Cells & organs ofthe immune system

CELLS & ORGANS OF THE IMMUNE SYSTEM

A Presentation By

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

Parasitology,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. The bone marrow and thymus are considered primary

lymphoid organs.2. Secondary lymphoid organs: Trap antigen, generally from

nearby tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with antigen. Secondary lymphoid organs include the lymph nodes,

spleen, and mucosa-associated lymphoid tissue (MALT), which also include gut associated lymphoid tissue (GALT) (e.g., Peyer’s patches) and bronchus associated lymphoid tissue (BALT) e.g., tonsils, appendix)

Introduction

• 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.

• 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.

The human body has a coordinated defense system

more sophisticated than any other defense system in the world.

The system is never outdated or obsolete.

Human Circulatory System

Human Lymphoid System


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Blood cells are

produced in bone

marrowwhere

fighter cells are trained or sent to

the thymus gland.

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, endothelial cells, fibroblasts, and macrophages.

• Stromal cells influence the differentiation of hematopoietic stem cells by providing a hematopoietic-inducing microenvironment (HIM) consisting of a cellular matrix anf factors that promote growth and differentiation.

Hematopoiesis

Self-renewing hematopoietic stem cells give rise to lymphoid and nyeloid progenitors. All lymphoid cells descend from lymphoid progenitor cells, and all cells of the myeloid lineage arise from myeloid progenitors.

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Hematopoiesis is Regulated At the Genetic Level

Hematopoietic HomeostasisInvolves Many Factors

• Hematopoiesis is a steady-state process in which mature blood cells are produced at the same rate at which they are lost.

• The principle cause of blood cell loss is aging. The average erythrocyte has a life-span of 120 days before it is

phagocytosed and digested by macrophages in the spleen. The various white blood cells have life spans ranging from a day , for

neutrophils, to as long as 20 to 30 years for some T lymphocytes.• To maintain steady-state levels, the average human being must produce

an estimated 3.7 × 1011 white blood cells per day.• This massive system is regulated by complex mechanisms that

affect all of the individual cell types, and ultimaytely, the number of cells in any hematopoietic lineage is set by a balance between the number of cells removed by cell death and the number that arise from division and differentiation.

Hematopoietic HomeostasisInvolves Many Factors

• Any one or a combination of regulatory factors can affect rates of cell reproduction and differentiation.

• These factors can also determine whether a hematopoietic cell is induced to die.

Programmed Cell Death is an Essential Homeostatic Mechanism

• Programmed cell death, an induced and ordered process in which the cell actively participates in bringing about it’s own demise, is a critical factor in the homeostatic regulation of many types of cell populations, including those of the hematopoietic system.

• Cells undergoing programmed cell death often exhibit distinctivew morphologic changes, collectively referred to as apoptosis.

• These changes include: A pronounced decrease in cell volume. Modification of the cytoskeleton, which results in membrane

blebbing. A condensation of the of the chromatin and degradation of the DNA

into fragments.• Following these morphologic changes, an apoptotic cell sheds tiny

membrane-bound apoptotic bodies containing intact organelles.• Macrophages phagocytose apoptotic bodies and cells in the advanced

stages of apoptosis.

Programmed Cell Death is an Essential Homeostatic Mechanism

• This ensures that their intracellular contents, including proteolytic and other lytic enzymes, cationic proteins, and oxidizing molecules, are not released into the surrounding tissue.

• As a consequence, apoptosis does not induce a local inflammatory response.

Comparison of Morphologic Changes that Occur in Apoptosis & Necrosis

• Apoptosis differs markedly from necrosis, the changes associated with cell death arising from injury.

• In necrosis, injured cells swell and burst, releasing their contents and possibly triggering a damaging inflammatory response.

Comparison of Morphologic Changes that Occur in Apoptosis & Necrosis

Apoptosis

Light micrographs of (a) normal thymocytes (developing T cells in the thymus) and apoptic thymocytes) and (b) apoptotic thymocytes. Scanning electron micrographs of © normal and © normal and (d) apoptotic thymocytes. [From B.A. Osborne and S. Smith, 1997, Journal of NIH Research 9: 35; courtesy of Osborne, University of Massachusetts at Amherst].

Genes that Regulate Apoptosis

• The expression of several genes accompanies apoptosis in leukocytes and other cell types.

• Some of the proteins specified by these genes induce apoptosis, others are critical as apoptosis progresses, and still others inhibit apoptosis.

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Apoptotic Genes & Regulation of Lymphocyte Life Span

Hematopoietic Stem Cells Can Be Enriched

• Irv Weissman and collegues developed a novel way of enriching the concentration of mouse hematopoietic stem cells, which normally constitute less than 0.05% of all bone marrow cells in mice.

