Innate immunity pdf

Second line 2- Phagocytes Specialized cells for capture, Ingestion and destruction of invading microorganisms. Polymorphoniclear leucocytes neutrophils granulocytes circulate in blood Mononuclear cells macrophages a. Nuesslein-Volhard: Drosophila Toll Identified a protein she called Toll meaning weird Helps the Drosophila embryo to differentiate its top from its bottom Neural tube development Toll receptor has an extracellular region which contains leucine rich repeats motifs LRRs Toll receptor has a cytoplasmic tail which contains a Toll interleukin-1 IL-1 receptor TIR domain.

TLR Recognize 1. PAMPs 1. Chemical structure 2. Localization 3. Origine 2. DAMPs 1. HSP 2. TLR dimers 2. Open navigation menu. Close suggestions Search Search. User Settings. Skip carousel. Carousel Previous. Carousel Next.

What is Scribd? Explore Ebooks. Bestsellers Editors' Picks All Ebooks. Explore Audiobooks. Bestsellers Editors' Picks All audiobooks. Explore Magazines. Editors' Picks All magazines. Explore Podcasts All podcasts. Difficulty Beginner Intermediate Advanced.

Explore Documents. Innate Immunity I. Uploaded by Ana Maria Naste. Document Information click to expand document information Description: Inate immunity. For such wily pathogens, these first lines of defense are insufficient to clear the infection, and adaptive immune responses are required to contain them. When a pathogen invades a tissue, it almost always elicits an inflammatory response.

This response is characterized by pain, redness, heat, and swelling at the site of infection, all caused by changes in local blood vessels. The blood vessels dilate and become permeable to fluid and proteins, leading to local swelling and an accumulation of blood proteins that aid in defense, including the components of the complement cascade.

At the same time, the endothelial cells lining the local blood vessels are stimulated to express cell adhesion proteins discussed in Chapter 19 that facilitate the attachment and extravasion of white blood cells, including neutrophils, lymphocytes, and monocytes the precursors of macrophages.

The inflammatory response is mediated by a variety of signaling molecules. Activation of TLRs results in the production of both lipid signaling molecules such as prostaglandins and protein or peptide signaling molecules such as cytokines discussed in Chapter 15 , all of which contribute to the inflammatory response.

The proteolytic release of complement fragments also contribute. Some of the cytokines produced by activated macrophages are chemoattractants known as chemokines. Some of these attract neutrophils, which are the first cells recruited in large numbers to the site of the new infection. Others later attract monocytes and dendritic cells. The dendritic cells pick up antigens from the invading pathogens and carry them to nearby lymph nodes, where they present the antigens to lymphocytes to marshal the forces of the adaptive immune system discussed in Chapter Other cytokines trigger fever , a rise in body temperature.

On balance, fever helps the immune system in the fight against infection, since most bacterial and viral pathogens grow better at lower temperatures, whereas adaptive immune responses are more potent at higher temperatures. Some proinflammatory signaling molecules stimulate endothelial cells to express proteins that trigger blood clotting in local small vessels. By occluding the vessels and cutting off blood flow, this response can help prevent the pathogen from entering the bloodstream and spreading the infection to other parts of the body.

The same inflammatory responses, however, which are so effective at controlling local infections, can have disastrous consequences when they occur in a disseminated infection in the bloodstream, a condition called sepsis. The systemic release of proinflammatory signaling molecules into the blood causes dilation of blood vessels, loss of plasma volume, and widespread blood clotting, which is an often fatal condition known as septic shock. Inappropriate or overzealous inflammatory responses are also associated with some chronic conditions, such as asthma Figure Inflammation of the airways in chronic asthma restricts breathing.

Light micrograph of a section through the bronchus of a patient who died of asthma. There is almost total occlusion of the airway by a mucus plug. The mucus plug is a dense inflammatory more Just as with phagocytosis , some pathogens have developed mechanisms to either prevent the inflammatory response or, in some cases, take advantage of it to spread the infection. Many viruses, for example, encode potent cytokine antagonists that block aspects of the inflammatory response. Some of these are simply modified forms of cytokine receptors, encoded by genes acquired by the viral genome from the host.

