Immunology test 3
Regulatory Effects of Ag
-1. Chemical composition: chemically distinct antigens can stimulate different types of IRs - -TD vs. TI antigens -Polysaccharide Ag induce B-cell tolerance. -2. The amount of antigen to which an individual is exposed influences the magnitude of the responses. -The immunogen must be of sufficient quantity to induce an IR but not so overwhelming in concentration that it can induce T-cell tolerance. -3. The IR to a particular antigen (immunogen) varies relative to the Ag portal of entry into the body or route of administration -SubQ, intra-dermal, or mucosal acquired antigens are usually very immunogenic due to the large numbers of APCs (Langerhans cells) present in these tissues. -Large concentrations of Ag administered IV typically induces tolerance.
Two mechanisms of Immunologic Tolerance
-1. Clonal Anergy: functional inactivation of a lymphocyte clone without cell death. (not killed) -2. Clonal Deletion: cell death (PCD)
Distribution of Lymphocytes and APC's within LN
-1. Follicles (rich B-cell Zones) -Primary- non-antigen stimulating B-cells -Germinal Centers: FDC's and stimulated B-cells undergoing clonal expansion -2. FDC's: found within germinal centers—here they are primary APC for presenting antigen to B-cells for expansion -3. Plasma cells: undergo final differentiation outside of GC and then go throughout peripheral immune system secreting antibody. -4. T-cells: 1 prime CD4 T-cells—located between follicles and in deep cortex. Paracortical area******LOOK UP -5. IDC's: located at high endothelial venules (HEV's) between follicles: present antigen to CD4 T cells
HEV Characteristics:
-1. HEV morphology promotes prolonged contact (rolling) of lymphocytes looking for receptor ligand interactions. -2. HEVs—due to location, are maintained by low level chemokine/cytokine activation -3. HEVs do not exist in gnotobiotic animals... i.e. animals raised in sterile or germ free environments. -4. HEVs are present in LN, Peyer's patches, but not spleen.
Early Functional Responses to B-cell activation stimuli
-1. Preparation for proliferation and subsequent differentiation -2. Up regulation of protein synthesis machinery -3. Increased surface expression of MHC II molecules and co-stimulatory molecules. -4. Increased membrane expression of receptors for CD4 cell derived cytokines
Humoral Responses to TI Antigens
-1. TI antigens (primarily CHO and lipids) include: polysaccharides, glycolipids, nucleic acids -2. TI antigens are usually in the form of large, repeating polymers that are capable of cross-linking smIg on B-cells and inducing the initial activation sequences of B-cell activation without T-cell help. -3. TI antigen humoral responses have the following characteristics: -Primarily IgM production (little to no isotype switching) -Poor memory cell development -Lower overall affinity of antibody produced -Lower overall antibody titers produced -Why?- No T-cell help
Lymphoid Follicle Germinal Center Reactions and Affinity Maturation:
-1. The generation of high affinity antibodies and memory cells in humoral responses occurs in germinal centers of follicles in peripheral lymphoid tissues—frequently in LN. -2. Interactions between CD4 T-cells and B-cells that initiate humoral responses occur in extra-follicular T-cell rich zones. -3. Follicular Dendritic Cells (FDC) in germinal centers present Ag from these initial responses to B-cells inducing proliferation and differentiation to further propagate these responses -4. Within a follicle in which an IR is taking place (a 2 prime (secondary) follicle w/ germinal center), only those B-cells with high affinity antigen receptors for the specific antigen being presented by the FDC are selected for survival. -5. This generates affinity maturation -6. Co-stimulatory molecules present on FDC (particularly the CD40 ligand) are important in this process -7. Memory B-cells and plasma cells (following differentiation within the germinal center) migrate out of the follicle/germinal center into extra-follicular sites for Ab production and surveillance for antigen. NOTE: it is predicted that a single clone can increase in number to 5000 within 5 days in a germinal center
-Optimal sites for recognition, activation, and effector phases or IRs:
-1. The peripheral lymphoid tissues, especially lymph nodes and spleen, are the sites where antigens are concentrated and also the sites where naïve lymphocytes preferentially migrate. -2. Effector and memory lymphocytes preferentially migrate to areas where microbes induce local inflammatory reactions. -3. Cooperative interactions between lymphocytes and adhesion molecules control the migration and tissue retention of cells that recognize specific antigens (i.e. lymphocyte clones) -4. The principle portals of antigen entry, e.g. skin, respiratory mucosa, and gut mucosa, have specialized lymphoid tissues where IRs can develop.
