Humoral Immunity PDF

HUMORAL IMMUNITY - To understand host defence mechanisms against infection Components of humoral response: - Complement - Antibodies - B cells - Plasma cells - Cytokines + chemokines B-cell formation: **1. Hematopoietic Stem Cell (HSC) Stage:** - **Location**: Bone marrow -...

HUMORAL IMMUNITY - To understand host defence mechanisms against infection Components of humoral response: - Complement - Antibodies - B cells - Plasma cells - Cytokines + chemokines B-cell formation: **1. Hematopoietic Stem Cell (HSC) Stage:** - **Location**: Bone marrow - B cells originate from **hematopoietic stem cells** (HSCs), which are multipotent cells that can give rise to all types of blood cells, including immune cells. - HSCs differentiate into **common lymphoid progenitors (CLPs)**, which then give rise to B cells, T cells, and natural killer (NK) cells. **2. Pro-B Cell Stage:** - **Location**: Bone marrow - The CLP differentiates into a **pro-B cell**. This is the first committed step toward becoming a B cell. - **Key event**: Pro-B cells undergo **immunoglobulin heavy chain gene rearrangement** (a process known as **VDJ recombination**), which begins the formation of the **B cell receptor (BCR)**. The BCR is essentially a membrane-bound antibody and is vital for recognizing antigens. - At this stage, the heavy chain (which forms part of the BCR) starts to rearrange from its genetic components---**variable (V), diversity (D), and joining (J) gene segments**. **3. Pre-B Cell Stage:** - **Location**: Bone marrow - After successful heavy chain gene rearrangement, the pro-B cell becomes a **pre-B cell**. - **Key event**: The pre-B cell expresses a pre-BCR, which contains the rearranged heavy chain and a surrogate light chain (temporary component) on its surface. This is a checkpoint to ensure that the heavy chain has been correctly assembled. - If the pre-BCR functions properly, the cell receives a signal to stop heavy chain rearrangement and proceed to light chain gene rearrangement. **4. Immature B Cell Stage:** - **Location**: Bone marrow - Once the **light chain genes** (composed of V and J gene segments) successfully rearrange, the pre-B cell becomes an **immature B cell**. - **Key event**: The immature B cell expresses a complete, functional B cell receptor (BCR) on its surface, composed of a heavy chain and a light chain. - At this stage, immature B cells are subjected to **negative selection** to ensure that they do not react against self-antigens (proteins from the body\'s own tissues). B cells that strongly bind to self-antigens undergo one of the following: - **Receptor editing**: The B cell attempts to rearrange its light chain again to change its BCR. - **Clonal deletion**: The B cell is eliminated via apoptosis (programmed cell death). - **Anergy**: The B cell becomes unresponsive and inactive. **5. Mature Naive B Cell Stage:** - **Location**: lymph nodes - Immature B cells that pass negative selection leave the bone marrow and migrate to the **spleen** or other secondary lymphoid organs, where they become **mature naive B cells**. - **Key event**: These B cells now express two classes of BCRs on their surface---**IgM** and **IgD**. They are considered naive because they have not yet encountered their specific antigen. - Mature naive B cells circulate in the blood and lymphatic system, awaiting activation by encountering their specific antigen. **6. Activation and Differentiation into Plasma Cells or Memory B Cells:** - **Location**: Peripheral lymphoid organs (spleen, lymph nodes) - When a mature naive B cell encounters an antigen that matches its BCR, it becomes activated with the help of **T cells** (specifically **T helper cells**) and other signals from the immune system. This typically occurs in the **germinal centers** of lymphoid tissues. - **Key events**: - **Clonal expansion**: The activated B cell proliferates and produces a large number of identical cells (clones), all specific to the same antigen. - **Class switch recombination**: B cells can change the class of antibodies they produce (from IgM to IgG, IgA, or IgE) without altering the antigen specificity of the BCR. - **Somatic hypermutation**: Mutations occur in the BCR genes, allowing for