They bind the cytokines with high affinity and block their activity. Some bacteria, such as Salmonella , induce an inflammatory response in the gut at the initial site of infection, thereby recruiting macrophages and neutrophils that they then invade. In this way, the bacteria hitch a ride to other tissues in the body. The pathogen -associated immunostimulants on the surface of bacteria and parasites that are so important in eliciting innate immune responses are generally not present on the surface of viruses.

Viral proteins are constructed by the host cell ribosomes, and the membranes of enveloped viruses are composed of host cell lipids. The only unusual molecule associated with viruses is the double-stranded RNA dsRNA that is an intermediate in the life cycle of many viruses.

Host cells can detect the presence of dsRNA and initiate a program of drastic responses in attempt to eliminate it. The program occurs in two steps. First, the cells degrade the dsRNA into small fragments about 21—25 nucleotide pairs in length. It also leads to the activation of a protein kinase that phosphorylates and inactivates the protein synthesis initiation factor eIF-2, shutting down most protein synthesis in the embattled host cell. Apparently, by destroying most of the RNA it contains and transiently halting most protein synthesis, the cell inhibits viral replication without killing itself.

In some cases, however, a cell infected with a virus is persuaded by white blood cells to destroy itself to prevent the virus from replicating. Another way that the interferons help vertebrates defend themselves against viruses is by stimulating both innate and adaptive cellular immune responses. In Chapter 24, we discuss how interferons enhance the expression of class I MHC proteins, which present viral antigens to cytotoxic T lymphocytes see Figure Here, we consider how interferons enhance the activity of natural killer cells NK cells , which are part of the innate immune system.

Like cytotoxic T cells, NK cells destroy virus -infected cells by inducing the infected cell to kill itself by undergoing apoptosis. Unlike T cells, however, NK cells do not express antigen -specific receptors. How, then, do they distinguish virus-infected cells from uninfected cells? NK cells monitor the level of class I MHC proteins, which are expressed on the surface of most vertebrate cells. The presence of high levels of these proteins inhibits the killing activity of NK cells, so that the NK cells selectively kill cells expressing low levels, including both virally-infected cells and some cancer cells Figure Many viruses have developed mechanisms to inhibit the expression of class I MHC molecules on the surface of the cells they infect, in order to avoid detection by cytotoxic T lymphocytes.

Herpes simplex virus and cytomegalovirus block the peptide translocators in the ER membrane that transport proteasome -derived peptides from the cytosol into the lumen of the ER; such peptides are required for newly-made class I MHC proteins to assemble in the ER membrane and be transported through the Golgi apparatus to the cell surface see Figure Cytomegalovirus causes the retrotranslocation of class I MHC proteins from the ER membrane into the cytosol, where they are rapidly degraded by proteasomes.

Proteins encoded by still other viruses prevent the delivery of assembled class I MHC proteins from the ER to the Golgi apparatus, or from the Golgi apparatus to the plasma membrane.

By evading recognition by cytotoxic T cells in these ways, however, a virus incurs the wrath of NK cells. The cells infected with a virus that blocks class I MHC expression are thereby exposed and become the victims of the activated NK cells. Thus, it is difficult or impossible for viruses to hide from both the innate and adaptive immune systems simultaneously. A natural killer NK cell attacking a cancer cell. The NK cell is the smaller cell on the left.

This scanning electron micrograph was taken shortly after the NK cell attached, but before it induced the cancer cell to kill itself. Courtesy of J. Hiserodt, more Both NK cells and cytotoxic T lymphocytes kill infected target cells by inducing them to undergo apoptosis before the virus has had a chance to replicate.

It is not surprising, then, that many viruses have acquired mechanisms to inhibit apoptosis, particularly early in infection. As discussed in Chapter 17, apoptosis depends on an intracellular proteolytic cascade, which the cytotoxic cell can trigger either through the activation of cell-surface death receptors or by injecting a proteolytic enzyme into the target cell see Figure Viral proteins can interfere with nearly every step in these pathways.

