IMMUNE RESPONSE Immunity refers to protection against infections. The immune system is the collection of cells and molecules that are responsible for defending the body against the countless pathogens that individuals encounter. Defects in the immune system render individuals easy prey to infections and are the cause of immunodeficiency diseases. But the immune system is itself capable of causing tissue injury and disease, which are often referred to as hypersensitivity disorders. Immune response is a complex of protective reactions, which helps organism to maintain antigenic peculiarities and cellular homeostasis during contacts with external environment. Defense against pathogens consists of two types of reactions: • • Innate immunity (also called natural, non-specific, or native, immunity) is mediated by cells and proteins that are always present (hence the term innate), poised to react against infectious pathogens. These mechanisms are called into action immediately in response to infection, and thus provide the first line of defense. Some of these mechanisms also are involved in clearing damaged cells and tissues. A major reaction of innate immunity is inflammation – It acts against various antigens. – It is genetically determined and is characteristic for species. Adaptive immunity is normally silent and responds (or adapts) to the presence of infectious agents by generating potent mechanisms for neutralizing and eliminating the pathogens. By convention, the terms immune system and immune response generally refer to adaptive immunity. Many pathogens have evolved to resist innate immunity, and protection against these infections requires the more specialized and powerful mechanisms of adaptive immunity (also called acquired, or specific, immunity). – Reactions are specific against antigen. Immune response is acquired by individual during its contacts with various antigens. – It can be: • Humoral • Cellular CELLS AND TISSUES OF THE IMMUNE SYSTEM The cells of the immune system consist of lymphocytes, most of which have specific receptors for antigens and mount adaptive immune responses; specialized APCs, which capture and display microbial and other antigens to the lymphocytes; and various effector cells, whose function is to eliminate microbes and other antigens. Specific immune response cells • • • T lympocytes (T helpers: Th1 and Th2, T cytotoxic cells, T memory cells) B lymphocytes → plasma cells→ IgG, IgM, IgA, IgE, IgD B memory cells Antigen presenting cells o Dendritic cells o Macrophages o B cells Lymphocytes Although all lymphocytes are morphologically similar, they actually consist of several functionally and phenotypically distinct populations. Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone marrow. Each T or B lymphocyte and its progeny, which constitute a clone, express a single antigen receptor, and the total population of lymphocytes can recognize tens or hundreds of millions of antigens. The enormous diversity of antigen receptors is encoded by variant DNA sequences that are created during lymphocyte maturation by the joining and diversification of different gene segments to form functional antigen receptor genes, a process that occurs only in B cells and T cells. Receptors that are expressed in B cells are called antibodies, while their T-cell counterparts are called T-cell receptors. Mature T and B lymphocytes recirculate through peripheral (secondary) lymphoid organs—the lymph nodes, spleen and mucosal tissues—and reside in these organs and in most tissues. Foreign antigens are concentrated in these organs, where they bind to and activate the clones of lymphocytes that express receptors for those antigens, a process known as clonal selection. All mature lymphocytes go through distinct phases during their lives: • naïve lymphocytes express antigen receptors but have not responded to antigens and do not serve any functions; • effector lymphocytes are induced by lymphocyte activation and perform the functions that eliminate microbes; and • memory lymphocytes, induced during activation, survive in a functionally silent state even after the antigen is eliminated and respond rapidly upon subsequent encounters with the antigen. T Lymphocytes Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and “help” B cells to produce antibodies against protein antigens. T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones. T cells cannot recognize free or circulating antigens; instead, the vast majority (>95%) of T cells sense only peptide fragments of proteins displayed by molecules of the major histocompatibility complex (MHC)*. Because T cell antigen receptors have evolved to see MHC-bound peptides on cell surfaces, T cells only recognize antigens presented by other cells. The outcome of this interaction varies dramatically depending on the type of T cell that is involved and the identity