Cells & organs of 1

CELLS & ORGANS OF THE IMMUNE SYSTEM

A Presentation By

Isaac U.M.,Associate Professor & HOD, Dept. of

Microbiology.College of Medicine, International Medical &

Technological University,Dar-Es-Salaam, Tanzania

Introduction

• The many cells, organs and tissues of the immune system are found throughout the body.

• They are functionally classified into two main groups.

1. Primary lymphoid organs: Provide appropriate microenvironment for the development and maturation of lymphocytes.

2. Secondary lymphoid organs: Trap antigen, generally from nearby tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with antigen.

• Blood vessels and lymphatic systems connect these organs, uniting them into a functional whole.

• Carried within the blood and lymph and populating the lymphoid organs are various white blood cells, or leukocytes, that participate in the immune response.

• Of these cells, only the antigen-specific lymphocytes posses the attributes of diversity, specificity, memory and self-nonself recognition, the hallmarks of an adaptive immune response.

Introduction

• Other leukocytes also play important roles, some as antigen presenting cells and others participating as effector cells in the elimination of antigen by phagocytosis or the secretion of immune effector molecules.

• Some leukocytes, especially T lymphocytes, secrete various protein molecules called cytokines.

• These molecules act as immunoregulatory hormones and play important roles in the coordination and regulation of immune responses.

Hematopoiesis

• All blood cells arise from a type of cell called the hematopoietic stem cell (HSC).

• Stem cells are cells that can differentiate into other cell types.• They are self renewing, maintaining their population level by cell

division.• In humans, hematopoiesis, the formation and development of red and

white blood cells, begins in the embryonic yolk sac during the first weeks of development.

• Yolk sac stem cells differentiate into primitive erythroid cells that contain embryonic hemoglobin.

• By the third month of gestation, hematopoietic stem cells have migrated from the yolk sac to the fetal liver and subsequently colinize the spleen; theses two organs have major roles in hematopoiesis from the third to the seventh months of gestation.

• After that, the differentiation of HSCs in the bone marrow becomes the major factor in hematopoiesis, and by birth there is little or no hematopoiesis in then liver and spleen.

Hematopoiesis

• Early in hematopoiesis, a multipotent stem cell differentiates along one of the two pathways, giving rise to either a lymphoid progenitor cell or a myeloid progenitor cell.

• Progenitor cells have lost the capacity for self-renewal and are committed to a particular cell lineage.

• Lymphoid progenitor cells give rise to B, T, and NK (natural killer ) cells.

• Myeloid stem cells generate progenitors of red blood cells (erythrocytes), many of the various white blood cells(neutrophils, basophils, monocytes, mast cells, dendritic cells), and platelet-generating cells called megacaryocytes.

• In bone marrow, hematopoietic cells and their descendants grow, differentiate, and mature on a mesh-like scaffold of stromal cells, which include fat cells

T Cells

T Cell Receptor

T Cell Selection

Co-stimulatory Molecules

Structure of Lymph Node

Figure 11-1 Morphology and lineage of cells involved in the immune response. Pluripotent stem cells and colony-forming units are long-lived cells capable of replenishing the more differentiated functional and terminally differentiated cells. (From Abbas K et al: Cellular and molecular immunology, ed 5, Philadelphia, 2003, WB Saunders.)

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Cells of the Immune Response

*Monocyte/macrophage lineage.APCs, antigen-presenting cells; CNS, central nervous system; DTH, delayed-type hypersensitivity; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, lymphotoxin; MHC, major histocompatibility complex; TNF, tumor necrosis factor.

