The danger model The Self/Non-self Model proposed by
Macfarlane Burnet and
Frank Fenner in 1949 faced challenges in the late 1980s as immunologists recognized that T cells depend on
antigen-presenting cells showcasing materials and sending co-stimulatory signals. Driven by the writings of
Thomas Kuhn on
paradigm shifts in science,
Charles Janeway made a 1989 proposal that the innate immune system was the real gatekeeper of immune system responses. He also theorized that the innate immune system used ancient pattern-recognition receptors to make these decisions, recognizing a
pathogen by its unchanging characteristics.
Danger signals In her 1994 article "Tolerance, Danger, and the Extended Family", Matzinger extended the danger model, arguing that antigen-presenting cells respond to "danger signals" released from cells undergoing unprogrammed cell death when injured or stressed, 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 occur 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.
Scope The danger model is broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines. Matzinger argued that prior models failed to explain why immune system responses vary based on the specific threat's location and severity. Prior models also fail to explain how the immune system rejects tumors, induces
autoimmune diseases, or generates allergic responses. Some immunologists still maintain Janeway's ideas, believing that the immune response is mainly fueled by innate evolutionarily conserved "pattern recognition receptors" that recognize similarities between microorganisms, minimizing the effects of unprogrammed cell death.
Pattern recognition and a tissue-driven immune system Seung-Yong Seong and Matzinger have proposed exposed hydrophobic regions on biological compounds as among the damage-associated molecular patterns (DAMPs) of the danger model. Facing stressors, cells misfold and denature their proteins, exposing hydrophobic regions that aggregate into clumps to avoid exposure to the water-filled environment. In a 2013 article in
Nature Immunology, Matzinger highlighted the danger model's primary implication that bodily tissues drive immune responses. As research continues to show the bacteria of each organ's
microbiome guiding its function and outputs, Matzinger theorizes that microbes may be shown as driving immune system responses. Matzinger argues that DAMPs may explain why
toll-like receptors respond to both external and endogenous ligand signals with her danger model suggesting a multitude of signalling pathways determining the extent and nature of each immune system response.
Challenges to Matzinger's theories Regulatory T cells have been shown suppressing immune responses, exemplified by the autoimmune
IPEX syndrome occurring when the master regulator of these Treg cells is dysfunctional. Matzinger has incorporated Treg cells into her danger model, arguing that their regulation activity is not absolute, based on transplant organs being rejected at higher rates if infected, showing that danger signals continue to dictate the immune response. Criticisms of the danger model focus on two key points: First, Matzinger argued that tumors persist to cause cancer because their cells undergo programmed cell death, failing to release danger signals for an immune response. However, recent research has shown the immune system detecting and destroying some tumors. Second, the danger model explains
transplant rejection as the result of surgery-induced damage, but this explanation fails to account for greater tolerance of
autotransplantation, the movement of tissue between parts of the same body. Terms coined by Matzinger, such as "professional antigen-presenting-cell", "danger signal", and "
DAMPs", are frequently repurposed for explanations of the self/non-self model of the immune system. The immunologist Russell E. Vance has argued that immunological paradigms like the danger model are inevitably inaccurate representations of distinct mechanisms generated under evolutionary pressure.
Dog co-author controversy In 1978, Matzinger published her fourth paper in the
Journal of Experimental Medicine, listing her
Afghan Hound, Galadriel Mirkwood, as a fictional
coauthor, so that she could write the paper in the first-person plural, active voice. When the journal editors discovered this, they banned her from publication. == Awards ==