The Danger Model proposes that the immune system responds to signals from damaged or distressed cells (danger signals) rather than distinguishing between self and nonself. Over the past 50+ years, the self-nonself model has been modified numerous times to account for new findings but still cannot explain certain fundamental immune processes. The Danger Model suggests that the immune system is more concerned with damage than foreignness. It has explanatory power for many immune responses and phenomena not fully addressed by prior self-nonself models.
Regulatory T cells, also known as T-regs, are a recently discovered subset of immune cells that play a key role in suppressing autoimmune responses and maintaining self-tolerance. T-regs express the cell surface marker CD25 and the transcription factor Foxp3, which gives them their suppressive properties. Ongoing research is helping to elucidate the mechanisms by which T-regs regulate other immune cells and prevent autoimmunity. Manipulation of T-regs may offer new therapies for autoimmune diseases and conditions involving transplant rejection or unwanted immune responses.
1) The document discusses two positions on HIV that are not fully compatible with scientific evidence: that HIV exists but is harmless, and that HIV does not exist.
2) It suggests that human endogenous retroviruses (HERVs) heavily interfere with AIDS research findings and may offer an alternative explanation for published data.
3) It argues that if a virus was responsible for AIDS, retroviral particles should be visible in electron micrographs of patient samples, but that no one has succeeded in visualizing retroviral particles in blood from AIDS patients.
Science article "False Positive" chronicles XMRV research controversydegarden
The article summarizes the ongoing controversy around the purported link between the mouse retrovirus XMRV and chronic fatigue syndrome (CFS). A 2009 study in Science linked XMRV to CFS in two-thirds of patients examined, but subsequent studies failed to replicate this finding. Now, a new study by nine labs, including the original proponents, also found no evidence of XMRV in blood samples from CFS patients. However, the lead researcher from the original 2009 study maintains her position that XMRVs may still infect CFS patients, even as most other researchers want to put this controversial line of research to rest.
Dr. Kurt Stevenson - Antimicrobial Resistance Surveillance and Management in ...John Blue
Antimicrobial Resistance Surveillance and Management in Hospital and Community Settings - Issues for Human Population Medicine - Dr. Kurt Stevenson, The Ohio State University Medical Center, from the 2012 NIAA One Health Approach to Antimicrobial Resistance and Use Symposium, October 26-27, 2012, Columbus, OH, USA.
More presentations at:
http://www.trufflemedia.com/agmedia/conference/2012-one-health-to-approach-antimicrobial-resistance-and-use
This document discusses a study analyzing the neutralizing antibody response in convalescent plasma from 3 survivors of Ebola virus disease (EVD). The plasma was tested for neutralizing activity against variants of Ebola virus as well as other ebolaviruses using a glycoprotein-pseudotyped lentiviral system with both full-length and cleaved glycoprotein. The results showed low neutralizing activity against full-length glycoproteins but broad and potent neutralizing activity against the cleaved glycoprotein forms, suggesting conserved epitopes are exposed upon cleavage. This could inform development of immunogens to induce broadly neutralizing antibodies.
The immune system recognizes foreign organisms through pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) shared by pathogens. The innate immune system responds first through phagocytic cells like granulocytes and antigen-presenting cells that engulf and kill pathogens. It also activates the adaptive immune system. Adaptive immunity recognizes pathogens through highly specific B and T cell receptors generated through genetic recombination, ensuring recognition of virtually any pathogen. Activated T cells then stimulate B cells and other T cells to eliminate the pathogen through targeted antibody production and cell-mediated responses.
Alfred I. Tauber "Reconceiving autoimmunity: An overview"Фатима Эркенова
Three interconnected positions are advocated: (1) although serving as a useful model, the immune self
does not exist as such; (2) instead of a self/nonself demarcation, the immune system ‘sees’ itself, i.e., it
does not ignore the ‘self’ or attack the ‘other;’ but exhibits a spectrum of responses, which when viewed
from outside the system appear as discrimination of ‘self’ and ‘nonself’ based on certain criteria of
reactivity. When immune reactions are conceived in terms of normal physiology and open exchange
with the environment, where borders dividing host and foreign are elusive and changing, host defense is
only part of the immune system’s functions, which actually comprise two basic tasks: protection, i.e., to
preserve host integrity, and maintenance of organismic identity. And thus (3) if the spectrum of
immunity is enlarged, differentiating low reactive ‘autoimmune’ reactions from activated immune
responses against the ‘other’ is only a matter of degree. Simply, all immunity is ‘autoimmunity,’ and the
pathologic state of immunity directed at normal constituents of the organism is a particular case of disregulation,
which appropriately is designated, autoimmune. Other uses of ‘autoimmunity’ and its
congeners function as the semantic remnants of Burnet’s original self/nonself theory and should be
replaced. A new nomenclature is proposed, concinnity, which more accurately designates the physiology
of the animal’s ordinary housekeeping economy mediated by the immune system than ‘autoimmunity’
when used to describe such normal functions.
Systemic and Mucosal Infection Program Protective Memory CD8 T Cells in the V...Likelika
In summary, our study demonstrates, using a TCR transgenic transfer model and LCMV
systemic or mucosal route of infection in mice, that functional, protective CD8 T cell memory
is achieved regardless of the route of infection, despite early differences in the magnitude and
quality of the Ag-specific CD8 effector population in the genital mucosa. Future studies will
address whether these early differences in genital tract CD8 T cell quality and quantity are
absent later due to a redistribution of these cells as they differentiate to memory.
Regulatory T cells, also known as T-regs, are a recently discovered subset of immune cells that play a key role in suppressing autoimmune responses and maintaining self-tolerance. T-regs express the cell surface marker CD25 and the transcription factor Foxp3, which gives them their suppressive properties. Ongoing research is helping to elucidate the mechanisms by which T-regs regulate other immune cells and prevent autoimmunity. Manipulation of T-regs may offer new therapies for autoimmune diseases and conditions involving transplant rejection or unwanted immune responses.
1) The document discusses two positions on HIV that are not fully compatible with scientific evidence: that HIV exists but is harmless, and that HIV does not exist.
2) It suggests that human endogenous retroviruses (HERVs) heavily interfere with AIDS research findings and may offer an alternative explanation for published data.
3) It argues that if a virus was responsible for AIDS, retroviral particles should be visible in electron micrographs of patient samples, but that no one has succeeded in visualizing retroviral particles in blood from AIDS patients.
Science article "False Positive" chronicles XMRV research controversydegarden
The article summarizes the ongoing controversy around the purported link between the mouse retrovirus XMRV and chronic fatigue syndrome (CFS). A 2009 study in Science linked XMRV to CFS in two-thirds of patients examined, but subsequent studies failed to replicate this finding. Now, a new study by nine labs, including the original proponents, also found no evidence of XMRV in blood samples from CFS patients. However, the lead researcher from the original 2009 study maintains her position that XMRVs may still infect CFS patients, even as most other researchers want to put this controversial line of research to rest.
Dr. Kurt Stevenson - Antimicrobial Resistance Surveillance and Management in ...John Blue
Antimicrobial Resistance Surveillance and Management in Hospital and Community Settings - Issues for Human Population Medicine - Dr. Kurt Stevenson, The Ohio State University Medical Center, from the 2012 NIAA One Health Approach to Antimicrobial Resistance and Use Symposium, October 26-27, 2012, Columbus, OH, USA.