of the other interacting cell, ranging from the killing of virus-infected cells to the activation of phagocytes or B lymphocytes that have ingested protein antigens. Peptide antigens presented by MHC molecules are recognized by the T-cell receptor (TCR), an heterodimer that in most T cells is composed of disulfide-linked α and β protein chains. Each chain has a variable region that participates in binding a particular peptide antigen and a constant region that interacts with associated signalling molecules. Major histocompatibility molecules • • The main physiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to T cells Class MHC I and MHC II are cell surface glycoproteins involved in antigen presentation • • Class MHC I molecules are expressed on all nucleated cells and platelets. It binds and displays peptides that are derived from proteins ( for ex. viral antigens) synthesized within the cell. CD8+ cytotoxic cells can recognize peptides only presented as a complex with self class I molecules. Class MHC II molecules are expressed on antigen presenting cells. Class II molecules present exogenous antigens that are first processed in the phagolysosomes. CD4+ can recognize peptides presented as a complex with self class II molecules. It is now known that the normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T lymphocytes. In each person, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are the only MHC molecules that the T cells normally encounter. This phenomenon is called MHC restriction. The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6 On the basis of their chemical structure, tissue distribution, and function, MHC gene products fall into two main categories: • Class I MHC molecules are expressed on all nucleated cells and are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C. Each of these molecules consists of a polymorphic α chain noncovalently associated with an invariant β2- microglobulin polypeptide. In chain is where the foreign peptides bind to MHC molecules. In general, class I MHC molecules bind and display peptides derived from protein antigens present in the cytosol of the cell (e.g., viral and tumor antigens). • Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR. Class II molecules are heterodimers of noncovalently linked α and β subunits. Unlike class I MHC molecules, which are expressed on all nucleated cells, expression of class II MHC molecules is restricted to a few cell types, mainly APCs (notably, dendritic cells), macrophages, and B cells. Several other proteins are encoded in the MHC locus, including complement components (C2, C3, and Factor B) and the cytokines tumor necrosis factor (TNF) and lymphotoxin. B Lymphocytes B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the mediators of humoral immunity. B cells make up 10% to 20% of the circulating peripheral lymphocyte population. They also are present in bone marrow and in the follicles of peripheral (secondary) lymphoid organs. B cells recognize antigen by means of membrane-bound antibody of the immunoglobulin M (IgM) class, expressed on the surface together with signaling molecules to form the B-cell receptor (BCR) complex (Fig. 5.7). Whereas T cells recognize only MHC-associated peptides, B cells recognize and respond to many more chemical structures, including soluble or cellassociated proteins, lipids, polysaccharides, nucleic acids, and small chemicals, without a requirement for the MHC. As with TCRs, each antibody has a unique amino acid sequence. This sequence diversity is a consequence of the rearrangement and assembly of a multitude of immunoglobulin (Ig) gene segments, a process that creates functional Ig genes. B cells express several invariant molecules that are responsible for signal transduction and B-cell activation. After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies. There are five classes, or isotypes, of immunoglobulins: IgG, IgM, and IgA constitute more than 95% of circulating antibodies. IgA is the major isotype in mucosal secretions; IgE is present in the circulation at very low concentrations and also is found attached to the surfaces of tissue mast cells; and IgD is expressed on the surfaces of B cells but is secreted at very low levels. These isotypes differ in their ability to activate complement and recruit inflammatory cells, and thus have different roles in host defense and disease states. Natural Killer Cells and Innate Lymphoid Cells NK cells are lymphocytes that arise from the same common lymphoid progenitor that gives rise to T lymphocytes and B lymphocytes. However, NK cells are innate immune cells, as they are functional without prior activation and do not express highly variable and clonally distributed receptors for antigens. Instead, NK cells have two types of receptors—inhibitory and activating. Inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells, whereas