lecture 23 studyguide- immunology.pdf

Immunologic tolerance The unresponsiveness to an antigen that is induced by previous exposure to that antigen Encountering an antigen can lead to either: 1. Lymphocyte activation and an immune response (what we have focused on so far) Or 2. Lymphocyte inactivation or elimination (which leads to tole...

Immunologic tolerance The unresponsiveness to an antigen that is induced by previous exposure to that antigen Encountering an antigen can lead to either: 1. Lymphocyte activation and an immune response (what we have focused on so far) Or 2. Lymphocyte inactivation or elimination (which leads to tolerance) Which occurs depends on: Affinity of receptor-antigen interaction Conditions of antigen exposure Presence or absence of co-stimulators Failure of self tolerance leads to immune reactions against self antigens (autoimmunity) Certainly! The transcript you provided seems to be a lecture or discussion on immunological tolerance, specifically focusing on self-tolerance. Let's break down the key points and explanations: 1.Immunologic Tolerance: This refers to the immune system's ability to not respond to self-antigens. It's often termed "self-tolerance." The definition provided is that immunologic tolerance is the lack of responsiveness to an antigen due to previous exposure to that antigen. 2.Self-Tolerance: This is a crucial aspect of immunologic tolerance, where the immune system learns not to react against its own antigens. 3.Lymphocyte Maturation: The discussion mentions lymphocyte maturation as a background concept. Lymphocytes are a type of white blood cell crucial for the immune response. Maturation involves the development of functional lymphocytes from precursor cells. 4.Central Tolerance and Peripheral Tolerance: These are two mechanisms by which the immune system maintains self-tolerance. Central tolerance refers to tolerance mechanisms that occur during lymphocyte development in central lymphoid organs like the thymus and bone marrow. Peripheral tolerance mechanisms operate outside of these organs, mainly in peripheral tissues, to prevent autoreactive lymphocytes from causing harm. 1 5. Possible Outcomes of Antigen Encounter: When a lymphocyte encounters an antigen, it can lead to two outcomes: activation and immune response or inactivation/elimination, leading to tolerance. The focus here is on the latter, which prevents immune reactions against self-antigens. 6.Factors Influencing Tolerance vs. Immune Response: 1. Affinity of Receptor-Antigen Interaction: The strength of the interaction between the lymphocyte receptor and the antigen influences whether activation or tolerance occurs. Higher affinity interactions may lead to activation, while lower affinity interactions may lead to tolerance. 2. Conditions of Antigen Exposure: The context in which the antigen is encountered, including signaling molecules like cytokines and the involvement of other immune cells, influences the outcome. 3. Presence/Absence of Co-stimulators: Co-stimulatory molecules, such as B7 and CD28, play a role in lymphocyte activation. Their presence or absence can determine whether tolerance or activation occurs. 7.Importance of Tolerance: Tolerance is crucial for preventing autoimmune diseases. Failure of self-tolerance leads to immune reactions against self-antigens, resulting in autoimmune diseases. Overall, the discussion provides a detailed overview of immunological tolerance, emphasizing the mechanisms and importance of self-tolerance in preventing autoimmunity. It covers both basic concepts and factors influencing tolerance mechanisms. 1 Central and peripheral tolerance to self antigens Central Immature lymphocytes Generative/primary/central lymphoid organs Three possible mechanisms Not perfect Peripheral Mature lymphocytes Peripheral tissues Three possible mechanism Backup for central mechanisms Maintain unresponsiveness to self antigens expressed only in peripheral tissues only in adults This transcript delves into the concepts of central and peripheral tolerance to self-antigens within the context of immunology. Let's break down the explanations provided: Central Tolerance: 1.Location and Mechanisms: Central tolerance occurs in the primary or central lymphoid organs, specifically the thymus and bone marrow. It involves immature lymphocytes recognizing self-antigens. Three possible outcomes are discussed: 1. Apoptosis: Immature lymphocytes that recognize self-antigens too strongly undergo apoptosis, effectively eliminating them. 2. Receptor Editing (B Cells): Some B cells undergo receptor editing if their receptors bind too tightly to self-antigens. This process allows for the generation of a new receptor that no longer recognizes selfantigens. 