The Role of Accessory Cells
-1. The presence of competent APCs with antigen administration leads to an IR. Their absence or deficiency in co-stimulatory activity leads to tolerance -2. CD4 T-cells must respond to antigenic stimulation if a fully functional IR to a protein antigen is to occur. -3. Adjuvants are important in vaccination and immunization to recruit APC involvement in initiating IRs.
Three Main factors that influence the nature and magnitude of Adaptive IRs
-1. The type of antigen, its physiochemical form (nature), and route of administration -2. The number and type of responding APCs -3. The nature (maturational state) of the responding lymphocyte.
Factors that Affect or Influence Humoral Responses
-1. Type of cytokines produced -Th1 vs. Th2 subsets -Th1 cytokines (IFN gamma) mediate CMI -Th2 cytokines (IL-4,5,6,10) mediate humoral -2. Site of antigen exposure -Oral or inhaled antigens are good at promoting IgA responses at mucosal surfaces. -3. Nature of antigenic stimulus -Generation of tolerance -4. Primary vs. secondary antigen exposure
TNF continued
-A little bit is great, but a lot is a problem -In severe infections (septicemia or systemic infection), TNF is produced in large amounts and causes systemic clinical and pathological conditions that are collectively labeled as the generalized condition of septic shock. These include: 1. Cachexia—state of wasting muscle and fat cells (TNF induced appetite suppression) 2. Inhibition of myocardial contractility and vascular tone 3. Vascular thrombosis (vascular plugging) 4. Severe metabolic disturbances...... fall in blood glucose, etc.
Innate lymphoid cells (ILCs) CONTD
-Activated by stress signals, microbial compounds and cytokines from cells in surrounding tissues rather than antigens. -fast acting, found in mucosal tissues -Also regulate fat metabolism and body temperature. -Regulating fever is the temp portion and the fat is to provide calories for immune responses -Mediates tissue repair, found in pathologies like crohns disease. -Have Fc receptors so they can interact with antibodies too
Primary mechanisms of peripheral tolerance
-Anergy induced by antigen recognition with defective co-stimulation -If CD4 T cells are presented antigen by an APC with deficient co-stimulation, the T cells do not clonally expand (proliferate and differentiate) and are rendered incapable of responding to the antigen even if it is later presented by an APC with sufficient co-stimulation
B-cell suppression: Antibody Feedback
-Antibodies act to regulate or control humoral responses in two ways: 1. Removal or neutralization of antigen (antigen elimination—removal of the antigenic stimulus) 2. B-cells possess an Fc receptor (distinct from the location of smIg), that when bound due to high local Ab concentration, down regulate synthesis and secretion of Ab by the clone. 3. Antibody feedback is a terrific example of self-regulation
Mechanisms of TD Antigen Antibody Responses
-Antibody responses to TD (protein) antigens require: 1. Recognition of the Ag by CD4 T-cells. 2. Cooperation between the Ag specific B and T-cells.
The Roles of Antigen
-Antigen recognition is the obligatory "first signal" for lymphocyte activation -Its removal inhibits the first signal of lymphocyte activation.
Signal transduction by the B-cell antigen receptor complex
-B-cell activation is initiated by antigen binding (cross-linking of smIg) by the B-cell antigen receptor--- smIg 1. The Ag/Ab interaction delivers a signal (signal transduction) to initiate the process of activation. 2. The Ag is internalized in endosomes, processed, and presented with MHC II to CD4 cells.
Chemokine (CCL) Involvement:
-CCL 21: most important CCL in naïve T cell homing -Secondary lymphoid tissue chemokine--- SLC. -Produced by T-cell zone epithelial (stromal) cells within the LN. -Also involved: -CCL 19: LN epithelial (stromal) cells. -CCL 18 (DC-CK): produced by mature dendritic cells. -All three chemokines bind to chemokine receptor CCR7 on naïve T-cells.
