Lymphatic System and Immunity Lymphatic System n n

Lymphatic System and Immunity:

Lymphatic System n n n n Lymphatic vessels Lymphatic tissue Lymphatic nodules Lymph nodes Tonsils Spleen Thymus

Lymphatic Vessels n n Carry lymph away from tissues Lymphatic capillaries n n More permeable than blood capillaries Epithelium functions as series of one-way valves

Functions of the Lymphatic System n Fluid balance n n Fat absorption n n Excess interstitial fluid enters lymphatic capillaries and becomes lymph Absorption of fat and other substances from digestive tract Defense n Microorganisms and other foreign substances are filtered from lymph by lymph nodes and from blood by spleen

Lymphatic Tissue and Nodules n Lymphatic tissue n n n Consists mainly of lymphocytes Encapsulated or not Lymphatic nodules n Numerous in loose connective tissue of digestive (Peyer’s patches), respiratory, urinary, reproductive systems

Tonsils n n n Large groups of lymphatic nodules in nasopharynx and oral cavity Provide protection against bacteria and other harmful material Groups n Palatine Pharyngeal n Lingual n

Lymph Nodes n n n Organized in cortex and medulla Substances removed by phagocytosis or stimulate lymphocytes or both Only structures to filter lymph n Afferent and efferent vessels

Figure 25 -16 Molecular Biology of the Cell (© Garland Science 2008)

Spleen n Located in left superior side of abdomen n n Blood flows through at 3 different rates n n Can be ruptured in traumatic abdominal injuries resulting in bleeding, shock, death Fast (most), slow, intermediate Functions Destroys defective RBCs n Detects and responds to foreign substances n Limited reservoir for blood n

Spleen

Thymus n n n Located in superior mediastinum Divisions: Cortex and medulla Site of maturation of T cells

Hassall's corpuscle n Found in the central region of each thymic lobule n n Sometimes referred to as a thymic corpuscle Function is unknown n Known source of Thymic Stromal Lymphopoietin (TSLP) n TSLP is a Cytokine which activates Antigen Presenting Cells (APCs), which in turn play a strong role in T-lymphocyte selection.

Immunity n n Ability to resist damage from foreign substances as microorganisms and harmful chemicals Categories n Innate or nonspecific resistance n n Mechanical mechanisms: Prevent entry or remove microbes Chemical mediators: Promote phagocytosis and inflammation Cells: Involved in phagocytosis and production of chemicals Adaptive or specific immunity n n Specificity: Ability to recognize a particular substance Memory: Ability to remember previous encounters with a particular substance and respond rapidly

An Overview of the Immune Response

n Innate immune Responses n Innate immune responses provide the first line of defense n The response lack specificity. n An invading agent first encounters a phagocytic cell. n Phagocytes have receptor proteins such as the Toll-like receptors (TLRs). n Activation of such receptors play a role in promoting immunity , by initiating secretion of inflammatory mediators (such as cytokines).

Model of a TLR 3 bound to a ds. RNA molecule

Innate responses are typically accompanied by the concentration of defensive agents at the site of infection— inflammation. n Another mechanism produces proteins called complement that bind to pathogens and initiate their lysis. n Innate responses against viruses include natural killer (NK) cell to induce apoptosis in the infected cell. n

Inflammatory Response n n n Tissue injury regardless of type can cause inflammation Response initiated by chemical mediators that produce vasodilation, chemotactic attraction, increased vascular permeability Types n n Local: Symptoms are redness, heat, swelling, pain, loss of function Systemic: Symptoms are increase in neutrophil numbers, fever and shock

Inflammatory Response

C 3 a stimulates mast cells and basophils, which then secrete inflammatory mediators

Innate Immunity: Cells n White blood cells n n Most important cellular components of immune system Methods n n n Chemotaxis Phagocytosis n n n Phagocytic and first cells to enter infected tissue Promote inflammation Eosinophils n n Monocytes that leave blood, enter tissues Large phagocytic cells Basophils and mast cells n Neutrophils n Macrophages Reduce inflammation Natural killer cells n Lyse tumor and virusinfected cells

