Immune System

· immune system – this provides defense or immunity against infectious agents ranging from viruses to multicellular parasites.

· what is the Histological components of the Immune system?

o consists of a large, diverse population of leukocytes

· where can you see this diverse population of leukocytes?

o within every tissue of the body and lymphoid organs interconnected only by the blood and lymphatic circulation

· autoimmune diseases – this is a medical problem in which immune cells begin to function abnormally and attack molecular components of the body’s own organs

· what are the two partially overlapping lines of defense against invaders and/or other abnormal, potentially harmful cells?

o innate immunity

o adaptive immunity

· innate immunity - is nonspecific defense against invaders, involves a wide variety of effector mechanisms, and is evolutionarily older than the second type

· what are the cells mediating innate immunity?

o most of the granulocytes and other leukocytes described

· adaptive immunity – this defense against invaders aims at specific microbial invaders, is mediated by lymphocytes and antigen-presenting cells (APCs) and produces memory cells that permit a similar, very rapid response if that specific microbe appears again.

· What are the cells mediating adaptive immunity?

o lymphocytes and APCs

· where can you find lymphocytes and APC?

o  are distributed throughout the body in the blood, lymph, and epithelial and connective tissues

· primary lymphoid organ – this includes the thymus and bone marrow  - this is where lymphocytes are formed initially

· secondary lymphoid organs – this organs includes the lymph nodes, the spleen, and diffuse lymphoid tissue found in the mucosa of the digestive system, including the tonsils, Peyer patches, and appendix where most lymphocyte activation and proliferation occur

· mucosa-associated lymphoid tissue (MALT) -these are the collections of the immune cells located diffusely in the digestive, respiratory, or urogenital mucosae

· lymphoid nodules – this are small spherical structure of how the proliferating B lymphocytes in the secondary structures of MALT are arranged

› INNATE & ADAPTIVE IMMUNITY

· innate immunity – this type of immunity involves immediate, nonspecific actions, including physical barriers such as the skin and mucous membranes of the gastrointestinal, respiratory, and urogenital tracts that prevent infections or penetration of the host body

· Bacteria, fungi, and parasites  - these invading organisms that manage to penetrate these barriers are quickly removed by neutrophils and other leukocytes in the adjacent connective tissue

· Toll-like receptors (TLRs) – these present on leukocytes that allow the recognition and binding of surface components of such invaders

· Natural killer (NK) cells – this cell destroy various unhealthy host cells, including those infected with virus or bacteria, as well as certain potentially tumorigenic cells. ‘

· What are the other antimicrobial chemicals produced by leukocytes and specific cells of the tissue barriers that also form a major part of innate immunity?

o ‘Hydrochloric acid (HCl) and organic acids

o Defensins

o Lysozyme

o Complement

o Interferons

· Hydrochloric acid (HCl) and organic acids in specific regions  - these lowers the pH locally to either kill entering microorganisms directly or inhibit their growth

· Defensins - this short cationic polypeptide produced by neutrophils and various epithelial cells that kill bacteria by disrupting the cell walls.

· Lysozyme – this is an enzyme made by neutrophils and cells of epithelial barriers, which hydrolyzes bacterial cell wall components, killing those cells

· Complement – this is a system of proteins in blood plasma, mucus, and macrophages that react with bacterial surface components to aid removal of bacteria

· Interferons – this are paracrine factors from leukocytes and virus-infected cells that signal NK cells to kill such cells and adjacent cells to resist viral infection.

· Adaptive immunity – this are acquired gradually by exposure to microorganisms, is more specific, slower to respond, an evolutionarily more recent development;  involves B and T lymphocytes, which become activated against specific invaders by being presented with specific molecules from those cells by APCs, which are usually derived from monocytes; responses are aimed at specific microbial invaders and involve production of memory lymphocytes so that a similar response can be mounted very rapidly if that invader ever appears again.

› CYTOKINES

· Cytokines – it is the way by which within lymphoid organs and during inflammation at sites of infection or tissue injury, cells in the immune system communicate with each other primarily to coordinate defensive measures; Involved in both innate and adaptive immunity; diverse group of peptides and glycoproteins; usually with low molecular masses (between 8 and 80 kDa); a paracrine mode of action; they coordinate cell activities in the innate and adaptive immune responses

· What are the major responses induced in target cells by cytokines?

o Directed cell movements, or chemotaxis, toward and cell accumulation at sites of inflammation, for example, during diapedesis. Cytokines producing this effect are also called chemokines. 

o Increased mitotic activity in certain leukocytes, both locally and in the bone marrow

o Stimulation or suppression of lymphocyte activities in adaptive immunity. A group of cytokines with such effects were named interleukins because they were thought to be produced by and to target only leukocytes

o Stimulated phagocytosis or directed cell killing by innate immune cells

· Chemokines – are cytokines whose effect as such to directed cell movements, or chemotaxis, toward and cell accumulation at sites of inflammation, for example, during diapedesis

· interleukins  - this are cytokines that act to Stimulation or suppression of lymphocyte activities in adaptive immunity

› ANTIGENS & ANTIBODIES

· antigen – this is a molecule that is recognized by cells of the adaptive immune system & typically elicits a response from these cells; may consist of soluble molecules (such as proteins or polysaccharides) or molecules that are still components of intact cells (bacteria, protozoa, or tumor cells)

· antigenic determinants or epitopes – a small molecular domains of the antigen that the Immune cells recognize and react to

· what are the immune responses to antigen?

o Cellular

o Humoral

o both

· cellular immune response - in which lymphocytes are primarily in charge of eliminating the antigen

· humoral immune response - in which antibodies are primarily responsible for the response

· An antibody – this is a glycoprotein of the immunoglobulin family that interacts specifically with an antigenic determinant.; are secreted by plasma cells that arise by terminal differentiation of clonally proliferating B lymphocytes whose receptors recognize and bind specific epitopes; it either accumulate in the blood plasma and in the interstitial fluid of tissues or are transported across epithelia into the secretion of glands such as mucous, salivary, and mammary glands;  each of it combines with the epitope that it specifically recognizes.