CXCL8 or Interleukin-8 (IL-8)
-Cellular Source: epithelial cells of the intestinal or respiratory mucosa, vascular endothelial cells, and macrophages. -Principle biologic action: chemotaxis of neutrophils (heterophils) to sites of microbial invasion. As such, IL-8 is a mediator of acute inflammatory responses, similar to TNF and IL-1
Interleukin-1 (IL-1)
-Cellular source: Macrophages -Principle biologic action: When secretion at low concentrations, IL-1 acts as a mediator of local inflammation. It acts as a mediator of local inflammation. It acts on endothelial cells to increase expression of surface molecules that mediate leukocyte adhesion, such as ligands for integrin. IL-1 can induce acute phase protein synthesis and release from the liver and will induce a "febrile response."(IL-6 will also induce acute phase protein synthesis) -While many of the actions of IL-1 are very similar to TNF, including systemic effects, IL-1 is not nearly as toxic as TNF and alone, will not induce septic shock.
Regulation of Humoral Responses
-Complement: -1. B-cells express a receptor (CR2) for compliment protein C3d. C3d binding to CR2 induces or furthers activation of B-cells. -2. FDC possess a receptor (CR1) for C3b. When C3b binds antigen, CR1 promotes the expression of antigen to B-cells in germinal centers. -This mechanism is now being proposed as a "second signal" for B-cell activation similar to co-stimulatory requirements of T-cells for activation -Imparts a control mechanism for ensuring B-cell activation when microbes have been present—Complement activation required -1000X more immunogenic antigens
Central tolerance
-Conferred in generative lymphoid organs (thymus, bone marrow, bursa) -Principle mechanism for protection against lymphocyte recognition of self antigens. -Positive/negative selection are the mechanisms through which central tolerance is achieved. (positive-positively identify antigen associated with MHC. Negative- have low affinity for self antigen-self recognition).
B-cell growth and differentiation induced by cytokines
-Cytokines serve two primary functions in antibody responses: 1. They determine the type of antibody isotype to be secreted by promoting heavy chain switching to different isotypes. 2. They provide activation/amplification mechanisms by augmenting proliferation and differentiation
Lymph Node Architecture
-Fibrous capsule: outer covering -Afferent lymphatics: Lymph enters the node at several sites -Cortex: outer region—contains follicles (dense lymphocyte collections and APC's) -Medulla: inner region—less dense lymphocytes and APC's -Follicles: -Primary: (B-cell rich zones): 1 prime Naïve or resting B-cells -Secondary: (with GC): FDC's and rapidly expanding B-cells -Single Efferent Lymphatic: all lymph leaves each node by this single vessel (lymph node consolidates vessels into one efferent lymphatic vessel)
Lymphocyte recirculation or homing relies upon:
-High endothelial venules (HEVs)- venules that are 1 cell thick and make it easy for immune cells to diapedes. They can change their shape to promote this. -Selectins (L-selectin, E-selectin, and P-selectin- important for inflammation and tissue repair/ thrombosis and clotting. Inflamed tissues express more selectin)(sial lewis x binds to all three kinds of selectin) -Chemokines (CCL)- CCL 21, CCL 19, CCL18, which bind to chemokine receptors (CCR 7 on naïve T cells) -Addressins- CD34, GlyCAM-1, and MAdCAM-1- cell surface molecules that act as addresses (for homing of immune cells)
Interferon-gamma (IFN-gamma)
-IFN-gamma is the principle macrophage activating cytokine of the immune system and is the best example of a cytokine being involved in mechanisms of both innate and adaptive immunity. -Cellular source: Th1 cells (signature) and NK cells -Principle biologic actions: 1. Stimulates macrophage killing of microbes 2. Stimulates expression of MHC II and MHC I on APCs 3. Promotes the differentiation to the Th1 subset in naïve and effector/memory CD4 T-cells of the Th2 subset. 4. Inhibits the differentiation, proliferation, and effector functions of naïve and effector/memory CD4 T-cells of the Th2 subset. 5. Promotes B-cell class switching to IgG2a (in mice) 6. Inhibits the IL-4 mediated switch to IgE in B-cells.
Interleukin 10 (IL-10)
-IL-10 is a regulatory or inhibitory cytokine that is involved in the control (self-limiting) of innate and CMI IRs—focus on Macrophages -Cellular source: Activated macrophages (negative feedback) and TH2 cells. -Biologic actions: Inhibit the production and synthesis of IL-12 by activated macrophages and dendritic cells. Also, Inhibit co-stimulator and MHC-II expression by activated macrophages and dendritic cells. It returns the immune response to baseline.