fine-tuning and increased affinity for the antigen (this process is called **affinity maturation**). Activated B cells differentiate into: **Plasma cells**: These are antibody-secreting cells that produce large quantities of antibodies specific to the encountered antigen. Plasma cells typically reside in the bone marrow and produce antibodies that circulate in the blood to neutralize pathogens. **Memory B cells**: These long-lived cells \"remember\" the specific antigen they encountered and remain in the body for years. If the same antigen is encountered again, memory B cells can quickly mount a robust immune response by rapidly differentiating into plasma cells and producing antibodies. ANATOMY OF ANTIBODY A diagram of a dna chain Description automatically generated VDJ: - Pro-B cells mix up antibody-coding DNA before becoming mature B cell - Rearranged DNA make lots of combos BCR recognition: - Proteins - Polysaccharides - Lipids - Bacteria - Virus Lymph -\> antigen presenting cell MHCII presents antigen -\> BCR / antigen complex -\> antigen broken into peptides -\> presented on MHCII -\> MHCII / antigen complex recognised by CD4+ T helper cells -\> t cell produces cytokines that activate b cell Humoral phase: Activation -\> effector -\> resolution **1. Activation Phase** This phase involves the recognition and initiation of the immune response. - **Antigen recognition**: B cells, which have specific receptors (BCRs) on their surface, bind to an antigen (a foreign molecule such as a virus or bacterium) that matches their receptor. - **Helper T cell involvement**: In most cases, B cells require help from **helper T cells (CD4+ T cells)**. These T cells recognize the same antigen that the B cell encountered and provide activating signals through the release of cytokines. - **Clonal expansion**: Once activated, the B cells undergo **clonal expansion**, multiplying to form a large population of cells capable of responding to the antigen. Some of these B cells differentiate into **plasma cells**, which are antibody-secreting cells, while others become **memory B cells**. **2. Effector Phase** In this phase, the immune system acts to neutralize or eliminate the pathogen. - **Antibody production**: The plasma cells produced during clonal expansion secrete large amounts of **antibodies** specific to the antigen -\> **IMMUNOGLxOBULIN** - **Neutralization**: Antibodies bind to the pathogen, neutralizing it by blocking its ability to infect cells - **Opsonization**: Antibodies coat the pathogen, marking it for ingestion and destruction by phagocytic cells such as macrophages and neutrophils. - **Complement activation**: Antibodies can also activate the **complement system**, which enhances the immune response by promoting inflammation and directly killing pathogens through the formation of the **membrane attack complex (MAC)**. - **Memory formation**: During this phase, some B cells become **memory B cells**, which are primed to respond more quickly if the same antigen is encountered again in the future. - **Increased expression of cell surface molecules** **3. Resolution Phase** After the pathogen is cleared, the immune system returns to its normal state, and the response is downregulated. - **Elimination of excess immune cells**: Once the pathogen is removed, most of the plasma cells and effector B cells die off through a process called **apoptosis** (programmed cell death). This prevents unnecessary immune activity and inflammation. - **Memory B cells remain**: Memory B cells persist in the body, providing long-term immunity. These cells can rapidly reactivate and mount a faster, stronger response if the antigen is encountered again. - **Restoration of homeostasis**: The immune system returns to a balanced state, maintaining surveillance without causing harm to the body\'s own tissues. Isotypes: - Monomer; IgD, IgE, IgG - Dimer; IgA - Pentamer; IgM ↑ important for info about stage of infection/type of immune challenge  A diagram of a cell cycle Description automatically generated  Antibody Dependant Cell Cytotoxicity: - **Antibody binding**: Antibodies (typically IgG) recognize and bind to antigens on the surface of target cells, such as cells infected with a virus or tumor