3. Conversion to Regulatory T Cells (Tregs): Certain CD4+ T cells, if they recognize self-antigens, may be redirected towards becoming regulatory T cells. Tregs play a crucial role in suppressing immune responses. 2 2. Imperfections: Despite these mechanisms, central tolerance is not perfect. Some immature lymphocytes may escape elimination and enter the peripheral tissues, where they can recognize self-antigens. Peripheral Tolerance: 1.Location and Mechanisms: Peripheral tolerance occurs in peripheral tissues where mature lymphocytes encounter selfantigens. Three main mechanisms are discussed: 1. Anergy: Mature lymphocytes that recognize self-antigens may become anergic, meaning they are functionally inactive and do not respond to antigen stimulation. 2. Programmed Cell Death (Apoptosis): Some self-reactive lymphocytes undergo programmed cell death, effectively removing them from the immune repertoire. 3. Regulatory T Cells (Tregs): Tregs generated in central tolerance can migrate to peripheral tissues and suppress the activity of mature lymphocytes that recognize self-antigens. 2.Backup Mechanism: Peripheral tolerance acts as a backup mechanism for cases where central tolerance fails. It aims to eliminate or suppress self-reactive lymphocytes that escape central tolerance mechanisms. 3.Importance: Peripheral tolerance is crucial for dealing with self-antigens that may not be encountered during central tolerance processes, such as those expressed only in peripheral tissues or later stages of development. Overall, central and peripheral tolerance mechanisms work together to prevent autoimmune responses by ensuring that the immune system does not mount attacks against self-antigens. However, their effectiveness may vary, leading to the potential for autoimmune diseases when tolerance mechanisms fail. 2 Central tolerance in T cells occurs in the thymus Occurs for both CD8+ and CD4+ immature lymphocytes with high-affinity receptor against self antigens Antigens in the thymus include: Many widely distributed circulating and cell-associated proteins Some found predominantly in specific peripheral tissues Ø Thymus has specialized expression mechanism for these Most thymocytes that recognize self Some CD4+ thymocytes that recognize self Unclear what factors determine outcome This excerpt provides further detail on central tolerance mechanisms in T cells, particularly within the thymus: 1.Location of Central Tolerance in T Cells: Central tolerance in T cells occurs within the thymus, a primary lymphoid organ where T cell maturation takes place. 2.Recognition of Self-Antigens: Immature T cells within the thymus encounter self-antigens. These antigens can be proteins that are widely distributed throughout the body, including those found in circulating and cell-associated proteins. Additionally, some self-proteins are unique to peripheral tissues and are not readily presented in the thymus. However, special mechanisms exist within the thymus to express certain peripheral tissue-specific proteins to expose T cells to a broader range of self-antigens. 3.Tolerance Mechanisms in the Thymus: 1. Negative Selection: The majority of thymocytes that recognize self-antigens undergo negative selection, leading to their deletion through apoptosis. This process eliminates T cells with high affinity for self-antigens, preventing them from causing autoimmune responses. 2. Differentiation into Regulatory T Cells (Tregs): Some CD4+ thymocytes that recognize self-antigens may differentiate into regulatory T cells. These Tregs play a role in suppressing immune responses and 3 maintaining self-tolerance. However, it's noted that only a relatively small portion of CD4+ T cells that recognize self-antigens become Tregs. 4. Role of Regulatory T Cells (Tregs): Regulatory T cells generated in the thymus eventually migrate to peripheral tissues. There, they continue to exert regulatory functions, helping to suppress immune responses against self-antigens. 