More presentations at:
http://www.trufflemedia.com/agmedia/conference/2012-one-health-to-approach-antimicrobial-resistance-and-use
This document discusses a study analyzing the neutralizing antibody response in convalescent plasma from 3 survivors of Ebola virus disease (EVD). The plasma was tested for neutralizing activity against variants of Ebola virus as well as other ebolaviruses using a glycoprotein-pseudotyped lentiviral system with both full-length and cleaved glycoprotein. The results showed low neutralizing activity against full-length glycoproteins but broad and potent neutralizing activity against the cleaved glycoprotein forms, suggesting conserved epitopes are exposed upon cleavage. This could inform development of immunogens to induce broadly neutralizing antibodies.
The immune system recognizes foreign organisms through pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) shared by pathogens. The innate immune system responds first through phagocytic cells like granulocytes and antigen-presenting cells that engulf and kill pathogens. It also activates the adaptive immune system. Adaptive immunity recognizes pathogens through highly specific B and T cell receptors generated through genetic recombination, ensuring recognition of virtually any pathogen. Activated T cells then stimulate B cells and other T cells to eliminate the pathogen through targeted antibody production and cell-mediated responses.
Alfred I. Tauber "Reconceiving autoimmunity: An overview"Фатима Эркенова
Three interconnected positions are advocated: (1) although serving as a useful model, the immune self
does not exist as such; (2) instead of a self/nonself demarcation, the immune system ‘sees’ itself, i.e., it
does not ignore the ‘self’ or attack the ‘other;’ but exhibits a spectrum of responses, which when viewed
from outside the system appear as discrimination of ‘self’ and ‘nonself’ based on certain criteria of
reactivity. When immune reactions are conceived in terms of normal physiology and open exchange
with the environment, where borders dividing host and foreign are elusive and changing, host defense is
only part of the immune system’s functions, which actually comprise two basic tasks: protection, i.e., to
preserve host integrity, and maintenance of organismic identity. And thus (3) if the spectrum of
immunity is enlarged, differentiating low reactive ‘autoimmune’ reactions from activated immune
responses against the ‘other’ is only a matter of degree. Simply, all immunity is ‘autoimmunity,’ and the
pathologic state of immunity directed at normal constituents of the organism is a particular case of disregulation,
which appropriately is designated, autoimmune. Other uses of ‘autoimmunity’ and its
congeners function as the semantic remnants of Burnet’s original self/nonself theory and should be
replaced. A new nomenclature is proposed, concinnity, which more accurately designates the physiology
of the animal’s ordinary housekeeping economy mediated by the immune system than ‘autoimmunity’
when used to describe such normal functions.
Systemic and Mucosal Infection Program Protective Memory CD8 T Cells in the V...Likelika
In summary, our study demonstrates, using a TCR transgenic transfer model and LCMV
systemic or mucosal route of infection in mice, that functional, protective CD8 T cell memory
is achieved regardless of the route of infection, despite early differences in the magnitude and
quality of the Ag-specific CD8 effector population in the genital mucosa. Future studies will
address whether these early differences in genital tract CD8 T cell quality and quantity are
absent later due to a redistribution of these cells as they differentiate to memory.
Novel research aimed at finding a cure for AIDS requires animal models responding to human antiretroviral drugs. However, there have been few antiretrovirals cross-active against the simian viruses. In this study, we expanded the arsenal of drugs active against the simian retrovirus SIVmac251 and showed that this virus is inhibited by the protease inhibitor, darunavir, and the CCR5 blocker, maraviroc. Administration of these two drugs in combination with the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the integrase inhibitor, raltegravir, resulted in prolonged plasma viral loads below assay detection limits, and, surprisingly, restricted the viral reservoir, a marker of which is viral DNA. We then decided to employ this multidrug regimen (termed “highly intensified ART”) in order to increase the potency of a previous strategy based on the gold drug auranofin, which recently proved able to restrict the viral reservoir in vivo. A short course of highly intensified ART following the previous treatment resulted, upon therapy suspension, in a remarkably spontaneous control of the infection, that may pave the way to a persistent suppression of viremia in the absence of ART. These results corroborate the robustness of the macaque AIDS model as a vanguard for potentially future treatments for HIV in humans.
02.09.09(a): Case Study: Type I Diabetes Overview of Immune Response Open.Michigan
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
Viral evolution theories suggest that viruses did not come from a single common ancestor. There are three main hypotheses for the origin of viruses: that they devolved from cellular organisms like bacteria and lost components over time; that genetic material escaped from cells wrapped in a protein coat; or that self-replicating particles co-evolved alongside cells and adapted to new cell types.
Viruses are molecular parasites that infect host cells by packaging their RNA or DNA genomes and producing mRNA to make new viruses. They have compact genomes that can be single or segmented, and they replicate in different ways. Viruses cause acute, chronic, latent, or oncogenic infections depending on how they interact with the host. They enter the body, attach to cells, spread through the bloodstream and tissues, replicate, and are released. Their virulence and the disease they cause depend on factors like their tropism, replication efficiency, and ability to interact with the host immune response. Understanding viruses helps explain disease manifestations and assess threats from new pathogens or strains.
Analysis of a Model for the Dynamics of Hepatitis B with Noncytolytic Loss of...Cruz Vargas-De-León
This document analyzes a mathematical model for the dynamics of hepatitis B virus (HBV) infection that includes noncytolytic loss of infected cells. It summarizes previous models of HBV dynamics and introduces a new model consisting of differential equations tracking uninfected cells, infected cells, and free virus over time. The document investigates the stability of infection-free and infected steady states and performs global stability analysis using Lyapunov functions and theory of competitive systems. Numerical simulations are presented to illustrate the results.
1) The study examined the effects of infliximab treatment on Crohn's disease patients infected with Mycobacterium avium ssp. paratuberculosis (MAP), which has been associated with Crohn's disease.
2) Patients treated with infliximab showed significantly decreased levels of antibodies against two MAP proteins compared to untreated patients, suggesting infliximab decreases secretion of these proteins.
3) The study also found infliximab treatment was detrimental to the survival of MAP within infected macrophages, with significantly decreased survival of MAP in macrophages exposed to infliximab.
There are three theories of viral evolution: 1) Viruses evolved from parasitic cellular organisms that lost unnecessary cellular components; 2) Viruses evolved from free-living organisms that later became parasitic on cells; 3) Viruses originated as leftover genetic material from cellular organisms (the most widely accepted theory), which explains why viruses target specific cell types.
The document discusses how systems biology approaches can help improve vaccine design and testing. Researchers are able to measure immune system responses to potential vaccines at the genetic, protein, and cellular levels. By analyzing these complex data sets, they can identify signature profiles of protective immunity and use them to guide vaccine development. This allows them to quickly evaluate many candidates and focus on improving the most promising ones. The approach has provided insights into why some vaccines like yellow fever are highly effective. Researchers are now applying these methods to develop an HIV vaccine by studying immune responses in monkeys infected with simian immunodeficiency virus.
The clonal selection theory proposes that lymphocytes recognize and respond to antigens. When B cells encounter an antigen, they clone into plasma cells that secrete antibodies specific to that antigen. Memory B cells are also formed that respond faster upon reexposure. The theory helped explain tolerance and laid the foundation for understanding transplantation. It has supported network theories of how immune cells regulate each other via interactions.
Applications of artificial immune system a reviewijfcstjournal
The Biological Immune System is a remarkable information processing and self-learning system that offers
stimulation to build Artificial Immune System (AIS).During the last two decades, the field of AIS is
progressing slowly and steadily as a branch of Computational Intelligence (CI). At present the AIS
algorithms such as Negative Selection Theory, Clonal Selection Theory, Immune Networks Theory, Danger
theory and Dendritic Cell Algorithm are widely used to solve many real world problems in a vast range of
domain areas such as Network Intrusion Detection (NID), Anomaly Detection, Clustering and
classification and Pattern recognition. This review paper critically discusses the theoretical foundation,
research methodologies and applications of the AIS.
