Polly Matzinger

The self/non-self model, the predominant model in immunology since the 1950s, began to encounter problems in the late 1980s when immunologists began to recognize that T cells depend on other cells to pick up and then present the things to which they will respond — and that the T cell response depends on whether the other cell (known as antigen-presenting cells) is sending activation signals to the T cells.

In 1989, drawing on the ideas of Thomas Kuhn, Charles Janeway proposed that the old immunological paradigm had reached the limits of its usefulness—or, as he described it, the asymptote of the increase in knowledge which it had brought. Janeway argued that the innate immune system was the real gatekeeper of whether the immune system responded or did not respond. He also argued that the innate immune system used ancient pattern-recognition receptors to make these decisions, recognizing a pathogen by its unchanging characteristics.

In a 1994 article entitled "Tolerance, Danger and the Extended Family", Matzinger went several steps further by laying out the idea that antigen-presenting cells respond to "danger signals" — most notably from cells undergoing injury, stress or "bad cell death" (as opposed to apoptosis, controlled cell death). The alarm signals released by these cells let the immune system know that there is a problem requiring an immune response. She argued that T cells and the immune response they orchestrate occurs not because of a neonatal definition of "self", as in the previous model, nor because of ancient definitions of pathogens, as in Janeway's argument, but because of a dynamic and constantly updated response to danger as defined by cellular damage.

The danger model is broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines, but Matzinger points out that the original model was designed to offer an explanation of how an immune response is triggered and how it ends, but did not offer an explanation of why the immune system responds in different ways to different situations. She has now extended the model to hypothesize that tissues not only send signals alerting the immune system to local damage and stress, but that the tissues also determine the immune response appropriate for that tissue. Before her lab was closed, it was working on experiments to test that hypothesis. She is currently seeking collaborations to continue the research.

The danger model has not won universal acceptance. Some immunologists, following Janeway's ideas more directly, believe that the immune response is mainly fueled by innate evolutionarily conserved "pattern recognition receptors" which recognize patterns expressed by microbes such as bacteria, and do not see cell death in the absence of pathogens as a primary driver of immune responses. These ideas however, do not explain how the immune system rejects tumors, induce autoimmune diseases, or generate allergy and asthma.

Seong and Matzinger have suggested that the "patterns" that the immune system recognizes on bacteria are not as different from the alarm signals released by damaged cells as one might have thought. They suggested that, because life evolved in water, the hydrophobic portions of molecules are normally hidden in the internal parts of molecules or other structures (like membranes) and that the sudden exposure of a hydrophobic portion is a sure sign that some injury or damage has occurred. They suggested that these are the most ancient alarm signals, that they are recognized by evolutionarily ancient systems of repair and remodeling, and that the modern immune system piggy-backed on this ancient system. Thus bacteria and other organisms may have very similar alarm systems. They describe these ancient signals as danger-associated molecular patterns, or DAMPs.

In a 2013 article in Nature Immunology, Matzinger makes a case for what she now views as the most important implication of the danger model: that the tissues of the body are a large part of what drive immune response. She argues that immunologists have had overly simplistic and schematic ideas about immune response because of the limits of their assays, and that organs are likely to induce immune responses that are best-suited to defending the organ from the damage of microbes but also from the damage of the immune system itself. She also asserts that the relationship of the immune system to commensal bacteria remains poorly understood but is likely to be important.[10]

Matzinger argues that the idea of DAMPs may explain why Toll-like receptors seem to respond both to external and endogenous signals (while acknowledging controversy over this issue). By emphasizing her theory that the tissues drive the nature of the immune response (i.e., the "what type" rather than the "whether" of immune response), Matzinger describes a dynamic immune system with complex webs of signalling, rather than an immune system that can be explained by a simple and easily reducible set of molecular signals that initiate response or by a small set of cells (e.g., regulatory T cells) that shut it down.

There is now a growing body of work on regulatory T cells which argues that immune activity is stopped by a special subset of T cells. These ideas challenge several of the key specifics of Matzinger's model. Matzinger argues that these cells are misinterpreted because their functions have not been explored enough. To date (with rare exceptions) these cells have been tested almost exclusively for their ability to suppress highly inflammatory immune response types. The exceptions are illustrative in that they show that regulatory T cells can also act as helper T cells for immune responses in the gut and mucosal tissue. Matzinger argues that their function is to maintain the right kinds of immune responses in the right places, and that they are controlled by signals from the tissues that they protect.

A student sitting in an immunology class today will likely hear many phrases coined by Matzinger, such as "professional antigen-presenting-cell", "danger signal", or "DAMPs", but will often hear them in the framework of a self/non-self explanation of immunity. Other immunologists have often adapted parts of Matzinger's ideas without adopting the danger model as a theoretical framework. Indeed, in an era of increasingly detailed molecular work, many immunologists simply avoid constructing an alternative broad theory of immune function. One immunologist believes that the immune system is not a single system at all, and is instead a set of mechanisms "cobbled together" by evolution.[11] If this is true, no single theory can explain the function of the system as a whole. For both of these reasons, Matzinger has had to defend her larger theory, but also has had to defend the value of grand theory itself. She argues that, without a theoretical framework on which to hang the data, much will be missed.

The University of Rhode Island Institute for Immunology and Informatics has named a scholarship for her: the Polly Matzinger Fearless Scientist Scholarship.[12]

In one of her first publications, a paper for the Journal of Experimental Medicine, she listed a dog as a coauthor.[13] Ted Anton described the decision in his book Bold Science: "Refusing to write in the usual scientific passive voice ('steps were taken') and too insecure to write in the first person ('I took the steps'), she instead invented [a] coauthor": her Afghan Hound, Galadriel Mirkwood.[14] Once the deception was discovered, papers on which she was a major author were barred from the journal until the editor died and was replaced by another.[15]