Interleukin 12 (IL-12)
-IL-12 is a principle mediator of the early innate immune response to intracellular microbes and is a key inducer of CMI in the adaptive phase of immunity to such pathogens. -Cellular source: Activated mononuclear phagocytes (macrophages) and dendritic cells. -Principle biologic action: a. IL-12 stimulates IFN-gamma synthesis and secretion by Th1 T cells and NK cells. b. In this role, IL-12 actually directs the differentiation of naïve CD4 T-cells to Th1 cells. c. IL-12 enhances the cytolytic functions of differentiated CTLs.
Interleukin-13 (IL-13)
-IL-13 has structural similarity to IL-4 and it is produced by Th2 cells and some epithelial cells. -Main biologic effects: -On non-lymphoid cells: same effects as IL-4. On macrophages for instance, IL-13 mimics the inhibitory effect of IL-4 (but it is weaker). -On B and T-cells: much less of an effect (if any) as compared to IL-4
Interleukin 17 (IL-17)
-IL-17 may be involved in tissue damage during hypersensitivity, but is more known for involvement in bacterial infections. -Cellular source: Th17 subset of Th cells (this is on test for sure) -Main biologic effects: following bacterial infection, dendritic cells or macrophages begin to produce/secrete IL-23 and IL-6, which influence the differentiation of Th17 cells which in turn produce IL-17 -IL-17 promotes neutrophil recruitment and activation to a local area to attack extracellular bacteria.
Interleukin 2 (IL-2)
-IL-2 is a growth factor for antigen stimulated T-cells and is responsible for clonal expansion of antigen- selected clones. -Cellular source: primarily CD4 T-cells, and to a lesser extent, CD8 T-cells. -Antigen stimulation causes both the secretion of IL-2 and the surface expression of IL-2R. Thus, a regulatory mechanism exists in that only antigen-activated T-cells express the receptor for IL-2 and as such, they are the T-cells selected for clonal expansion by IL-2. -Principle biologic actions: 1. Autocrine and paracrine proliferation of T-cells and B-cells following antigen recognition 2. Proliferation and differentiation of NK cells (to LAK cells)
Cytokines that Regulate Adaptive Immunity
-IL-2, IL-4, IL-5, IFN-gamma, TGF-beta, LT, IL-13, Il-17
Proliferation:
-IL-2, IL-4, IL-5- Induces proliferation of resting B-cells. -IL-6- Induces proliferation of activated B-cells.
Ab Secretion:
-IL-4 and IL-5- Very potent secretory functions -IL-2, IL-6, IL-10- Secretory function demonstrated IN VITRO only.
Interleukin 5 (IL-5)
-IL-5 is an eosinophil activator and serves as a linkage between T-cell activation and eosinophil-mediated inflammatory response. -Cellular source: Th2 cells. -Principle Biologic action: Stimulate the growth and differentiation of eosinophils and to activate mature eosinophils. -Initiate a class switch to IgA in effector B-cells
Innate lymphoid cells (ILCs)
-ILCs are thought to bridge the innate and adaptive immune systems -Lymphoid cells similar to CD4 T helper cells -No BCR or TCR, but have MHC II (so they might be able to express exogenous antigen) -Do not undergo clonal selection/expansion -ILC1, ILC2, ILC3, NK
B-cell Supression—Anti-idiotypic Regulation—Theoretical
-Idiotype- The discrete amino acid sequence of the hypervariable regions of each Fab arm that determine antigenic specificity of each B-cell clone/antibody molecule. -Immune responses against idiotypes are anti-idiotypic -Anti-idiotypic immune responses can be directed against secreted antibody to down-regulate humoral immune responses.
-Secondary response
-IgG predominates (class switching) -Short latency period -Much longer duration -Higher antibody titer -Affinity maturation NOTE: 1. Secondary response characteristics are due to memory 2. Memory is antigen specific
-Humoral antibody responses to TI antigens are characterized by the following:
-IgM is the predominant (and usually only) isotype -Low affinity antibody produced -Little memory cell generation
-Primary response
-IgM predominates -Long latency period -Short duration -Overall low antibody titer
Interleukin-4 (IL-4)
-Il-4 is the major signal for a class switch to IgE in B-cells and is also the major stimulus for the differentiation of Naïve CD4 T-cells to the Th2 subtype. -Cellular source: Th2 Cells. -Principle biologic actions: 1. Initiation of a class switch to IgE in B-cells 2. Stimulates differentiation of Th2 cells. 3. Promotes IgE and mast cell/eosinophil responses 4. Down-regulates macrophage responses
The Primary Inhibitory Mechanisms of the Immune system
-Immunologic tolerance (two forms): -Central tolerance -Peripheral tolerance
Migration/Trafficking of Activated T cells: Memory and Effector T-cells:
-In activated/differentiated lymphocytes, L-selectin is down regulated and as such, these lymphocytes no longer effectively migrate to LN at HEVs -Instead, they begin to express the integrins and migrate to/ reside in areas where inflammatory responses are occurring. These sites represent locations of antigen retention or persistence. - Integrin expression is upregulated (by chemokines) in locations in the body where inflammatory responses are taking place.