Introduction to Immunity Antibody Function & Diversity 2006 L1&2-overview & AbLionel Wolberger
This document provides an overview of a lecture on antibody function and diversity. It introduces antibody gene rearrangement and discusses how antibodies recognize an almost infinite number of antigens through genetic diversity mechanisms like variable gene segments and junctional diversity during lymphocyte development. Key textbooks on immunology are also referenced.
The document provides an overview of the immune system. It discusses that the immune system consists of innate and adaptive immunity. The innate immune system provides non-specific defenses like skin, mucus, cilia and phagocytes. The adaptive immune system has antigen-specific responses mediated by B cells, T cells and antibodies that provide long-lasting immunity. Major cells involved are macrophages, neutrophils, NK cells, T helper cells, cytotoxic T cells, B cells and plasma cells. The adaptive immune response involves processes like clonal selection, antibody production and immunological memory.
chapter 1 overview of the immune system.pptxNabdNabd
The immune system protects the body from pathogens and cancer through a complex network of cells and molecules. It has two main functions: recognition of foreign substances and response to eliminate them. The immune response involves both humoral immunity through antibodies and cell-mediated immunity through immune cells. Over time, the immune system has evolved improved methods of inducing immunity, from variolation to modern vaccination.
The Nobel Prize is awarded annually for achievements in physics, chemistry, physiology or medicine, literature, and peace. The prizes were first awarded in 1901 in accordance with Alfred Nobel's will. The 1901 prizes in physiology or medicine were awarded to Emil von Behring for his work on diphtheria antitoxin and Paul Ehrlich for his work on immunity and chemotherapy. Subsequent prizes have been awarded for major advances in understanding the immune system, including discoveries of monoclonal antibodies, the major histocompatibility complex, immune tolerance, and the roles of dendritic cells and innate immunity.
This lecture discusses tumour immunology. The key points covered are:
1. Immune surveillance acts against viruses, not tumors. While immunosuppression increases risk of virus-associated cancers, it does not generally increase risk of non-viral tumors.
2. Tumors express tumor-associated antigens that can be recognized by the immune system. These include viral antigens in virus-associated tumors and mutated or overexpressed normal proteins in non-viral tumors.
3. Both T-cells and antibodies can detect tumor-associated antigens. Studies using mixed lymphocyte tumor cultures or monoclonal antibodies have helped identify some of these antigens.
4. Many tumor-associated antigens are normal proteins that are aberrant
The immune system consists of innate and adaptive components. The innate system provides initial defense against infection, while the adaptive system responds specifically to challenges through antigenic specificity, diversity, immunological memory, and self/non-self discrimination. Adaptive immunity involves lymphocytes and antigen-presenting cells working cooperatively. B lymphocytes mature in the bone marrow and express unique antibody receptors, becoming activated upon antigen binding to differentiate into plasma cells that secrete large amounts of antibodies. T lymphocytes mature in the thymus and express unique T cell receptors.
EVIDENCE FOR EFFECTS ON THE IMMUNE SYSTEM - EMF Sensitivity Not Relevant
The document discusses the immune system and its response to electromagnetic fields. It provides background on the basic components and functions of the immune system. It then discusses how the immune system can have hypersensitivity reactions to environmental substances, including electromagnetic fields. It notes several types of hypersensitivity reactions and cells involved. Finally, it discusses natural and human-made sources of electromagnetic fields and how different frequencies interact with the body.
Natural killer (NK) cells are a type of lymphocyte that plays a major role in the innate immune system by killing tumor cells and virally infected cells. NK cells are cytotoxic and contain granules with proteins like perforin and granzymes that can induce apoptosis in target cells. Patients deficient in NK cells are highly susceptible to herpes virus infections. NK cells recognize and kill tumor or infected cells but can also communicate signals to block destruction of tumors or viruses depending on the signals they receive. They are activated through killer activating receptors. [END SUMMARY]
That’s important because right now, doctors have to rely on a set of 11 criteria, which can overlap with many other diseases, to try to make a diagnosis.
“It is one of the most complex clinical diagnoses,” says Pascual, who is also a practicing pediatric rheumatologist.
“It might lead to better diagnostic tests, but we don’t know that yet,” Pascual says. Other experts say the discoveries will most certainly lead to new drug targets.
Systemic lupus erythematosus (also called SLE or lupus)
is an autoimmune condition. The normal role of your
body’s immune system is to fight off infections and
diseases to keep you healthy. In an autoimmune disease
like lupus, your immune system starts attacking your
own healthy tissues. For some people lupus may just
affect the skin and/or joints. In other people the lungs,
kidneys, blood vessels,
Novel research aimed at finding a cure for AIDS requires animal models responding to human antiretroviral drugs. However, there have been few antiretrovirals cross-active against the simian viruses. In this study, we expanded the arsenal of drugs active against the simian retrovirus SIVmac251 and showed that this virus is inhibited by the protease inhibitor, darunavir, and the CCR5 blocker, maraviroc. Administration of these two drugs in combination with the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the integrase inhibitor, raltegravir, resulted in prolonged plasma viral loads below assay detection limits, and, surprisingly, restricted the viral reservoir, a marker of which is viral DNA. We then decided to employ this multidrug regimen (termed “highly intensified ART”) in order to increase the potency of a previous strategy based on the gold drug auranofin, which recently proved able to restrict the viral reservoir in vivo. A short course of highly intensified ART following the previous treatment resulted, upon therapy suspension, in a remarkably spontaneous control of the infection, that may pave the way to a persistent suppression of viremia in the absence of ART. These results corroborate the robustness of the macaque AIDS model as a vanguard for potentially future treatments for HIV in humans.
02.09.09(a): Case Study: Type I Diabetes Overview of Immune Response Open.Michigan
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
Viral evolution theories suggest that viruses did not come from a single common ancestor. There are three main hypotheses for the origin of viruses: that they devolved from cellular organisms like bacteria and lost components over time; that genetic material escaped from cells wrapped in a protein coat; or that self-replicating particles co-evolved alongside cells and adapted to new cell types.
Viruses are molecular parasites that infect host cells by packaging their RNA or DNA genomes and producing mRNA to make new viruses. They have compact genomes that can be single or segmented, and they replicate in different ways. Viruses cause acute, chronic, latent, or oncogenic infections depending on how they interact with the host. They enter the body, attach to cells, spread through the bloodstream and tissues, replicate, and are released. Their virulence and the disease they cause depend on factors like their tropism, replication efficiency, and ability to interact with the host immune response. Understanding viruses helps explain disease manifestations and assess threats from new pathogens or strains.
Analysis of a Model for the Dynamics of Hepatitis B with Noncytolytic Loss of...Cruz Vargas-De-León
This document analyzes a mathematical model for the dynamics of hepatitis B virus (HBV) infection that includes noncytolytic loss of infected cells. It summarizes previous models of HBV dynamics and introduces a new model consisting of differential equations tracking uninfected cells, infected cells, and free virus over time. The document investigates the stability of infection-free and infected steady states and performs global stability analysis using Lyapunov functions and theory of competitive systems. Numerical simulations are presented to illustrate the results.
1) The study examined the effects of infliximab treatment on Crohn's disease patients infected with Mycobacterium avium ssp. paratuberculosis (MAP), which has been associated with Crohn's disease.
2) Patients treated with infliximab showed significantly decreased levels of antibodies against two MAP proteins compared to untreated patients, suggesting infliximab decreases secretion of these proteins.
3) The study also found infliximab treatment was detrimental to the survival of MAP within infected macrophages, with significantly decreased survival of MAP in macrophages exposed to infliximab.