· What is the design of the Immunoglobulins of all antibody molecules?

o two identical light chains

o two identical heavy chains bound by disulfide bonds

· Fc region – this is the isolated carboxyl-terminal portion of the heavy-chain molecules which is constant; this region in some immunoglobulins are recognized by cell surface receptors on basophils and mast cells, localizing these antibodies to the surface of these cells

· variable region – this is called of the first 110 amino acids near the amino-terminal ends of the light and heavy chains that vary widely among different antibody molecules, this portions of one heavy and one light chain make up an antibody’s antigen-binding site; DNA sequences coding for these regions undergo recombination and rearrangement after B lymphocytes are activated against a specific antigen and the progeny of those cells all produce antibodies that specifically bind that antigen. Each antibody has two antigen-binding sites, both for the same antigen ‘

Classes of Antibodies

· five major classes – number of Immunoglobulins classes of humans

· what are the 5 major classes of immunoglobulins in humans?

o G (IgG), IgA, IgM, IgE, and IgD,

· IgG – this is the most abundant class of immunoglobulin representing 75%-85% of the immunoglobulin in blood; production increases during immune responses following infections; unlike the other classes of antibodies, it is highly soluble, stable (half-life > 3 weeks), and crosses the placental barrier into the fetal circulation; this confers passive immunity against certain infections until the newborn’s own adaptive immune system is acquired.

· IgA – this immunoglobulin is present in almost all exocrine secretions as a dimeric form in which the heavy chains of two monomers are united by a polypeptide called the J  chain; it is produced by plasma cells in mucosae of the digestive, respiratory, and reproductive tracts; another protein bound to this immunoglobulin, the secretory component, is released by the epithelial cells as IgA undergoes transcytosis resulting into a structure that is relatively resistant to proteolysis and reacts with microorganisms in milk, saliva, tears, and mucus coating the mucosae in which it is made.

· IgM – this immunoglobulin constitutes 5%-10% of blood immunoglobulin and usually exits in a pentameric form united by a J chain;  it is mainly produced in an initial response to an antigen; it is bound to antigen & is the most effective antibody class in activating the complement system.

· IgE – this immunoglobulin is usually a monomer, it is much less abundant in the circulation and exists bound at its Fc region to receptors on the surface of mast cells and basophils; When this immunoglobulin encounters the antigen that elicited its production, the antigen-antibody complex triggers the liberation of several biologically active substances, such as histamine, heparin, and leukotrienes this characterizes an allergic reaction

· How does IgE contribute to the allergic reaction?

o When this immunoglobulin E encounters the antigen (allergen) that elicited its production, the antigen-antibody complex triggers the liberation of several biologically active substances, such as histamine, heparin, and leukotrienes this characterizes an allergic reaction

· IgD -this immunoglobulin is the least abundant immunoglobulin in plasma, it is also the least understood class of antibody; its monomers are bound to the surface of B lymphocytes where they (along with IgM monomers) act as antigen receptors in triggering B-cell activation.

Actions of Antibodies

·  antigen-binding sites of IgG and IgA antibodies – these immunoglobulins are able to bind specifically and neutralize certain viral particles and bacterial toxins, agglutinate many bacterial cells, and precipitate most soluble antigens.

· the Fc portions  - this portion of the immunoglobulin structure and other antibodies also bind receptors for this sequence and thereby optimize three important actions of innate immunity

· what are the 3 important actions of innate immunity?

o Complement activation

o Opsonization

o NK cells activation

· Complement activation – this action of innate immunity whereby Antigen-antibody complexes containing IgG or IgM bind polypeptides of this system, a group of around 20 plasma proteins produced mainly in the liver, and activate them through a cascade of enzymatic reaction, wherein after activation, specific complement components bind and rupture membranes of invading cells, clump antigen-bearing bacteria or cells, and elicit arrival of relevant leukocytes.

· Opsonization - the action of innate immunity whereby this refers to the ability of receptors on macrophages, neutrophils, and eosinophils to recognize and bind the Fc portions of antibodies attached to surface antigens of microorganisms; this greatly increases the efficiency of phagocytosis by these leukocytes at the sites of infection.

· NK cells activation  - the action of innate immunity whereby antibodies bound to antigens on virus-infected cells of the body are recognized by the primitive lymphocytes called NK cells, which are then activated to kill the infected cell by releasing perforin and various granzymes & together enter the infected cell via other receptors and cause apoptosis.

· NK cells  - this recognize the virus infected cells of the body and when activated  kill the infected cell

· perforin and various granzymes – released by the NK cells, they enter the infected cell via other receptors and cause apoptosis.