Lymphatics and lymph nodes:
-In mammals, lymph nodes sample the lymph on its way back to the bloodstream. This is why the LN are so important in peripheral immune system function in mammals. In birds, the spleen assumes these functions. -The respiratory and intestinal mucosa-serve as peripheral immune organs in two capacities: 1. They are well vascularized with lymph capillaries and serve as large sites for antigen collection due to lymph drainage. 2. They also possess well defined areas of lymphoid and accessory cell accumulation and primary IRs are routinely initiated at the sites.
-Humoral responses to TD antigens are much more specific with the following characteristics:
-Isotype switching -Abundant memory cell generation -Affinity maturation of antibodies produced during IRs
L-selectin and addressins: Naïve T-cell homing:
-L in L selectin is for lymphocyte -Ligands present on HEVs are generally referred to as addressins -The most important receptor on naïve lymphocytes for these addressins is L-Selectin -Specific addressins (ligands) on HEVs: -Lymph Node: GlyCAM-1 and CD34 -Peyer's Patch: mucosal addressin cell adhesion molecule-1 ( MAD CAM-1) -Specific binding of addressins by L-selectin to naïve T-cells causes the T-cell to attach to the HEV for a few seconds, then detach and attach again...thus they "roll" along the endothelial surface. -This rolling allows the T-cells to encounter chemokines which are causing their chemotaxis and eventually increase the strength of adhesion with the HEV. Once the strength of the attachment is strong enough, the T-cell will squeeze through the endothelial cells and enter the node.......following the chemokine gradient
Lymphotoxin (LT) (also known as TNF-beta)
-LT, also known as TNF-beta, possess many similar properties to TNF-alpha in function -Cellular source- predominantly T-cells -Principle biologic action: promote adhesion of leukocytes by increasing expression of surface molecules on VECs to direct leukocytes to inflamed tissues. -Unlike TNF-alpha, LT is not produced during large amounts during IRs and as such doesn't have systemic side effects.
What does CCL (chemokine) secretion do for T cell homing:
-Maintain HEV morphology -Upregulate selectin and addressin expression -Establish the chemical gradient for chemotaxis
Peripheral tolerance
-Maintained in the peripheral immune system (outside generative lymphoid organs. In spleen/ lymph nodes etc.). -Foreign antigens can either be immunogens or tolerogens dependent on: -Physiochemical form of the antigen -Route of administration of the antigen- some routes have stronger responses than others
High endothelial Venules (HEVs):
-Naïve lymphocytes migrate out of circulation into LNs (and other peripheral organs) at discrete locations within the vascular endothelium. These sites are known as HEVs -Lymphocytes recognize surface molecules on the surface of HEVs that aid in this process. These surface molecules aid in the process of diapedesis.
TI antigens
-Non-protein antigens (polysaccharides, lipids, etc) induce humoral responses without T-helper cell cooperation.
Receptor Ligand Interactions at HEVs: Effector and Memory T-cells
-Once activated, T cells begin to express ligands for another class of receptors on endothelial cells...E or P selectin ligand. -They also begin to express beta1 and beta2 integrins: LFA-1 and VLA-4 which bind to ICAM-1 and VCAM-1 present on endothelial cells. -E or P selectin and these integrins and their respective ligands promote two important functions in lymphocyte mediated responses and trafficking. 1. They allow for lymphocyte retention by aiding in cell to cell contact between lymphocytes and other accessory cells in a LN to allow for activation and clonal expansion (i.e. development of memory cells and effector function). 2. They also aid in cell to cell contact between lymphocytes the vascular endothelium/ lymphatic that aid in activated or memory lymphocyte migration/ trafficking to other tissues where IRs are taking place. -The key point is that there is differential expression based upon the activation state or maturational state of the lymphocyte. This is key in directing lymphocyte recirculation patterns.
