Polly Matzinger | |
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| Born | July 21, 1947 |
| Alma mater | University of California, Irvine (BS) University of California, San Diego (PhD) |
| Known for | Danger model |
| Scientific career | |
| Fields | Immunology |
| Institutions | National Institute of Allergy and Infectious Diseases |
Polly Celine Eveline Matzinger (born July 21, 1947) is a French-born immunologist who proposed the danger model theory of how the immune system works. [1]
Polly Matzinger was born on July 21, 1947, in France, to a French mother (Simone) and a Dutch father (Hans). [1] In 1954, she immigrated to the US with her sister, Marjolaine, and parents. Her prior jobs included being a bass jazz musician, carpenter, dog trainer, waitress, and Playboy Bunny. [2] [3] Although it took her eleven years to finish her undergraduate degree, she finished her BS in biology at the University of California, Irvine, in 1976. [3] She was talked into going to graduate school by Professor Robert Schwab of UC Davis and finished her PhD in biology at the University of California, San Diego in 1979. [4] [5] She then did four years of postdoctoral work at the University of Cambridge [3] and was a scientist at the Basel Institute for Immunology for six years, before heading to the National Institutes of Health in Bethesda, Maryland. [5]
Matzinger is chief of the T-Cell Tolerance and Memory Section at the U.S. National Institute of Allergy and Infectious Diseases (NIAID). The lab has been referred to as the "Ghost Lab" for Matzinger's choice to conduct the first nine months of her research alone with a focus on chaos theory. In 2013, while reorganizing the Laboratory of Cellular and Molecular Immunology, NIAID transferred Matzinger's section to the Laboratory of Immunogenetics. [6]
In 2015, Matzinger recorded an eight-part series on the danger model of the immune system, covering transplant rejection, tumors, autoimmunity, T cells, parasites, and alarmins. [7]
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.
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 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. [8]
The danger model is broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines. Matzinger argues 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.
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. [9]
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. [10] 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.
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. [11] 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. [12]
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. [13]
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. [14]
In 1978, Matzinger published her fourth paper in the Journal of Experimental Medicine , listing her Afghan Hound, Galadriel Mirkwood, as a coauthor to write in a third-person active voice. [15] Upon identifying this, she was banned from publishing in the journal. [16]
At the 1986 Köln Film Festival, Polly Matzinger won the Award for Special Excellence in Educational Films for the German translation of Immunity: The Inside Story. In 1996, she was inducted as an honorary lifetime member of the Scandinavian Society of Immunology. In 2002, Discover magazine recognized Matzinger as one of the fifty most important women in science. [17] In 2003, she received an honorary doctorate from Hasselt University. In 2008, she was listed as a "Highly Cited" research among the top 1% of citations for her field on the Web of Science. [6]
Since 2009, the biotechnology company EpiVax has funded the Polly Matzinger Fearless Scientist Scholarship for women scientists at the University of Rhode Island's Institute for Immunology & Informatics that overcome challenges. [18]
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.
Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.
The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.
Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.
In immunology, clonal selection theory explains the functions of cells of the immune system (lymphocytes) in response to specific antigens invading the body. The concept was introduced by Australian doctor Frank Macfarlane Burnet in 1957, in an attempt to explain the great diversity of antibodies formed during initiation of the immune response. The theory has become the widely accepted model for how the human immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens.
In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.
Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR. This highlights the importance of structural homology in the theory of molecular mimicry. Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is one of several ways in which autoimmunity can be evoked. A molecular mimicking event is more than an epiphenomenon despite its low probability, and these events have serious implications in the onset of many human autoimmune disorders.
In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.
Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor (PRR). Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.
Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.
The danger model of the immune system proposes that it differentiates between components that are capable of causing damage, rather than distinguishing between self and non-self.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.
Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, they are secondary, tertiary and other subsequent immune responses to the same antigen. The adaptive immune system and antigen-specific receptor generation are responsible for adaptive immune memory.
Seung-Yong Seong is a South Korean immunologist and microbiologist known for his study of innate immune system response and his development of the damage-associated molecular pattern (DAMP) model of immune response initiation in collaboration with Polly Matzinger. Seong is also known for his research on the bacterium Orientia tsutsugamushi and his research on immunological adjuvant when he was a student. Since 2013 he has served as Director of the Wide River Institute of Immunology – Seoul National University in conjunction with his Professor position in the Microbiology and Immunology department of Seoul National University College of Medicine. In 2012, he became Editor in Chief of the World Journal of Immunology.
Mitchell Kronenberg is an American immunologist and the chief scientific officer at La Jolla Institute for Immunology. He served as president of the institute from 2003 to 2021.
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