There are three theories of viral evolution: 1) Viruses evolved from parasitic cellular organisms that lost unnecessary cellular components; 2) Viruses evolved from free-living organisms that later became parasitic on cells; 3) Viruses originated as leftover genetic material from cellular organisms (the most widely accepted theory), which explains why viruses target specific cell types.
The document discusses how systems biology approaches can help improve vaccine design and testing. Researchers are able to measure immune system responses to potential vaccines at the genetic, protein, and cellular levels. By analyzing these complex data sets, they can identify signature profiles of protective immunity and use them to guide vaccine development. This allows them to quickly evaluate many candidates and focus on improving the most promising ones. The approach has provided insights into why some vaccines like yellow fever are highly effective. Researchers are now applying these methods to develop an HIV vaccine by studying immune responses in monkeys infected with simian immunodeficiency virus.
The clonal selection theory proposes that lymphocytes recognize and respond to antigens. When B cells encounter an antigen, they clone into plasma cells that secrete antibodies specific to that antigen. Memory B cells are also formed that respond faster upon reexposure. The theory helped explain tolerance and laid the foundation for understanding transplantation. It has supported network theories of how immune cells regulate each other via interactions.
Applications of artificial immune system a reviewijfcstjournal
The Biological Immune System is a remarkable information processing and self-learning system that offers
stimulation to build Artificial Immune System (AIS).During the last two decades, the field of AIS is
progressing slowly and steadily as a branch of Computational Intelligence (CI). At present the AIS
algorithms such as Negative Selection Theory, Clonal Selection Theory, Immune Networks Theory, Danger
theory and Dendritic Cell Algorithm are widely used to solve many real world problems in a vast range of
domain areas such as Network Intrusion Detection (NID), Anomaly Detection, Clustering and
classification and Pattern recognition. This review paper critically discusses the theoretical foundation,
research methodologies and applications of the AIS.
Introduction to Immunity Antibody Function & Diversity 2006 L1&2-overview & AbLionel Wolberger
This document provides an overview of a lecture on antibody function and diversity. It introduces antibody gene rearrangement and discusses how antibodies recognize an almost infinite number of antigens through genetic diversity mechanisms like variable gene segments and junctional diversity during lymphocyte development. Key textbooks on immunology are also referenced.
The document provides an overview of the immune system. It discusses that the immune system consists of innate and adaptive immunity. The innate immune system provides non-specific defenses like skin, mucus, cilia and phagocytes. The adaptive immune system has antigen-specific responses mediated by B cells, T cells and antibodies that provide long-lasting immunity. Major cells involved are macrophages, neutrophils, NK cells, T helper cells, cytotoxic T cells, B cells and plasma cells. The adaptive immune response involves processes like clonal selection, antibody production and immunological memory.
chapter 1 overview of the immune system.pptxNabdNabd
The immune system protects the body from pathogens and cancer through a complex network of cells and molecules. It has two main functions: recognition of foreign substances and response to eliminate them. The immune response involves both humoral immunity through antibodies and cell-mediated immunity through immune cells. Over time, the immune system has evolved improved methods of inducing immunity, from variolation to modern vaccination.
The Nobel Prize is awarded annually for achievements in physics, chemistry, physiology or medicine, literature, and peace. The prizes were first awarded in 1901 in accordance with Alfred Nobel's will. The 1901 prizes in physiology or medicine were awarded to Emil von Behring for his work on diphtheria antitoxin and Paul Ehrlich for his work on immunity and chemotherapy. Subsequent prizes have been awarded for major advances in understanding the immune system, including discoveries of monoclonal antibodies, the major histocompatibility complex, immune tolerance, and the roles of dendritic cells and innate immunity.
This lecture discusses tumour immunology. The key points covered are:
1. Immune surveillance acts against viruses, not tumors. While immunosuppression increases risk of virus-associated cancers, it does not generally increase risk of non-viral tumors.
2. Tumors express tumor-associated antigens that can be recognized by the immune system. These include viral antigens in virus-associated tumors and mutated or overexpressed normal proteins in non-viral tumors.
3. Both T-cells and antibodies can detect tumor-associated antigens. Studies using mixed lymphocyte tumor cultures or monoclonal antibodies have helped identify some of these antigens.
4. Many tumor-associated antigens are normal proteins that are aberrant
The immune system consists of innate and adaptive components. The innate system provides initial defense against infection, while the adaptive system responds specifically to challenges through antigenic specificity, diversity, immunological memory, and self/non-self discrimination. Adaptive immunity involves lymphocytes and antigen-presenting cells working cooperatively. B lymphocytes mature in the bone marrow and express unique antibody receptors, becoming activated upon antigen binding to differentiate into plasma cells that secrete large amounts of antibodies. T lymphocytes mature in the thymus and express unique T cell receptors.
EVIDENCE FOR EFFECTS ON THE IMMUNE SYSTEM - EMF Sensitivity Not Relevant
The document discusses the immune system and its response to electromagnetic fields. It provides background on the basic components and functions of the immune system. It then discusses how the immune system can have hypersensitivity reactions to environmental substances, including electromagnetic fields. It notes several types of hypersensitivity reactions and cells involved. Finally, it discusses natural and human-made sources of electromagnetic fields and how different frequencies interact with the body.
Natural killer (NK) cells are a type of lymphocyte that plays a major role in the innate immune system by killing tumor cells and virally infected cells. NK cells are cytotoxic and contain granules with proteins like perforin and granzymes that can induce apoptosis in target cells. Patients deficient in NK cells are highly susceptible to herpes virus infections. NK cells recognize and kill tumor or infected cells but can also communicate signals to block destruction of tumors or viruses depending on the signals they receive. They are activated through killer activating receptors. [END SUMMARY]
That’s important because right now, doctors have to rely on a set of 11 criteria, which can overlap with many other diseases, to try to make a diagnosis.
“It is one of the most complex clinical diagnoses,” says Pascual, who is also a practicing pediatric rheumatologist.
“It might lead to better diagnostic tests, but we don’t know that yet,” Pascual says. Other experts say the discoveries will most certainly lead to new drug targets.
Systemic lupus erythematosus (also called SLE or lupus)
is an autoimmune condition. The normal role of your
body’s immune system is to fight off infections and
diseases to keep you healthy. In an autoimmune disease
like lupus, your immune system starts attacking your
own healthy tissues. For some people lupus may just
affect the skin and/or joints. In other people the lungs,
kidneys, blood vessels,
The study in immunology provides the fundamental understanding of how the human body defend itself against foreign organisms, materials or particles that have the ability to cause harm to host tissues.
Embryonic stem cells – Promises and IssuesTania Jabin
Introduction, Embryonic Stem Cells, Promises of Embryonic Stem cell research, Figure: The Promise of Stem Cell Research, Issues in Embryonic Stem cells - New embryonic stem cell lines from frozen embryos Informed consent for donation of materials for stem cell research Waiver of consent Consent from gamete donors Confidentiality of donor information Ethical concerns about oocyte donation for research (1. Medical risks of oocyte retrieval, 2. Protecting the reproductive interests of women in infertility treatment, 3. Payment to oocyte donors, 4. Informed consent for oocyte donation).
Behavioral immunology ( Behavioral immunology” refers to the branch of behavioral medicine concerned with bidirectional interactions between behavior and the immune system).
The document discusses behavioral immunology and the bidirectional relationship between behavior and the immune system. It provides examples of how the immune system interacts with behavior in swordfish, electric eels, and sex differences in immune response. The thymus is described as an organ that helps develop T-cells. The behavioral immune system can influence prejudices and disease avoidance behaviors in humans.