Innate immunity

Antigenic Determinants n Antigenic determinants n n Specific regions of a given antigen recognized by a lymphocyte Antigenic receptors n Surface of lymphocyte that combines with antigenic determinant

An Overview of the Immune Response

n Another innate antiviral response is initiated by virus-infected cells that produce interferon. n Interferon binds to the surface of non-infected cells making them resistant to infection. n A type of interferon may induce synthesis of mi. RNAs that target viral RNA genomes.

n Adaptive Immune Responses Adaptive (or acquired) immune responses require a lag period for an attack against a foreign agent. n This response is specific and occurs only in vertebrates. n There are two broad categories of adaptive immunity: n n Humoral immunity n Cell-mediated immunity

n Humoral immunity is carried out by antibodies, which are globular proteins of the immunoglobulin superfamily (Ig. SF). n Cell-mediated immunity is carried out by cells. n Both types of immunity are mediated by lymphocytes, which are leukocytes that circulate between the blood and lymphoid organs.

n Humoral immunity is mediated by B lymphocytes, which differentiate into antibody-secreting plasma cells when activated. n Cell-mediated immunity is carried out by T lymphocytes (or T cells), which recognize and kill infected cells when activated. n B and T cells arise from hematopoietic

Origin and Development of Lymphocytes n B and T cells n Originate in red bone marrow n Move to lymphatic tissue from processing sites and continually circulate n Clones are small groups of identical lymphocytes

Adaptive immunity involves the ability to recognize, respond to, and remember a particular substance (stimulant). n Stimulants n Antigens: Large molecules n n Foreign: Not produced by body, introduced from outside Self-antigens: Produced by body Haptens: Small molecules and capable of combining Types n n Humoral or Antibody-mediated: B cells Cell-mediated: T cells

Major Histocompatability Complex (MHC) n Most lymphocyte activation involves glycoproteins of cell surfaces called MHC molecules Class I molecules display antigens on surface of nucleated cells, resulting in destruction of cells n Class II molecules display antigens on surface of antigen-presenting cells (APCs), resulting in activation of immune cells n

n The MHC proteins hold fragments of antigen in place on APCs. n The TCR interacts with an APC when it docks with MHC proteins. n Cytotoxic T cells recognize their antigen in association with MHC I molecules. n Helper T cells recognize their antigen in association with MHC II molecules.

Peptides produced by antigen processing bind within a groove of the MHC protein molecule

MHC class I

Origin and Development of Lymphocytes n Positive selection n n Negative selection n n Ensures survival of lymphocytes that react against antigens Eliminates lymphocytes that react against selfantigens Primary lymphatic organs (red bone marrow, thymus) n n Where lymphocytes mature into functional cells Secondary lymphatic organs n Where lymphocytes produce an immune response

Thymus n n n Located in superior mediastinum Divisions: Cortex and medulla Site of maturation of T cells

n T-cells, activated by clonal selection, interact with antigens through a surface protein called a T-cell receptor. n T cells are activated by fragments of antigens that are displayed on the surface of antigenpresenting cells (APCs). n Dendritic cells ingest antigens by endocytosis. n Macrophages ingest antigens by phagocytosis. n These cells process and present the antigen to other cells.

n T cells release cytokines that alter the activity of the target cell.

Any students interested in partaking in a directed study group led by a past graduate of the course (one of the good ones), on Fridays from 1 -2: 30 pm, Please email Sorouch Safa at: soroush. safa@yahoo. ca

n Three classes of T cells are distinguished by the proteins on their surfaces and their biological functions: Cytotoxic T lymphocytes (CTLs) kill target cells by inducing apoptosis. n Helper T (TH) lymphocytes are regulatory cells activated by APCs. n Regulatory T lymphocytes (TReg cells) suppress the activities of other immune cells. n

T-cell receptor synthesis n The ability of T cells to recognize foreign antigens is mediated by the T-cell receptor (TCR). n Unlike most genes, the TCR gene is made up of a series of alternative gene fragments. n In order to create a functional T cell receptor, immature T -lymphocyte precursors use a series of DNA-interacting enzymes to bring separate gene fragments together. n The outcome of this process is that the TCR for EACH and EVERY T-lymphocyte has a different sequence.