5.Factors Influencing Tolerance Mechanisms: The precise mechanisms that determine whether a thymocyte undergoes negative selection or differentiation into Tregs are still under investigation. Factors such as the strength of antigen recognition and the specific context in which self-antigens are encountered likely play roles in determining the fate of T cells during central tolerance processes. Overall, central tolerance mechanisms in T cells aim to eliminate or regulate self-reactive T cells to prevent autoimmune responses. The thymus serves as a crucial site for the education and selection of T cells, ensuring the maintenance of immune tolerance to self-antigens. 3 Peripheral tolerance in T cells Interaction with activated DC displaying both foreign peptide antigen and B7 costimulator Three mechanisms provide T cell tolerance to tissue-specific self antigens not normally abundant in the thymus This segment discusses peripheral tolerance mechanisms in T cells, contrasting them with the normal T cell response: 1.Normal T Cell Response: 1. In the normal T cell response, an activated dendritic cell interacts with a T cell, leading to T cell activation, differentiation, and proliferation. 2. The activated dendritic cell presents foreign peptides on its MHC class II proteins and expresses costimulatory molecules like B7, which are necessary for T cell activation. 2.Peripheral Tolerance Mechanisms: 1. Anergy: Anergy refers to a state of functional inactivation in which T cells fail to respond to antigen stimulation. This mechanism can induce tolerance to self-antigens that T cells encounter in peripheral tissues. Anergic T cells remain present but do not contribute to immune responses. 2. Suppression: Suppression involves the action of regulatory T cells (Tregs) that actively suppress the activation and function of other immune cells, including T cells. Tregs play a crucial role in maintaining peripheral tolerance by preventing excessive immune responses and autoimmunity. 4 3. Deletion: Deletion refers to the elimination of self-reactive T cells from the immune repertoire. This mechanism removes potentially harmful T cells that recognize self-antigens. Deleted T cells undergo apoptosis, effectively removing them from the immune system. 1.Role of Peripheral Tolerance: 1. Peripheral tolerance mechanisms are essential for maintaining self-tolerance to tissue-specific self-antigens that may not be encountered during central tolerance processes in the thymus. 2. These mechanisms ensure that T cells do not mount immune responses against self-antigens present in peripheral tissues, thereby preventing autoimmune diseases. 2.Contribution to Tolerance: 1. Peripheral tolerance mechanisms contribute to the overall immune tolerance by providing additional layers of regulation beyond central tolerance processes in the thymus. 2. They help address the challenge of recognizing and tolerating self-antigens that may be encountered in peripheral tissues but were not presented during T cell maturation in the thymus. In summary, peripheral tolerance mechanisms such as anergy, suppression by Tregs, and deletion play crucial roles in preventing immune responses against self-antigens encountered in peripheral tissues, thereby maintaining immune tolerance and preventing autoimmune diseases. 4 Mechanisms of T cell anergy Anergy favored when T cell experiences prolonged exposure to self antigen presented by “resting” DCs DCs not activated by self antigen so don’t express B7 or other costimulators The process by which self-reactive T cells become functionally unresponsive to self-antigen Recruitment of phosphatases or degradation of signal pathway proteins 2 Two recognized mechanisms 1 Unresponsive T cell typically survives for a few days or weeks in a quiescent state and then dies. CTLA-4 or PD-1 This passage elaborates on the concept of T cell anergy, which is the process by which self-reactive T cells become functionally unresponsive to self-antigens. Here's a breakdown of the mechanisms and implications of T cell anergy: 1.Causes of Anergy: 1. T cell anergy is favored when a T cell experiences prolonged exposure to self-antigens presented by non-activated dendritic cells. Although the dendritic cells are not activated by self-antigens, they still present them to T cells. 2. Anergy can occur when a T cell recognizes self-antigen but doesn't receive the necessary co-stimulatory signals for activation. 2.Mechanisms of Anergy: 1. Engagement of Inhibitory Receptors: In this mechanism, the T cell expresses inhibitory receptors in response to self-antigen recognition without co-stimulation. These inhibitory receptors produce proteins that interact with inhibitory molecules on the surface of dendritic cells, leading to a blockage of signaling. Examples of inhibitory receptors include CTLA-4 and PD-1. 