Download to read offline
The Immune System – Anatomy and Physiology BCCM dentistry.pptx
- 1. The Immune System– Anatomy and Physiology
- 2. Objectives Discuss the functionof the immune system Discuss Discuss the components of the innate immune response Discuss Discuss the components of the adaptive immune response Discuss Correlate the concepts of immunity and its role in fighting infection. Correlate
- 3. The Immune Response • Responsegenerated against a potential pathogen • Pathogen, is rapidly mobilized at the initial site of infection but lacks immunologic memory and is called innate immunity • The second defense system is called adaptive immunity • Adaptive immunity can specifically recognize and destroy the pathogen because lymphocytes carry specialized cellular receptors and produce specific antibodies. • A protein that is produced in response to a particular pathogen is called the antibody, and the substance that induces the production of antibodies is called the antigen.
- 6. Innate Immunity • Innate immunityis an immediate response to a pathogen that does not confer long- lasting protective immunity. • It is a nonspecific defense system and includes barriers to infectious agents, such as the skin (epithelium) and mucous membranes. • It also includes many immune components important in the adaptive immune response, including phagocytic cells, natural killer (NK) cells, toll-like receptors (TLRs), cytokines, and complement.
- 7. Barrier Functions of Innate Immunity • Epithelialcell layer • Defensin • are positively charged peptides located primarily in the GI and lower respiratory tracts that create holes in bacterial cell walls • Mucus • Effect of the chemical environment
- 8. Mechanis ms of Innate Immunity • MicrobialSensors • There are three major groups of microbial sensors: • TLRs • NOD-like receptors (NLRs) • RIG-1- like helicases • MDA-5
- 11. Cellular Components and Phagocytosis • Phagocytesinclude: • monocytes and macrophages • granulocytes, including neutrophils, eosinophils, and basophils; • dendritic cells
- 12. Cellular Components and Phagocytosis • Phagocytesinclude: • monocytes and macrophages • granulocytes, including neutrophils, eosinophils, and basophils; • dendritic cells
- 13. Cellular Components and Phagocytosis • Phagocytesinclude: • monocytes and macrophages • granulocytes, including neutrophils, eosinophils, and basophils; • dendritic cells
- 15. Natural Killer Cells • arelarge, granular lymphocytes morphologically related to T cells, which make up 10–15% of blood leukocytes. • NK cells contribute to innate immunity by providing protection against viruses and other intracellular pathogens. • NK cells have the ability to recognize and kill virus-infected cells and tumor cells.
- 16.
- 18. Cytokines • lymphokines (lymphocyte-derived),monokines (monocyte-derived), and several other polypeptides that regulate immunologic, inflammatory, and reparative host responses • Short-acting • Interleukins • mediate communications between leukocytes
- 19. Cytokines • Cytokines thatmediate innate (natural) immunity. • IL-1, TNF (tumor necrosis factor, also called TNF- α), type 1 interferons, and IL-6 • Some cytokines, such as IL-12 and IFN-γ, are involved in both innate and adaptive immunity against intracellular microbes • Cytokines that regulate lymphocyte growth, activation, and differentiation. • IL-2, IL-4, IL-12, IL-15, and transforming growth factor-β (TGF-β). • Other cytokines in this group, such as IL-10 and TGF-β, down-regulate immune responses.
- 20. Cytokines • Cytokines thatactivate inflammatory cells. • IFN-γ, which activates macrophages • IL-5, which activates eosinophils • TNF and lymphotoxin (also called TNF-β), which induce acute inflammation by acting on neutrophils and endothelial cells. • Cytokines that affect leukocyte movement are also called chemokines • Cytokines that stimulate hematopoiesis. • colony-stimulating factors (CSFs) • GM-CSF and G-CSF
- 21. Cytokines • Properties: • Manyindividual cytokines are produced by several different cell types. • The actions of cytokines are pleiotropic, meaning that any one cytokine may act on many cell types and mediate many effects • Cytokines are also often redundant, meaning that different cytokines may stimulate the same or overlapping biologic responses. • Cytokines mediate their effects by binding to specific high-affinity receptors on their target cells.