Selected CD Markers of Importance

ADCC, antibody-dependent cellular cytotoxicity; APCs, antigen-presenting cells; CTLA, cytotoxic T-lymphocyte associated protein; EBV, Epstein Barr virus; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; IL, interleukin; LCA, leukocyte common antigen; LFA, leukocyte function-associated antigen; LPS, lipopolysaccharide; MHC, major histocompatibility complex; TAC, T-cell activation complex; TCR, T-cell antigen receptor; VLA, very late activation (antigen).Modified from Male D et al: Advanced immunology, ed 3, St Louis, 1996, Mosby. This table shows the recognized CD markers of hemopoietic cells and their distribution. A filled rectangle or + means cell population present; a half-filled triangle is subpopulation; *, activated cells only; **, markers that identity or are critical to the cell type.

Normal Blood Cell Counts

From Abbas AK, Lichtman AH, Pober JS: Cellular and molecular immunology, ed 4, Philadelphia, 2000, WB Saunders.

Major Cytokine-Producing Cells

• Innate (acute phase responses) Dendritic 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.

Cytokines & Chemokines

Figure 11-2 Organs of the immune system. Thymus and bone marrow are primary lymphoid organs. They are sites of maturation for T and B cells, respectively. Cellular and humoral immune responses develop in the secondary (peripheral) lymphoid organs and tissues; effector and memory cells are generated in these organs. The spleen responds predominantly to blood-borne antigens. Lymph nodes mount immune responses to antigens in intercellular fluid and in the lymph, absorbed either

through the skin (superficial nodes) or from internal viscera (deep nodes). Tonsils, Peyer's patches, and other mucosa-associated lymphoid tissues (blue boxes) respond to antigens that have penetrated the surface mucosal barriers. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Figure 11-3 Organization of the lymph node. Beneath the collagenous capsule is the subcapsular sinus, which is lined with phagocytic cells. Lymphocytes and antigens from surrounding tissue spaces or adjacent nodes pass into the sinus via the afferent lymphatic system. The cortex contains aggregates of B cells (primary follicles), most of which are stimulated (secondary follicles) and have a site of active proliferation or germinal center. The paracortex contains mainly T cells and dendritic cells (antigen-presenting cells). Each lymph node has its own arterial and venous supplies. Lymphocytes enter the node from the circulation through the specialized high

endothelial venules in the paracortex. The medulla contains both T and B cells, as well as most of the lymph node plasma cells organized into cords of lymphoid tissue. Lymphocytes can leave the node only through the efferent lymphatic vessel. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Figure 11-4 Organization of lymphoid tissue in the spleen. The white pulp contains germinal centers and is surrounded by the marginal zone, which contains numerous macrophages, antigen-presenting cells, slowly recirculating B cells, and natural killer cells. The red pulp contains venous sinuses separated by splenic cords. Blood enters the tissues via the trabecular arteries, which give rise to the many-branched central arteries. Some end in the white pulp, supplying the germinal centers and mantle zones, but most empty into or near the marginal zones. PALS, Periarteriolar lymphoid sheath. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Figure 11-5 Lymphoid cells stimulated with antigen in Peyer's patches (or the lungs or another mucosal site) migrate via the regional lymph nodes and thoracic duct into the bloodsteam, then to the lamina propria of the gut and probably other mucosal surfaces. Thus lymphocytes stimulated at one mucosal surface may become distributed

throughout the MALT (mucosa-associated lymphoid tissue) system. IgA, Immunoglobulin A. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Figure 11-6 Macrophage surface structures mediate cell function. Bacteria and antigens either bind directly to receptors or through antibody or complement receptors (opsonization) and can then be phagocytized; the cell is activated and presents antigen to T cells. The dendritic cell shares many of these characteristics.

Comparison of T & B Cells

*Depending on subset.CTL, Cytotoxic lymphocyte; DTH, delayed-type hypersensitivity; Ig, immunoglobulin; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 11-7 Surface markers of human B and T cells.

Figure 12-1 Comparative structures of the immunoglobulin (Ig) classes and subclasses in humans. IgA and IgM are held together in multimers by the J chain. IgA can acquire the secretory component for the traversal of epithelial cells.

