Immune System Cells and Functions PDF

T Cells (T Lymphocytes) T cells are a type of white blood cell that play a central role in adaptive immunity, which is the body's tailored response to specific pathogens. They mature in the thymus gland and are involved in identifying and eliminating infected or cancerous cells. Types of T Cells:...

T Cells (T Lymphocytes) T cells are a type of white blood cell that play a central role in adaptive immunity, which is the body's tailored response to specific pathogens. They mature in the thymus gland and are involved in identifying and eliminating infected or cancerous cells. Types of T Cells: a. Helper T Cells (CD4+ T Cells) Function: Assist other immune cells by secreting cytokines, which are signaling molecules that enhance the immune response. Roles: ○ Activate B cells to produce antibodies. ○ Stimulate cytotoxic T cells and macrophages. ○ Coordinate the overall immune response. Subtypes: ○ Th1 Cells: Promote responses against intracellular pathogens like viruses. ○ Th2 Cells: Support responses against extracellular parasites and allergens. ○ Th17 Cells: Involved in responses against fungi and extracellular bacteria; also play a role in autoimmune diseases. ○ Regulatory T Cells (Tregs): Suppress immune responses to maintain tolerance to self-antigens and prevent autoimmune diseases. b. Cytotoxic T Cells (CD8+ T Cells) Function: Directly kill infected or cancerous cells. Mechanism: ○ Recognize infected cells by detecting foreign antigens presented on MHC I molecules. ○ Release perforin and granzymes that induce apoptosis (programmed cell death) in target cells. Importance: Crucial for controlling viral infections and eliminating tumor cells. c. Memory T Cells Function: Provide long-lasting immunity by remembering past infections. Roles: ○ Quickly respond to previously encountered antigens upon re-exposure. ○ Ensure a faster and more effective immune response during subsequent infections. 2. B Cells (B Lymphocytes) B cells are another critical component of adaptive immunity. They mature in the bone marrow and are primarily responsible for producing antibodies that neutralize pathogens. Functions of B Cells: Antibody Production: ○ Produce and secrete antibodies (immunoglobulins) that specifically bind to antigens on pathogens. ○ Antibodies neutralize pathogens, mark them for destruction, or prevent their entry into cells. Antigen Presentation: ○ Internalize antigens and present them on MHC II molecules to helper T cells, enhancing the immune response. Differentiation into Plasma and Memory Cells: ○ Plasma Cells: Effector B cells that produce large quantities of antibodies during an active infection. ○ Memory B Cells: Long-lived cells that provide rapid and robust antibody responses upon re-exposure to the same antigen. Types of Antibodies Produced: IgM: First antibody produced during an initial immune response. IgG: Most abundant antibody in circulation; provides long-term protection. IgA: Found in mucosal areas and secretions like saliva and tears; protects body surfaces. IgE: Involved in allergic responses and protection against parasitic infections. IgD: Functions mainly as an antigen receptor on B cells. 3. Macrophages Macrophages are large phagocytic cells derived from monocytes (a type of white blood cell). They are integral to both innate and adaptive immunity. Functions of Macrophages: Phagocytosis: ○ Engulf and digest pathogens, dead cells, and debris. Antigen Presentation:  ○ Process and present antigens on MHC II molecules to helper T cells, linking innate and adaptive immunity. Cytokine Production: ○ Release cytokines that modulate immune responses, promote inflammation, and recruit other immune cells to infection sites. Tissue Repair and Remodeling: ○ Involved in healing processes by clearing dead cells and stimulating tissue regeneration. Types of Macrophages: ○ M1 Macrophages: Pro-inflammatory; combat infections and promote inflammation. ○ M2 Macrophages: Anti-inflammatory; aid in tissue repair and resolving inflammation. 4. Other Important Immune Cells a. Dendritic Cells Function: Professional antigen-presenting cells that initiate and regulate adaptive immune responses. Roles: ○ Capture antigens in peripheral tissues and migrate to lymph nodes. ○ Present antigens to naive T cells, activating them and directing their differentiation. Importance: Act as messengers between innate and adaptive immunity; critical for initiating primary immune responses. b. Natural Killer (NK) Cells Function: Part of the innate immune system; recognize and kill virus-infected cells and tumor cells without prior sensitization. Mechanism: ○ Detect cells lacking MHC I molecules or displaying stress-induced ligands. ○ Induce apoptosis through the release of perforin and granzymes. Roles: ○ Early defense against viral infections and cancer. ○ Produce cytokines like interferon-gamma (IFN-γ) that enhance immune responses. c. Neutrophils  Function: The most abundant type of white blood cells; first responders to sites of infection and inflammation. Roles: ○ Phagocytose and destroy bacteria and fungi. ○ Release enzymes and reactive oxygen species to kill pathogens. ○ Form neutrophil extracellular traps (NETs) to trap and neutralize microbes. Lifespan: Short-lived; their accumulation and death contribute to pus formation at infection sites. d. Eosinophils Function: Combat multicellular parasites and participate in allergic reactions. Roles: ○ Release toxic granule proteins and reactive oxygen species to kill parasites. ○ Involved in modulating inflammatory responses. Associated Conditions: Elevated in parasitic infections, asthma, and allergic diseases. e. Basophils and Mast Cells Basophils: ○ Function: Circulating cells involved in allergic and inflammatory responses. ○ Roles: Release histamine and other mediators upon activation. Participate in defense against parasites. Mast Cells: ○ Function: Reside in tissues, especially mucosal surfaces and skin; play a key role in allergy and anaphylaxis. ○ Roles: Release histamine, heparin, and cytokines upon activation. Contribute to inflammation and recruit other immune cells. Involved in wound healing and defense against pathogens. f. Monocytes Function: Circulate in the bloodstream and differentiate into macrophages or dendritic cells upon migrating into tissues. Roles: ○ Act as phagocytes, ingesting pathogens and debris. ○ Serve as antigen-presenting cells after differentiation. ○ Produce cytokines that regulate immune responses. 5. Overview of Immune Responses Innate Immunity Characteristics: ○ Non-specific, immediate response to pathogens. ○ Involves cells like macrophages, dendritic cells, neutrophils, NK cells, eosinophils, basophils, and mast cells. ○ Provides the first line of defense and informs adaptive immunity. Adaptive Immunity Characteristics: ○ Specific, delayed response tailored to particular pathogens. ○ Involves lymphocytes: T cells and B cells. ○ Features immunological memory, leading to faster and stronger responses upon re-exposure to the same pathogen. Interactions Between Immune Cells Activation and Coordination: ○ Dendritic cells present antigens to naive T cells, activating them. ○ Helper T cells stimulate B cells and other immune cells through cytokine secretion. ○ B cells produce antibodies that opsonize pathogens, marking them for destruction by phagocytes like macrophages and neutrophils. Regulation: ○ Regulatory T cells maintain immune tolerance and prevent overactivation. ○ Cytokines released by various cells modulate the intensity and type of immune responses. Memory Formation: ○ After clearing an infection, memory T and B cells persist, ensuring rapid and effective responses to future exposures. Major Histocompatibility Complex (MHC) molecules are essential for the immune system to recognize foreign molecules and distinguish them from the body's own cells. They play a critical role in antigen presentation, which is the process by which immune cells display antigen fragments to T cells, triggering an immune response. MHC Class I (MHC I) MHC I molecules are present on the surface of almost all nucleated cells in the body. They play a crucial role in the immune system's ability to detect and eliminate cells infected with viruses or transformed into cancer cells. Key Features: Structure: MHC I molecules are composed of a heavy chain (alpha chain) and a smaller protein called β2-microglobulin. The heavy chain has three domains (α1, α2, α3), with the α1 and α2 domains forming the peptide-binding groove. Peptide Presentation: MHC I molecules present endogenous antigens (peptides) derived from proteins synthesized within the cell, such as viral proteins or abnormal proteins produced by cancer cells. ○ These peptides are typically 8-10 amino acids long. ○ The antigenic peptides are processed in the cytoplasm by the proteasome and then transported into the endoplasmic reticulum by a protein complex called TAP (Transporter Associated with Antigen Processing). Recognition by T Cells: ○ MHC I molecules present these peptides on the cell surface to CD8+ T cells (Cytotoxic T cells). ○ When a cytotoxic T cell recognizes a foreign peptide presented by MHC I, it becomes activated and can directly kill the infected or cancerous cell by inducing apoptosis. Ubiquitous Expression: MHC I molecules are expressed on almost all nucleated cells, allowing the immune system to monitor nearly every cell in the body for signs of infection or transformation. MHC Class II (MHC II) MHC II molecules are primarily found on the surface of certain immune