› ANTIGEN PRESENTATION

· antigen-presenting proteins – a specialized integral membrane protein complexes on cell surfaces where antigens recognized by lymphocytes are often bound; are part of the major histocompatibility complex (MHC)

· major histocompatibility complex (MHC) which includes antigen presenting cells includes the two key types what are these?

o MHC class I and class II

· major histocompatibility complex - these proteins were first recognized by their roles in the immune rejection of grafted tissue or organs; proteins of both classes, which on human cells are often called human leukocyte antigens (HLAs), are encoded by genes in large chromosomal loci having very high degrees of allelic variation between different individuals; Like all integral membrane protein complexes, MHC molecules are made in the rough ER and Golgi apparatus

· lymphocytes – this WBC are specialized to recognize both classes of MHC proteins and the antigens they present

· If the MHCs on cells of a tissue graft are not similar to those that T lymphocytes encountered during their development of the recipient tissue, what will happn to the grafted tissue?

o grafted cells will induce a strong immune reaction by T cells of the recipient

o To lymphocytes, the unfamiliar MHC epitopes on the graft’s cells are recognized as markers of potentially tumorigenic, infected, or otherwise abnormal (“non-self ”) cells that they must eliminate.

· MHC class I proteins - before leaving the ER, MHC of this class of proteins bind a wide variety of proteasome-derived peptide fragments representing the range of all proteins synthesized in that cell; all nucleated cells produce and expose on their surfaces of this MHC class molecules presenting such “self-antigens,” which T cells recognize as a signal to ignore those cells, and by this same mechanism, some virally infected cells or cells with proteins altered by gene mutation also have this class of proteins displaying peptides that T cells do not recognize as “self,” helping lead to the elimination of such cells.

· MHC class II – this proteins are synthesized and transported to the cell surface similarly but only in cells of the mononuclear phagocyte system and certain other cells under some conditions; before joining the plasmalemma, the Golgi derived vesicles with this MHC class complexes first fuse with endolysosomal vesicles containing antigens ingested by receptor-mediated endocytosis, pinocytosis, or phagocytosis,  allowing the this MHC class proteins to bind fragments of whatever proteins the cells had ingested, including those from dead, infected, or abnormal cells and atypical proteins of all kinds; the surface of these cells, the class II complexes display the peptides from these potentially pathogenic cells, signaling T lymphocytes and activating their responses against sources of these antigens.

› CELLS OF ADAPTIVE IMMUNITY

· lymphocytes and the monocyte-derived cells – these are specialized for antigen presentation to lymphocytes are the major players in adaptive immune responses.

Antigen-Presenting Cells

· what are the most specialized APCs?

o are part of the mononuclear phagocyte system, including all types of macrophages & specialized dendritic cells in lymphoid organs

· what are features common to all APCs?

o an active endocytotic system

o expression of MHC class II molecules for presenting peptides of exogenous antigens

· what are the professional APC’s?

o dendritic cells (not to be confused with cells of nervous tissue)

o all monocyte-derived cells

o thymic epithelial cells

· During inflammation transient expression of MHC class II is induced by“ nonprofessional” APCs. What cells are these?

o  interferon-γ in certain local cell

o fibroblasts and vascular endothelial cells.

Lymphocytes

· Lymphocytes – this WBC regulate and carry out adaptive immunity; do not stay long in the lymphoid organs; they continuously recirculate through the body in connective tissues, blood, and lymph; most lymphocytes are morphologically indistinguishable in either the light or electron microscope

· red ‘bone marrow - in adults, it is where stem cells for all lymphocytes are located; but cells of the major lymphoid lineages mature and become functional in two different central or primary lymphoid organs; it is where cells destined to become B lymphocytes remain and differentiate further;

· thymus – it is where the progenitors of T lymphocytes move via the circulation to develop

· what are the primary lymphoid structure?

o Thymus

o Bone marrow

·  Thymus & bone marrow - After maturation of the B and T lymphocytes in these primary structures, B and T cells circulate to the peripheral secondary lymphoid organs; lymphocytes do not stay long in the lymphoid organs; they continuously recirculate through the body in connective tissues, blood, and lymph. Because of the constant mobility of lymphocytes and APCs, the cellular locations and microscopic details of lymphoid organs differ from one day to the next

· What are the secondary lymphoid organs?

o include the MALT

o lymph nodes

o the spleen

· reticular connective tissue – this is the type of CT the Lymphoid tissue is; filled with large numbers of lymphocytes

· lymphoid tissue - It can be either diffuse within areas of loose connective tissue or surrounded by capsules, forming discrete (secondary) lymphoid organs

· what is the histological picture of lymphoid tissue?

o Because lymphocytes have prominent basophilic nuclei and very little cytoplasm, lymphoid tissue packed with such cells usually stains dark blue in hematoxylin and eosin (H&E) -stained sections

· reticulin fiber network of type III collagen – this supports the lymphocytes in all secondary lymphoid tissue, produced by fibroblastic reticular cells, which extend numerous processes along and around the fibers

· what are the cells comprising the lymphoid tissue?

o Lymphocytes

o reticular cells

o various APCs and plasma cells

· “cluster of differentiation” or CD markers - Although most lymphocytes are morphologically indistinguishable in either the light or electron microscope, this various surface proteins allow them to be distinguished as B cells and subcategories of T cells by immunocytochemical methods

· B lymphocytes – with surface receptors involved in activating their different responses to antigens; its receptor are immunoglobulins that bind antigens directly