Central tolerance mechanisms aim to eliminate self-reactive immune cells in the thymus through clonal deletion and anergy. Peripheral tolerance mechanisms such as clonal anergy, antigen blockade, and immunologically privileged sites help maintain unresponsiveness to self-antigens outside the thymus. A breakdown of tolerance leads to autoimmunity, where the immune system attacks the body's own tissues and organs.
Therapeutic cloning involves harvesting somatic cells from a patient and using them to create patient-specific embryonic stem cells via somatic cell nuclear transfer. These stem cells could potentially be used to treat various diseases by replacing damaged tissues and organs, repairing autoimmune disorders, or delivering gene therapy. However, significant technological and moral barriers remain, including the inability to reliably create human embryonic stem cells through cloning and opposition from groups who believe such embryos should be considered viable human life. Further research is still needed to ensure stem cells can safely differentiate, survive in patients, and function properly without harm. A legal definition of when an embryo becomes an organism could help resolve some moral debates over therapeutic cloning.
This document summarizes recent findings that challenge the traditional definitions of innate and adaptive immunity. It provides three examples of studies that found evidence of immune specificity and memory in invertebrates like water fleas and copepods. It also notes that while mammals use immunoglobulins for antigen recognition, other phyla use different receptor systems, and that innate immune systems may be more complex than originally believed. The growing evidence from diverse species suggests a blurring of the lines between innate and adaptive immunity.
The document provides an overview of the human immune system and how it responds to pathogens. It discusses the four main stages of the immune response: 1) phagocytosis where phagocytes engulf pathogens, 2) T-cell activation where T-cells recognize antigens, 3) B-cell activation and plasma cell production where B-cells secrete antibodies, and 4) antibody production where plasma cells secrete antibodies specific to the pathogen. It also covers primary versus secondary immune responses, vaccines, antigenic variation in pathogens, and the potential use of monoclonal antibodies to fight diseases like cancer.
El documento describe las diferentes especializaciones de la membrana celular en plantas, bacterias y células animales. En plantas, la pared celular proporciona estructura, protección y control de la presión osmótica. En bacterias, la pared celular mantiene la forma y protege de agentes externos. En animales, la matriz extracelular contiene colágeno, elastina y proteoglicanos que dan soporte a los tejidos, mientras que las uniones intercelulares como las adherentes y comunicantes coordinan la actividad entre células.
Las membranas celulares están compuestas principalmente por lípidos y proteínas. Los lípidos forman una bicapa que separa el interior de la célula del exterior, mientras que las proteínas cumplen funciones como el transporte a través de la membrana. El modelo actual de la estructura de la membrana es el modelo de mosaico fluido, en el que las proteínas se distribuyen de forma dinámica en la bicapa fluida de lípidos. Las membranas cumplen funciones vitales como la protección, el transporte selectivo,
This document discusses innate immunity in Drosophila and mammals. In Drosophila, innate immunity involves phagocytosis, proteolytic cascades, and production of antimicrobial peptides. The peptides are produced in the fat body and barrier epithelia. In mammals, innate immunity recognizes pathogens and distinguishes self from nonself. It also links to adaptive immunity. Innate defenses are highly conserved between insects and mammals, pointing to a common ancestry.
This document provides a brief history of immunobiology, listing some of the key figures who contributed to early discoveries, including Edward Jenner, Louis Pasteur, Robert Koch, Paul Ehrlich, and Elie Metchnikoff. It also lists some references for anatomy of the immune system from Blackwell in 2001 and Rodney Langman's 1989 book on the immune system which applied evolutionary principles to understanding this complex biological defense system.
The document summarizes key ideas and evidence regarding the origin of life on Earth, including:
1) Early Earth conditions like the Urey atmosphere could have enabled the abiotic synthesis of organic molecules and compounds found in meteorites.
2) Experiments in the 1950s and 1960s demonstrated plausible prebiotic synthesis routes for important biomolecules like amino acids and nucleotides.
3) RNA molecules could have served both genetic and catalytic functions in a hypothetical "RNA world" before the emergence of DNA and proteins.
1. Christian de Duve used centrifugation techniques to separate rat liver cell components into fractions based on density, allowing him to identify discrete organelles like lysosomes.
2. He observed that the enzyme uricase was concentrated in the light mitochondrial fraction, separate from lysosomal enzymes, suggesting it was contained in another organelle.
3. Through repeated equilibrium density gradient centrifugation, de Duve found that uricase consistently separated from lysosomal and mitochondrial enzymes, confirming it was located in a distinct organelle involved in peroxide metabolism that he named the peroxisome.
Este documento presenta el programa de una asignatura de Biología Celular que incluye seis unidades temáticas y fechas de sesiones plenarias. También incluye breves descripciones sobre la definición de Biología Celular, los niveles de organización biológica, la teoría celular, y técnicas usadas para el estudio de células.
How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
The complex relationship between human activities and the environment has been the focus
of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
more evident. A crucial element of this impact is the alteration of vegetation cover, which plays a
significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
This slide is special for master students (MIBS & MIFB) in UUM. Also useful for readers who are interested in the topic of contemporary Islamic banking.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
This presentation was provided by Steph Pollock of The American Psychological Association’s Journals Program, and Damita Snow, of The American Society of Civil Engineers (ASCE), for the initial session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session One: 'Setting Expectations: a DEIA Primer,' was held June 6, 2024.
Strategies for Effective Upskilling is a presentation by Chinwendu Peace in a Your Skill Boost Masterclass organisation by the Excellence Foundation for South Sudan on 08th and 09th June 2024 from 1 PM to 3 PM on each day.
1. REFLECTIONS ON SELF: IMMUNITY AND BEYOND
VIEWPOINT
The Danger Model: A Renewed
Sense of Self
Polly Matzinger
For over 50 years immunologists have based their thoughts, experiments, the discovery that activated B lymphocytes
and clinical treatments on the idea that the immune system functions by hypermutate, creating new, potentially self-
making a distinction between self and nonself. Although this paradigm has reactive cells. Realizing that autoimmunity
often served us well, years of detailed examination have revealed a would be rare if immunity required the coop-
number of inherent problems. This Viewpoint outlines a model of immu- eration of two cells, Bretscher and Cohn (14 )
nity based on the idea that the immune system is more concerned with added a new cell (the helper, later found to be
entities that do damage than with those that are foreign. a T cell) and a new signal (help), proposing
that the B cell would die if it recognized
First, do no harm. been incorporated into previous models [for antigen in the absence of help (Fig. 1B). In
–Hippocratic oath example, why major histocompatibility com- 1975, Lafferty and Cunningham (15) dealt
plex (MHC)–mismatched kidney transplants with the finding that T cells respond more
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Of all the mysteries in modern science, the from living donors often perform better than strongly against foreign cells of their own
mechanisms of self versus nonself recognition MHC-compatible kidneys from cadavers (4); species than against cells of another species,
in the immune system ranks at or near the why liver transplants are rejected less vigor- by adding another cell and another signal.
top. ously than hearts; why women seem to be They proposed that T cells also need a second
–D. E. Koshland Jr. (1) more susceptible than men to certain autoim- signal (named “costimulation”), which they
As a graduate student, I was taught that mune diseases; why Rh disease of the new- receive from “stimulator” cells [now called
the immune system functions by discriminat- born is a problem in the second pregnancy, antigen-presenting cells (APCs)], and sug-
ing between self (defined early in life) and but not the first; why graft-versus-host dis- gested that this signal is species specific (Fig.
nonself (anything that comes later), tolerating ease is less severe in recipients that have had 1C).