5 2. Recruitment of Phosphatases: When T cells receive signals without co-stimulation, phosphatases are recruited instead of the usual phosphorylation of tyrosines in ITAM sequences. These phosphatases remove phosphates from the tyrosines, effectively shutting down the signaling pathway. This leads to a blockage of signaling similar to inhibitory receptor engagement. 1.Consequences of Anergy: 1. In both mechanisms, the result is a signaling block that renders the T cell unresponsive or anergic to further activation signals. 2. An anergic T cell typically survives for a limited period (days to weeks) in a quiescent state before eventually dying. 3. While anergic T cells are not immediately eliminated like those undergoing programmed cell death during negative selection, they are effectively removed from the immune repertoire over time, reducing the risk of self-reactive T cells contributing to autoimmune responses. Overall, T cell anergy serves as a mechanism to prevent self-reactive T cells from mounting immune responses against selfantigens encountered in peripheral tissues. It is a regulatory mechanism that helps maintain immune tolerance and prevent autoimmune diseases. 5 Regulatory T cells (Tregs) Natural regulatory cells Inducible or Adaptive regulatory cells This passage introduces regulatory T cells (Tregs) and discusses their origin and classification: 1.Overview of Regulatory T Cells (Tregs): 1. Regulatory T cells are a specialized subset of T cells known for their ability to suppress immune responses. 2. They play a crucial role in maintaining immune tolerance and preventing autoimmune reactions by suppressing the activity of other immune cells. 2.Origin of Regulatory T Cells: 1. Regulatory T cells can be generated in two main locations: 1. Centrally: Tregs generated centrally originate in the thymus. They arise through the recognition of self-antigens during T cell development and negative selection processes in the thymus. 2. Peripherally: Tregs generated peripherally originate in peripheral tissues or lymph nodes. They are induced by the recognition of self-antigens present in the peripheral tissues. 3.Classification: 1. Regulatory T cells generated in the thymus are often referred to as natural regulatory T cells. This term 6 reflects their origin from central tolerance mechanisms in the thymus. Regulatory T cells generated in peripheral tissues or lymph nodes are referred to as inducible or adaptive regulatory T cells. They are induced in response to antigens encountered in peripheral tissues. 1.Quantity of Tregs: 1. The bulk of regulatory T cells are produced centrally in the thymus, as indicated by the larger arrow in the figure. This suggests that a significant portion of regulatory T cells originate from thymic development. 2. However, regulatory T cells can also be induced peripherally, contributing to the overall population of Tregs in the body. 2.Function of Regulatory T Cells: 1. Regardless of their origin, regulatory T cells function to suppress immune responses and maintain tolerance to self-antigens. 2. They exert their suppressive effects by inhibiting the activation and function of other immune cells, such as T cells, B cells, and antigen-presenting cells. Overall, regulatory T cells are essential for immune homeostasis and preventing autoimmunity. They can be generated both centrally in the thymus and peripherally in response to antigens encountered in peripheral tissues, contributing to the maintenance of immune tolerance throughout the body. 2. 6 Development and survival of regulatory T cells (Tregs) Requires: IL-2 => Tregs express high levels of IL-2R FoxP3 transcription factor The development and survival of regulatory T cells (Tregs) are driven by specific molecular signals and transcription factors: 1.Interleukin 2 (IL-2) and IL-2 Receptor (IL-2R): 1. Development of regulatory T cells requires the detection of interleukin 2 (IL-2), a signaling molecule involved in immune regulation. 2. To detect IL-2, regulatory T cells express the IL-2 receptor (IL-2R) on their surface. The IL-2R consists of multiple subunits, including IL-2Rα (CD25), IL-2Rβ, and IL-2Rγ. 2.Transcription Factor FOXP3: 1. Another critical component for the development and function of regulatory T cells is the transcription factor FOXP3. 2. FOXP3 is a master regulator of regulatory T cell development and function. It plays a central role in programming T cells to become regulatory T cells. 