Figure 12-2 Proteolytic digestion of immunoglobulin G (IgG). Pepsin treatment produces a dimeric F(ab')2 fragment. Papain treatment produces monovalent Fab fragments and an Fc fragment. The F(ab')2 and the Fab fragments bind antigen but lack a functional Fc region. The heavy chain is depicted in blue; the light chain in

orange.

Figure 12-3 Rearrangement of the germline genes to produce the human immunoglobulin κ light chains. Genetic recombination juxtaposes one of the 100 V-region genes with a J-region gene and a Cκ gene during differentiation into a pre-B cell. The remaining intervening sequences are removed by splicing the messenger

RNA. L, Leader sequence.

Figure 12-4 Rearrangement of the germline genes to produce the human immunoglobulin (Ig) heavy chains. A V-region gene (of 100 possible) combines with a D-region gene (of 12 possible) and a J-region gene (of six possible). Constant-region genes (corresponding to IgM [μ], IgD [δ], IgG [γ], IgE [ε], and IgA

[α]) are attached to the VDJ region. M, Membrane-spanning segment.

Figure 12-5 Differentiation of the B cell promotes genetic recombination and class switching. Switch regions in front of the constant-region genes (including immunoglobulin [lg] G subclasses) allow attachment of a preformed VDJ region with different heavy-chain constant-region genes, genetically removing the μ,

δ, and other intervening genes. This produces an immunoglobulin gene with the same VDJ region (except for somatic mutation) but different heavy-chain genes. Splicing of messenger RNA (mRNA) produces the final IgM and IgD mRNA.

Figure 12-6 B-cell activation. Binding of antigen, cross-linking of cell surface receptors, and the C3d product of complement, endotoxin, and cytokines activate the growth and differentiation of B cells. Specific cytokines direct the development of the B cell to produce TH1, TH2, or TH3 associated antibodies. APC, Antigen-presenting cell;

Ifnγ, interferon-γ; Ig, immunoglobulin; IL, interleukin; TGF-β, transforming growth factor-β.

Figure 12-7 Time course of immune responses. The primary response occurs after a lag period. The immunoglobulin (Ig) M response is the earliest response. The secondary immune response (anamnestic response) reaches a higher titer, lasts longer, and consists predominantly of IgG.

Figure 12-8 The classical, lectin, and alternate complement pathways. Despite different activators, the goal of these pathways is cleavage of C3 and C5 to provide chemoattractants and anaphylotoxins (C3a, C5a), an opsonin (C3b) that adheres to membranes, and to initiate the membrane attack complex to kill cells. MASP, MBP-

associated serine protease; MBP, mannose-binding protein. (Redrawn from Rosenthal KS, Tan JS: Rapid review microbiology and immunology, St. Louis, 2002, Mosby.)

Figure 12-9 Cell lysis by complement. Activation of C5 initiates the molecular construction of an oil-well-like membrane attack complex (MAC).

Figure 13-1 Human T-cell development. T-cell markers are useful for the identification of the differentiation stages of the T cell and for characterizing T-cell leukemias and lymphomas. Tdt, Cytoplasmic terminal deoxynucleotide transferase.

Figure 13-2 MHC restriction and antigen presentation to T cells. Left, Antigenic peptides bound to class I MHC molecules are presented to the T-cell receptor (TCR) on CD8 T killer/suppressor cells. Right, Antigenic peptides bound to class II MHC molecules on the antigen-presenting cell (APC) (B cell, dendritic cell, or macrophage) are

presented to CD4 helper cells and delayed-type hypersensitivity T cells.

Figure 13-3 T-cell receptor (TCR). The TCR consists of different subunits. Antigen recognition occurs through the α/β or γ/δ subunits. The CD3 complex of γ, δ, ε, and ζ subunits promotes T-cell activation. C, Constant region; V, variable region.

Figure 13-4 Structure of the embryonic T-cell receptor (TCR) gene. Note the similar approach to generation of a diverse recognition repetoire as for the immunoglobulin genes.