In some cases, however, viruses encode proteins that act late in their replication cycle to induce apoptosis in the host cell, thereby releasing progeny virus that can infect neighboring cells.

The battle between pathogens and host defenses is remarkably balanced. At present, humans seem to be gaining a slight advantage, using public sanitation measures, vaccines, and drugs to aid the efforts of our innate and adaptive immune systems. However, infectious and parasitic diseases are still the leading cause of death worldwide, and new epidemics such as AIDS continue to emerge.

The rapid evolution of pathogens and the almost infinite variety of ways that they can invade the human body and elude immune responses will prevent us from ever winning the battle completely.

The innate immune responses are the first line of defense against invading pathogens. They are also required to initiate specific adaptive immune responses. Innate immune responses rely on the body's ability to recognize conserved features of pathogens that are not present in the uninfected host. These include many types of molecules on microbial surfaces and the double-stranded RNA of some viruses. Many of these pathogen -specific molecules are recognized by Toll-like receptor proteins, which are found in plants and in invertebrate and vertebrate animals.

In vertebrates, microbial surface molecules also activate complement, a group of blood proteins that act together to disrupt the membrane of the microorganism, to target microorganisms for phagocytosis by macrophages and neutrophils, and to produce an inflammatory response.

The phagocytic cells use a combination of degradative enzymes, antimicrobial peptides, and reactive oxygen species to kill the invading microorganisms. In addition, they release signaling molecules that trigger an inflammatory response and begin to marshal the forces of the adaptive immune system. Cells infected with viruses produce interferons, which induce a series of cell responses to inhibit viral replication and activate the killing activities of natural killer cells and cytotoxic T lymphocytes.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed. Turn recording back on. National Center for Biotechnology Information , U. New York: Garland Science ; Search term. Innate Immunity. Epithelial Surfaces Help Prevent Infection In vertebrates, the skin and other epithelial surfaces, including those lining the lung and gut Figure , provide a physical barrier between the inside of the body and the outside world.

Figure Epithelial defenses against microbial invasion. Human Cells Recognize Conserved Features of Pathogens Microorganisms do occasionally breach the epithelial barricades. For example, Gram positive organisms, such as Streptococcus pneumoniae, are initially recognized by TLR1, 2, 4, 6 and 9, which in turn interact with a range of downstream signaling molecules to activate an inflammatory cascade. TLR signaling pathways have been the focus of considerable attention reviewed in 11 , 12 and depicted in Figure 2.

Human mutations and polymorphisms in many of the genes encoding elements of these pathways appear to alter susceptibility to infectious and inflammatory diseases. Naturally-occurring genetic mutations in humans, causing extreme immunodeficiency phenotypes, present powerful opportunities to determine the relationship between specific immunological defects and human disease processes in vivo.

Recent description of human primary immunodeficiencies associated with abnormal TLR signaling demonstrate that this pathway is critical for human defense against infection.

Empowered by technological advances in genotyping and bioinformatics, we are now beginning to appreciate how common genetic variation and polymorphisms in genes controlling the innate immune response alters infectious susceptibility in a subtle but specific fashion. Importantly, human primary immunodeficiencies associated with abnormal TLR signaling provide unique insights into the immunological pathways vital for host defense and identify candidate genes that may cause subtle immunodeficiencies in the broader population of apparently healthy people The narrow spectrum of infections experienced by affected individuals is striking in light of their profound impairment of TLR function and pathogen sensing.

IRAK4- and MyDdeficient patients predominantly suffer from recurrent infections caused by pyogenic Gram-positive bacteria, with Streptococcus pneumoniae causing invasive infection in all reported cases while Staphylococcus aureus and Pseudomonas aeruginosa caused infections in about half the patients. Arguably one of the most powerful messages to arise from the recognition of IRAK4- and MyDdeficiency is the value of studying humans to understand human immune function!

While MyDdeficient patients are susceptible to Streptococcus pneumoniae and a limited number of pyogenic bacteria, they are able to resist infection by most common bacteria, viruses, fungi, and parasites. In contrast, MyDdeficiency renders mice profoundly susceptible to most pathogens tested. At the population level susceptibility to common diseases, such as infections, seldom follows the simple pattern of Mendelian inheritance seen in IRAK4- and MyDdeficiency.