· T lymphocytes -  with surface receptors involved in activating their different responses to antigens; its receptor react only with antigen on MHC molecules and this requires the additional cell surface proteins CD4 or CD8. ‘

· are immunocompetent but naive and unable to recognize antigens – this describes the lymphocytes in the marrow and thymus of a newborn infant not yet exposed to antigens

· how can naïve lymphocytes of the newborn be activated?

o After circulating to the various secondary lymphoid structures, lymphocytes are exposed to antigens on APCs and become activated, proliferating to produce a clone of lymphocytes all able to recognize that antigen ‘

T Lymphocytes

· T cells – these are long-lived lymphocytes and constitute nearly 75% of the circulating lymphocytes; they recognize antigenic epitopes via surface protein complexes termed T-cell receptors (TCRs); said to be MHC restricted. ‘

· What are the 2 TCRs?

o include two glycoproteins called the α and β chains

· T-cell receptors – it is how T cells recognize antigenic epitopes; each with variable regions produced similarly to those of immunoglobulins; only recognize antigenic peptides when presented as part of MHC molecules (interacting with both the MHC and the peptide it presents)

· What are the important subpopulations of T cells?

o T-Helper

o Cytotoxic T cells

o Regulatory T cells

o γδ T lymphocytes

· Helper T cells (Th cells) – are subpopulations of T cells are characterized by CD4, the coreceptor with the TCR for binding MHC class II molecules and the peptides they are presenting; activated by such binding, helper T cells greatly assist immune responses by producing cytokines that promote differentiation of B cells into plasma cells, activate macrophages to become phagocytic, activate cytotoxic T lymphocytes (CTLs), and induce many parts of an inflammatory reaction; some specifically activated helper T cells persist as long-lived memory helper T cells, which allow a more rapid response if the antigen appears again later.

·  CD4 – this is the  coreceptor with the TCR for binding MHC class II molecules and the peptides they are presenting; this characterize the  Helper T cells subpopulations

· cytotoxic T lymphocytes – these are CD8+; their TCRs together with CD8 coreceptors bind specific antigens on foreign cells or virus infected cells displayed by MHC class I molecules; also called killer T cells, they attach to the cell sources of the antigens and remove them by releasing perforins and granzymes, which trigger apoptosis, representing cell mediated immunity and its mechanism is largely similar to that of NK cells; its activation also results in a population of memory cytotoxic T cells.

· CD8 – this is the  coreceptor with the TCR for binding MHC class I molecules

· interleukin-2 (IL-2) from helper T cells - In its presence the cytotoxic T cells that have recognized such antigens are activated and proliferate

· Regulatory T cells (Tregs or suppressor T cells) – these subpopulation of T cells are CD4+CD25+ and serve to inhibit specific immune responses; these cells, also identified by the presence of the Foxp3 transcription factor, play crucial roles in allowing immune tolerance, maintaining unresponsiveness to self-antigens and suppressing excessive immune responses; these cells produce peripheral tolerance, which acts to supplement the central tolerance that develops in the thymus.

· γδ T lymphocytes – this represent a smaller subpopulation of T lymphocytes whose TCRs contain γ (gamma) and δ (delta) chains instead of α and β chains; this T cells migrate to the epidermis and mucosal epithelia, becoming largely intraepithelial, and do not recirculate to secondary lymphoid organs; they function in many ways like cells of innate immunity, in the front lines against invading microorganisms

B Lymphocytes

·  In B lymphocytes – this type of T cells has  surface receptors for antigens are monomers of IgM or IgD, with each B cell covered by about 150,000 such B-cell receptors (BCRs)

· B-cell receptors (BCRs) – this bind an antigen, which may be free in solution, on an exposed part of an infectious agent, or already bound to antibodies, and the surface complexes then undergo endocytosis, degraded in endosomes & peptides from the antigens are presented on MHC class II molecules of the B cell; a helper T cell then binds this B cell and activates it further with a cytokine, inducing recombination in the immunoglobulin genes and stimulating several cycles of cell proliferation

· follicular dendritic cells (FDCs) – scattered with long filamentous processes; it is where B lymphocytes interact in all secondary lymphoid tissues; are mesenchymal in origin and their function does not involve MHC class II molecules; surfaces of these cells are covered with antibody-antigen complexes bound to receptors for complement proteins and for immunoglobulin Fc regions, causing B cells to attach, become activated, and aggregate as a small primary lymphoid nodule (or follicle). 

· small primary lymphoid nodule (or follicle) – this is formed by the B cells attaching to surfaces of follicular cells covered with antibody-antigen complexes bound to receptors for complement proteins and for immunoglobulin Fc regions, b cells became activated and aggregate as such

· secondary lymphoid nodule -  formed by the B cells that now form a much larger and more prominent than primary lymphoid nodule that  is formed with the help of adjacent T cells; are characterized by a lightly stained germinal center filled with large lymphoblasts (or centroblasts) undergoing immunoglobulin gene recombination, rapid proliferation, and quality control

· germinal center – this characterize the secondary nodule; filled with large lymphoblasts (or centroblasts) undergoing immunoglobulin gene recombination, rapid proliferation, and quality control;  the naive, nonproliferating B cells to be pushed aside and produce the more darkly stained peripheral mantle since the growth of activated B cells in germinal centers is exuberate and very rapid

· After 2-3 weeks of proliferation – this duration of proliferation when most cells of the germinal center and mantle are dispersed and the structure of the secondary lymphoid nodule is gradually lost. ‘

· plasma cells – the new B lymphocytes differentiate into this cells and secrete antibodies that will bind the same epitope recognized by the activated B cell

· humoral immunity – this type of immunity is provided by the B cells because the antibodies specified by B cells circulate in lymph and blood throughout the body

· activated T cells & B cells – this lymphocytes remain as long-lived memory B cells.

