Download Cells of the Immune Response

Kuby, Chapter 2 February 22,2013 Cells and Organs of the Immune System Cells, Organs, and Tissues of Immune System •  Found throughout the body •  Two main groups: –  Primary lymphoid organs: Bone marrow and thymus Provide appropriate microenvironment  development and maturaBon of lymphocytes • 
–  Secondary lymphoid organs: lymph nodes, spleen, mucosa-­‐associated lymphoid Bssue (MALT) 1. 
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Gut-­‐associated lymphoid @ssue (GALT) (e.g., Peyer’s patches) Bronchus associated lymphoid @ssue (BALT) (e.g., tonsils, appendix) Trap anBgen, generally from nearby Bssues or vascular spaces sites where mature lymphocytes interact effecBvely with anBgen 1’ 1’ Figure 2-­‐13 Human Lympha@c System Interacts with Blood System •  Consists of lymph glands found in: –  Neck –  Armpits –  Groin •  LymphaBcs – small vessels •  Lymph -­‐ watery fluid Introduc@on •  Blood vessels and lymphaBc systems –  connect organs involved in immune response (IR) –  unite them  funcBonal whole •  Cells of immune system: –  Carried within the blood and lymph –  Populate lymphoid organs Introduc@on •  Only anBgen (Ag)-­‐specific lymphocytes posses aUributes of diversity, specificity, memory and self-­‐
nonself recogniBon -­‐-­‐-­‐ all hallmarks of adapBve immune response •  Other leukocytes also play important roles: –  anBgen presenBng cells –  effector cells that eliminate anBgen by phagocytosis –  Effector cells that secrete immune effector molecules •  Some leukocytes, especially T lymphocytes, secrete various protein molecules called cytokines: –  immunoregulatory hormones and play important roles in the –  coordinate and regulate immune responses Hematopoiesis • 
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All blood cells arise from hematopoie@c stem cell (HSC) Stem cells have 2 important characterisBcs: – 
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self renewing, maintaining their populaBon level by cell division differenBate into other cell types During human development, main site of hematopoesis changes – 
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begins in the embryonic yolk sac during first weeks; yolk sac stem cells differenBate into primiBve erythroid cells (RBCs) that contain embryonic hemoglobin Month 3 of gestaBon, HSCs have migrated to fetal liver and later months 3-­‐7 of gestaBon By month 8, HSC differenBaBon in bone marrow has major role in hematopoesis, and By birth, liUle or no hematopoesis in liver and spleen FORMATION OF BLOOD CELLS What is a progenitor? QUESTION: 1.  How many terminally differen;ated cell types are there in each lineage? 2.  Are there any common cells? Hematopoiesis is Regulated At the Gene@c Level – this is why you complete molecular biology first •  Can remove HSCs •  Grow outside body using animal cell culture techniques –  Maintain as HSCs –  Add right factors and differenBate them DifferenBaBon •  Make different cell types requires expression of different sets of –  lineage-­‐determining and lineage-­‐specific genes –  at appropriate Bmes –  In correct order –  Part of regulatory network •  Cell surfaces have clusters of differenBaBon (CD) markers on them; permits idenBficaBon and purificaBon of cell types Hematopoiesis •  In bone marrow, hematopoieBc cells and their descendants grow, differenBate, and mature on a mesh-­‐like scaffold of stromal cells, which include: –  fat cells –  endothelial cells –  fibroblasts –  macrophages •  Stromal cells influence differenBaBon by: –  providing the right microenvironment (HIM): • 
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cellular matrix growth and differenBaBon factors Steady-­‐State RegulaBon •  Control levels and types of cytokines produced by bone-­‐marrow stromal cells •  ProducBon of cytokines with hematopoieBc acBvity by other cell types, such as acBvated T cells and macrophages •  Regulate expression of receptors for hematopoieBcally acBve cytokines in stem cells and progenitor cells •  Remove some cells by controlled inducBon of cell death Hematopoie@c Homeostasis Involves Many Factors •  Hematopoiesis = steady-­‐state (SS) process –  produces ~ 3.7 x 1011 white blood cells per day mature blood cell produc@on = loss •  Loss due to aging –  Erythrocyte life-­‐span ~ 120 days; phagocytosed and digested by macrophages in spleen –  White blood cells (WBCs) depends on cell type: •  Neutrophils ~ 1 day •  T lymphocytes-­‐ for some 20-­‐30 y •  Regulated by complex mechanisms –  affect all of the individual cell types –  balance between number of cells removed by cell death and number that arise from division and differenBaBon Programmed