Cells & Organs of the Immune System.pdf

Cells and Organs of the Immune System Dr Felix N. Toka Professor, Veterinary Virology & Immunology Department of Biomedical Sciences What is Immunology? „Immunology is a branch of biomedical science concerned with the responses of organisms to immunogenic (antigen) challenges, the recognition of sel...

Cells and Organs of the Immune System Dr Felix N. Toka Professor, Veterinary Virology & Immunology Department of Biomedical Sciences What is Immunology? „Immunology is a branch of biomedical science concerned with the responses of organisms to immunogenic (antigen) challenges, the recognition of self from non-self, and all the biological (in vivo), serological (in vitro), physical, and chemical aspects of the immune phenomena” Illustrated Dictionary of Immunology, 3rd Edition JM Cruise & RE Lewis, CRC Press, 2009 „The immune system evolved to protect the body against infectious agents” Immunology is not an easy course Problem Too many details that distract from understanding the most important concepts Solution for now Concentrate only on important aspects Too many exceptions from the rules Present the rules only Knowledge in immunology is still evolving Present knowledge as it stands today Immune response is a network of many components that interact to provide immunity Present only important components and a summary of how they function The body’s response to infection with a pathogen or to the presence of a tumor requires interaction of a large number of diverse cells of the immune system Origin of cells of the immune system from what know originates what any response immune Innate L III Jaaartiveimmuneresp.nu 2d types Two arms of (immunity) defense Innate immunity arriers response rapid tea 1 Y.is 2typesofresponses Adaptive immunity response Delayed IT B cells Differences know Cells of the innate immunity - First response Granulocytes OR polymorphonuclear leukocytes - are a subgroup of white blood cells characterized by the presence of cytoplasmic granules They are produced in the bone marrow Are classified as basophils, eosinophils or neutrophils They are named as such because of their distinct staining characteristics using hematoxylin and eosin (H&E) histological preparations Basophils Granules in basophils stain dark blue Important for host defence against parasites and may be involved in allergic and inflammatory reactionsPresentwheneosinophilsare Basophils contain toxic granules which are used to destroy pathogens during the process of phagocytosis smallrole phagocytosesmall parasite substances Basophils express several adhesion molecules which play a critical role in their circulation, including LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) and CD44 Eosinophils Eosinophils stain bright red Differentiate from myeloid precursor cells in response to IL-3, IL-5 and GMCSF Important for host defence against parasites and may be involved in allergic reactionsType reactions hypersensitive remembers ameasbasopniis.su basopmisaisoaointiam.ae todirectwheretogo Respond to chemokines such as CCL5/RANTES, CCL11/eotaxin-1, and CCL24/eotaxin-2 secreted by neutrophils or lymphocytes cytokines Recruited eosinophils release the toxic substances contained in their granules to destroy pathogens and fight infection Neutrophils cellsinweblikeprojections Theytrap Formedin bone marrow release toblood 6 hrs migrateto tissueFewdays Neutrophilic components in neutrophils stain a neutral pink The most numerous innate immune cell (50-70% of all white blood cells) Cbandlotsofyoungproblem Immature neutrophils have a distinct band-shaped nucleus which changes into a segmented nucleus following maturation They circulate in the bloodstream looking for foreign objects to phagocytose (ingest) and degrade (e.g., bacteria) function h ousekeeping Alsohave Acutebacteriali nfections Whichcellisresponsibleforcausingneurophilia The number of circulating neutrophils is estimated using the absolute neutrophil count (ANC) neutrophil count Absolute An ANC may be high (neutrophilia) e.g., due to kidney failure or bacterial infection Leukemia or bone marrow damage results in a lower number of neutrophils (neutropenia) and an increased risk of infection Leukemia neutropenia lowneutrophils Granulocytes at work http://www.dailymail.co.uk/sciencetech/article-2957265/Whenwhite-blood-cells-ATTACK-Amazing-video-captures-moment-immunetakes-parasitic-worm.html Granulocytes can be identified by expression of CD16, CD34 (immature state) and CD11b/CD18 (activated state); winam Additionally, activated basophils can be identified by CD13/Aminopeptidase N, CD107a/LAMP1 or CD164; eosinophils by CD44, CD69, IL-5, and neutrophils by CD16, L-selectin (CD62L) Aision teens staff cens knowdifferencesbetween Mast cells Staindarkblue Generated in the bone marrow Mast cells are similar to basophilic leukocytes They have a common progenitor i.e., CD34+ precursor cells There are two types of mast cells: connective tissue mast cells – local allergic reactiononskin allergicruns