cells known as antigen-presenting cells (APCs), which include dendritic cells, macrophages, and B cells. MHC II is crucial for the immune system's response to extracellular pathogens, such as bacteria and parasites. Key Features: Structure: MHC II molecules are composed of two chains: an alpha (α) chain and a beta (β) chain. Both chains contribute to the formation of the peptide-binding groove. Peptide Presentation: MHC II molecules present exogenous antigens, which are peptides derived from proteins that have been taken up by the cell from the external environment (e.g., through phagocytosis or endocytosis). ○ These peptides are typically 13-25 amino acids long. ○ After uptake, the exogenous antigens are processed in endosomes/lysosomes into smaller peptides, which are then loaded onto MHC II molecules. Recognition by T Cells:  ○ MHC II molecules present these peptides on the cell surface to CD4+ T cells (Helper T cells). ○ When a helper T cell recognizes a foreign peptide presented by MHC II, it becomes activated and can then assist other immune cells, such as B cells (in antibody production) and cytotoxic T cells (in killing infected cells). Expression on APCs: MHC II molecules are expressed primarily on antigen-presenting cells (APCs), which specialize in capturing and displaying foreign antigens to T cells. Summary of MHC I vs. MHC II Feature MHC I MHC II Expression All nucleated cells Antigen-presenting cells (APCs) Antigen Endogenous (intracellular) Exogenous (extracellular) Origin Peptide 8-10 amino acids 13-25 amino acids Length Presented to CD8+ T cells (Cytotoxic T CD4+ T cells (Helper T cells) cells) Role Monitoring cells for infection or Activating immune responses against cancer external pathogens Importance in Immune Responses: MHC I is crucial for the immune system to detect cells that are infected with viruses or have become cancerous, as it enables cytotoxic T cells to target and destroy these cells. MHC II is essential for initiating immune responses to extracellular pathogens, as it helps activate helper T cells, which in turn coordinate the broader immune response, including antibody production by B cells and the activation of cytotoxic T cells. Clinical Relevance: Transplantation: MHC molecules are also known as Human Leukocyte Antigens (HLA) in humans, and they play a significant role in organ transplantation. Matching MHC (HLA) types between donor and recipient is critical to reduce the risk of transplant rejection. Autoimmune Diseases: Aberrations in MHC function can lead to autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. Certain MHC alleles are associated with an increased risk of specific autoimmune conditions. Cross-presentation is a unique process by which certain antigen-presenting cells (APCs), particularly dendritic cells, can present extracellular antigens on MHC Class I molecules, rather than the usual MHC Class II molecules. This mechanism is especially important for initiating an immune response against viruses and tumors that do not directly infect dendritic cells. Understanding Cross-Presentation 1. The Traditional Pathways MHC Class I Pathway (Endogenous Pathway): ○ Normally, MHC I molecules present antigens derived from proteins synthesized within the cell (endogenous antigens). ○ These peptides are processed in the cytoplasm by the proteasome and transported into the endoplasmic reticulum (ER) by the Transporter Associated with Antigen Processing (TAP). ○ The peptides are then loaded onto MHC I molecules and presented on the cell surface for recognition by CD8+ T cells (cytotoxic T cells). MHC Class II Pathway (Exogenous Pathway): ○ MHC II molecules typically present antigens from extracellular sources (exogenous antigens). ○ These antigens are taken up by APCs through phagocytosis or endocytosis, processed in endosomal/lysosomal compartments, and loaded onto MHC II molecules for presentation to CD4+ T cells (helper T cells). 2. The Need for Cross-Presentation Infection and Tumor Surveillance: ○ Some viruses and tumors may not infect dendritic cells directly, yet an effective immune response requires the activation of CD8+ T cells that recognize these pathogens. ○ For CD8+ T cells to be activated, viral or tumor antigens must be presented on MHC I molecules. ○ Cross-presentation allows dendritic cells to take up extracellular antigens from infected or cancerous cells and present them on MHC I, thereby activating CD8+ T cells. 