DNA rearrangements that lead to the formation of genes for an immunoglobulin (such as the Tcell receptor)

n DNA Rearrangement of Genes Encoding B- and T-Cell Antigen Receptors n Two separate genes (a C gene and V gene) are combined (with a joining segment) through rearrangement to form one continuous gene that encodes one antibody chain.

n DNA rearrangement (continued) n The process is catalyzed by V(D)J recombinase which joins V and J segments of the gene, and deleting the intervening DNA. n Rearrangement is facilitated by signal sequences which are similar in V and J segments.

n DNA rearrangement (continued) n Variability in polypeptide chains is achieved by: n The variety of V and J exons in the DNA of the germ line. n Varying the site at which J and V sequences are joined. n The n enzymatic insertion of nucleotides. Somatic hypermutation refers to a high mutation rate in V elements of B cells.

T-cell receptor assembly n The TCRβ chain is paired with the pre-Tα to generate the pre-TCR. n The disadvantage in the gene-rearrangement process is that many of the combinations of the TCR gene fragments are non-functional. n Cells that fail to produce a functional pre-TCR are eliminated by apoptosis (β-selection). n Following β-selection, the cells undergo TCRα rearrangement, resulting in completely assembled TCR in its final form.

T-cell receptor (general structure)

TCR interactions with MHC I and MHC II

Positive T-cell receptor selection n Thymocytes which pass ‘β-selection’ now express a TCR which is capable of assembling on the cell surface. n However many of these TCRs will still be non-functional (unable to bind MHC I or II). n Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis (panel b). n The remaining thymocytes will undergo negative selection.

Negative T-cell receptor selection n The key disadvantage in the process of TCR assembly is that by random chance, some arrangements will create a TCR capable of binding self-peptides presented on MHC class I or II. n Such T cells would be capable of activating an immune response against self, resulting in an autoimmune disease. n During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to undergo apoptosis (panel a). n Cells which do not have a high affinity for self antigens survive negative selection (panel c).

Determining the fate of a newly formed T cell in the thymus Stromal cell

B-cells undergo a process of positive selection to eliminate selfrecognition. n Features of the B-cell clonal selection: n Antibody production follows selection of B cells by antigen. n Each B cell becomes committed to produce one species of antibody. n. B cells become committed to antibody formation in the absence of antigen.

Antigen Processing

Phagocytosis n n n Phagocytosis also involves membrane invagination. This process does not involve clathrin. Pseudopods extend around a particle, forming a phagosome. Phagosome will fuse with a lysosome, containing digestive enzymes. There are smaller transport mechanisms in the wall of the secondary lysosome.

Costimulation

Proliferation of Helper T Cells

n Binding of an antigen to the B-cell receptor “primes” the B-cell

Proliferation of B Cells

Comparison of the structure of a B cell and a plasma cell

Antibody-Mediated Immunity n Antibodies or Immunoglobulins (Ig) n n Classes: Ig. G, Ig. M, Ig. A, Ig. E, Ig. D Structure n n Variable region: Part that combines with anitgenic determinant of antigen Constant region: Responsible for activities

Actions of Antibodies

Figure 25 -11 Molecular Biology of the Cell (© Garland Science 2008)

Antibody Production

Ways to Acquire Adaptive Immunity

Effects of Aging Little effect on lymphatic system n Decreased ability of helper T cells to proliferate in response to antigens n Decreased primary and secondary antibody responses n Decreased ability of cell-mediated immunity to resist intracellular pathogens n

Immune System Problems Hypersensitivity reactions n Autoimmune disease n Severe combined immunodeficiency disease (SCID) n Transplantation n Acute rejection n Chronic rejection n