3. Expression of FOXP3 is essential for the conversion of CD4+ T cells into regulatory T cells. It drives the expression of genes associated with the regulatory phenotype. 7 3. Role of IL-2 and FOXP3 in Development: 1. IL-2 signaling, through the IL-2 receptor, is crucial for initiating the differentiation of CD4+ T cells into regulatory T cells. 2. Activation of the IL-2 receptor leads to the upregulation of FOXP3 expression in CD4+ T cells, promoting their differentiation into regulatory T cells. 3. FOXP3 acts as a transcription factor that controls the expression of genes involved in regulatory T cell function, including genes encoding immunosuppressive molecules and regulatory cytokines. 4.Promotion of Survival: 1. Once regulatory T cells are generated, their survival and maintenance are supported by various factors, including the presence of IL-2. 2. IL-2 signaling contributes to the survival and proliferation of regulatory T cells, helping to maintain their population in the immune system. In summary, the development and survival of regulatory T cells depend on the expression of specific proteins, including the IL-2 receptor and the transcription factor FOXP3. IL-2 signaling and FOXP3 expression are critical for the differentiation of CD4+ T cells into regulatory T cells and for maintaining their regulatory function and survival within the immune system. 7 Regulatory T cells (Tregs) suppress immune response at multiple points Defects in Treg-mediated suppression of immune response can contribute to various autoimmune diseases 4. NK proliferation & differentiation 5. IL-10 production inhibits DCs & macrophages 3. B cell activation 1. T cell activation 2. Effector T cell activity This passage explains how regulatory T cells (Tregs) suppress immune responses at multiple points and outlines their inhibitory actions on various immune cells: 1.Targets of Treg-Mediated Suppression: 1. Tregs can suppress immune responses by acting on different immune cell types, including T cells, B cells, natural killer (NK) cells, dendritic cells, and macrophages. 2.Inhibition of T Cell Responses: 1. Tregs inhibit the activation of T cells, preventing their activation and proliferation. 2. They also suppress the activity of effector T cells, which are responsible for carrying out immune responses. 3.Inhibition of B Cell Activation: 1. Tregs can inhibit the activation of B cells, preventing their differentiation into plasma cells and the production of antibodies. 4.Inhibition of NK Cell Activity: 1. Tregs suppress the proliferation and differentiation of natural killer (NK) cells, which are involved in the 8 innate immune response. 5. Production of Immunosuppressive Cytokines: 1. Tregs produce immunosuppressive cytokines such as interleukin-10 (IL-10) and transforming growth factorbeta (TGF-β). 2. These cytokines inhibit the activity of dendritic cells and macrophages, key antigen-presenting cells involved in initiating immune responses. 6.Contribution to Autoimmune Diseases: 1. Dysregulation of Treg-mediated suppression can contribute to various autoimmune diseases by allowing excessive immune responses against self-antigens. 2. Tregs play a crucial role in maintaining peripheral tolerance to self-antigens, preventing autoimmune reactions. 7.Broad Actions of Tregs: 1. Tregs have broad actions in both peripheral tolerance to self-antigens and the regulation of overall immune responses. 2. They limit excessive immune responses and help maintain immune homeostasis. Overall, regulatory T cells play a critical role in suppressing immune responses and preventing autoimmune reactions by inhibiting the activation and function of various immune cells. Dysfunction of Tregs can lead to autoimmune diseases due to unchecked immune responses against self-antigens. 8 Antibody avidity is important for B cell tolerance Avidity = total strength of interaction between antibody and antigen Depends on following factors 1. Affinity of binding to antigen 2. Number of antigen-binding sites in antibody complex (valency) For example, IgG has 2 binding sites, IgM has 10 binding sites 3. Arrangement and number of antibody binding sites on antigen Repetitive polymer? Abundant cell surface protein? As each of these factors increases, so does avidity of antibody or BCR Avidity, in the context of B cell tolerance, refers to the total strength of the interaction between an antibody and an antigen. It depends on three main factors: 1.Affinity: Affinity refers to how tightly the antibody's binding region (paratope) binds to the epitope on the antigen. A higher affinity means a stronger binding interaction. 