· Formation of long lived memory lymphocytes – this is the key feature of adaptive immunity, which allows a very rapid response upon subsequent exposure to the same antigen

› THYMUS

· bone marrow – it is where the immature B lymphocytes emerge from

·  thymus – it is where the primary or central lymphoid organ in which T cells are produced; is a bilobed structure in the mediastinum; its main function is induction of central tolerance, which along with regulatory T cells prevents autoimmunity; it is fully formed and functional at birth;

· Puberty - this is the time when the thymus remains large and very active in T-cell production until after this, it normally undergoes involution, with decreasing lymphoid tissue mass and cellularity and reduced T cell output

· Where does the thymus originate from?

o originates from the embryo’s third pair of pharyngeal pouches (endoderm), with precursor lymphoblasts circulating from the bone marrow to invade and proliferate in this unique thymic epithelium during its development

· what is the histologic picture of the thymus?

o capsule - vascularized connective tissue that extends septa into the parenchyma

o septa dividing the organ into many incompletely separated lobules

o lobule has an outer darkly basophilic cortex surrounding a more lightly stained medulla

· what is the cause of the staining differences in the thymus lobule: outer darkly basophilic cortex & lightly stained medulla?

o reflect the much greater density of lymphoblasts and small lymphocytes in the cortex than the medulla

· the thymic cortex is basophilic and dark; what does it contains?

o extensive population of T lymphoblasts (or thymocytes)

o venules where some newly arrived thymocytes have arrived

o numerous macrophages

o unique thymic epithelial cells (TECs)

· thymic epithelial cells (TECs) – found in the cortex of the thymus, have certain features of both epithelial and reticular cells; these cells usually have large euchromatic nuclei but are morphologically and functionally diverse.

· What are the three major types of TECs in the cortex of the thymus?

o Squamous TECs

o stellate TECs

o Other squamous cortical TECs

· Squamous TECs – this type of TEC cell in the thymus’ cortex form a layer, joined by desmosomes and occluding junctions, line the connective tissue of the capsule and septa and surround the microvasculature; this creates an isolated cortical compartment and, together with the vascular endothelial cells and pericytes, forms a blood-thymus barrier preventing unregulated exposure of thymocytes to antigens

· stellate TECs – this type of TEC is found throughout this compartment, has processes containing keratin tonofilaments joined by desmosomes, form a cytoreticulum to which macrophages and developing lymphocytes attach instead of to reticulin fibers; these cells are APCs, expressing MHC class II molecules in addition to MHC class I; they also secrete numerous cytokines for T-cell development and other immune functions, justifying this organ’s inclusion among endocrine glands.

· squamous cortical TECs – this type of TEC also express MHC class II molecules but form a sheetlike structure contributing to a functional corticomedullary barrier between these two regions of each lobule. ‘

· thymic medulla – this portion of the thymus has a more lightly stained; contains fewer and larger, more mature lymphocytes; its microvasculature is not surrounded by a tight layer of TECs, and mature T lymphocytes exit the thymus by passing through the walls of venules and efferent lymphatics in this region

· what are the 3 related types of medullary TECs?

o A second layer of the boundary between cortex and medulla

o Cytoreticulum

o Hassall corpuscles

· A cytoreticulum – this portion of the thymic medulla (1) supports T lymphocytes, dendritic cells, and macrophages (all less densely packed than in the cortex), and (2) expresses many specialized proteins specific to cells of other organs

· Hassall corpuscles  - this is called of the large aggregates of TECs, sometimes concentrically arranged, up to 100 μm in diameter; are unique to the medulla; their cells secrete several cytokines that control activity of local dendritic cells, including factors promoting development of regulatory T cells for peripheral tolerance.

Role of the Thymus in T-Cell Maturation & Selection

· thymus – this is the site of T-lymphocyte differentiation and the selective removal of T cells reactive against self-antigens, a key part of inducing central self-tolerance

· describe the T lymphoblasts upon arriving in the thymus:

o do not yet express CD4, CD8, or a TCR

o it populate the cortex and begin to proliferate

o recombine variable regions of the TCR α and β chain genes

o then express these TCR proteins as well as both CD4 and CD8

· what is the end goal of thymocyte on having two-stage selection process of quality control of T cells?

o To ensures that mature T cells have TCRs that are fully functional

o fully functional but do not recognize and strongly bind MHC with self-antigens.