self and attacking nonself. Although this el- gentle rather than harsh preconditioning treat-
egantly simple idea seemed to make a lot of ments (5, 6 ); and so on] without adding The Infectious-Nonself (INS) Model
sense, it had problems from the beginning special new situation-specific assumptions. The need for costimulation posed a major
and has failed over the years to explain a This Viewpoint will first trace the history problem for SNS models. If, as they assumed,
great number of findings. For example, what of the self-nonself (SNS) model, showing the decision to respond is made by antigen-
happens when “self ” changes? How do or- how it had to be modified over the years to specific cells, and if self-reactive ones are
ganisms go through puberty, metamorphosis, accommodate new data, then give a brief deleted, then immunity can be directed
pregnancy, and aging without attacking new- description of the Danger model, and show against nonself. If, however, responses are
ly changed tissues? Why do mammalian how it is leading us to a new way of thinking initiated by APCs, which are not antigen
mothers not reject their fetuses or attack their about self-recognition. Those readers who specific (they capture all sorts of self and
newly lactating breasts, which produce milk may already have encountered some of these foreign substances), then immunity cannot be
proteins that were not part of earlier “self ”? concepts (2, 7–9) will find more details in the directed only against nonself. The concept of
Why do we fail to make immune responses to supplementary Web material on Science On- costimulation was therefore essentially ig-
vaccines composed of inert foreign proteins line (10). nored until it was rediscovered experimental-
unless we add noxious substances, collective- ly by Jenkins and Schwartz in 1986 (16 ). In
ly known as “adjuvants”? Why do we fail to The Self-Nonself Models 1989, Janeway offered an ingenious solution
reject tumors, even when many clearly ex- Burnet’s original model (11) suggested (Fig. (17), suggesting that APCs have their own
press new or mutated proteins? Why do most 1) that (i) each lymphocyte expresses multi- form of SNS discrimination and can recog-
of us harbor autoreactive lymphocytes with- ple copies of a single surface receptor specif- nize evolutionarily distant pathogens. He pro-
out any sign of autoimmune disease, while a ic for a foreign entity, (ii) signaling through posed that APCs are quiescent (a very impor-
few individuals succumb? this surface antibody initiates the immune tant and previously unappreciated point) until
To answer some of these questions, I pro- response, and (iii) the self-reactive lympho- they are activated via a set of germ line–
posed the Danger model, which suggests that cytes are deleted early in life [based on encoded pattern recognition receptors (PRRs)
the immune system is more concerned with Owen’s discovery that nonidentical cattle that recognize conserved pathogen-associated
damage than with foreignness, and is called twins were mutually tolerant of each other’s molecular patterns (PAMPs) on bacteria. On
into action by alarm signals from injured blood cells (12)]. This straightforward model activation, APCs up-regulate costimulatory
tissues, rather than by the recognition of non- gained general acceptance when Medawar et signals, process the bacterial antigens, and
self (2, 3). In the intervening 7 years, in al. found that adult mice would accept for- present them to passing T cells (Fig. 1D). The
conversations with a wide variety of people, I eign skin grafts if they had been injected as PRRs, he wrote, allow APCs to discriminate
discovered that this simple idea not only of- babies with cells from the donors (13). In between “infectious-nonself ” and “noninfec-
fers answers to broad immunological ques- 1960, Burnet and Medawar shared the Nobel tious-self ” (18).
tions, it also covers many details that had not Prize for their work, and the SNS discrimi- Although the essence of SNS recognition
nation model has dominated the field ever was temporarily saved, Janeway’s infectious-
since. nonself (INS) model created new complexi-
Ghost Lab, Laboratory for Cellular and Molecular Im-
munology, National Institute of Allergy and Infectious
The original SNS model has changed, ties while solving old problems. It could not
Diseases, National Institutes of Health, Bethesda, MD however, to accommodate incompatible new explain why viruses stimulate immunity, why
20892, USA. E-mail: pcm@helix.nih.gov findings. It was first modified in 1969, after transplants are rejected, what induces autoim-
www.sciencemag.org SCIENCE VOL 296 12 APRIL 2002 301
2. REFLECTIONS ON SELF: IMMUNITY AND BEYOND
munity, why tumors are sometimes spontane- forth (Fig. 1e). Although purely theoretical at predictive power of this model provides insight
ously rejected, or how nonbacterial adju- the time (20), many alarm signals have since into many of the things that the immune system
vants, such as alum, work. Over the years, been empirically revealed (9). Alarm signals does right, as well as many of the things it
Janeway’s model has been modified to ac- can be constitutive or inducible, intracellular seems to get wrong (21).
count for some of these issues (see Viewpoint or secreted, or even a part of the extracellular
by Medzhitov and Janeway in this issue) matrix. Because cells dying by normal pro- Danger Signals: Common Ground for
(19), suggesting, for example, that viral dou- grammed processes are usually scavenged the INS and Danger Models?
ble-stranded mRNA is a signature of foreign- before they disintegrate, whereas cells that Although they differ greatly in detail, both
ness. What then of viruses that do not gener- die necrotically release their contents, any the INS and the Danger models assume that
ate double-stranded RNA, adjuvants that do intracellular product could potentially be a resting APCs can be activated by signals
not incorporate bacterial products, trans- danger signal when released. Inducible alarm from their immediate environment. The INS
plants, and autoimmunity? Even with all of signals could include any substance made, or model has found support in the recent discov-
the modifications that SNS/INS models have modified, by distressed or injured cells. The ery of the evolutionarily conserved membrane-
undergone over the years, they still have dif- important feature is that danger/alarm signals bound Toll-like receptors (TLRs), which act as
ficulty with some of these fundamental pro- should not be sent by healthy cells or by cells PRRs for components of bacteria and fungi,
cesses. undergoing normal physiological deaths. and initiate immune responses in organisms
Although this may seem to be just one more as distant as flies and mammals (22–26 ).
The Danger Model step down the path of slowly increasingly com- There are presently 10 known mammalian
Standing on the shoulders of the SNS models, plex cellular interactions, this small step drops TLRs, which bind a wide range of biological
Downloaded from www.sciencemag.org on October 1, 2009
the Danger model added another layer of us off a cliff, landing us in a totally different molecules and awaken resting APCs (27 ).
cells and signals (2), proposing that APCs are viewpoint, in which the “foreignness” of a The Danger model has been supported by
activated by danger/alarm signals from in- pathogen is not the important feature that trig- the discovery of endogenous, nonforeign alarm
jured cells, such as those exposed to patho- gers a response, and “self-ness” is no guarantee signals (9), including mammalian DNA (28),
gens, toxins, mechanical damage, and so of tolerance. The surprising explanatory and RNA, heat shock proteins (Hsps), interferon-
Fig. 1. A history of immunological models.