mucosal mast cells, which are found in areas of the body that are exposed to the external environment (i.e., lung mucosa, digestive tract, mouth and Producessimilarallergicrunsintheseareas nose) Mast cells are also important for defense against parasites Mast cells found in tissues can mediate allergic reactions by releasing inflammatory mediators like histamine TypeI hypersensitivity that can astonine bestoredwigranuelsmusclecens to macrophages monocytesdifferentiate become Biggerstrongcapacitytophagocytose Monocytes/macrophages In blood In tissue They are found in the bloodstream and in tissues Monocytes circulate in the peripheral blood before entering tissues to replenish tissue-specific macrophage populations (i.e., osteoclasts, Bone microglia cells, histiocytes, and Kupffer cells) Brain Liver Macrophage, "big eater" in Greek, named for their ability to ingest and mimacrophage degrade bacteria PHAGOCYTOSIS iiiiiiigiifiiii.EE mine ena signIE aanaana Upon activation, monocytes and macrophages coordinate an immune response by notifying other immune cells of existing infection MHCI Macrophages can present antigens to lymphocytes Macrophages also have important non-immune functions, such as recycling dead cells, like red blood cells m2macrophages These "housekeeping" functions occur without activation of an immune response intramation promote Yesantigenpresentingmolecules Natural killer cells Phagocytic cytotoxiccellsNot Innate immune cells Certain subpopulations of NK cells have features of both innate and adaptive immunity (e.g., NKT cells) They recognize and kill virus-infected cells or tumor cells They contain granules, which are filled with proteins that can form holes in the target cell and also cause apoptosis (programmed cell death) Besides their function as cytolytic effectors they are also regulators of immune response Functions of NK cells Prime.NLEgs Nkcellscankill cells imaturedentritic by Nkcellshavereceptors thatrecognizeMHCclassI molecules Dendritic cells (DC) Professionalantigenpresentingcells insanenames iiiinitiates iii iii Specialized sentinel cells that constantly sense and respond to their immediate environment All DCs are hematopoietic bone marrow-derived cells, although they undergo maturation in either, the bone marrow, lymphoid, or non-lymphoid tissues I in this DCs capture, process, and present antigens to T cellsdoes and thus areofcrucial for bridging innate and adaptive immunity as well as promoting self-tolerance context MHC Upon exposure and uptake of pathogens, maturing DCs travel to secondary lymphoid organs where they become potent T cell activators DCs are classified as, classical/conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) pDCs have the ability to secrete large amounts of type I interferons upon activation through TLR7 and TLR9 Cells of the adaptive immunity - Lymphocytes in ruminants ftp.fggy dogs Producedin B lymphocytes (B cells) pigs Produceantibodies Are an essential component of the humoral immune response BCR B cells mature in the bone marrow B cells In birds they mature in the Bursa of CloacalBursa Fabricius, hence the name B cells B cells are activated when they bind antigens through their receptors (BCR) 2 deins racism am meFypeot.ae niigen fi B cells are responsible for generating antibodies to specific antigens Antibodies Testify.isffn Iiiife Antibodies coat the surface of a pathogen and serve three major roles: neutralization, opsonization, and complement activation Neutralization occurs when the pathogen is covered in antibodies and cannot further infect host cells In opsonization, an antibody-bound pathogen serves to alert immune cells such as neutrophils and macrophages, to engulf and digest the pathogen promotephagocytosis callsneutrophils macrophages toinducephagocytosis Complement activation is a process for directly destroying or lysing pathogens e.g., bacteria Some complement components act as opsonins – can opsonize pathogens 3 BasicFunctions of Antibodies T lymphocytes (T cells) – express an antigen specific receptor TCRBars IBcellshave They begin as thymocytes (precursors to T cells) and end as lymphocytes Thymocytes develop from hematopoietic stem cells in the bone marrow and then move to mature in the thymus They undergo several stages of selection and quality control to ensure that maturation results in functional T cells T cells are an essential component of the cellular immune response mince T cells are divided into two broad categories: CD8+ T cells and CD4+I T cells based on which co-receptor protein is present on the cell surface mac CD8+ T cells also are called cytotoxic T cells or cytotoxic T lymphocytes (CTLs) They recognize and kill infected or cancer cells CTLs have cytotoxic granules, containing cytotoxins that kill target cells There are four major CD4+ T-cell subsets: Th1, interleukin Th2,Jroducea large ofshort Th17, T regulatory cells Th refers to T helper cell cytokines Th1 cells coordinate immune responses against intracellular pathogens They produce and secrete