- 22. Cytokines • Cytokines inducetheir effects in three ways: (1) They act on the same cell that produces them (autocrine effect), such as occurs when IL-2 produced by antigen-stimulated T cells stimulates the growth of the same cells (2) They affect other cells in their vicinity (paracrine effect), as occurs when IL-7 produced by bone marrow or thymic stromal cells promotes the maturation of B-cell progenitors in the marrow or T-cell precursors in the thymus, respectively; (3) They affect many cells systemically (endocrine effect), the best examples in this category being IL- 1 and TNF, which produce the systemic acute- phase response during inflammation.
- 23. Adaptive Immunity • The adaptiveimmune response involves antibody-mediated and cell-mediated immune responses. • Unlike innate immunity, adaptive immunity is highly specific, has immunologic memory, and can respond rapidly and vigorously to a second antigen exposure
- 24. T Lymphocytes • Thymus-derived lymphocytes •Mature T-cells are found in the blood, T-cell zones of peripheral lymphoid organs (paracortical areas of lymph nodes and periarteriolar sheaths of the spleen. • constitute 60% to 70% of lymphocytes
- 25. Source: Robbins andCotran Pathologic Basis of Disease.
- 26. T Lymphocytes • EachT cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen- specific T-cell receptor (TCR).
- 27. T Lymphocytes αβ TCR• Found in 95% of T-cells • recognize peptide antigens that are displayed by a major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells. γδ TCR • recognize peptides, lipids, and small molecules, without a requirement for display by MHC proteins • They tend to aggregate at epithelial surfaces, such as the mucosa of the respiratory and GI tracts, which suggest that these cells are sentinels that protect against microbes that try to enter through these epithelia • their precise functions are not known. NK-T cells • T-cells that express markers similarly found on NK cells • express a very limited diversity of TCRs • recognize glycolipids that are displayed by the MHC-like molecule CD1 • functions are also not well-defined
- 28. T Lymphocytes • CD4 •Expressed in approximately 60% of T-cells • Bind to Class II MHC molecules on antigen-presenting cells • CD8 • Expressed in approximately 30% of T-cells • Bind to Class I MHC molecules
- 29. Source: Robbins andCotran Pathologic Basis of Disease.
- 30. T Lymphocytes • CD4+T cells • Master regulator • Influence functions of other cells of the immune system • Two subtypes: • T-helper-1 (TH1) – synthesizes and secretes IL-2 and INF γ • T-helper-II (TH2) – IL-4 which is involved in synthesis of IgE, and IL-5 involved in activation of eosinophils • CD8+ T cells • Function mainly as cytotoxic cells to kill other cells • Can also secrete cytokines, primarily of TH1 type.
- 32. B Lymphocytes • Developfrom immature precursors in the bone marrow • Mature B-cells constitute 10-20% of the circulating peripheral lymphocyte population • Also present in peripheral lymphoid tissues • In lymph nodes, they are found in superficial cortex • In spleen, they are found in the white pulp • B-cell zones of lymphoid organs - follicles
- 33. B Lymphocytes • ImmunoglobulinM (IgM) and IgD, present on the surface of all naive B cells, constitute the antigen- binding component of the B-cell receptor complex Source: Robbins and Cotran Pathologic Basis of Disease 7th ed.
- 35. B Lymphocytes The endresult of B-cell activation is their differentiation into antibody- secreting cells called plasma cells. B-cell responses to antigens require help from CD4+ Tcells. Activated helper T cells express CD40 ligand which specifically bind to CD40 on B cells. • Essential for B-cell maturation and secretion of IgG, IgA, and IgE antibodies.
- 37. Macrophages • Involved inthe induction and effector phase of immune responses • Macrophages that have phagocytosed microbes and proteins process the antigens and present peptide fragments to T cells. • Activated by TH1, which enhances its microbicidal properties and augments their ability to kill tumor cells. • Phagocytose microbes that are opsonized by IgG or C3b.
- 38. Dendritic Cells • 2types: • Interdigitating dendritic cells • Located under the epithelia and in interstitia of tissues • Immature dendritic cells- Langerhans cells • express many receptors for capturing and responding to microbes (and other antigens), including TLRs and mannose receptors • express the same chemokine receptor as do naive T cells and are thus recruited to the T- cell zones of lymphoid organs • express high levels of MHC class II molecules as well as the costimulatory molecules B7-1 and B7-2 • possess all the machinery needed for presenting antigens to and activating CD4+ T cells
- 39. Dendritic Cells • 2types: • Follicular dendritic cells • present in the germinal centers of lymphoid follicles in the spleen and lymph nodes • bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins • presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen, thus improving the quality of the humoral immune response
- 40. Source: Robbins andCotran Pathologic Basis of Disease.