3. Mechanisms of Cross-Presentation Cross-presentation involves the capture of exogenous antigens by dendritic cells and their processing for presentation on MHC I molecules. There are two main pathways through which this can occur: a. Cytosolic Pathway  Antigen Uptake: Dendritic cells phagocytose or endocytose extracellular antigens (e.g., viral particles or tumor antigens). Escape to Cytosol: The internalized antigens escape from the phagosome or endosome into the cytosol. Proteasomal Processing: Once in the cytosol, these antigens are degraded by the proteasome into peptide fragments. Peptide Loading: The peptides are transported into the ER via the TAP transporter, where they are loaded onto MHC I molecules. Presentation: The MHC I-peptide complexes are then transported to the cell surface for presentation to CD8+ T cells. b. Vacuolar Pathway Antigen Uptake: Similar to the cytosolic pathway, dendritic cells take up antigens from the extracellular environment. Processing in Phagosomes/Endosomes: Instead of escaping into the cytosol, antigens are processed within the endosomal or phagosomal compartments. Direct Loading onto MHC I: In these compartments, peptides are directly loaded onto MHC I molecules. Presentation: The MHC I-peptide complexes are transported to the cell surface to be recognized by CD8+ T cells. 4. Importance of Cross-Presentation a. Initiation of CD8+ T Cell Responses: Cross-presentation is critical for initiating CD8+ T cell responses against viruses that infect cells other than APCs and against tumors that do not directly affect dendritic cells. Without cross-presentation, many intracellular pathogens might evade detection by the immune system. b. Immune Surveillance: Cross-presentation helps in the early detection of viral infections and tumorigenesis by enabling the immune system to recognize and respond to antigens derived from infected or cancerous cells that might otherwise go unnoticed. 5. Dendritic Cells and Their Role in Cross-Presentation Dendritic cells are specialized APCs that are particularly adept at cross-presentation. There are different subsets of dendritic cells, but two main types are primarily involved in cross-presentation: a. Conventional Dendritic Cells (cDCs)  Subsets: cDC1 and cDC2 are the main subsets. ○ cDC1: Highly efficient at cross-presenting antigens on MHC I molecules. They express receptors and machinery (e.g., TLR3, TAP) that make them particularly suited for this task. ○ cDC2: More specialized in presenting antigens on MHC II molecules but can still contribute to cross-presentation. b. Plasmacytoid Dendritic Cells (pDCs) Role: While primarily known for producing large amounts of interferon-alpha (IFN-α) in response to viral infections, pDCs can also engage in cross-presentation under certain conditions. 6. Additional Factors Involved in Cross-Presentation a. Toll-like Receptors (TLRs) TLRs are pattern recognition receptors (PRRs) on dendritic cells that recognize pathogen-associated molecular patterns (PAMPs). Activation of TLRs by viral components enhances the ability of dendritic cells to perform cross-presentation by upregulating the necessary machinery and cytokine production. b. Cytokines Type I Interferons (IFN-α/β): These cytokines are produced during viral infections and enhance the cross-presentation capacity of dendritic cells. IL-12 and IL-15: These cytokines promote the activation and proliferation of CD8+ T cells following their priming through cross-presentation. c. Cross-Dressing A less common mechanism where dendritic cells acquire preformed MHC I-peptide complexes from other infected or dying cells and present them to CD8+ T cells. This process does not involve the processing of antigens by the dendritic cell itself but rather the transfer of existing complexes. 7. Clinical Relevance of Cross-Presentation a. Vaccine Development Many modern vaccines aim to enhance cross-presentation to generate strong CD8+ T cell responses, especially against intracellular pathogens like viruses and against cancers. b. Immunotherapy  Cancer immunotherapies, such as checkpoint inhibitors, often rely on the effective cross-presentation of tumor antigens to activate CD8+ T cells that can then target and destroy cancer cells. c. Autoimmunity Aberrant cross-presentation can lead to autoimmune responses if self-antigens are inappropriately presented to CD8+ T cells, resulting in the attack on healthy tissues. Cytoplasmic and Endosomal DAMPs DAMPs (Damage-Associated Molecular Patterns) are molecules released by stressed or damaged cells, and they are recognized by the immune system as signals of tissue damage. Role in Viral Recognition: DAMPs are not primarily involved in recognizing viral infections. They are more associated with detecting cell damage or stress rather than directly identifying viral components. 2. Extracellular TLR-2 TLR-2 (Toll-Like Receptor 2) is a pattern recognition receptor located on the surface of innate immune cells. It recognizes components of bacterial cell walls, such as lipoproteins, but also some viral envelope proteins. Role in Viral Recognition: While TLR-2 can recognize certain viral components, it is more commonly associated with recognizing bacterial infections. It is not the primary receptor for most viral recognition. 