Cell Death = Essen@al Homeosta@c Mechanism ✔ •  Programmed cell death: disBncBve morphologic changes called apoptosis:    cell volume  Cytoskeleton changes  membrane blebbing  CondensaBon of chromaBn and degradaBon of DNA into fragments  Sheds Bny membrane-­‐bound apoptoBc bodies containing intact organelles •  At advanced stages of apoptosis, MΦ phagocytose apoptoBc bodies and cells –  MEANING: intracellular contents (proteolyBc and other lyBc enzymes, caBonic proteins, and oxidizing molecules) are not released into the surrounding Bssue •  Apoptosis does not induce local inflammatory response Comparison of Morphologic Changes that Occur in Apoptosis & Necrosis Genes Regulate Apoptosis •  Several new genes/proteins expressed -­‐ apoptoBc -­‐ in leukocytes and other cell types –  Some induce apoptosis; others criBcal as apoptosis progresses –  Some inhibit apoptosis - - Peripheral Blood Cells Lymphoid Cells Lymphocytes: • 
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= 20% -­‐ 40% of white blood cells = 99% of cells in lymph ~ 1 trillion (1012) lymphocytes in body Circulate conBnuously in blood and lymph Can migrate into Bssue spaces and lymphoid organs = bridge between parts of immune system = 3 major populaBons – B cells, T cells, and natural killer cells -­‐ disBnguished by funcBon and cell membrane components −  B cells and T cells have own disBncBve anBgen receptors/
surface markers, CD −  Natural killer (NK) cells: large granular lymphocytes; part of innate immune system; not express B and T cell surface markers Cluster of DifferenBaBon (CD) - Fate of An@gen-­‐Ac@vated Small Lymphocyte  - Natural Killer (NK) Cells Monocyte & Macrophage Phagocytosis Mononuclear Phagocyte System MΦ AcBviBes Granulocy@c Cells PhagocyBc, 1’ and 2’ granules, anBmicrobial substances The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic-­‐staining characterisBcs non-­‐ phagocyBc phagocyBc Different Kinds of Dendri@c Cells & Their Origins APCs, no acBvaBon required, MHC II, co-­‐sBmulatory B7 Migrate to draining lymph nodes to present to Th Follicular DCs do not present but have Ab receptors DendriBc cells iniBate immune responses • 
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Immature DCs constantly internalize and process proteins, debris, and microbes microbial components bind to Toll-­‐Like Receptors (TLRs) and acBvate DC maturaBon  no more internalizaBon so that it ceases to internalize any new material, moves to lymph node, up-­‐regulates MHC II, B7 and B7.1 molecules for anBgen presentaBon, and produces cytokines to acBvate T cells. Release of IL-­‐6 inhibits release of TGF B; and IL-­‐10 by T regulatory cells. The cytokines produced by DC and its interacBon with TH0 cells iniBate immune responses. IL-­‐12 and IL-­‐2 promote TH1 responses while IL-­‐4 promotes TH2 responses. Most of the T cells divide to enlarge the response, but some remain as memory cells. Memory cells can be acBvated by DC, macrophage, or B cell presentaBon of anBgen for a secondary response Toll Like Receptors (TLRs) •  PRRs (PaUern RecogniBon Receptors) acBvate phagocytes and DCs PaUern RecogniBon Receptors (PRRs) Recognize Many Bacterial Molecules •  Pep@doglycans in bacterial cell wall •  Mannans, bacterial cell surface polysaccharides •  Gram negaBve bacteria (such as E. coli, Pseudomonas, Salmonella etc) all make Lipopolysaccharide (LPS/endotoxin), which is made up Lipid A and carbohydrates. •  Teichoic acids and lipoteichoic acids, not found in vertebrate cells. Teichoic acids are phosphate linked polymers of ribitol or glycerol •  The N-­‐terminal amino acid of most bacterial proteins is formyl-­‐
methionine. •  Bacterial lipoproteins (BLPs) contain a unique N-­‐terminal lipo-­‐
amino acid, N-­‐acyl S-­‐diacylglyceryl cysteine. •  Bacterial DNA contains specific unmethylated CpG repeats that are not found in vertebrate DNA Cells of the Immune Response Cells of the Immune Response Cells of the Immune Response Cells of the Immune Response Cells of the Immune Response Cells of the Immune Response *Monocyte/macrophage lineage. APCs, anBgen-­‐presenBng cells; CNS, central nervous system; DTH, delayed-­‐type hypersensiBvity; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, lymphotoxin; MHC, major histocompaBbility complex; TNF, tumor necrosis factor. Major Cytokine-­‐Producing Cells •  Innate (acute phase responses)   DendriBc cells and macrophages: IL-­‐1, TNF-­‐α, TNF-­‐β, IL-­‐6, IL-­‐12, GM-­‐CSF, chemokines, interferons α,β. •  Immune: T cells (CD4 and CD8)   TH1 cells: IL-­‐2, IL-­‐3, GM-­‐CSF, interferon-­‐γ, TNF-­‐α, TNF-­‐β.   TH2 cells: IL-­‐4, IL-­‐5, IL-­‐6, IL-­‐10, IL-­‐3, IL-­‐9, IL-­‐13, GM-­‐CSF, TNF-­‐α. Organs of the Immune System Thymus • 
