structure has started to become more explanatory central. I argue that these different meanings of ‘structure’ and ‘function’ should be clearly distinguished, as well as the separate explanatory roles which can be attributed to these structure-function pairs.


Immunological “recognition” provides an excellent case study to show the usefulness of this distinction. In immunology, the molecular structures and their specific binding sites of anti- bodies and pattern recognition receptors has given rise to the so-called “Janeway paradigm”, according to which the three-dimensional shape of molecules is the key to understanding their immunological function: microbial pathogen-associated molecular patterns bind specifically to pattern recognition receptors of the host, and by “recognizing” signature molecular motifs of pathogens an immunological reaction is triggered (Medzhitov and Janeway, 1997). If correct, these molecular structures would be crucial for solving the riddle of how the immune system is able to “recognize” self and non-self – distinguish between harmful and beneficial components.


However, this narrative faces a major challenge, as molecular motifs are being shared among pathogenic and symbiotic microbes alike. Both express a similar set of molecular patterns that are specific for prokaryotes (Rumbo et al., 2006). Other instances are known in which one and the same molecular structure can trigger opposing immune functions, depending on the presence or absence of additional signals in the cellular context (Sansonetti, 2011). It is speculated that a second “danger” signal might be needed in order to trigger an immune response. Whatever the nature of this second signal might be, it will require stepping away from the fixation on molecular structures. I argue that it is rather structural motifs of networks which carry the explanatory weight in these immunological processes. While the three-dimensional shape of signature molecules (structure1) can be used to explain their function1 – understood as biochemical properties and activities – their immunological function2 – biological roles, like immunogenicity – can only be explained with respect to higher-level structures2, i.e. the interaction network of molecules and cells. These different explanatory roles also imply different explanatory accounts. The former remains within a physico-chemical framework, whereas the latter rather calls for mechanistic and topological explanations (Machamer et al., 2000; Huneman, 2010).


Studying the interaction topology and dynamics of structures with mathematical tools promises to shed new light on these interaction processes that increasingly get to be described as equilibrium states between multiple interaction partners by immunologists (Muraille, 2013). Rather than focusing only on the presence or absence of molecular structures1, topological properties explain the features of these networks and their activities beyond the molecular interactions between pathogen-associated molecular patterns and pattern recognition receptors. This way, opposing effects resulting from the same kind of molecular structure1 can be explained by differences in their “downstream” organizational structure2. While still preserving the centrality of the structure-function relationship, I suggest to keep these conceptually different notions of ‘structure’ and ‘function’ and their respective explanatory roles apart.

 

In particular, the notion of immunological “recognition” can thus be reconstructed as two different processes. (i) recognition1: the specific biochemical binding activities (function1) of pattern recognition receptors and pathogen-associated molecular patterns (structure1); and (ii) recognition2: the physiological reaction (function2) of immunological signaling networks (structure2). Differences in these interaction networks can also explain what goes wrong in the case of autoimmune diseases and allergies, namely that some molecular patterns (structure1) are no longer recognized2 as “harmless”, although still being recognized1 by the same molecular receptors, triggering an immune response in cases where there is no physiological need to do so. In other words, although the function1 of structure1 remains the same, a change in structure2 results in a different function2. Clarifying the structure-function relationship by disambiguating different notions of ‘structure’ and ‘function’ can explain two forms of immunological “recognition”, respectively.

 

References
Cummins, R. (1975). Functional analysis. Journal of Philosophy, 72(20):741–765. doi:10.2307/2024640.

Godfrey-Smith, P. (1993). Functions: Consensus without unity. Pacific Philosophical Quarterly, 74(3):196–208. doi:10.1111/j.1468-0114.1993.tb00358.x.

Huneman, P. (2010). Topological explanations and robustness in biological sciences. Synthese, 177(2):213–245. doi:10.1007/s11229-010-9842-z.

Machamer, P., Darden, L., and Craver, C. F. (2000). Thinking about mechanisms. Philosophy of Science, 67(1):1–25. doi:10.1086/392759.
Medzhitov, R. and Janeway, Jr., C. A. (1997). Innate immunity: The virtues of a nonclonal system of recognition. Cell, 91(3):295–298. doi:10.1016/S0092-8674(00)80412-2.

Muraille, E. (2013). Redefining the immune system as a social interface for cooperative processes. PLoS Pathogens, 9(3):e1003203. doi:10.1371/journal.ppat.1003203.

Rumbo, M., Nempont, C., Kraehenbuhl, J.-P., and Sirard, J.-C. (2006). Mucosal interplay among commensal and pathogenic bacteria: Lessons from flagellin and Toll-like receptor 5. FEBS Letters, 580:2976–2984. doi:10.1016/j.febslet.2006.04.036.
Sansonetti, P. J. (2011). To be or not to be a pathogen: that is the mucosally relevant question. Mucosal Immunology, 4:8–14. doi:10.1038/mi.2010.77.
Wright, L. (1973). Functions. The Philosophical Review, 82(2):139–168. doi:10.2307/2183766.

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