3. Cytoplasmic NOD-like Receptor NOD-like Receptors (NLRs) are a family of receptors located in the cytoplasm of immune cells. They typically recognize bacterial components, such as peptidoglycans, and activate inflammatory responses. Role in Viral Recognition: NLRs are more involved in detecting bacterial infections and intracellular pathogens. They are not the primary mechanism for viral recognition. 4. Endosomal TLR-3 TLR-3 (Toll-Like Receptor 3) is a pattern recognition receptor located within endosomes (intracellular compartments) of immune cells. TLR-3 specifically recognizes double-stranded RNA (dsRNA), a molecular pattern often associated with viral infections.  Role in Viral Recognition: TLR-3 plays a crucial role in recognizing viral infections, particularly those that involve RNA viruses. When a virus infects a cell, it can produce dsRNA during its replication cycle, which TLR-3 can detect, leading to the activation of an antiviral immune response. Complement System Overview The complement system is a group of proteins in the blood and other body fluids that enhances (complements) the ability of antibodies and phagocytic cells to clear pathogens. It plays a significant role in the defense against extracellular pathogens through: Opsonization: Coating pathogens with complement proteins to enhance phagocytosis by immune cells like macrophages and neutrophils. Lysis: Forming the membrane attack complex (MAC) that can directly lyse and kill certain pathogens, particularly Gram-negative bacteria. Inflammation: Promoting inflammation through the release of anaphylatoxins (e.g., C3a, C5a), which recruit and activate immune cells. Complement's Role with Intracellular Bacteria For intracellular bacteria, which can survive and replicate within host cells, the role of the complement system is more limited: 1. Before Entry into Host Cells: ○ Opsonization: Complement proteins can coat the surface of intracellular bacteria while they are still outside host cells, making them more susceptible to phagocytosis by immune cells. ○ Phagocytosis Enhancement: Once bacteria are opsonized, they can be more readily recognized and engulfed by phagocytic cells like macrophages. This is critical because macrophages can then destroy the bacteria within specialized compartments (phagosomes) or present their antigens to other immune cells. 2. After Entry into Host Cells: ○ Limited Direct Role: Once the bacteria are inside host cells, particularly within macrophages or other cells, the complement system has little direct access to them. The intracellular environment is beyond the reach of circulating complement proteins, which are primarily effective against pathogens in extracellular spaces. ○ Cell-Mediated Immunity: At this stage, the immune response relies more on cell-mediated immunity, particularly the actions of CD8+ cytotoxic T cells, which can recognize and kill infected host cells, and CD4+ T cells, which help activate macrophages to kill intracellular bacteria. 3. Immune Complex Formation:  ○ In some cases, intracellular bacteria may lead to the formation of immune complexes (antigen-antibody complexes) when they cause extracellular release of antigens. These complexes can activate the complement system, leading to inflammation and recruitment of immune cells to the site of infection. Summary Direct Role: The complement system is less effective against intracellular bacteria once they have entered host cells because it operates primarily in extracellular environments. Indirect Role: The complement system can still contribute to the initial immune response by opsonizing bacteria before they invade host cells, promoting their phagocytosis, and possibly contributing to immune complex formation. Main Defense: Once bacteria are intracellular, the immune system relies more on cell-mediated immunity, particularly the activation of macrophages and cytotoxic T cells, to control and eliminate the infectio Humoral immunity is a key component of the adaptive immune system, primarily involving the production of antibodies by B cells to neutralize and eliminate extracellular pathogens, such as bacteria and viruses, as well as toxins they produce. The term "humoral" refers to body fluids (historically called "humors"), where these antibodies circulate to protect the body. Key Components of Humoral Immunity 1. B Cells (B Lymphocytes): ○ Activation: B cells are activated when they encounter an antigen that binds specifically to their B cell receptor (BCR). This activation is usually aided by helper T cells (CD4+ T cells). ○ Differentiation: Once activated, B cells differentiate into plasma cells and memory B cells. Plasma Cells: These are the effector B cells that produce large quantities of antibodies specific to the antigen. Memory B Cells: These cells provide long-term immunity by "remembering" the specific antigen, allowing for a faster and more robust response if the antigen is encountered again. 