- 41. Histocompatibility Molecules • The principalphysiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells. • Major Histocompatibility Complex • Chromosome 6 • Human Leukocyte Antigen Complex (HLA)
- 42. Histocompatibility Molecules • Three Categories: •Class I and Class II genes encode cell surface glycoproteins involved in antigen resentation • Class III genes encode components of the complement system
- 43. HLA and Disease Association • Thediseases that show association with the HLA locus can be broadly grouped into the following categories: 1. Inflammatory diseases, including ankylosing spondylitis and several postinfectious arthropathies, all associated with HLA-B27 2. Inherited errors of metabolism, such as 21- hydroxylase deficiency (HLA-BW47) and hereditary hemochromatosis (HLA-A) 3. Autoimmune diseases, including autoimmune endocrinopathies, associated mainly with alleles at the DR locus.
- 44.
- 45. References • Jawetz, Melnick,& Adelberg's Medical Microbiology. 23rd ed. New York, N.Y.: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2004. • Robbins, Stanley L., eds. Robbins Basic Pathology. Philadelphia, PA : Elsevier/Saunders, 2020
Editor's Notes
- #3 In summary, the innate immune response is effective and critical in eliminating most pathogens. However, if this initial mechanism fails, the adaptive immune response is induced that specifically confronts the pathogen and establishes immunity to that invading pathogen. Hence, both systems interact and collaborate to achieve the final goal of destroying the pathogen.
- #6 Innate immunity is an immediate response to a pathogen that does not confer long-lasting protective immunity. It is a nonspecific defense system and includes barriers to infectious agents, such as the skin (epithelium) and mucous membranes. It also includes many immune components important in the adaptive immune response, including phagocytic cells, natural killer (NK) cells, toll-like receptors (TLRs), cytokines, and complement.
- #7 The epithelial cell layer has tight junctions and produces a number of powerful antimicrobial peptides that help provide protection against invading pathogens. Lysozyme is an example of an antimicrobial peptide that dissolves some bacterial cell walls. Another major peptide of innate host defense with antimicrobial properties is defensin. Defensins are positively charged peptides located primarily in the GI and lower respiratory tracts that create holes in bacterial cell walls and hence disrupt the bacterial membrane. Neutrophils in the small intestine contain azurophilic granules that house the α-defensins that are released following TLR activation, whereas epithelial cells in the respiratory tract secrete a different defensin, called β-defensin. The α-defensins have also been shown to possess antiviral activity. For example, α-defensins can inhibit HIV (human immunodeficiency virus) binding to the CXCR4 (C-X-C chemokine receptor type 4) receptor and in this way interfere with virus entry into the cell. The mucosal epithelium of the respiratory tract offers another mode of protection from infection. Mucus, a complex mixture of mucins, proteins, proteases, and protease inhibitors, is a major component of the mucosal epithelium. Some bacteria attach to the surface epithelial cells by means of adhesive bacterial surface proteins (eg, the pili of gonococci and Escherichia coli). However, the presence of mucus limits bacterial adhesion to these cell surfaces. Also, once entrapped in the mucus, the bacteria are removed by ciliary clearance. Thus, the mucosal surface and the ciliated epithelial cells tend to inhibit microbial adhesion and limit exposure time. Likewise, the GI tract has mechanisms to inhibit bacteria. The acidity of the stomach and the proteolytic enzymes of the small intestine make this environment hostile to many bacteria. An additional barrier to microbial invasion is the effect of the chemical environment. For example, the presence of an acidic pH in sweat and sebaceous secretions and, as mentioned previously, the low pH of the stomach have antimicrobial properties. Moreover, the production of fatty acids on the skin also tends to eliminate pathogenic organisms.