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Derived from the third and fourth pharyngeal pouches during the embryonic life and aUracts (by chemoaUracBve molecules) circulaBng T-­‐ cell precursors derived from HSC in the bone marrow. Site of T-­‐cell development and maturaBon Flat, bilobed organ situated behind the sternum, above and in front of the heart. Each lobe surrounded by a capsule and divided into lobules, which are separated from each other by strands of connecBve Bssue called trabeculae. Each lobule is organized into two compartments. 1.  Cortex: The outer compartment, is densely packed with immature T cells, called thymocytes. 2.  Medulla: The inner compartment, is sparsely populated with thymocytes. Thymus • 
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Both the cortex and the medulla are criss-­‐crossed by a three dimensional stromal cell network composed of epithelial cells, dentriBc cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturaBon of the thymocytes. The accessory cells are important in the differenBaBon of the immigraBng T cell precursors and their educaBon (posiBve and negaBve selecBon), prior to their migraBon into the secondary lymphoid Bssues. Thymic epithelial cells produces the hormones thymosin and thymopoie@n and in concert with cytokines such as IL-­‐7 are probably important for the development and maturaBon of thymocytes into mature cells. The thymic cortex is the major site of acBvity and thymocyte proliferaBon, with a complete turnover of cells approximately every 72 hours. Thymus • 
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These thymocytes then move into the medulla, where they undergo further differenBaBon and selecBon and finally migrate via circulaBon to the secondary lymphoid organs/ Bssues where they are able to respond to microbial anBgens. Most (95%) of the thymocytes generated each day in the thymus die by apoptosis with less than 5% surrviving. Molecules important to T cell funcBon such as CD4, CD8 and T cell receptor develop at different stages during the differenBaBon process. The main funcBons of the thymus as a primary lymphoid organ are: 1.  To produce sufficient numbers (millions) of different T cells each expressing unique T cell receptors such that, within this group, there are at least some cells potenBally specific for huge number of microbial anBgens in our environment (generaBon of diversity). 2.  To select for survival those T cells which bind weakly to self MHC molecules (posiBve selecBon), but then to eliminate those which bind too strongly to these same self MHC molecules (negaBve selecBon) so that the chance for an autoimmune response is minimized. Changes in the Thymus with Age •  Thymic funcBon declines with age –  maximal size at puberty and then atrophies •  significant decrease in both corBcal and medullary cells •  increase in the total fat content –  average weight in human infants is 30 grams and only 3 grams in the elderly •  Loss in mass is accompanied by a decline in T-­‐cell output –  By age 35, thymic generaBon of T cells has dropped to 20% of producBon in newborns –  by age 65, the output has fallen to only 2% of the newborn rate Thymus DiagrammaBc cross secBon ofa porBon of the thymus, showing several lobules separated by connecBve Bssue strands (trabeculae). The densely populated outer cortex contains many immature thymocytes (blue), which undergo rapid proliferaBon coupled with an enormous rate of cell death. The medulla is sparsely populated and contains thymocytes that are more mature. During their stay within the thymus, thymocytes interact with various stromal cells, including corBcal epithelial cells (light red), medullary epithelial cells (tan), dendriBc cells (purple), and macrophages (yellow). These cells produce regulatory factors and express high levels of class I and class II MHC molecules. Hassall’s corpuscles, found in the medulla, contain concentric layers of degeneraBng epithelial cells. [Adapted with permission from W.van Ewijk, 1991, Annual Review of Immunology 9:591 by Annual Reviews.] Structure of a Lymph Node The three layers of a lymph node support disBnct microenvironments. Structure of a Lymph Node Leq: arrangement of reBculum and lymphocytes within various regions. Macrophages and dendriBc cells, which trap anBgen, are present in the cortex and paracortex. THcells are concentrated in the paracortex; B cells are primarily in the cortex, within follicles and germinal centers. The medulla is populated largely by anBbody-­‐producing plasma cells. Lymphocytes circulaBng in the lymph are carried into node by afferent lymphaBc vessels, they either enter the . reBcular