activating receptors recognize molecules that are expressed or upregulated on stressed or infected cells. Normally, the effects of inhibitory receptors dominate over those of activating receptors, preventing spontaneous activation of the NK cells. Infections (especially viral infections) and stress are associated with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors. The net result is that the NK cells are activated and the infected or stressed cells are killed and eliminated. NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK cells provide early defense against intracellular microbial infections. Innate lymphoid cells (ILCs) are populations of lymphocytes that lack TCRs but produce cytokines similar to those that are made by T cells. Lymphoid organs • • • Central or primary lymphoid organs o Bone marrow and thymus Peripheral or secondary lymphoid organs o Lymph nodes,spleen, gut associated lymphoid tissue, mucosa associated lymphoid tissue The peripheral lymphoid organs are the site of lymphocytes activation by antigen . Lymph node • • Lymphatics drain extracellular fluid (or lymph) from peripheral tissues, through lymph nodes Lymph carries antigen and antigen bearing cells to the lymph nodes Spleen Red pulp – RBC destruction White pulp • Periarteriolar lymphoid sheath _ T lymphocytes • Follicles_B lymphocytes NB! • • Spleen collects antigen from the blood Lymph nodes collects antigen from sites of infection of tissues Barriers against infection • The simplest way to avoid infection is to prevent the microorganism to enter the organism. Body surface is protected by epithelium: o Skin o Mucous membranes in gastrointestinal, respiratory, and urinogenital tracts -------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 1.Innate Immunity The major components of innate immunity are epithelial barriers that block the entry of microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells (DCs), natural killer (NK) cells and other innate lymphoid cells, and several plasma proteins, including the proteins of the complement system. Phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that sense the presence of infectious agents and substances released from dead cells. Receptors of Innate Immunity Pattern recognition receptors are located in all the cellular compartments where pathogens may be present: plasma membrane receptors detect extracellular pathogens, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm Cellular receptors for microbes and products of cell injury. Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The major classes of innate immune receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors, RIG-like receptors for viral RNA, named after the founding member RIG-I, and cytosolic DNA sensors Reactions of Innate Immunity The innate immune system provides host defense by the following two main reactions: • Inflammation. Cytokines and products of complement activation, as well as other mediators, are produced during innate immune reactions and trigger the vascular and cellular components of inflammation. The recruited leukocytes destroy pathogens and ingest and eliminate damaged cells. • Anti-viral defense. Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit viral replication. 2.Adaptive Immunity The adaptive immune system consists of lymphocytes and their products, including antibodies. In contrast to the limited repertoire of the innate immune system, the adaptive immune system can recognize a vast array of foreign substances. There are two types of adaptive immunity: • Humoral immunity, mediated by soluble proteins called antibodies that are produced by B lymphocytes (B cells) • Cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells). Antibodies provide protection against extracellular pathogens in the blood, mucosal surfaces, and tissues. T lymphocytes are important in defense against intracellular microbes. They work by either directly killing infected cells (accomplished by cytotoxic T lymphocytes) or by activating phagocytes to kill ingested microbes, via the production of soluble protein mediators called cytokines (made by helper T cells). We next turn to the main properties and functions of the cells of the immune system. Humoral immune response • • • Humoral immunity is mediated by antibodies, which are produced by plasma cells deriving from B lymphocytes It eliminates extracellular microbes and microbial toxins (neutralization, opsonization, complement system activation). Antibodies : IgA, IgE, IgD, IgG, IgM Activation of naÏve T cells requires 2 independent signals 1.Binding of peptid-MHC complex by T cell receptor 2.Co-stimulatory signal delivered by the same APC Cytotoxic cells requires: 1. Activation by dendritic cell 2. Requires presence of CD4Tcells TH2 drives B cells to differentiate to plasma cells and produce Ig Immune granulomas • Certain