Cytokines as stimulators of Hematopoesis
-Produced by bone marrow stromal cells, leukocytes, and other cells to stimulate growth and maturation of immature leukocytes.
Cytokines as mediators and regulators of adaptive immunity
-Produced mainly by T-cells in response to specific recognition and activation by foreign antigen. Some of the members of this group of cytokines promote and regulate growth and differentiation of lymphocytes during immune responses and thus play a very important role in the activation phase of a T-dependent response.
TD antigens
-Protein antigens rarely induce humoral responses in the absence of T helper cell assistance.
Pathways and mechanisms of lymphocyte recirculation:
-Recirculation of naïve T-cells through Lymphoid organs: -Naïve T-cells migrate out of the blood stream into LN. They then traverse the lymphatics and LN and return to the circulation via the thoracic duct and the cycle continues. This is all done to maximize a potential encounter with antigen. It is estimated that the complete passage of a lymphocyte out of the blood, into a LN, through the lymphatics, and back to the blood takes about 1 hour. -It is further estimated that the total number of lymphocytes which circulate daily in humans is about 25x 10^9.
-Lymphocyte inhibitory mechanisms
-Removal of antigen (stimulus) -Regulation by Tcell subset cytokines -Regulatory T-cells -Fas/Fas ligand in T cells -Antibody feedback in B cells
Activation-induced cell death (deletion) in T cells- Fas and Fas ligand
-Repeated (hyper) stimulation of lymphocytes by antigen may result in the induction of apoptosis of that specific clone. This is referred to as activation induced cell death. -The physiological importance of this is to prevent uncontrolled T cell activation -The mechanism of deletion is controlled by the fas surface protein -Lymphocytes co-express fas and fas ligand -fas expression is regulated by IL-2 -Lymphocytes repeatedly stimulated by antigen and IL-2 show an increased expression of fas and fas ligand. -When fas, located on one T-cell binds with fas ligand on another T-cell, the lymphocyte is induced into activation induced cell death and dies via apoptosis -Some bacterial toxins, referred to as Super Antigens, are most commonly associated with this hyper-stimulation. They are very large, antigenically diverse proteins and therefore are very immunogenic and commonly over stimulate lymphocytes.
Self-Limitation
-Self limitation is one of the "Cardinal Features" or inherent characteristics of immune responses. It is manifested by a decline of immune responses over time following immunization or infection. -What is the principle underlying reason for this decline? -Removal of the antigenic stimulus accomplished by the mechanism of acquired/innate immunity.
Signal Transduction by the B-cell Antigen Receptor Complex
-Signal transduction capabilities of the B-cell antigen receptor are similar to that of the TCR -smIg or smIgD of B-cells have very short cytoplasmic tails and as such possess very little signal transduction capacity. -Justas with the TCR, these responsibilities are bestowed upon accessory membrane proteins. Ig(alpha) and Ig(beta). -These proteins are mutually expressed with smIg -Ig(alpha) and Ig(beta) serve the same functions for the smIg as CD3 and zeta proteins for the TCR complex.
Transforming growth factor-beta (TGF-beta)
-TGF-beta is involved in IRs by inhibiting the activation and proliferation of lymphocytes and other leukocytes. -Cellular Source: antigen activated T-cells and LPS stimulated macrophages -Principle biologic actions: 1. Inhibit the proliferation and differentiation of T-cells and the activation of macrophages..... i.e. down regulates IRs. 2. Promote a class switch to IgA in B-cells in mice.
Tumor Necrosis Factor: TNF or TNF alpha
-TNF is the principle mediator of the acute inflammatory response to Gram (-) bacteria and other microbes. -Cellular Source- macrophages -Peripheral Biologic Action: The main function of TNF in early phase inflammatory responses is to recruit (chemotaxis) neutrophils (heterophils) and monocytes to sites of infection and to activate these cells to remove microbes.
Cytokines of innate immunity
-TNF, IL-1, Chemokines (multiple), IL-12, Type 1 IFN (alpha and beta), IL-10, IL-6, IL-15, IL-18, IL-23, IL-27.
CD4 T-cell "Contact Mediated" Activation of B-cells
-The physical contact between B- and T-cells is between multiple receptor ligand pairs. a. CD28 (T-cell): B71/B72 (B-cell) b. CD40 ligand (CD154 on T-cell): CD 40 (B-cell) (ligand means that it is going to bind to the receptor and the receptor for CD40 ligand (or CD154) is CD40 -What do these ligand/receptor interactions accomplish? a. Stabilize cell: cell interactions b. Signal transduction
The Cutaneous Immune System:
-The skin is one of the largest organs in the body and the principle barrier between an organism and its outside environment. -The skin can generate and support local inflammatory reactions.