• This approach relied on the use of antibodies specific for molecules known as differentiation antigens, which are expressed only by particular cell types.

• Removal of the hematopoietic cells by selecting for the differentiation antigens allowed a 50- to 200-fold enrichment of pluripotent stem cells.

• A refinement of this approach, H. Nakauchi and his colleagues have devised procedures so effective that in one out of five lethally irradiated mice, a single hematopoietic cell can restore both myeloid and lymphoid lineages.

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Enrichment of the Pluripotent Stem Cells from Bone Marrow

Differentiated hematopoietic cells (white) are removed by treatment with fluorescently labeled antibodies (Fl-antibodies) specific for membrane molecules expressed on differentiated lineages but absent from the undifferentiated stem cells (S) and progenitor cells (P). Treatment of the resulting partly enriched preparation with antibody specific for Sca-1, an early differentiation antigen, removed most of the progenitor cells. M = monocyte; B = basophil; N = neutrophil; Eo = eosinophil, L= lymphocyte; E = erythrocyte.

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Enrichment of the Pluripotent Stem Cells from Bone Marrow

Enrichment of stem cell preparations is measured by their ability to restore hematopoiesis in lethally irradiated mice. Only animals in which hematopoiesis occurs survive. Progressive enrichment of stem cells is indicated by the decrease in the number of injected cells needed to restore hematopoiesis. A total enrichment of about 1000-fold is possible by this procedure.

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Stem Cells – Clinical Uses & Potential

• Stem cell transplantation holds great promise for the regeneration of diseased, damaged, or defective tissue.

• Stem cells are classified according to their descent and developmental potential into four types.

1. Totipotent: Totipotent cells can give rise to an entire organism. e.g., zygote.

2. Pluripotent: Pluripotent cells arise from totipotent cells and can give rise to most but not all of the cell types necessary for fetal development. e.g. human pluripotent cells can give rise to all of the cells of the body but cannot generate a placenta.

3. Multipotent: Multipotent cells can give rise to only a limited number of cell types.

4. Unipotent: Unipotent cells can generate only the same cell type as themselves.

Stem Cells – Clinical Uses & Potential• The transplantation of HSCs is an important therapy for patients whose

hematopoietic systems must be replaced. It has three major applications.

1. Providing a functional immune system to individuals with a genetically determined immunodeficiency, such as severe combined immunodeficiency (SCID).

2. Replacing a defective hematopoietic system with a functional one to cure patients with life-threatening nonmalignant genetic disorders in hematopoiesis, such as sickle-cell anaemia or thalassemia.

3. Restoring the hematopoietic system of cancer patients after treatment with doses of chemotherapeutic agents and radiation so high that they destroy the system. These high-dose regimens can be much more effective at killing tumor cells than therapies using more conventional doses of cytotoxic agents. Stem cell transplantation makes it possible to recover from such as some cases of acute myeloid leukemia, can be cured only by destroying the source of the leukemia cells, the patient’s own hematopoietic system.

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Therapeutic Uses of Enriched Populations of HSC’s

Cells of the Immune System

• Lymphocytes bearing antigen receptors are the central cells of the adaptive immunity and are responsible for its signature properties of diversity, specificity, and memory.

• Important as lymphocytes are, other types of white blood cells also play essential roles in adaptive immunity, presenting antigens, secreting cytokines, and engulfing and destroying microorganisms.

• Furthermore, the innate immune system, which shares many cells with the adaptive immune system, plays an indispensable collaborative role in the induction of adaptive responses.

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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Peripheral Blood Cells

Lymphoid Cells

• Lymphocytes: Constitute 20% to 40% of the bodies white blood cells and 99% of

the cells in the lymph. There are approximately a trillion (1012) lymphocytes in the human

body. Circulate continuously in the blood and lymph and are capable of

migrating into the tissue spaces and lymphoid organs, serving thereby as a bridge between parts of the immune system.

Broadly subdivided into three major populations – B cells, T cells, and natural killer cells – on the basis of function and cell membrane components.

Key cells of adaptive immunity, B cells and T cells each bear their own distinctive antigen receptors.

Natural killer (NK) cells are large granular lymphocytes (granular refers to their grainy appearance under a microscope) that are the part of the innate immune system and do not express the set of surface markers that characterize B or T cells.

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Fate of Antigen-Activated Small Lymphocyte

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Fate of Antigen-Activated Small Lymphocyte A small resting (naïve or unprimed)

lymphocyte resides in the G0 phase of the cell cycle . At this stage, B and T lymphocytes cannot be distinguished morphologically. After antigen activation, a B or T cell enters the cell cycle and enlarges into a lymphoblast, which undergoes several rounds of cell division and, eventually, generates effector cells and memory cells. Shown here are cells of the B-cell lineage.