cells. - **Effector cell recognition**: Immune cells, such as **natural killer (NK) cells**, macrophages, or neutrophils, have receptors on their surface called **Fc receptors** that bind to the **Fc region** of the antibody attached to the target cell. - **Target cell destruction**: Once the effector cell binds to the antibody, it is activated to release cytotoxic molecules, such as perforins and granzymes, which directly kill the target cell. NK cells are the primary effectors of ADCC, but other immune cells can also participate. - Basis for understanding medical emergencies that arise as a result of defective humoral immune responses Auto-reactive B cells disease -\> Graves - Makes thyroid stim immunoglobulins - Leads to hyperthyroidism - To understand which treatments to give to a patient undergoing such a medical emergency and what those treatments are doing Anaphylaxis: - Mast cells loaded w IgE -\> mast cell degranulation + histamine release - ↑ vasodilation - Vascular permeability - Huge drop in BP - Airway constriction -\> swelling of epiglottis Asthma: - Mast cells in airways w IgE -\> bronchial constriction - Increases secretion of fluid - To understand oral and systemic diseases that arise from defective humoral responses GFC: - Contains IgM, IgG, IgA, leukocytes + plasma CELL MEDIATED IMMUNITY **1. Antigen Recognition** - T cells recognize antigens presented by antigen-presenting cells (APCs), such as dendritic cells, macrophages, or infected cells. - Antigen recognition occurs when a T cell\'s receptor (TCR) binds to the antigen presented on the surface of the APC, which is displayed in conjunction with *major histocompatibility complex (MHC)* molecules. - CD8+ cytotoxic T cells recognize antigens presented by MHC Class I molecules. - CD4+ helper T cells recognize antigens presented by MHC Class II molecules. **2. T Cell Activation** - Upon antigen recognition, T cells require a second signal for full activation, known as *co-stimulation*. Co-stimulatory molecules on the APC bind to receptors on the T cells, providing this second signal. - Activated T cells then proliferate (expand in number) through *clonal expansion*. - CD4+ helper T cells differentiate into various subsets (Th1, Th2, Th17, or T regulatory cells), while CD8+ cytotoxic T cells become capable of killing infected cells. **3. T Cell Differentiation** - Activated T cells differentiate into effector T cells with specific functions: - *CD8+ cytotoxic T cells* directly kill infected cells or cancerous cells by releasing cytotoxic molecules like perforin and granzymes. - *CD4+ helper T cells* secrete cytokines to activate other immune cells like macrophages, B cells, and additional T cells. - *Memory T cells* are formed during differentiation and provide long-term immunity, allowing a faster response upon re-exposure to the same antigen. **4. Effector Phase** - Effector T cells migrate to the site of infection or inflammation. - Cytotoxic T cells (CD8+) recognize and kill infected cells by inducing apoptosis (cell death). - Helper T cells (CD4+) activate other immune cells (macrophages, neutrophils, and B cells), enhancing their pathogen-fighting abilities. - This phase involves the direct elimination of infected cells or coordinating the broader immune response. **5. Contraction and Memory Formation** - After the infection is cleared, most effector T cells undergo apoptosis, a process called *contraction*, to avoid an overactive immune response. - A small population of T cells becomes *memory T cells*, which persist long-term and are capable of quickly responding if the same pathogen is encountered in the future. - Give examples of the types of pathogen that initiate a cell mediated response. A diagram of a cell division Description automatically generated - Explain how T cells become activated.  **Antigen Presentation**: APCs process and present antigens on their surface using molecules called *major histocompatibility complexes* (MHC). There are two main types: - *MHC Class I* for cytotoxic T cells (CD8+). - *MHC Class II* for helper T cells (CD4+).  **Recognition**: A T cell\'s receptor (TCR) recognizes and binds to the specific antigen-MHC complex on the APC. This is the first signal for activation.  **Co-stimulation**: To fully activate the T cell, a second signal is needed. This comes from additional molecules on the APC binding to co-stimulatory receptors on the T cell (like CD28).  **Cytokine Signaling**: Once the T cell is activated, APCs and other cells release cytokines, which help to guide the differentiation of the T cell into specific functional types (e.g., helper T cells, cytotoxic T cells, regulatory T cells).  **Activation and priming**: T cells are first activated in the lymph nodes by antigen-presenting cells (APCs) that present antigens from pathogens.  **Circulation**: Once activated, T cells enter the bloodstream, where they circulate through the body, searching for sites of infection or injury.  **Chemokine signaling**: At the site of infection or inflammation, infected or damaged tissues release chemical signals called *chemokines*. These chemokines attract T cells to the affected area.  **Adhesion and migration**: T cells respond to these chemokines by adhering to the blood vessel walls near the site of infection. They then migrate through the blood vessel walls (a process called *extravasation*) and enter the infected tissue.  **Effector function**: Once in the tissue, T cells perform their specific immune functions, such as killing infected cells (cytotoxic T cells) or helping other immune cells respond (helper T cells). - Differentiate between CD4 and CD8 T cells and their functions. CD8 = cytotoxic -\> kill cells via apoptosis CD4 = t helper -\> cytokine to immune cells (macrophage, neutrophil, B cell), doesn't kill anything **1. Th1 Cells** - **Cytokines**: - **Interferon-gamma (IFN-γ)**: Activates macrophages, enhances antigen presentation, and boosts the killing ability of cytotoxic T cells (CD8+). - **Tumor necrosis factor-alpha (TNF-α)**: Promotes inflammation and helps to eliminate intracellular pathogens. **2. Th2 Cells** - **Cytokines**: - **Interleukin-4 (IL-4)**: Promotes B cell class switching to IgE, which is important in allergic reactions and parasitic infections. - **Interleukin-5 (IL-5)**: Stimulates the growth and differentiation of eosinophils, important in fighting parasitic infections. - **Interleukin-13 (IL-13)**: Involved in promoting IgE production and enhancing mucus production in allergic responses. **3. Th17 Cells** - **Cytokines**: - **Interleukin-17 (IL-17)**: Induces production of pro-inflammatory cytokines and recruits neutrophils to fight extracellular pathogens like bacteria and fungi. - **Interleukin-22 (IL-22)**: Helps maintain epithelial barrier integrity and promotes tissue repair, while also enhancing immune responses. **4. T regulatory (Treg) Cells** - **Cytokines**: - **Interleukin-10 (IL-10)**: Suppresses immune responses, especially Th1 and Th17 responses, helping to regulate inflammation and prevent autoimmunity. - **Transforming growth factor-beta (TGF-β)**: Promotes immune tolerance, inhibits the activation of immune cells, and plays a role in tissue repair. **5. T follicular helper (Tfh) Cells** - **Cytokines**: - **Interleukin-21 (IL-21)**: Promotes B cell maturation and differentiation, helping to produce high-affinity antibodies, especially in germinal centers of lymph nodes. - Apply understanding of CMI to pathology **1. Viral Infections** - **Normal Role of CMI**: Cytotoxic T cells (CD8+) are critical in identifying and destroying cells infected with viruses. Helper T cells (CD4+ Th1) secrete cytokines, like IFN-γ, which activate macrophages and enhance viral clearance. - **Pathology Example**: In *HIV*, the virus directly infects and destroys CD4+ T cells, leading to a weakened CMI response. As a result, the body becomes vulnerable to opportunistic infections, such as viral, fungal, and bacterial infections that a healthy immune system would usually control. **2. Bacterial Infections** - **Normal Role of CMI**: Th1 cells produce IFN-γ, activating macrophages to destroy intracellular bacteria, such as *Mycobacterium tuberculosis*. - **Pathology Example**: In *tuberculosis (TB)*, the body forms granulomas, clusters of immune cells that attempt to contain the bacteria. If CMI is insufficient, the bacteria can escape the granulomas, leading to active TB disease, tissue damage, and chronic inflammation.