Lymph Node Follicles: Dendritic Cells and B/T-cell Zones
-Two distinct types of dendritic cells participate in the establishment of B and T cell zones in LN (and other peripheral tissues): -Interdigitating DC- Are in the HEVs between follicles, present antigen primarily to T cells -Follicular DC- In B cell zones so they are presenting antigen to B cells
Type 1 Interferon: IFN-alpha and IFN-beta
-Type 1 interferon mediates the early innate response to viral infections. -Cellular source: IFN-alpha- mononuclear phagocytes (macrophages), IFN-beta- many host cells (including fibroblasts) -Biologic Actions: Inhibit viral replication, Increases MHC 1 expression/antigen presentation.
Synergistic
1+1=10
Presentation of Protein Ag to CD4 T-cells by B-cells
1. Ag specific B-cells bind the native protein, internalize it, process it, and present it with MHC II to Ag specific CD4 cells. -B-cells in the fashion are acting as professional APCs. 2. While B-cells are acting as professional APCs, they're also being activated at the same time. -this includes the increased expression of co-stimulatory molecules such as B7. -The presence of B7 on B-cells acts to further activate T-cells. -B-cells respond to T-cell activation by becoming further activated themselves. -This activation is in the form of both cytokines and physical contact (co-stimulatory molecules) NOTE: B-cells (with high affinity Ag receptors) are the primary APCs for CD4 cells in situations of low antigen concentration
Lymphocyte Regulatory Mechanisms
1. Removal of antigen (stimulus) 2. Regulation by T cell subset cytokines -Th2 cells are producing things that the Th1 cells do not like. Gamma interferon can actually inhibit Th2 cells from proliferating. It is great for cell mediated immunity but it down regulates the humoral immunity by preventing Th2 cells from proliferating. Th2 cells produce IL-10 which prevents Th1 cells from becoming activated.) Th1 and Th2 cells can produce stuff that prevents Th17 cells from activating neutrophils. Th1 is a type 1 immune response (cell mediated- usually intracellular pathogens) and Th2 is a type 2(humoral)-for allergies and parasites. Type three is Th17 (neutrophils- really focused on extracellular stuff like bacteria and fungi). 3. Regulatory T cells -Natural T-reg Cells: Develop in the Thymus and comprise approximately 10-15% of total CD4 t cells in humans. -Adaptive T-reg Cells: develop under conditions of high TGF beta production with low IL-6 or IL-23 4. Fas/Fas ligand in T cells- T cells has the fas receptor and the fas ligand expressed at the same time. This allows T cells to determine if there are too many of them around. If there are, the cells bump into eachother and the fas receptor on one binds to the fas ligand on the other and this causes one of the T cells to shut down (PCD). It regulates immune responses and prevents them from being too strong. Fas ligand expression is regulated by the cytokine IL-2.(IL-2 increases the expression). There are things called super antigens that cause an extreme immune response, Fas/Fas ligand helps to prevent damaging immune responses. 5. Antibody feedback in B cells. B cells have MHC receptors, so the Fc portion can bind antibodies. If there are too many antibodies, then there is a lot of Fc bound antibody and the B cell will down regulate. (Another way to down regulate B cells is through removal of the stimulus). (yet another way is anti-idiotypic regulation- this is the blocking/ inactivation of a receptor with an antibody) (you can make an antibody against another antibody if you have to).
Effective B-cell Responses in Peripheral Organs: Lymph Nodes
1. Small nodular aggregates of lymphoid tissue positioned along lymphatic vessels. 2. Epithelial tissues of skin, gut, and lung all have very efficient lymphatic drainage 3. Lymph vessels collect antigens in fluid (lymph) and return it to the blood stream after traveling through LN. All material in lymph enters the general circulation at a site known as the thoracic duct. 4. The lymphatics are a very well-designed antigen collecting system 5. LN containing lymphocytes and APCs sample lymph for antigens.
Cytokines can exert the following effects:
Autocrine, paracrine, Endocrine, Neurocrine, Pleiotrophic, synergistic, Additive, inhibitory and stimulatory
Interleukin 23 and 27
Both are related to IL-6 and IL-12. Like IL-12, they bridge the functions of innate and adaptive immunity. Both are produced by macrophages and dendritic cells in response to microbial infection.