Electron micrographs of a small

lymphocyte (left) showing condensed chromatin indicative of a resting cell, an enlarged lymphoblast (center) showing decondensed chromatin, and a plasma cell (right) showing abundant endoplasmic reticulum arranged in concentric circles and a prominent nucleus that has been pushed to a characteristically eccentric position. The three are shown at different magnifications.

[Micrographs courtesy of Dr. J.R. Goodman, Dept of Pediatrics, University of California at San Francisco]

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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.


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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.


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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.


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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.


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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.


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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.)


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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.


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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.)


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Comparison of T & B Cells

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.


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Natural Killer (NK) Cells

Monocyte & Macrophage

Phagocytosis

Mononuclear Phagocyte System

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.


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Granulocytic Cells

• The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic-staining characteristics.

Morphology and Staining of Blood Cells

Granulocytic Cells

Different Kinds of Dendritic Cells &

Their Origins

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.


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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



Lymphoid Organs

• A number of morhologically and functionally diverse organs and tissue contribute to the development of immune responses.

• These organs can be distinguished by function as th e primary and secondary organs.

• The thymus and bone marrow are the primary (or central) lymphoid organs, where maturation of lymphocytes takes place.

• The secondary (or peripheral) lymphoid organs include lymph nodes, the spleen, the various mucosa-associated lymphoid tissues (MALT) such as gut-associated lymphoid tissue (GALT) and bronchus associated lymphoid tissue (BALT). These organs provide sites for mature lymphocytes to interact with antigen.

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.)


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Thymus

Thymus

• Derived from the third and fourth pharyngeal pouches during the embryonic life and attracts (by chemoattractive molecules) circulating T- cell precursors derived from HSC in the bone marrow.

• Site of T-cell development and maturation.• 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 connective tissue 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

• Both the cortex and the medulla are criss-crossed by a three dimensional stromal cell network composed of epithelial cells, dentritic cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturation of the thymocytes.

• The accessory cells are important in the differentiation of the immigrating T cell precursors and their education (positive and negative selection), prior to their migration into the secondary lymphoid tissues.

• Thymic epithelial cells produces the hormones thymosin and thymopoietin and in concert with cytokines such as IL-7 are probably important for the development and maturation of thymocytes into mature cells.

• The thymic cortex is the major site of activity and thymocyte proliferation, with a complete turnover of cells approximately every 72 hours.

Thymus

• These thymocytes then move into the medulla, where they undergo further differentiation and selection and finally migrate via circulation to the secondary lymphoid organs/ tissues where they are able to respond to microbial antigens.

• Most (95%) of the thymocytes generated each day in the thymus die by apoptosis with less than 5% surrviving.

• Molecules important to T cell function such as CD4, CD8 and T cell receptor develop at different stages during the differentiation process.

• The main functions 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 potentially specific for huge number of microbial antigens in our environment (generation of diversity).

2. To select for survival those T cells which bind weakly to self MHC molecules (positive selection), but then to eliminate those which bind too strongly to these same self MHC molecules (negative selection) so that the chance for an autoimmune response is minimized.

Thymus

Diagrammatic cross section ofa portion of the thymus, showing several lobules separated by connective tissue strands (trabeculae). The densely populated outer cortex contains many immature thymocytes (blue), which undergo rapid proliferation 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 cortical epithelial cells (light red), medullary epithelial cells (tan), dendritic 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 degenerating epithelial cells. [Adapted with permission from W.van Ewijk, 1991, Annual Review of Immunology 9:591 by Annual Reviews.]

Changes in the Thymus with Age• Thymic function is known to decline with age.• The thymus reaches its maximal size at puberty and then atrophies, with

a significant decrease in both cortical and medullary cells and an increase in the total fat content of the organ.

• The average weight of the thymus in human infants is 30 grams and only 3 grams in the elderly.

• The age dependent loss in mass is accompanied by a decline in T-cell output.

• By age 35, the thymic generation of T cells has dropped to 20% of production in newborns, and by age 65, the output has fallen to only 2% of the newborn rate.

Changes in the Thymus with Age

Generation of T cell Diversity

• Each of the very large numbers of T cells produced in the thymus has only one specificity, coded for by its antigen receptor.

• Millions of T cell, each with receptors specific for different antigens, are generated by gene rearrangement from multiple (inherited) germ-line genes.

• The T cell receptor consists of two polypeptide chains, α and β or γ and δ.