matrix of the node or pass through it and leave by the efferent lymphaBc vessel. Right: lymphaBc artery and vein and the postcapillary venules. Lymphocytes in the circulaBon can pass into the node from the postcapillary venules by a process called extravasaBon (inset) Structure of the Spleen The spleen, which is about 5 inches long in the adult, is the largest lymphoid organ. It is specialized for trapping blood-­‐borne anBgens. DiagrammaBc cross secBon of the spleen. The splenic artery pierces the capsule and divides into progressively smaller arterioles, ending in vascular sinusoides that drain back into the splenic vein. The erythrocyte-­‐filled red pulp surrounds the sinusoids. The white pulp forms a sleeve, the periarteriolar lymphoid sheath (PALS), around the arterioles; this sheath contains numerous T cells. Closely associated with PALS is the marginal zone, an area rich in B cells that contains lymphoid follicles that can develop into secondary follicles containing germinal centers. Mucosa Associated Lymphoid Tissue (MALT) Cross-­‐secBonal diagram of the mucous membrane ling the intesBne, showing a Peyer’s patch lymphoid nodule in the submucosa. The intesBnal lamina contains loose clusters of lymphoid cells and diffuse follicles. Mucosa Associated Lymphoid Tissue (MALT) AnBgen transported across the epithelial layer by M cells at an inducBve site acBvates B cells in the underlying lymphoid follicles. The acBvated B cells differenBate into IgA-­‐
producing plasma cells, which migrate along the submucosa. The outer mucosal epithelial layer contains intraepithelial lymphocytes, of which are T cells. Cutaneous Associated Lymphoid Tissue (CALT) The skin is the largest organ in the body and plays an important role in nonspecific (innate ) defences. The epidermal (outer) layer of the skin is composed of specialized cells called keraBnocytes. These cells secrete a number of cytokines that may funcBon in local inflammatory reacBon. ScaUered among the epithelial-­‐cell matrix of the epidermis are Langerhann’s cells, atype of dendriBc cell, which internalize anBgen by phagocytosis or endocytosis. They undergo maturaBon and migrate from the epidermis to regional lymph nodes, where they funcBon as potent acBvators of naïve TH cells. In addiBon to Langerhans cells, the epidermis also contaions so-­‐
called intraepidermal lymphocytes, which are mostly T cells. The underlying dermal layer of the skin also contains scaUered T cells and macrophages. Most of these dermal cells appear to be either previously acBvated cells or memory cells. Bronchus Associated Lymphoid Tissue (BALT) Summary •  The humoral (anBbody) and cell mediated responses of the immune system result from the coordinated acBviBes of many cell types of cells, organs, and Bssues found throughout the body. •  Many of the body’s cells, Bssues, and organs arise from different stem cell populaBons. Leukocytes develop from a pluripotent hematopoieBc stem cell during a highly regulated process called hematopoiesis. •  Apoptosis, a type of programmed cell death, is a key factor in regulaBng the levels of hematopoieBc and other cell populaBons. •  There are three types of lymphoid cells: B cells, T cells, and natural killer (NK) cells. Only B and T cells are members of cloned populaBons disBnguished by anBgen receptors of unique specificity. B cells synthesize and display membrane anBbody, and T cells synthesize and display T-­‐cell receptors. Most NK cells do not synthesize anBgen-­‐specific receptors, although a small subpopulaBon of this group, NK-­‐T cells, do synthesize and display a T cell receptor. •  Macrophages and neutrophils are specialized for the phagocytosis and degradaBon of anBgens. Macrophages also have the capacity to present anBgen to T cells. Summary •  Immature forms of dendriBc cells have the capacity to capture anBgen in one locaBon, undergo maturaBuon , and migrate to another locaBon, where they present anBgen to TH cells. DendriBc cells are the major populaBon of anBgen presenBng cells. •  Primary lymphoid organs are the sites where lymphocytes develop and mature. T cells arise in the bone marrow and develop in the thymus; in humans and mice, B cells arise and develop in bone marrow. •  Secondary lymphoid organs provide sites where lymphocytes encounter anBgen, become acBvated, and undergo clonal expansion and differenBaBon into effector cells. •  Vertebrate orders differ greatly in the kinds of lymphoid organs, Bssues, and cells they posses. The most primiBve, the jawless fish, lack B and T cells and cannot mount adapBve immune responses; jawed vertebrates have T and B cells, have adapBve immunity, and display an increasing variety of lymphoid Bssues.