microorganisms having been phagocytosed by macrophages avoid intracellular killing and survive • In such case T helpers are producing gamma interferon or other macrophage activating factor • Immune granuloma will be formed in places where persistent antigen or toxic materials occurs Composed of • Epitheliod cells – derived from macrophages • Giant cells – formed by fusion of macrophages • Necrosis – caused by lysosomal enzymes released by macrophages or cytotoxic materials as TNF • Lymphocytes • Other cells : can be also plasma cells, neutrophils, eosinophils Formation of Immune Granulomas induce: • • • • • • Mycobacterium tuberculosis Treponema pallidum Mycobacterium leprae Yersinia pseudoturbeculosis Echinococcus Foreign body granuloma Epithelial barriers against infection • • • Mechanical: o Epithelial cells joined by thight junctions, o Longitudinal flow of air or fluid across epithelium, o Movement of mucous by cilia Chemical: o Fatty acids (skin), lysozyme (saliva, tears, sweat), low pH (stomach) Microbiological: o Antagonism associated with normal flora of the body. INFLAMATOIN, COMPLEMENT SYSTEM (CHPTR 3, lo q he estado metiendo es del chptr 5) Inflammation • • • Inflammation is a complex of vascular reactions in the connective tissue to the exogenous and endogenous injurious agents like: o Biological o Chemical o Physical The reaction of blood vessels leads to the accumulation of fluid and leucocytes in extravascular tissues. The main protective mechanism in inflammation is phagocytosis Inflammation at the site of infection is initiated by the response of macrophage to pathogen: • Secretion of cytokins (IL1, TNF-alfa, IL6, IL8, IL12; • • Engulfing and formation of phsgolysosomes to digest pathogen Antigen presentation Complement system Complement system is made up of a large number of distinct plasma proteins that is activated (via classical, MB-lectin, alternative patways) to induce series of inflammatory responses by activation of C3 convertase to split C3: • • • C3a, C5a increases vascular permeability, phagocyte recruitment, activates mast cells C3b Opsonization of pathogens C5b, C6-9 Membrane attack complex for cell lysis Infammation (deep) The inflammatory response involves vascular and cellular events mediated by variuos mediators. • Cytokines produced by macrophages, • Plasma factors (produced by liver) – acute phase proteins, complement system, kinin system, coagulation factors… • Vasoactive amines – histamine (mast cells, platelets, basophils); serotonin (platelets); causes dilatation of arterioles and increases permeability of venules. • Arachidonic acid metabolites – prostaglandins and thromboxane (cyclooxygenase pathway) leukotriens (lipoxygenase pathway) • The signs of inflammation by Celsus (25 BC—50 AD) o Rubor o Tumor o Calor o Dolor by Virchow: o Functio laesa Vascular phase: • Vasoconstriction • Vasodilatation-involves arterioles and opening of capillary beds in the area • Increased vascular permeability due to formation of endothelial gaps in the venules of microcirculation • Increased vascular permeability • Exudation of fluid from capillaries helps: o Dilute toxic or irritating agents o To bring antibodies, complement, leukocytes... o To bring antigen presenting cells to lymphoid organs • Edema – denotes an excess of fluid (exudate or transudate) in the interstitial tissue • An exudate is an inflammatory extravascular fluid that has a high protein concentration, much cellular debris, and a specific gravity above 1.020. • A transudate is a fluid with low protein content, most albumin, and specific gravity less than 1.012. It results from hydrostatic imbalance across vascular endothelium, while permeability of endothelium is normal Leukocytic events in inflammation: A. Migration • In the lumen of the vessel: margination, rolling, adhesion • Transmigration across endothelium • Migration in interstitial tissues toward a chemotactic agent B. Phagocytosis • Recognition and attachment (opsonization by C3b, IgG) • Engulfment and formation phagosome and phagolysosome • Killing or degradation by toxic oxygen nitrogen products, lysozymes, proteases etc According to the exudate inflammation is classified in: • • • • Serous inflammation (inflammatio serosa) Purulent inflammation (inflammatio purulenta) Fibrinous inflammation (inflammatio fibrinosa): Hemorrhagic inflammation (inflammatio haemorrhagica) Serous inflammation (inflammatio serosa) Exudate is transparent with small amount of desquamated epithelium or mesothelium Causes: viruses (blisters in herpetic infection), physical agents Catarrhal inflammation (inflammation catarrhalis) is a serous inflammation in mucous membranes. Catarrhus of upper respirotary tract – rhinitis, nasopharingitis Outcomes- healing or progress to other type, most commonly purulent Purulent inflammation (inflammatio purulenta) Pus or purulent exudate consists of