- #8 Although innate immunity does not generate antigen specific protective immunity and does not rely on specific pathogen recognition, it, nevertheless, provides a powerful line of defense. In addition, to the physiologic barriers of protection, the innate system has both cells and proteins (such as, cytokines and complement) at its disposal. Phagocytic leukocytes, such as polymorphonuclear neutrophilic leukocytes (neutrophils), and macrophages along with NK cells are the primary cellular components to combat microbes. The interaction of the invading microbe with these cells and other cells throughout the body triggers the release of complement and numerous cytokines. Many of these cytokines are proinflammatory molecules such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and the interferons (IFNs), and are induced through TLR interactions. Armed with these special tools, the host initiates its defense against the invading pathogen. The TLRs are the best studied of the microbial sensors. They are a family of evolutionary conserved pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). They constitute a first line of defense against a variety of pathogens and play a critical role in initiating the innate immune response. TLRs are type 1 transmembrane proteins with an extracellular domain, a single transmembrane α-helix, and a cytoplasmic domain. TLR recognition of these specific microbial patterns leads to a signal transduction cascade that generates a rapid and robust inflammatory response marked by cellular activation and cytokine release. To date, 10 human TLRs have been identified, and each receptor appears to be involved in the recognition of a unique set of microbial patterns. For example, TLR2 recognizes various ligands (eg, lipoteichoic acid) expressed by Grampositive bacteria, whereas TLR3 engages double-stranded RNA (dsRNA) in viral replication. TLR1 and TLR6 recognize multiple diacyl peptides (eg, mycoplasma), whereas TLR4 is specific for Gram-negative lipopolysaccharides (LPS). TLR5, on the other hand, recognizes bacterial flagellin, and TLR7 and TLR8 interact with single-stranded RNA (ssRNA) in viral replication and TLR9 binds bacterial and viral DNA. At present, TLR10 remains an orphan receptor. Another large family of innate receptors, NLRs, are located in the cytoplasm and serve as intracellular sensors for microbial products. They activate the nuclear factor kappalight- chain-enhancer of activated B cells (NF-κB) pathway and drive inflammatory responses similar to the TLRs. The third group of microbial sensors is the RIG-1-like helicases and melanoma differentiation-associated protein 5 (MDA5). These are cytoplasmic sensors of viral ssRNA. The engagement of ssRNA with these sensors triggers the production of the type 1 IFNs. These IFNs are highly effective inhibitors of viral replication.
- #9 The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non immune cells (epithelial and endothelial cells, and fibroblasts).[3] The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[4][5] Upon activation, TLRs recruit adaptor proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity.[5] If the ligand is a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons. Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells.[6] Flagellin, a TLR5 ligand, induces cytokine secretion on interacting with TLR5 on human T cells.[6]
- #11 Monocytes are small leukocytes that circulate in the blood and mature into macrophages that can be found in almost all tissues. For example, they are known as Kupffer cells in the liver and microglial cells in the nervous tissue. Macrophages are critical cells that engulf and kill pathogens, process and present antigen, and regulate immune reactivity by producing a variety of molecules (eg, cytokines). Granulocytes are leukocytes that contain densely staining granules. Neutrophils have a short half-life and are important phagocytic cells that destroy pathogens within intracellular vesicles. Eosinophils and basophils are less abundant and store granules containing enzymes and toxic proteins that can be released upon activation of the cells. Dendritic cells are also phagocytic and can degrade pathogens; however, their main role is to activate T cells in the adaptive immune response by acting as an antigen -presenting cell and by producing regulatory cytokines (eg, IFN-α).