302 12 APRIL 2002 VOL 296 SCIENCE www.sciencemag.org
3. REFLECTIONS ON SELF: IMMUNITY AND BEYOND
(an inducible protein often made by virus-in- cific for a bacterial LPS, cellular Hsp70 pro- nals, and the microbes subsequently evolved
fected cells), interleukin-1 , CD40-L (a surface tein, and hyaluron? mechanisms to use these receptors to enhance
molecule on activated platelets and activated T One possibility is that we may be looking at their own survival. From this vantage point, it
cells), and breakdown products of hyaluron the PRRs completely backwards (7). Perhaps may no longer be surprising that the TLRs
(made when vessels are damaged). PRRs have not evolved to bind to pathogens at bind to so many different kinds of molecule,
There is no reason why APCs should not all. Perhaps the pathogens have evolved to bind as each type of pathogen will have evolved its
respond to both endogenous and exogenous to them! Many cell surface molecules involved own way of binding to a TLR.
signals. Vertebrates and bacteria have shared in normal physiological functions are targeted S. Y. Seong has suggested the even more
eons of evolutionary time and space, and thus by pathogens. Human immunodeficiency virus, intriguing possibility (34) that the same
receptors for endogenous and exogenous sig- for example, binds to CD4, CCR5, and CxCR4, alarm signals may be used by many different
nals may have evolved simultaneously. In- and Toxoplasma also seems to bind to CCR5 organisms. Because life evolved in water, any
deed, there is evidence that these receptors (30), whereas Staphylococcus and Streptococ- hydrophobic portion (Hyppo) of a given mol-
are often the same molecules. For example, cus bind to a conserved loop on T cell receptors ecule is usually buried in the depths of that
TLR4 is a receptor for the bacterial product and to the Fc portion of antibodies. Coxsackie molecule, or hidden in the lipid membrane of
lipopolysaccharide (LPS), the endogenous virus binds to intracellular cell adhesion mole- the cell, and could act as an alarm signal if
cellular molecule Hsp70, and the extracellu- cule–1 (ICAM-1), rabies to N-CAM, and Ep- exposed (34 ). For example, the hydrophobic
lar breakdown products of hyaluron; TLR2 stein-Barr virus to complement receptor 2, thus part of LPS is crucial for its immunostimu-
binds bacterial lipoproteins and Hsp 60; and activating a B cell as it enters. No one suggests lating properties, yet LPS is normally an in-
TLR9 binds to DNA CpG sequences (found that these molecules have evolved to act as tegral bacterial membrane molecule and its
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in all living creatures). Thus, it appears that receptors for pathogens. We assume instead Hyppos are hidden in the membrane. How-
the TLRs can recognize both endogenous and that the pathogen’s ability to bind to these ever, when released by damaged or dead
exogenous molecules. The binding character- molecules serves the pathogen’s agenda, not bacteria, the newly exposed Hyppos could act
istics of a newly discovered family of intra- ours. Similarly, the PRRs may be misnamed. as a bacterial alarm signal (or perhaps a type
cellular proteins, called nucleotide-binding For example, CD14, which recognizes ap- of quorum sensor (35), perhaps signaling the
oligomerization domain (NOD) receptors, are optotic cells (31), has been called a PRR surviving bacteria to sporulate or otherwise
not yet as well worked out, but it is beginning because it also binds to bacterial LPS (32). change their behavior. Plant and animal cells
to appear that they too can respond to both However, mice lacking CD14 resist Gram- also have an abundant supply of hidden Hyp-
injury/pathogen-related signals and normal negative bacteria more vigorously than pos in their membranes and cytoplasm. Dur-
physiological signals involved with apoptosis their normal littermates (33), suggesting ing protein synthesis, Hsps and other chaper-
(29). Indeed, one of the puzzling features of that the LPS-CD14 interaction is more fa- ones bind to the Hyppos of nascent proteins
TLRs and NODs is that each one can bind to vorable to the bacterium than to the host. to prevent their aggregation. Should a cell be
many different kinds of molecules. How can Thus, perhaps TLRs and NODs originally disrupted, the Hyppos of both the nascent
one receptor—TLR4, for example— be spe- evolved as receptors for injury-related sig- proteins and their chaperones would be ex-
posed. Future evidence may show that our
Fig. 2. Partitioning the immune systems may thus be using TLRs and
universe of antigens. other receptors to respond to truly ancient
SNS models split all multipurpose signals of distress that cross
antigens into two sets:
self and nonself (sets
species barriers.
a and b). The INS
model divides anti- Dangerous Self and Harmless Foreign:
gens into “noninfec- The Uncommon Ground Between the
tious self ” (set a) and Two Models
“infectious nonself ” Although the INS version of the SNS models
(set f ), suggesting the
and the Danger model have some common
existence of patho-
gen-associated molec- features, their basic assumptions about what
ular patterns (PAMPs) initiates immunity are fundamentally differ-
that are evolutionarily ent. Is it microbial nonself or is it danger? As
conserved on patho- nonself is sometimes dangerous, the defini-
gens that are evolu- tions overlap, but they are not identical (Fig.
tionarily very distant
2). For dangerous foreign pathogens (Fig. 2,
from their hosts, and
that the host APCs can sets d and e) or harmless self (Fig. 2, set a),
therefore have germ the two models make the same predictions.
line– encoded pattern However, some things (Fig. 2, sets b and f)
recognition receptors are foreign but harmless (e.g., fetuses),
(PRRs) to detect them. whereas others (Fig. 2, set c) are self but
It tends to ignore the
subsets b and f. The
harmful (e.g., some mutations). For these en-
Danger model parti- tities lying outside the overlapping sets, the
tions antigens into INS and Danger models make different pre-
those associated with dictions, and these are therefore the interest-
dangerous entities or ing test cases. Below I will briefly cover a
harmless ones, defin- few of these (10).
ing as dangerous anything that induces stress or nonphysiological death of a cell. Dangerous
entities may be self (set c), such as mutations that lead to stress or inappropriate cell death or
Foreign entities that are not associated with
inefficient scavenging; or nonself, such as pathogens (set e), environmental toxins (set d), and such. microbes include transplants and fetuses. Why
Set f would contain evolutionarily distant organisms that have PAMPs, but that are not dangerous should the former be rejected and the latter not?
(e.g., symbiotic organisms, well-adapted viruses). Although the INS model would suggest that
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4. REFLECTIONS ON SELF: IMMUNITY AND BEYOND
neither should be rejected because they are not teresting aspect of the Danger model has been a because they respond to stress-induced self mol-
associated with microbial stimulators, and the deep-rooted shift in thinking that it inspired. The ecules rather than to the foreign entities seen by
old SNS models would suggest that both should shift came in two phases that abruptly expanded the “adaptive” lymphocytes (45). These cells
be rejected because they are nonself, the Dan- the model’s explanatory range. Originally con- have no place in the SNS and INS models, and
ger model suggests that healthy fetuses should ceived to answer the first question the immune they have remained on the fringe of respectabil-
not be rejected because they do not send alarm system must consider when faced with a poten- ity. But, seen from the standpoint that immunity
signals. Transplants, however, cannot be per- tial threat—namely, whether to respond—the is governed by the tissues, these self-reactive
formed without surgical and/or ischemic dam- model now also offers a suggestion for the next cells do not seem so odd (7), and Bendelac calls
age. Thus, to induce the acceptance of trans- question—having decided to respond, what this “autoimmunity by design” (45). For exam-
plants without lifelong immunosuppression, we kind of response should it make? How does the ple, the dendritic epidermal T cells ( T cells)
should mimic the body’s own way of inducing immune system know whether to generate killer found in mouse and bovine skin all express
tolerance, i.e., by blocking the endogenous T cells to eliminate a virus or immunoglobulin E exactly the same receptor (46), arise late in fetal
alarm and/or costimulatory signals. Most of the (IgE) antibody to catch a worm? In immunolog- life, and emigrate in one wave to the skin, where
current immunosuppressive drug protocols en- ical terms, how does it determine the effector they settle quietly. When stimulated by the ap-
deavor to block Signal One (antigen recogni- “class” of the response? pearance of stress-induced molecules on kera-
tion). Although this effectively blindfolds the The first shift came from the realization tinocytes (47), they produce epidermal cell
lymphocytes, it also prevents them from be- that the immune system may not be the ulti- growth factor, IL-2, and IFN- . These cells are
coming tolerant, and consequently the drugs mate controller of immunity. Like most im- clearly not the kind of lymphocytes we are
must be given for life. In contrast, studies in munologists, I had thought that immunity is accustomed to. They seem to be there to pro-
Downloaded from www.sciencemag.org on October 1, 2009
rodents and monkeys (36–38) have shown that controlled by the cells of the “adaptive” im- duce cytokines that heal damaged skin by in-
short-term treatment with costimulation block- mune system (lymphocytes) or the more an- ducing cell growth and nudging local immunity
ers, or blockers of alarm signaling (39), can cient “innate” immune system (such as mac- toward a DTH. In human gut, T cells expressing
lead to long-term graft acceptance in the ab- rophages, dendritic cells, and the complement self-reactive V 6 receptors also respond to
sence of long-term immunosuppression. Per- system). I now believe that the ultimate pow- stress-induced molecules (48). Many other T
haps the lower extent of damage can explain er lies with the tissues. When healthy, tissues cells may be similar, responding to endogenous
why kidneys from living donors are accepted induce tolerance. When distressed, they stim- stress signals rather than to foreign antigens.