The complexity of common infectious diseases has made them, until very recently, largely impervious to genetic analysis. However, advances in high throughput genotyping techniques and bioinformatics is now allowing us to understand how common genetic variants alter human susceptibility to infection. Although humans are identical at most of the 3 billion base pairs in their genome, inter-individual variation is present in approximately 3 million nucleotides i.

There is convincing evidence that common TLR SNPs regulate cellular signaling events, cytokine production and susceptibility to infection based on the specific pathogens recognized by the TLR. Arguably the best evidence implicates amino acid changing i. Given the role of TLRs in sensing the extracellular environment and shaping inflammatory response, the TLR pathway has been hypothesized to influence the development of atopy and asthma.

The best studied example is CD CD14 is encoded on chromosome 5q Initial investigations showed remarkable variation with some studies indicating the T-allele as a risk factor, others the C-allele, and others finding no association.

Consequently, if we fail to integrate genetic and environmental factors in our study of asthma and allergy, we will only generate an impoverished appreciation of the etiology of atopic disease. While a rapidly growing number of genetic association studies suggest that TLR polymorphisms may be associated with susceptibility to different infectious and immunologically-mediated diseases, very few of these studies have been replicated in a convincing fashion.

While TLRs are outward looking innate immune receptors detecting microbial signatures either in the extracellular milieu or engulfed in the lumen of endocytic vesicles, nucleotide oligomerization domain NOD -like receptors or NLRs are a recently appreciated family of receptors that survey the intracellular environment.

The human NLR family consists of at least 23 members and can be structurally divided into four subfamily designations N-terminal effector domains. In addition to sensing microbial products, NLRs can sense metabolic stress related to infection and sterile inflammation. Other clinically relevant NLRP3 activators include uric acid, asbestos, silica and alum.

Although our molecular appreciation of NLRs is very recent, this class of innate immune receptors plays a central role in several human inflammatory diseases and mediates the adjuvant effect of a common vaccine component, alum. The convergence of clinically defined autoinflammatory disease with the biology of innate immunity and NLRs came with the discovery that three well-established autoinflammatory diseases are all caused by activating, gain-of-function mutations in NLRP3.

A unifying paradigm addressing this paradox is that NOD2 appears to provide homeostatic signals to maintain the gut environment in a state that is tolerant of its flora and cells with NOD2 mutations are deficient in their production of IL, an immunomodulatory and tolerogenic cytokine. Increased understanding of NLRs has allowed us to shed light on the mechanism of action of vaccine adjuvants.

Despite the fact that most people reading this review have received vaccines containing alum, it is only very recently that we have begun to fully appreciate the molecular mechanism of alum adjuvancy. With increased appreciation of the contribution of innate immunity to human health and disease, attention quickly shifted to the possibility of therapeutic modulation of innate immunity. This is an area of active investigation, so rather than attempting to survey the field broadly, we will focus our review on recent attempts to harness the TLR system to modulate infectious and allergic diseases.

As TLRs are highly expressed on dendritic cells but not on T cells, the goal of TLR based therapies in allergy and asthma is to activate dendritic cells to produce a cytokine milieu IL, IFNs, etc that favors inhibition of Th2 immune response. Thus, TLR based therapies target the innate immune response to consequently inhibit the adaptive Th2 immune response and do not directly target T cells. Studies have examined whether activation of TLRs can modulate allergic immune responses in pre-clinical animal models of allergy and asthma as well as in more limited studies in human subjects.

Studies of the TLR9 agonist CpG DNA have demonstrated that it inhibits eosinophilic airway inflammation, Th2 cytokine responses, mucus expression, airway remodeling, and airway responsiveness in a mouse model. These studies suggest that either TLR9 based therapies will not be effective in human subjects with asthma, or that different doses, routes of administration i.

In mouse models of asthma TLR4 ligands either inhibit or potentiate allergic responses depending upon the timing of administration of the TLR4 ligand and associated allergen sensitization or challenge.