2.Valency: Valency relates to the number of antigen-binding sites present in the antibody complex. Antibodies with more binding sites, such as IgM pentamers, have higher valency, allowing them to bind to multiple antigen molecules simultaneously. 3.Arrangement and Number of Antibody Binding Sites on the Antigen: This factor considers the arrangement and abundance of antigenic determinants (epitopes) on the antigen. If the antigen has multiple binding sites or is present in a repetitive pattern, it enhances the likelihood of multiple binding interactions with the antibody, leading to increased avidity. As these factors increase (higher affinity, more binding sites on the antibody, and abundant or repetitive antigenic 9 determinants), the avidity of the antibody-antigen interaction increases. This heightened avidity results in a stronger and more stable binding between the antibody (or B cell receptor) and the antigen. Understanding avidity is crucial for comprehending the strength of B cell responses and tolerance mechanisms. In the context of B cell tolerance, maintaining appropriate avidity helps regulate the immune response, preventing excessive activation against self-antigens while allowing effective responses against pathogens. 9 Central tolerance for immature B cells occurs in bone marrow B cell tolerance important for: Preventing Ab responses to self antigen Various types of macromolecule antigens If recombination successful Will eventually die B cell tolerance, particularly in the bone marrow, is crucial for preventing antibody responses to self-antigens. This process is essential for maintaining immune homeostasis and preventing autoimmune reactions. Additionally, B cell tolerance plays a significant role in the recognition or non-recognition of various non-protein antigens, including polysaccharides, nucleic acids, and lipids. Unlike T cells, which primarily recognize protein antigens, B cells have the ability to recognize a broader range of antigens, as long as there is some repeating structure present. In the context of self-recognition, if B cells encounter self-antigens with high avidity, leading to strong binding interactions, several outcomes may occur. One possibility is receptor editing, where the B cell undergoes rearrangement of its immunoglobulin genes to generate a new IG light chain, potentially resulting in a non-selfreactive cell. Alternatively, if receptor editing is unsuccessful or not initiated, apoptosis may occur, leading to the removal of the self-reactive B cell from the repertoire. On the other hand, if B cells recognize self-antigens with low affinity or avidity, resulting in weaker binding interactions, energy may ensue. This leads to reduced receptor expression and signaling, rendering the B cell functionally unresponsive or "anergic." Eventually, the anergic B cell undergoes apoptosis, effectively removing it from the immune system. 10 Overall, the mechanisms of B cell tolerance in the bone marrow are essential for eliminating or inactivating self-reactive B cells, thereby preventing the production of autoantibodies and autoimmune reactions. 10 Peripheral tolerance for mature B cells Similar possible outcomes as for T cells Self antigens don’t trigger innate immune responses => B cells will not be activated => antigen recognition w/o additional stimuli leads to tolerance In the context of peripheral tolerance for mature B cells, similar outcomes can occur when encountering selfantigens. If self-antigens fail to trigger innate immune responses, mature B cells will not be activated. Consequently, antigen recognition without additional stimuli may lead to tolerance. This parallels the mechanisms observed in T cells. Peripheral tolerance mechanisms for mature B cells include anergy, deletion, or regulation by regulatory cells. Anergy refers to the functional unresponsiveness of B cells upon encountering self-antigens without appropriate co-stimulatory signals. Deletion involves the removal of self-reactive B cells from the repertoire, typically through apoptosis. Regulation by regulatory cells, such as regulatory T cells, can suppress the activity of self-reactive B cells, contributing to peripheral tolerance. Overall, the mechanisms of peripheral tolerance ensure that mature B cells do not mount harmful immune responses against self-antigens, thereby maintaining immune tolerance and preventing autoimmune reactions. 11