Figure 13-5 Structure of class I and class II major histocompatibility (MHC) molecules. The class I MHC molecules consist of two subunits, the heavy chain and β2-microglobulin. The binding pocket is closed at each end and can only hold peptides of eight to nine amino acids. Class II MHC molecules consist of two subunits, α

and β and hold 11 or more amino acid peptides.

Figure 13-6 Genetic map of the major histocompatibility complex (MHC). Genes for class I and class II molecules, as well as complement components and tumor necrosis factor (TNF), are within the MHC gene complex.

Figure 13-7 Antigen presentation. A, Class I MHC: Endogenous antigen (produced by the cell and analogous to cell trash) is targeted by attachment of ubiquitin (u) for digestion in the proteosome. Peptides of eight to nine amino acids are transported through the TAP (transporter associated with antigen processing) into the endoplasmic

reticulum (ER). The peptide binds to a groove in the heavy chain of the class I MHC molecule, allowing association with β2 microglobulin. The complex is processed through the Golgi apparatus and delivered to the cell surface for presentation to CD8 T cells. B, Class II MHC: Class II MHC molecules assemble in the ER with an invariant chain protein and are transported in a vesicle through the Golgi apparatus. Exogenous antigen (phagocytosed) is degraded in lysosomes, which then

fuse with a vesicle containing the class II MHC molecules. The invariant chain is degraded, and peptides of 11 to 13 amino acids bind to the class II MHC molecule. The complex is then delivered to the cell surface for presentation to CD4 T cells.

Figure 13-8 The molecules involved in the interaction between T cells and antigen-presenting cells (APCs). The various cytokines and their direction of action are also shown. GM-CSF, Granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule 1, IFN-γ, interferon-γ; TNF, tumor necrosis

factor. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Figure 13-9 Dendritic cells initiate immune responses. Immature dendritic cells constantly internalize and process proteins, debris, and microbes, when present. Binding of microbial components to Toll-Like Receptors (TLRs) activates the maturation of the DC so that it ceases to internalize any new material, moves to the lymph node, up-regulates MHC II, B7 and B7.1 molecules for antigen presentation, and produces cytokines to activate T cells. Release of IL-6 inhibits release of TGF β and IL-10

by T regulatory cells. The cytokines produced by DC and its interaction with TH0 cells initiate 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 activated by DC, macrophage, or B

cell presentation of antigen for a secondary response.

Figure 13-10 Cytokines produced by TH1 and TH2 cells and their effects on the immune system. TH1 responses are initiated by IL-12 and interferon-γ, and TH2 responses by IL-4. TH1 cells promote inflammation and production of complement and macrophage-binding antibody (solid blue lines) and inhibit TH2 responses (dotted

blue lines). TH2 cells promote humoral responses (solid red lines) and inhibit TH1 responses (dotted red lines). Colored square denotes end result. ADCC, Antibody-dependent cellular cytotoxicity; APC, antigen-presenting cell; CTL, cytotoxic T cell; DTH, delayed-type hypersensitivity; GM-CSF, granulocyte-macrophage colony-

stimulating factor; TNF, tumor necrosis factor.

Figure 13-11 Interactions between CD8 cytotoxic T lymphocyte (CTL) and target cells. The Fas-FasL interaction promotes apoptosis. ICAM-1, Intercellular adhesion molecule 1. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.)