· two-stage selection process of quality control of T cells – this process of ensuring full functional selection process for each pre–T lymphocyte  begins in the cortex, ends in the medulla, and lasts about 2 weeks

· TECs in the cytoreticulum of the cortex  - this cell present the developing thymocytes with peptides on both MHC class I and class II proteins, which are important for development of CD8+ and CD4+ T cells, respectively

· Thymocytes with peptides on both MHC class I and class II proteins interaction  - this interaction determines whether the newly made TCR proteins of these cells are functional

· How does thymocyte cells in the cortex examined T lymphocyte by positive selection?

o cell’s survival depending on whether its TCRs can recognize and bind antigens on the MHC molecules properly

o cell cannot pass this test if with faulty gene recombination and expression of α and β chains, they are nonfunctional and completely useless; cells (as many as 80% of the total) undergo apoptosis and are removed by the macrophages

o T cells with normal binding to antigens on either MHC class I or class II are positively selected and move to the medullary compartment

· How does thymocyte cells in the medulla examined T lymphocyte by negative selection?

o Here the focus is on removing T cells whose TCRs strongly bind self-antigens selection because survival depends on a cell not binding to MHC molecules with such peptides

o In the medulla T cells with functional TCRs encounter antigens presented on both cytoreticular TECs and dendritic cells; this antigen are those from proteins specific for many tissues other than the thymus; occurs because medullary thymic epithelial cells express high levels of the gene Aire an autoimmune regulator

· negative selection – this is the process in the thymic medulla, where the focus is on removing T cells whose TCRs strongly bind self-antigens; it is because the survival depends on a cell not binding to MHC molecules with such peptides

· gene Aire – this is an autoimmune regulator whose product promotes expression of a multitude of such tissue-specific antigens in medullary thymic cells

· dendritic cells – this cell plays the major role in presenting antigen encountered by the T cells to developing thymocytes.

· What happen to T cells that strongly bind MHCs containing these self peptides in the process of negative selection?

o undergo apoptosis

· this is what happen if the cells that strongly bind MHCs containing these self peptides in the process of negative selection is not destroyed?

o Lead to damaging autoimmune response

· 2% of all developing T lymphocytes  - this is the percentage of the developing t Lymphocytes that pass both the positive and negative selection tests and survive to exit the thymus as immunocompetent T cells

· MHC interaction - This is the factor that the T lymphocytes will interact to which depend what T lymphocytes will become,  expressing either CD8 or CD4, and become either helper T cells or cytotoxic T cells

· Deletion of self-reactive helper and cytotoxic T lymphocytes in the thymus – this is the basis for the central immunotolerance produced in the thymus

· peripheral tolerance  - this supplements the central immune tolerance, mediated by regulatory T cells, which also develop initially in the thymic medulla under the influence of cytokines from Hassall corpuscles.

› MUCOSA-ASSOCIATED LYMPHOID TISSUE

· Secondary lymphoid structure – this lymphoid structure is where most lymphocytes are activated by antigen presentation

· What are the secondary lymphoid tissues?

o include the MALT, the lymph nodes, and the spleen

· MALT – this is the site of protection found in the mucosal connective tissue of these tracts of this organs inner lining such as digestive, respiratory, and genitourinary tracts where they are common site of invasion by pathogens because their lumens open to the external environment; collectively is one of the largest lymphoid organs, containing up to 70% of all the body’s immune cells; diffused & extends from the pharynx along the entire gastrointestinal tract but becomes very well-developed again in the mucosa and submucosa of the ileum

· What comprises the MALT?

o contains large and diffuse collections of lymphocytes, IgA-secreting plasma cells, APCs, and lymphoid nodules

· in what form can you see most of the immune cells in MALT?

o dispersed diffusely in the connective tissue

o in aggregates forming large, conspicuous structures such as the tonsils, the Peyer patches in the ileum, and the appendix.

· B cells – this is the most common lymphocytes in the MALT

· CD4+ helper T cells – this is the T cells that predominate in the MALT

· Tonsils – these are large irregular masses of lymphoid tissue in the mucosa of the posterior oral cavity and nasopharynx where their cells encounter antigens entering the mouth and nose; here the lymphoid tissue is closely associated with the surface epithelium;

· What are the different types of tonsils?  

o the palatine, lingual, and pharyngeal tonsils

· Palatine tonsils – this is located posteriorly on the soft palate, are covered by stratified squamous epithelium; surface area of each is enlarged with 10-20 deep invaginations or tonsillar crypts in which the epithelial lining is densely infiltrated with lymphocytes and other leukocytes; lymphoid tissue is filled diffusely with lymphocytes, with many secondary lymphoid nodules around the crypts; is underlain by dense connective tissue acting as a partial capsule.

· Lingual tonsils – this is located along the base of the tongue, are also covered by stratified squamous epithelium with crypts, and have many of the same features as palatine tonsils but lack distinct capsules.

· pharyngeal tonsil – single; is situated in the posterior wall of the nasopharynx, is covered by pseudostratified ciliated columnar epithelium, and has a thin underlying capsule; its mucosa with diffuse lymphoid tissue and lymphoid nodules is invaginated with shallow infoldings but lacks crypts

· Peyer patches - large aggregates of lymphoid nodules; each containing dozens of nodules with no underlying connective tissue capsule found in the mucosa and submucosa of the ileum

· M cells – this large epithelial cell with apical microfolds rather than the brush border with glycocalyx typical of the neighboring enterocytes, this is included in the simple columnar epithelium that covers the lymphoid nodules of Peyer patches; are a unique epithelial cell type specialized for uptake of particles and intact microorganisms; its  basolateral surface is deeply invaginated to form a large “pocket” open to the underlying lymphoid tissue through a uniquely porous or sieve-like basement membrane and containing a transient population of lymphocytes and dendritic cells; at the apical surface of this cells antigens   in the intestinal lumen are continuously sampled and transferred to the immune cells in the pockets.