Chemokines
CC and CXC families -Chemokines are small in overall size when compared to other cytokines. They attract othe white blood cells to the sites of infection. -CC- based on number/ location of cysteine -CXC-cysteine residues are separated by another AA -One of the first described of all chemokines is IL-8, now CXCL8, mediator of acute inflammation in the host response to invasive microbes at mucosal sites.
Types of Responding Lymphocytes
CD4 T-cells must respond to antigenic stimulation if a fully functional IR to a protein antigen is to occur.
Immunologic Tolerance
Definition: the phenomenon of Ag-induced "inactivation" or death of a specific lymphocyte resulting in inability of an organism to respond to that particular antigen -Antigens that induce tolerance- Tolerogens.-don't stimulate an immune response (ex. Self antigen). -Thus is to be distinguished from- Immunogens-do stimulate an immune response -Self antigens are- tolerogens
IL-18
Is homologous structurally to IL-1. Produced by macrophages in response to LPS and other microbial products. Main functions are to stimulate IFN-gamma production in both NK cells and Th1 cells (where it synergizes with IL-12)
IL-15-
Is produced by macrophages in response to viral infection, LPS, and other stimuli. The best documented function for IL-15 is NK cell proliferation.
Affinity maturation
Means that you get better antibodies as you go (higher affinity). The antibodies with the best affinity for a ligand are selected for somatic hypermutation. AID (Activation induced deaminase) helps affinity maturation occur and is very important for class switching. It causes somatic mutations to occur and then the B cells will be selected for proliferation. AID causes somatic hypermutation of the good B cells- somatic hypermutation is when mutation s occur 1000x more than normal. T cell dependent antigens are the only ones that cause affinity maturation to occur because the T cell independent antigens do not have T cells there to help it happen. *If T cells aren't involved, the humoral immune response is going to be weak.
-Interleukin-3 (IL-3)-
Promotes growth and differentiation of Mast cells
Autocrine
Self stimulation (slap yourself in the face to wake up) ex. IL-2
Hormones
Signal molecules of the endocrine system. Usually produced by a single cell type. Actions are usually at distal sites.
Cytokines
Soluble proteins... signal molecules of the immune system. Produced by many cell types. Actions can be local, peripheral, or distal (systemic).
Endocrine
Stimulating cells that are not nearby (walk across class room and slap someone)
IL-27
Targets are NK cells and T cells where it promotes Th1 differentiation and promotion of IFN-gamma secretion.
IL-23
Targets are T-cells and NK cells. Main function is to influence differentiation of Th17 cells to produce IL-17
Type 1 immune response
Th1 cells and cell mediated immunity
Type 2 immune response
Th2 cells and humoral immunity
Isotype switching
This represents the most selective influence of cytokine activities on B-cells. -IL-4- switch to IgE (important for parasitic infections and allergies) -IL-5- switch to IgA
B cell receptor editing
When a B cell doesn't recognize antigen, it usually dies or undergoes clonal anergy, but sometimes it can undergo receptor editing so that the receptor does what it is supposed to do.
Neurocrine
affecting the nervous system
IL-6
during innate responses it is produced by macrophages, VECs, and fibroblasts in response to infection or other cytokines (IL-1/ TNF). It functions to stimulate acute phase protein responses in innate IRs. In adaptive responses it's produced by Th2 cells and has effects on effector B-cell proliferation and differentiation for antibody production. Pro-inflammatory (IL-1, 6 and TNF are the other primary pro inflammatory cytokines)
Stem cell factor (c-Kit ligand):
involved in T-cell maturation in the thymus
Pleiotropic
means they can activate many different things in different ways. (example: guy likes sardines and spilled the juice in Dr. Farnells car. Dr. Farnell hates the smell and wants to avoid sardines while the other guy likes them.)
Type 3 immune response
neutrophil response
-By and large, IRs (antigen recognition and activation) are initiated in
peripheral lymphoid tissues or organs.
-Interleukin-7 (IL-7)-
pre-lymphocyte growth factor in both generative organs
Granulocyte-Monocyte CSF (GM-CSF):
stimulates bone marrow production of PMNs (granulocytes) and mononuclear phagocytes (monocytes)
Paracrine
stimulating nearby cells (slap neighbor to wake them up)