molecules (cytokines) that alert and activate other immune cells, like bacteria-ingesting macrophages Th2 cells coordinate immune responses against extracellular pathogens, like helminths (parasitic worms), by alerting B cells, granulocytes and mast cells I t T.EE If granules Preventsautoimmuneresponses Th17 cells are named for their ability to produce interleukin 17 (IL-17), a signalling molecule that activates immune and nonimmune cells. Th17 cells protect surfaces (skin, gut) against extracellular bacteria (recruitment of neutrophils) Regulatory T cells (Tregs), as the name suggests, monitor and inhibit the activity of other T cells Communication of immune cells Immune cells communicate in a number of ways, either by cell-to-cell contact or through secreted signalling molecules Receptors and ligands are fundamental for cellular communication Receptors are protein structures that may be expressed on the surface of a cell or in intracellular compartments The molecules that activate receptors are called ligands, which may be free-floating or membrane-bound By altering the expression and density of various receptors and ligands, immune cells can dispatch specific instructions tailored to the situation at hand Molecules involved in immune cell communication Cytokines – small proteins with diverse function such as cell growth, activation, etc. Toll-like receptors TLR expressed on innate immune cells, like macrophages and dendritic cells TLRs recognize general microbial patterns and they are essential for innate immune-cell activation and inflammatory responses B-cell receptors (BCRs) and T-cell receptors (TCRs) - expressed on B cells and T cells, respectively – they recognize foreign antigens Major histocompatibility complex (MHC) MHC proteins function as carriers to present antigens on cell surfaces MHC proteins also signal whether a cell is a host cell or a foreign cell Complement (particularly, C3a and C5a) Complement consists of a series of proteins found in the blood Complement literally punches small holes into the pathogen, creating leaks that lead to cell death Complement proteins also serve as signalling molecules that alert immune cells and recruit them to inflammatory sites Organs of the Immune System Lymphatic organs Clinical Correlation A five-year-old intact male cat presents at a small-animal clinic with lethargy and will not eat or drink. A quick examination of the cat reveals a fever (>40°C, 104°F) and swollen superficial cervical and mandibular lymph nodes. The biopsy reveals areas of focal necrosis and lymphoid hyperplasia The serum shows a titer of 1/80 for Francisella tularensis (amount of antibodies against F. tularensis) After antibiotic treatment, the lymphadenopathy resolved, and the cat recovered. Challenge question What do you think was the cause of the lymphadenopathy? Organs of the immune system Lymphoid cells are first produced in the yolk sac, fetal omentum and liver Later, in older fetuses and adults, lymphoid cells are mainly produced in bone marrow* Bone marrow is a hematopoietic organ that gives rise to all blood cells *Bone marrow – soft tissue within bone cavities that contains hematopoietic precursor cells cancerlabtechperspective.blogspot.com Two types of lymphoid organs Primary lymphoid organs – bone marrow, thymus, Bursa of Fabricius in birds Secondary lymphoid organs – spleen, lymph nodes, nonencapsulated lymphoid tissue, Peyer’s patches Primary lymphoid organs organs that regulate the development of lymphocytes T lymphocytes develop in bone marrow and mature in the thymus B lymphocytes develop and mature in different primary lymphoid organs depending on the species Bursa of Fabricius – in birds only Bone marrow in primates and rodents Intestinal lymphoid tissue in rabbits, dogs, ruminants and pigs (B cells) Primary lymphoid organs are usually not sites of lymphocyte interaction with microbial antigens ir Thymus Located in the thoracic cavity in front and below the heart (pig) Large in newborns but small to invisible in adult animals – undergoes involution Structure Covered by a connective tissue capsule and consists of lobules The outer part of each lobule, called the cortex contains thymocytes (lymphocytes) The inner part of the lobule, medulla contains only few lymphocytes No lymphatic vessels leave the thymus Function – maturation of T lymphocytes Here, T lymphocytes learn to recognize self antigen* They must not respond strongly to self antigens Thymocytes with receptors that bind strongly to self-antigens are destroyed through a process called apoptosis – negative selection Thymocytes that cannot bind any MHC II molecules are also removed *reminder Function - cont’d Thymocytes that recognize MHC II/Ag complexes with moderate affinity are allowed to live – positive selection The positively selected cells leave the thymus as mature T lymphocytes and populate the secondary lymphoid organs The maturation process is highly regulated by a mixture of cytokines and thymic hormones such as thymosins, thymopoietins, thymulin