· secondary lymphoid nodules – formation of this, results from the interaction of lymphocytes & dendritic that initiate adaptive responses to the antigens cells leaving the M cell pockets through the basement membrane pores

· secreting IgA - what Immunoglobulin is locally produced by the B cells that give rise to this plasma cells, which is transported by enterocytes into the intestinal lumen to bind and neutralize potentially harmful antigens. ‘

· the appendix – this is a short, small-diameter projection from the cecum; another significant collection of MALT, that occurs in its mucosa; typically, its mucosa is almost completely filled with lymphoid tissue, effacing the glands otherwise found in the large intestine wall; its lumen contains the normal bacterial flora of the large intestine and may serve to retain some of these beneficial bacteria there during diarrheal illnesses ‘

› LYMPH NODES

· Lymph nodes – these are bean-shaped, encapsulated structures, generally only 10 mm by 2.5 cm in size, distributed throughout the body along the lymphatic vessels; it constitute a series of in-line filters of lymph that defend against the spread of microorganisms and tumor cells and provide enclosed environments for antigen presentation and development of plasma cells secreting non-IgA antibodies; it filter blood and add antibodies before merging with the bloodstream;  Unlike the thymus its major regions are not compartmentalized by epithelium. ‘

· Where can you find the lymph node?

o a total of 400-450 lymph nodes are present in the axillae (armpits) and groin, along the major vessels of the neck, and in the thorax and abdomen, and especially in the visceral mesenteries. ‘

· loose CT  - this is the tissue in which the LN is embedded

· how does the lymph node looks like?

o a convex surface where afferent lymphatics enter

o a concave depression, the hilum, where an efferent lymphatic leaves and where an artery, vein, and nerve penetrate the organ

o a dense connective tissue capsule surrounds it

o a dense CT extending trabeculae internally through which the blood vessels branch.

· Valves – its presence in the  lymphatics ensure unidirectional lymph flow

· What are the most abundant cells of lymph nodes?

o  lymphocytes of all types, plasma cells, dendritic cells, macrophages, and other APCs

· lymphoid nodules - this is where in the LN the FDC are present within

· reticulin fibers and reticular cells - this is the stroma of the LN where all cells are arranged

· what are the 3 major regions within the stroma within each lymph node?

o outer cortex

o paracortex

o medulla

· cortex – this outer region of the LN contains the nodules

· paracortex  - this region of the LN is a deeper extension of cortex, which lacks nodules

· medulla – this region of the LN has a prominent draining sinusoids adjacent to the hilum

· what re the component of the Cortex of the LN?

o subcapsular sinus

o Lymphoid nodules

· A subcapsular sinus, - this part of the LN’s cortex, lie immediately inside the capsule, receives lymph from the afferent lymphatics; from this space cortical sinuses (or trabecular sinuses) branch internally among the lymphoid nodules along trabeculae; are lined by a very thin, discontinuous endothelium penetrated by reticulin fibers and processes of dendritic cells; lymph containing antigens, lymphocytes, and APCs passes through these and percolates easily into the surrounding lymphoid tissue

· Lymphoid nodules with or without germinal centers – this part of the LN’s cortex consist largely of developing B lymphocytes and occupy much of the cortex not filled with helper T lymphocytes; each of this is organized around the long, interdigitating processes of FDCs, but these are not readily seen by routine light microscopy; numerous macrophages are also present for removal of newly formed defective B cells that undergo apoptosis.

· the paracortex – this is the region between the cortex and medulla that does not have precise boundaries but can be distinguished from the outer cortex by its lack of nodules; unlike the superficial cortex, this area contains lymphoid tissue rich in T cells distinguishable by immunohistochemistry

· high endothelial venules (HEVs) - specialized postcapillary venules located mainly in the paracortex, represent an important entry point for most (90%) circulating lymphocytes into lymph nodes; endothelial cells become unusually enlarged or cuboidal and express specific apical surface glycoproteins that mediate the tethering and diapedesis of B and T cells from the blood into the paracortex of the lymph node; also occur in the large accumulations of MALT discussed previously, but are less well-characterized in those tissues

· what are the two major components of medulla of a lymph node?

o Medullary cords

o Medullary sinuses

· Medullary cords – this component of the medulla of the LN are branched cordlike masses of lymphoid tissue extending from the paracortex; it contains T and B lymphocytes and many plasmas cells

· Medullary sinuses - are dilated spaces lined by discontinuous endothelium that separate the medullary cords; its lumens include a meshwork of processes from reticular cells, which represent a final lymph filter; this portion of medulla contain many macrophages and sometimes neutrophils if the lymph node is draining an infected region; they are continuous with the cortical sinuses and converge at the hilum as the efferent lymphatic vessel

Role of Lymph Nodes in the Immune Response

· What is the nature of the antigen in the lymph arriving at a lymph node?

o contains antigens free in solution

o antigen bound to antibodies or complement

o antigen still on microorganisms

o antigen already internalized and transported by APCs

· what is the content of the Lymph that is draining from an infected or inflamed region?

o lymph may also contain microorganisms and cytokines

· what happen to antigens in the blood that is not yet phagocytosed upon reaching the  LN?

o it will be internalized by APCs in the lymph nodes

o & will be presented on MHC class II molecules

· What is the role of circulating B and T lymphocytes that traffic from node to node, entering via the lymph or HEVs?

o B cells contact antigens on FDCs

o T cells sample antigens presented on dendritic cells and other APCs.

o Lymphocytes whose receptors recognize such antigens will be activated

o B cells will proliferate rapidly in germinal centers of follicles with the help of Th cells, often enlarging the entire lymph node.

o Activated cytotoxic T cells in the paracortex proliferate to a much lesser extent without forming follicles.