neutrophils, necrotic cells, bacteria, plasma proteins Causes – pyogenic bacteria (staphylococcus, streptococcus, Neiseria meningitidis, Neiseria gonorrhoeae) Forms of purulent inflammation • Abscess (it has pyogenic capsule) • Phlegmone • Empyema Outcomes: Healing; Abscessus can drain through fistula; when tissue defect large – formation of connective tissue or scarring; can develop sepsis; in chronc inflammation can develop amyloidosis; Fibrinous inflammation (inflammatio fibrinosa) When is greater vascular permeability larger molecules such as fibrinogen passes the vascular barrier and fibrinogen is converted to fibrin Causes – bacteria (streptococcus pneumonia, corynebacterium diphteriae, mycobacteria tuberculosis, shigella dysenteriae), toxic agents (uraemia) Fibrinous inflammation can be in serous body cavities lined by mesothelium, mucous membranes, and parenchymal organs (lungs) Fibrinous inflammation is classified: • Fibrinous inflammation. It occures in serous body cavities and lungs • Fibrinous ulcerative (dyphteric or pseudomembraneous inflammation); it develops in diphteria, dysentery, uremia, Outcomes – resolution (fibrinous exudate removed by fibrinolysis, and other debris by macrophages; can be restored normal tissue structure); organisation (fibrinous exudate is converted to connective tissue; it leads to synechiae or adhesion formation in serous cavities, can develop obliteration of the cavity); Fibrinous ulcerative inflammation in respiratory tract can lead to asphyxia; Fibrinous ulcerative inflammation leads to scarring of mucous linings. Haemorrhagic inflammation Haemorrhagic inflammation (inflammation haemorrhagica) – exudate with great amount of RBC. Haemorrhagic feature can have other types of inflammation (serous, fibrinous) when is other pathological states affecting small vessels; It can be in vit. C deficiency, thrombocytopenia Causes: viruses, bacterial toxins (antrax, pestis); medicines Outcomes depends on the main disease Examination Program 1. Morphogenesis of inflamation, its morphological manifestations, course, outcomes and significance. 2. Causative factors of the serous and fibrinous inflammation, morphological manifestations, outcomes and significance. 3. Causative factors of the purulent inflammation, morphological manifestations, outcomes and significance. 4. Morphological manifestations of the specific immune reactions and immunogenesis. 5. Morphology, outcomes and significance of peculiar specific immune response (immune granulomas). 6. Morphological peculiarities of the tuberculous and other kinds of immune granulomas. 7. Hyperergic immune reactions, its types and morphological peculiarities. 8. Classification of the immunodeficiencies, its morphological manifestations and significance. 9. Amyloidosis, its essence and pathogenesis, classification, morphology and significance. 10. Anemias, its classiffication, pathogenesis, general and pecular morphological features of various forms, complications and causes of death. 11. Neutropenia (agranulocytosis), thrombocytopenia, its pathogenesis, morphology, complications and causes of death. 12. Myeloid neoplasms, its classification, morphology, complications and causes of death. 13. Lymphoid neoplasms, its classification, morphology, complications and causes of death. 14. Hodgkin lymphoma, its morphology, complications and causes of death. 15. Radiation disease, its morphology, complications and causes of death. For lab: Self – learning questions What is the immune response? Enumerate the factors and phenomena of the immune response which prevent the antigen getting into the internal environment and which are under way its getting inside. What is the classification of immune cells? What is the classification of the immune system organs? What is inflammation? What is the main protective mechanism of inflammation? Enumerate the main phases of phagocytosis. What is the role of mast cells and granulocytes in inflammation? Enumerate the main groups of mediators of inflammation. What are the phases of inflammation? What forms inflammatory infiltration? Enumerate the main clinico-morphological features of inflammation. What determines it? 46 (2012) What is the possible outcome of inflammation? What is chronical inflammation? What do lymphocytes and plasma cells indicate at the site of inflammation? What medical terms are used for characterization of inflammation? What is serous exudate formed of? What are the most frequent etiological factors of fibrinous inflammation? What are the forms of fibrinous inflammation? What components form purulent exudate? What are the forms of purulent inflammation? What is abscess, phlegmona, empyema? What is furunculus, carbunculus? What is the outcome of purulent inflammation? What is catarrhal inflammation? What are the components of catarrhal exudate? When is hemorrhagical inflammation in process?