- #12 Phagocytosis is a multistep process whereby a phagocytic cell, like a neutrophil, recognizes the pathogen, ingests it, and then destroys the engulfed organism. Once a pathogen enters the blood or tissue, the phagocytic cell migrates to that site. This migration is dependent on the release of chemoattractant signals produced by either the cells of the host or the pathogen. One chemoattractant is IL-8 (CXCL8), a potent chemotactic cytokine, that attracts neutrophils. More recently IL-17 has been shown to induce IL-8 and as a consequence, this chemokine now recruits immune cells to peripheral tissues. In the initial stage of the migration process, neutrophils attach to the endothelial cell surface by means of adhesion molecules, such as P-selectin. Neutrophils follow the chemokine attraction and migrate from the circulation through the endothelium into the tissues and to the site of infection. Here the neutrophil recognizes, engulfs, and internalizes the pathogen into an endocytic vesicle called a phagosome. Once inside the neutrophil, the pathogen is killed
- #13 There are several antimicrobial mechanisms used by phagocytes to eliminate the pathogen. For example, (1) acidification occurs within the phagosome. The phagosome pH is 3.5–4.0, and this level of acidity is bacteriostatic or bactericidal. (2) Toxic oxygen-derived products are generated and include superoxide O2 −, hydrogen peroxide H2O2, and singlet oxygen O2. (3) Toxic nitrogen oxides are also produced, and nitric oxide NO is formed. (4) Phagocytic cells generate antimicrobial peptides that participate in pathogen killing. In the macrophage, cathelicidin and macrophage elastase-derived peptides are found. The neutrophil, on the other hand, is rich in α-defensins, β-defensin, cathelicidin, and lactoferricin. All of these mechanisms are used by the phagocytes to destroy the pathogen. When the neutrophil completes its mission, it undergoes apoptosis and dies
- #14 As already mentioned, phagocytosis can occur without antibody. However, phagocytosis is more efficient when antibodies are available to coat the surface of bacteria and facilitate their ingestion. This process is called opsonization, and it can occur by the following mechanisms: (1) antibody alone can act as opsonin, (2) antibody and antigen can trigger the complement system (via the classic pathway) to generate opsonin, and (3) opsonin may be produced when the alternative pathway is activated and C3 is generated. Macrophages have receptors on their membranes for the Fc portion of an antibody and for the complement component C3. Both of these receptors facilitate the phagocytosis of the antibodycoated pathogen.
- #15 The function of NK cells is to recognize and destroy severely stressed or abnormal cells, such as virus-infected cells and tumor cells. NK cells make up approximately 5% to 10% of peripheral blood lymphocytes. NK cells express CD16, a receptor for IgG Fc tails that confers on NK cells the ability to lyse IgG-coated target cells. This phenomenon is known as antibody-dependent cellular cytotoxicity (ADCC). Killing of target cells by NK cells is regulated by signals from activating and inhibitory receptors (Fig. 6.4). There are many types of activating receptors, which recognize surface molecules that are induced by various kinds of stress, such as infection and DNA damage. Thus, these receptors enable NK cells to recognize damaged or infected cells. NK cell inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells. The inhibitory receptors prevent NK cells from killing normal cells. Virus infection or neoplastic transformation often enhances expression of ligands for activating receptors and at the same time reduces the expression of class I MHC molecules. As a result, when NK cells engage these abnormal cells the balance is tilted toward activation, and the infected or tumor cell is killed. NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK cells provide an early defense against intracellular microbial infections. The activity of NK cells is regulated by many cytokines, including the interleukins IL-2, IL-15, and IL-12. IL-2 and IL-15 stimulate proliferation of NK cells, whereas IL-12 activates the killing of target cells and the secretion of IFN-γ.
- #16 The complement system is another key component of innate immunity. This system consists of approximately 30 proteins found in the serum or on the membrane of selected cells that interact in a cascade. When complement is activated, it initiates a series of biochemical reactions that ultimately culminate in cellular lysis or destruction of the pathogen. As described later in this chapter, there are three complement pathways: classical, alternative, and lectin. Even though each has a different initiating mechanism, they all result in the lysis of the offending invader. The alternative and lectin pathways serve as critical first lines of defense and provide immediate protection against microorganisms. The alternative complement pathway can be activated by microbial surfaces and it can proceed in the absence of antibody. Likewise, the lectin pathway also bypasses antibody and uses a lectin, mannosebinding lectin (MBL), to initiate events. The complement proteins can achieve their defense mission in several ways, including opsonization, lysis of bacteria, and amplification of inflammatory responses through the anaphylatoxins, C5a and C3a. The complement system is described in more detail later in this chapter. Some microbes have acquired mechanisms to sabotage the complement system and evade the immune response. For example, poxviruses, such as vaccinia virus and smallpox, encode a soluble protein with complement regulatory activity that leads to inhibition of the complement system.
- #23 Unlike innate immunity, adaptive immunity is highly specific, has immunologic memory, and can respond rapidly and vigorously to a second antigen exposure (Table 8-1). The adaptive immune response involves antibody-mediated and cell-mediated immune responses. An overview of the components and their interactions during the adaptive immune response is outlined as follows, and details are presented throughout this chapter