2. Antibodies (Immunoglobulins): ○ Structure: Antibodies are Y-shaped proteins composed of two heavy chains and two light chains. The tips of the "Y" contain variable regions that bind specifically to antigens. ○ Functions: Neutralization: Antibodies can directly neutralize pathogens by binding to them and preventing them from entering or infecting host cells. Opsonization: Antibodies coat pathogens, making them easier for phagocytes (like macrophages and neutrophils) to recognize and engulf.  Complement Activation: Antibodies can activate the complement system, a group of proteins that enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells. 3. Antigen-Antibody Complexes: ○ When antibodies bind to antigens, they form antigen-antibody complexes. These complexes can facilitate the clearance of pathogens through various mechanisms, including phagocytosis and complement activation. 4. Types of Antibodies: ○ IgM: The first antibody produced in response to an infection. It is effective at agglutinating pathogens and activating the complement system. ○ IgG: The most abundant antibody in circulation, providing long-term protection and capable of crossing the placenta to protect the fetus. ○ IgA: Found in mucosal areas (e.g., gut, respiratory tract) and in secretions like saliva, tears, and breast milk, it protects against infections at mucosal surfaces. ○ IgE: Involved in allergic reactions and protection against parasitic infections. ○ IgD: Functions mainly as a receptor on B cells during their development. Humoral Immune Response Process 1. Antigen Encounter: When a pathogen enters the body, its antigens are recognized by B cells with matching BCRs. 2. B Cell Activation: The antigen binds to the BCR, and the B cell processes and presents the antigen on MHC II molecules to helper T cells. Helper T cells then provide necessary signals (e.g., cytokines) that fully activate the B cell. 3. Clonal Expansion: The activated B cell proliferates, producing a clone of cells that all recognize the same antigen. 4. Differentiation into Plasma Cells: Most of these B cells become plasma cells, which produce and secrete large quantities of antibodies specific to the antigen. 5. Antibody Function: The antibodies circulate in the blood and lymphatic fluid, where they bind to the pathogen, neutralize it, and mark it for destruction. 6. Memory B Cells: A subset of B cells becomes memory B cells, which remain in the body for years or even a lifetime, ready to mount a rapid response if the same antigen is encountered again. Importance of Humoral Immunity Protection Against Extracellular Pathogens: Humoral immunity is especially effective against pathogens that are free in the blood or extracellular spaces, such as bacteria, viruses (before they infect cells), and toxins. Vaccination: Many vaccines work by stimulating humoral immunity, leading to the production of memory B cells and antibodies that can quickly respond to future infections.  Long-Term Immunity: The production of memory B cells ensures that the body can respond more efficiently to repeat exposures to the same pathogen, often preventing reinfection or reducing its severity. Clinical Relevance Immunodeficiencies: Individuals with defects in B cells or antibody production (e.g., X-linked agammaglobulinemia) are particularly susceptible to infections by extracellular pathogens. Autoimmune Diseases: In some cases, humoral immunity can become dysregulated, leading to the production of autoantibodies that target the body’s own tissues, resulting in autoimmune diseases such as systemic lupus erythematosus (SLE). Obligate intracellular" refers to organisms, typically pathogens like certain bacteria, viruses, and protozoa, that must live and replicate within the cells of a host to survive and reproduce. These organisms are dependent on the host cell's machinery for critical processes like energy production, reproduction, or acquiring nutrients, as they often lack the necessary components to carry out these functions independently. Examples of Obligate Intracellular Pathogens: Viruses: All viruses are obligate intracellular because they rely entirely on the host cell's machinery to replicate and produce new viral particles. Certain Bacteria: Examples include Chlamydia and Rickettsia species, which must live inside host cells to reproduce. Protozoa: Plasmodium (the causative agent of malaria) and Toxoplasma gondii are examples of obligate intracellular protozoa.