· B lymphocytes - When this type of lymphocytes whose receptors recognize such antigens will be activated, it will proliferate rapidly in germinal centers of follicles with the help of Th cells, often enlarging the entire lymph node; this activated lymphocyte  differentiate as plasma cells and move to the medulla or to downstream sites beyond the lymph node where they produce antibodies

› SPLEEN

· The spleen – this organ contains the largest single accumulation of lymphoid tissue in the body and is the only lymphoid organ involved in filtration of blood, making it an important organ in defense against blood-borne antigens; it is also the main site of old erythrocyte destruction; as secondary lymphoid organ, it is a production site of antibodies and activated lymphocytes, which here are delivered directly into the blood; located high in the left upper quadrant of the abdomen and typically about 12 × 7 × 3 cm in size; its volume varies with its content of blood and tends to decrease very slowly after puberty

· What is the histologic parts of the spleen?

o surrounded by a capsule of dense connective tissue from which emerge trabeculae to penetrate the parenchyma or splenic pulp

o trabeculae originate at the hilum, on the medial surface of the spleen, and carry branches of the splenic artery, vein, lymphatics, and nerves into the splenic pulp

· Functions of Splenic White & Red Pulp

· what is the content of the spleen parenchyma?

o filled with reticular tissue containing reticular cells and fibers

o many lymphocytes and other blood cells

o macrophages, and APCs

· what are the 2 two components of the spleen?

o the white pulp (20% of the spleen)

o the red pulp

· white pulp - small masses portion of the spleen; consist of lymphoid nodules and the periarteriolar lymphoid sheaths (PALS)

· the red pulp – this portion of the spleen consists of blood-filled sinusoids and splenic cords.

· periarteriolar lymphoid sheaths – this envelops the small trabecular arteries that leave the trabecular connective tissue and enter the parenchyma blood vessels as it enters branching from the hilum; consists primarily of T cells with some macrophages, DCs, and plasma cells as part of the white pulp ‘

· central arterioles – this portion of the trabecular artery that is surrounded by PALS; In growing nodules this is pushed to an eccentric position; send capillaries throughout the white pulp and to small sinuses in a peripheral marginal zone of developing B cells around each lymphoid nodule

· how is the lymphoid nodule formed in the spleen?

o B cells within the PALS may be activated by a trapped antigen from the blood and form a temporary lymphoid nodule like those of other secondary lymphoid organs

· penicillar arterioles  - several short straight branches from the centra arteriole, as it eventually leaves the white pulp and enters the red pulp losing its sheath of lymphocytes and branch as this; continue as capillaries;  Some of these capillaries are sheathed with APCs for additional immune surveillance of blood ‘

· The red pulp - is the site where effete RBCs in blood are removed

· What is the composition of the red pulp?

o is composed almost entirely of splenic cords (of Billroth) and splenic sinusoids

· the splenic cords – this portion of the red pulp; it contain a network of reticular cells and fibers filled with T and B lymphocytes, macrophages, other leukocytes, and red blood cells; this is separated by the sinusoids

· stave cells - this line these sinusoids; an unusual elongated endothelial cells oriented parallel to the blood flow and sparsely wrapped in reticular fibers and highly discontinuous basal lamina

· what are the 2 routes of blood flow through the splenic red pulp?

o Closed circulation

o Open circulation

· spleen closed circulation -  capillaries branching from the penicillar arterioles connect directly to the sinusoids and the blood is always enclosed by endothelium ‘

· spleen open circulation -  capillaries from about half of the penicillar arterioles are uniquely open-ended, dumping blood into the stroma of the splenic cords; the plasma and all the formed elements of blood must reenter the vasculature by passing through narrow slits between the stave cells into the sinusoids

· stave cells  - these small openings present no obstacle to platelets, to the motile leukocytes, or to thin flexible erythrocytes; the plasma and all the formed elements of blood must reenter the vasculature by passing through its narrow slits, but  the stiff or effete, swollen RBCs at their normal life span of 120 days are blocked from passing between its cells and undergo selective removal by macrophages

· red pulp – this is its normal function: removal of defective RBCs and recycling of their iron are major functions of the

· macrophages - this is where the iron released from hemoglobin during the degradation of RBCs is stored within complexes of ferritin proteins or bound to transferrin, returned to the circulation, and reused primarily for erythropoiesis

· what happen to iron-free heme after the RBC have been  destroyed in the spleen?

o bound to its transport protein, hemopexin

o is metabolized to bilirubin and excreted in the bile by liver cells

· if the spleen is removed by surgical removal of the spleen (splenectomy) what happen the old RBC?

o abnormal erythrocytes in the circulation increases

o most such cells are then removed by macrophages in sinusoids of the bone marrow and liver

· in the spleen circulation, where does blood proceed after passing by the sinusoids?

o From the sinusoids blood proceeds to small red pulp veins that converge as the trabecular veins which in turn form the splenic vein

o trabecular veins lack significant smooth muscle and resemble endotheliumlined channels hollowed out in the trabecular connective tissue