• Each chain is a member of the immunoglobulin superfamily and thus has a uniform domain structure produced by intrachain disulfide bonding.

• Unlike most proteins produced in the body, each polypeptide chain of the T cell receptor is coded for by several different genes.

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.


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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.


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Bone Marrow

Bone Marrow

• Bone marrow is a complex tissue that is site of hematopoisis and fat deposit.

• In fact, with the passage of time, fat eventually fills 50% or more of the marrow compartment of bone.

• Hematopoietic cells generated in bone marrow move through the walls of blood vessels and enter the blood stream, which carries them out of the marrow and distributes these various types to the rest of the body.

Blood cells are

produced in bone

marrowwhere

fighter cells are trained or sent to

the thymus gland.

Lymphatic Vessels

Interstitial fluid enters small closed (“blind”) lymphatic capillaries, by moving between the loosely joined flaps of the thin layer of endothelial cells that form the vessel wall. The fluid, now called lymph, is carried through progressively larger lymphatic vessels to regional lymph nodes. As lymph leaves the nodes, it is carried through larger efferent lymphatic vessels, which eventually drain into the circulatory system at the thoracic duct or right lymphatic duct.

Structure of a Lymph Node

The three layers of a lymph node support distinct microenvironments.

Structure of a Lymph Node

.

The left side depicts the arrangement of reticulum and lymphocytes within the various regions of a lymph node. Macrophages and dendritic cells, which trap antigen, 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 antibody-producing plasma cells. Lymphocytes circulating in the lymph are carried into the node by afferent lymphatic vessels, they either enter the reticular matrix of the node or pass through it and leave by the efferent lymphatic vessel.

The right side depicts the lymphatic artery and vein and the postcapillary venules. Lymphocytes in the circulation can pass into the node from the postcapillary venules by a process called extravasation (inset)

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

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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 antigens.

Diagrammatic cross section 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.

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.)


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Mucosa Associated Lymphoid Tissue (MALT)

Cross-sectional diagram of the mucous membrane ling the intestine, showing a Peyer’s patch lymphoid nodule in the submucosa. The intestinal lamina contains loose clusters of lymphoid cells and diffuse follicles.


Structure of the M cells and production of Ig A at inductive sites. M cells,situated in mucous membranes, endocytose antigen from the lumen of the digestive, respiratory, and urogenital tracts. The antigen is transported into the large basolateral pocket.


Antigen transported across the epithelial layer by M cells at an inductive site activates B cells in the underlying lymphoid follicles. The activated B cells differentiate into IgA-producing plasma cells, which migrate along the submucosa. The outer mucosal epithelial layer contains intraepithelial lymphocytes, of which are T cells.

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.)


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Bronchus Associated Lymphoid Tissue (BALT)

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 keratinocytes. These cells secrete a number of cytokines that may function in local inflammatory reaction. Scattered among the epithelial-cell matrix of the epidermis are Langerhann’s cells, atype of dendritic cell, which internalize antigen by phagocytosis or endocytosis. They undergo maturation and migrate from the epidermis to regional lymph nodes, where they function as potent activators of naïve TH cells. In addition 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 scattered T cells and macrophages. Most of these dermal cells appear to be either previously activated cells or memory cells.

Summary

• The humoral (antibody) and cell mediated responses of the immune system result from the coordinated activities of many cell types of cells, organs, and tissues found throughout the body.

• Many of the body’s cells, tissues, and organs arise from different stem cell populations. Leukocytes develop from a pluripotent hematopoietic stem cell during a highly regulated process called hematopoiesis.

• Apoptosis, a type of programmed cell death, is a key factor in regulating the levels of hematopoietic and other cell populations.

• 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 populations distinguished by antigen receptors of unique specificity. B cells synthesize and display membrane antibody, and T cells synthesize and display T-cell receptors. Most NK cells do not synthesize antigen-specific receptors, although a small subpopulation of this group, NK-T cells, do synthesize and display a T cell receptor.

• Macrophages and neutrophils are specialized for the phagocytosis and degradation of antigens. Macrophages also have the capacity to present antigen to T cells.

Summary

• Immature forms of dendritic cells have the capacity to capture antigen in one location, undergo maturatiuon , and migrate to another location, where they present antigen to TH cells. Dendritic cells are the major population of antigen presenting 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 antigen, become activated, and undergo clonal expansion and differentiation into effector cells.

• Vertebrate orders differ greatly in the kinds of lymphoid organs, tissues, and cells they posses. The most primitive, the jawless fish, lack B and T cells and cannot mount adaptive immune responses; jawed vertebrates have T and B cells, have adaptive immunity, and display an increasing variety of lymphoid tissues.

Technology

Cells & organs ofthe immune system