and thymostimulins Bursa of Fabricius – found in birds only! Round sac located just before the cloaca Like the thymus - undergoes involution Structure Epithelium embeds the lymphocytes and lines a hollow sac connected to the cloaca by a duct Epithelium makes folds that extend into the sac called follicles Each follicle has a cortex and medulla The cortex contains lymphocytes, plasma cells and macrophages Function Maturation of B lymphocytes Negative and positive selection of B lymphocytes Differentiation of antibody-forming cells (B lymphocytes) Secondary lymphoid organs Broadly divided into: Encapsulated organs (lymph nodes, spleen) Non-encapsulated tissue (mucosal lymphoid aggregates) Secondary lymphoid organs lymph nodes, spleen and other tissue such as MALT, BALT They develop late in fetal life and persist in adult life Enlarge in response to antigenic stimulation Surgical removal does not impair immune capability They contain dendritic cells (DCs) which trap and process antigens, and later present these antigens to lymphocytes to initiate an adaptive immune response Lymph nodes Round-shaped or bean-shaped encapsulated organ Act as filters of lymph to trap antigens Contain two important regions, the outer cortex and inner medulla, between these two there is the paracortex B lymphocytes are found in the cortex in what are called germinal centers surrounded by capsules T cells and DCs are mainly found in the paracortex The medullar contains many different types of cells Lymph node cont’d Afferent lymph flows into the node from local tissue and carries lymphocytes, DCs and antigens Lymph enters the subcapsular sinus and then percolates through the node to the medullary sinus Lymph exits through the efferent lymphatic vessel Lymph nodes have arterial and venous blood supply The principal function of LN is to facilitate the interaction between dendritic cells and antigensensitive T and B lymphocytes Spleen A large encapsulated organ found in almost all vertebrate animals Structured by a network of connective tissue trabeculae Structural differences exist between animals (e.g., nonsinusal spleen in cats) Spleen Consists of two types of tissue Red pulp – blood filtering and RBC storage White pulp – where immune induction occurs – rich in lymphocytes Primary immune function - filters blood for blood-borne antigens, cellular debris and aged blood cells Stores red blood cells, platelets, recycles iron Peyer’s Patches (PP) non-encapsulated lymphoid tissue located in the wall of the small intestines In ruminants, pigs, dogs and rabbits – PP are found in the ileum = Primary lymphoid organ for B cell development In young ruminants the PP may be as long as 2 meters Contain densely packed lymphoid follicles containing only B lymphocytes Undergo involution In rabbits and rodents – PP are located at random intervals in the ileum and jejunum. In rabbits and rodents PP develop 2-4 weeks after birth and do not undergo involution Function – similar to Bursa of Fabricius Non-encapsulated lymphoid aggregates Scattered throughout the mucosal surfaces of the body Makes up a large portion of the total lymphoid tissue Mostly located in the intestinal mucosal Generally, called Mucosal-Associated Lymphoid Tissue (MALT) which includes: Gastrointestinal-associated lymphoid tissue (GALT) Bronchial-associated lymphoid tissue (BALT) Nasal-associated lymphoid tissue (NALT) Conjunctiva-associated lymphoid tissue (CALT) GALT is the best known mucosal-associated lymphoid tissue It is the inductive site of intestinal immune response It is the effector site of intestinal immune response STOP Clinical Correlation A five-year-old intact male cat presents at a small-animal clinic with lethargy and will not eat or drink. A quick examination of the cat reveals a fever (>40°C, 104°F) and swollen superficial cervical and mandibular lymph nodes. The biopsy reveals areas of focal necrosis and lymphoid hyperplasia The serum shows a titer of 1/80 for F. tularensis (amount of antibodies against F. tularensis) After antibiotic treatment, the lymphadenopathy resolved, and the cat recovered. Challenge question What do you think was the cause of the lymphadenopathy? The observed lymphadenopathy was lymphadenitis, a result of the bacterial infection as well as the cat’s immune response to the bacterium. Two possible reasons of why this occurred: 1. it is possible for the nodes themselves to become infected, resulting in inflammation (lymphadenitis). Immune cells and fluid move into the lymph nodes making it enlarged 2. lymphadenopathy is the result of protective immune responses against infectious agents Once antigens (pathogens or pieces of pathogens), T cells, and B cells arrive inside of lymph nodes, immune responses develop. Immune responses involves massive proliferation of lymphocytes or lymphoid hyperplasia. The increase in cell populations cause lymph nodes to swell beyond their normal size = lymphadenopathy. Lymphadenopathy is a common presenting symptom for several diseases of cats (other animals too).