In human studies in ragweed allergic rhinitis subjects, administration of a topical intranasal TLR4 ligand was safe but did not inhibit allergic responses in asymptomatic subjects challenged intranasally with ragweed allergen.

Imiquimod is an FDA-approved therapy which is used as a topical treatment for genital warts, actinic keratoses, and superficial basal cell cancer. Studies have also examined whether administering a TLR9 agonist conjugated to an allergen would enhance the immunogenicity of the allergen when used as a TLR9 conjugated allergen vaccine in allergic rhinitis or asthma.

Studies in mouse models have demonstrated that a conjugate of a TLR9 agonist and an allergen had a fold enhanced uptake by antigen presenting cells compared to TLR9 ligand alone. In mouse models, the TLR9 allergen conjugate significantly reduces rhinitis and asthma responses. Thus, based on this enhanced immunogenicity of the TLR9 allergen conjugate, studies have examined whether a TLR9 ragweed allergen conjugate would reduce allergic responses in human subjects with allergic rhinitis.

Studies in humans have demonstrated mixed results in terms of the effectiveness of the TLR9 ragweed allergen vaccine. Studies in ragweed allergic rhinitis subjects in Canada demonstrated that administration of the TLR9 ragweed allergen vaccine reduced nasal mucosal biopsy eosinophil counts and Th2 cytokines, but did not reduce nasal symptom scores during the ragweed season.

Interestingly, although the study subjects immunized with the TLR9 ragweed vaccine only received six injections of the vaccine prior to the first ragweed season, the beneficial reduction in symptoms persisted through the second ragweed season without administration of additional vaccine.

At present there are limited numbers of published human studies with either administration of TLRs alone or with TLRs conjugated to allergens. Further studies are thus needed to determine whether the interesting observations regarding TLRs in pre-clinical models will, or will not, translate into safe and effective therapeutic advances in allergy and asthma.

Potential safety concerns of TLR based therapies in allergy and asthma include the induction of autoimmune disease.

However, induction of autoimmune disease has not been observed in the limited number of clinical trials with TLR-9 based therapies. Vaccination has proved extremely effective in preventing infectious diseases, but knowledge of the immunological mechanisms that allow vaccines to be so successful is rather limited.

In contrast to live vaccines, subunit vaccines which consist of specific components of pathogens have little inherent immunogenicity and need to be supplemented with adjuvants to promote a protective immune response. However, there is a paucity of licensed adjuvants for clinical use and, thus, there is a critical need to develop safe and effective adjuvants.

The renaissance in innate immune biology is facilitating the rational design of novel vaccine adjuvants. An illustrative example is development of the novel adjuvant, monophosphoryl lipid A MPL. MPL combined with aluminum salt referred to as the AS04 adjuvant system shows efficacy in a vaccine against human papilloma virus 51 , and as a hepatitis B vaccine for patients with advanced renal disease.

Further advances in this area are almost certain as many other TLR ligands are being developed as potential vaccine adjuvants. In the last decade we have witnessed exhilarating advances in our understanding of the molecular mechanisms used by the innate immune system to sense infection and trigger a protective immune response. For clinicians and scientists alike, the challenge is to now translate this basic mechanistic understanding into a more complete appreciation of the role of innate immunity in health and disease.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. J Allergy Clin Immunol.

Author manuscript; available in PMC Feb 1. Stuart E. Broide , MB ChB 2. Find articles by Stuart E. David H. Find articles by David H. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at J Allergy Clin Immunol.

See other articles in PMC that cite the published article. Abstract Recent years have witnessed an explosion of interest in the innate immune system. Keywords: host defense, innate immunity, Toll-like receptors, NOD-like receptors. Open in a separate window. Figure 1. Integrated Human Immune System The human microbial defense system can be simplistically viewed as consisting of three levels: i anatomical and physiological barriers; ii innate immunity; and iii adaptive immunity.

Table 1 Overview of Defining Features of Innate and Adaptive Immunity Comparing and contrasting some of the defining features of the innate and adaptive immune systems. Non-hematopoietic cells: epithelial cells e.