more easily than those from cadavers (4). Sim- ulate immunity, and (continuing down this T cells bearing / receptors can also be
ilarly, fetuses should not elicit immunity, in path) they may also determine the effector usefully self-reactive. The thymus, bone mar-
spite of being foreign, as long as they are class of a response. Although it has long been row, and liver contain NK1 T cells specific for
healthy and do not send alarm signals (10). thought that the effector class is tailored to the ancient MHC-like molecule, CD1, which is
Tumors are entities for which both the INS the targeted pathogen (e.g., virus or worm), I expressed by activated but not resting APCs
and the Danger models have the same predic- now think that it is tailored to the tissue in (49). Activated NK1 T cells from the thymus
tion, namely, that tumors should not stimulate which the response occurs. produce copious amounts of IL-4, a cytokine
immunity, either (INS) because they are not Different tissues seem to have different that skews local immune responses away from
associated with microbial stimulators, or (Dan- means of determining the effector class of a a DTH and toward the production of IgG1 and
ger) because they are healthy growing cells that response. For example, the class of response IgE. Furthermore, T cells specific for brain
do not send alarm signals. Thus, to eradicate a that occurs most often in the skin (e.g., after proteins can lessen the secondary damage that
tumor, we should infect it (40), or cause it exposure to poison ivy, TB tests, or subcutane- follows neural injury (50).
repeated damage to alert the local APCs [as Bill ous vaccinations), called “delayed type hyper- All of these tissue-localized cells appear
Coley did in the late 1800s (41, 42)], or we sensitivity” (DTH), is characterized by swell- to be useful self-reactive cells involved in
should vaccinate repeatedly with a tumor vac- ing, redness, an influx of macrophages, and the local immunity, and there may be many other
cine that stimulates immunity. production of tumor necrosis factor (TNF) and localized and/or circulating cells doing simi-
For autoimmunity, the Danger model of- interferon- (IFN- ). Unlike skin, however, lar jobs. For example, a lot of effort has gone
fers a unique suggestion that would not arise both the gut and the eye can be destroyed by into the search for the foreign ligands recog-
from the SNS or the INS models. Starting DTH responses, and the most common re- nized by circulating T cells. After more
with the view that “bad” death or cell stress sponse in these organs is the production of IgA, than a decade, very few have been found, and
can elicit an immune response, the model an antibody found at high levels in tears, saliva, these include such ubiquitous cellular mole-
suggests that some autoimmune diseases may milk, and gut secretions. To ensure that IgA is cules as polyprenyl pyrophosphate (51) and
be caused by mutations in genes governing made, and TNF and IFN- are not, the cells of phosphorylated nucleotides (52).
the normal physiological death and clearance the anterior chamber of the eye produce vaso- Perhaps, if we move from the idea that
processes, or by environmental pathogens or active intestinal peptide (VIP) and transforming every lymphocyte should be directed against
toxins that cause cellular stress or death. In growth factor– (TGF- ), two cytokines that non-self antigens whose appearance stimulates
these cases, the immune system is not at fault; are also made by the gut and that promote a the response, and consider instead the possibil-
it is doing its job of responding to alarm switch to IgA and suppress the DTH response ity that immunity is controlled by an internal
signals (but, in these cases, to the detriment (43, 44). Thus, local tissue cells strongly influ- conversation between tissues and the cells of
of the host). If we could pinpoint these mu- ence the local immune response. the immune system (53), we may regain a
tations or environmental agents, we might be The second shift came from the realization renewed sense of the self that we have lost.
able to reduce the incidence of autoimmune that tossing out the idea that the immune system
diseases. uses SNS discrimination to decide whether to References and Notes
1. D. E. Koshland Jr., Science 248, 1273 (1990).
respond leaves us free to use self-recognition in 2. P. Matzinger, Annu. Rev. Immunol. 12, 991 (1994.)
A Renewed Sense of Self: Expanding a positive way to control other aspects of the 3. The model arose from 2 years of discussions with
the Horizons of the Danger Model response. Many organs harbor special popula- Ephraim Fuchs (54).
There is inherent beauty in a model that uses tions of lymphocytes that appear to be evolu- 4. A. M. D’Alessandro et al., Surgery 124, 604 (1998).
5. P. J. Heidt, J. M. Vossen, J. Med. 23, 161 (1992).
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VIEWPOINT
Recognition and Rejection of Self
in Plant Reproduction
June B. Nasrallah
Plant self-incompatibility (SI) systems are unique among self/nonself ments that are tolerated and do not elicit a
recognition systems in being based on the recognition of self rather than response. In SI, self is the condition that
nonself. SI in crucifer species is controlled by highly polymorphic and elicits the response and is inhibited, where-
co-evolving genes linked in a complex. Self recognition is based on as nonself is the condition that is ignored
allele-specific interactions between stigma receptors and pollen ligands and does not elicit a response.
that result in the arrest of pollen tube development. Commonalities and
differences between SI and other self/nonself discrimination systems are A Variety of Plant SI Systems
discussed. As an advantageous outbreeding device, SI
is widely distributed in flowering plants
The concept of self/nonself discrimination outcome, namely the inhibition of self-related (2). It evolved independently in several
was elaborated by Burnet (1) as a way to pollen tube development and, consequently, lineages, and the SI systems adopted by
describe specificity in the immune response the prevention of sperm cell delivery to the different plant families vary with respect to
and is most often associated with the field of ovules. site and mechanism of self inhibition. In
immunology. It is perhaps less well known SI systems are said to discriminate be- self-incompatible species of the crucifer
that, in the plant kingdom, sophisticated self- tween self and nonself because they pro- family (e.g., Brassica species and close
recognition systems have evolved that allow duce different outcomes in self- and cross- relatives of Arabidopsis thaliana), SI dis-
plants with perfect (hermaphroditic) flowers pollinations. Specificity in SI is typically rupts hydration and germination of a pollen
to avoid inbreeding. These intraspecific controlled by one or more highly polymor- grain on the stigma epidermis, thus pre-
prefertilization mating barriers are collective- phic genetic loci. In the context of SI, self venting growth of pollen tubes into the
ly known as self-incompatibility (SI). This and nonself mean, respectively, genetic subepidermal tissues of the pistil. In other
term encompasses several systems that are identity and nonidentity at the SI locus (or families, SI acts after pollen germination
mechanistically distinct but have the same loci) in pistils and pollen. The outcome of and pollen tube ingress into the pistil, either
this discrimination is the converse of that of within the stigmatic zone (as in the poppy
Department of Plant Biology, Cornell University, the immune response, in which case self family), or later, within the style (as in the
Ithaca, NY 14853, USA. *E-mail: jbn2@cornell.edu has been classically defined as those ele- tobacco, rose, and snapdragon families).
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