Eosinophil. These cells have the purpose of giving large parasites such as helminths, a hard time. They attach via C3b receptors, the C3b having been produced during the course of alternative pathway complement activation by the helminth. The eosinophils release various substances from their eosinophilic granules. These include major basic protein (MBP), plus cationic proteins, peroxidase, arylsulphatase B, phospholipase D and histaminase. The granule contents are

capable of damaging the parasite membrane

Neutrophil polymorph. Neutrophils, or neutrophil polymorphonuclear leucocytes, respond to chemotactic signals and leave capillaries by a complex process, involving margination (flowing nearer to the endothelial lining of blood vessels), rolling and then attaching (margination), following which they emigrate between the endothelial cells (extravasation, or diapedesis). Several mediators are involved. They include substances produced by micro-organisms, and by the cells participating in the inflammatory process. One such is a substance called interleukin-1 (IL-1), which is released by macrophages as a result of infection or tissue injury. Another is histamine, released by circulating basophils, tissue mast cells, and blood platelets. It causes capillary and venular dilatation. C3a and C5a produced during complement activation, are chemotactic for phagocytic cells. Another group of substances produced are the acute phase proteins. As a consequence of tissue damage, the liver produces a substance called C-reactive protein (CRP), which is so called on account of its ability to attach to the C-polysaccharide component of the cell wall of bacteria and fungi. This activates the complement system by the classical pathway, and as a result C3a is formed and coats the organism, facilitating its phagocytosis.

Conventions for Naming Leukocyte Surface MoleculesBy one convention, cell surface molecules are named according to a particular function affected by an anti-leukocyte mAb. For example, the lymphocyte function-associated antigen 1, or LFA-1, was so named because antibodies recognizing this structure interfere with lymphocyte cell adhesion events and optimal lymphocyte function. The second convention is effectively no convention at all. Molecules are named arbitrarily according to individual laboratory preferences. For example, no obvious logic follows in the designations B7 and B220, except that the leading "B" reminds us that these antigens are typically expressed on B lymphocytes. By a third convention, leukocyte cell surface molecules are named systematically by assigning them a cluster of differentiation (CD) antigen number that includes any antibody having an identical and unique reactivity pattern with different leukocyte populations.

The use of in vitro studies to identify cytokines and growth factors regulating hematopoiesis

–Ex. Colony stimulating factors (CSFs) and erythropoietin (EPO)

Genetic regulation of HSC differentiation

General intracellular signaling pathway-

Apoptotic genes and regulation of lymphocyte life span

Importance of cytokines

Enrichment of HSC’s

•Weisman’s technique

•Use of SCID mice

Therapeutic uses of enriched populations of HSC’s

General overview

B and T Lymphocytes-Activation

Site of maturation

•Membrane receptors

–Membrane bound immunoglobulin

•Markers of a mature B cell

–Class II MHC

–B220

–CR1 and CR2

–FcRII

–B7-1, B7-2

–CD40

B Lymphocytes

T Lymphocytes

•Site of maturation

•Membrane receptors

–T Cell Receptor (TCR)

–CD4

–CD8

–CD28

–CD45

•Classes of T cells

–T helper cells (TH)

–T cytotoxic cells (TC)

–Function of TH and TC

•Class restriction

Natural Killer Cells (Natural Suppressor Cells) •Morphology•Function

•Membrane receptors–NK cell receptor

–CD16 receptor

–Antibody-dependent cell-mediated cytotoxicity (ADCC)

•Disfunction

–Chediak-Higashi syndrome

•NK1-T cells

Mononuclear Phagocyte System

–Types of macrophages and their locations

Cytotoxic Activity of Macrophages

Macrophage Secretory Products

Granulocytes

Neurotrophil(polymorphonuclear leukocyte, PMN)

–Morphology

–Function

–Origin, development, and life span

–Leukocytosis and infection

•Eosinophil

–Morphology

–Function

–More in Chapter 17

•Basophil

–Morphology

–Function

–Importance in allergic responses

•Mast Cells

–Origin

–Location

–Function

–Importance in allergic responses

Dendritic cells

–Morphology

–Origin

–Types

–Function

–Follicular dendritic cell

•Follicular dendritic cell and regulation of B cell activity

Lymphoid Organs

Lymphatic System

•Age, thymus size and function of the immune system

•Mucosal-Associated Lymphiod Tissue (MALT)

–Tonsils

•Three locations

•Structure and function

Systemic Function of the Immune System

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