Junquiera 14 Immune System and Lymphoid Organs

Introduction to the Immune System & Lymphoid Organs

  • The immune system provides diverse and layered defenses against infectious agents, ranging from microscopic viruses and bacteria to multicellular parasites. These defenses include both innate (non-specific) and adaptive (specific) mechanisms, working cooperatively.

  • Histologically, the immune system is not a single organ but a diffuse network of specialized cells (leukocytes) and lymphoid tissues strategically located throughout the body, interconnected by the circulatory and lymphatic systems.

General Overview of the Immune System

  • A large, dynamic population of leukocytes (white blood cells) is present in virtually every tissue, constantly surveilling for threats. These cells are interconnected by the blood and lymphatic circulation, allowing for rapid communication and coordinated responses across the body.

  • The importance of immunity extends significantly into medical contexts, particularly concerning autoimmune diseases, where the immune system mistakenly targets self-components, and in areas like transplantation and cancer immunotherapy.

Types of Immunity
Innate Immunity

  • Encompasses the body's non-specific effector mechanisms, forming the first line of defense. It reacts rapidly (within minutes to hours) to common patterns found on pathogens but does not confer immunological memory.

  • Evolves earlier than adaptive defenses phylogenetically and developmentally.

  • Important innate immunity cells include: granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages, dendritic cells, and Natural Killer (NK) cells.

  • Mechanisms include:

    • Physical and Anatomical Barriers (e.g., intact skin, mucous membranes lining respiratory, gastrointestinal, and urogenital tracts; cilia in the respiratory tract; commensal microbiota that outcompete pathogens).

    • Cytokines and Chemokines: Small signaling proteins released by cells that coordinate immune responses, induce inflammation, and attract other immune cells to the site of infection.

    • Recognition of Pathogens: Achieved through Pattern Recognition Receptors (PRRs), such as Toll-like receptors (TLRs), which recognize highly conserved microbial components called Pathogen-Associated Molecular Patterns (PAMPs) (e.g., bacterial lipopolysaccharide (LPS), viral nucleic acids) and Damage-Associated Molecular Patterns (DAMPs) released from damaged host cells.

    • Natural Killer (NK) Cells: Lymphocyte-like cells that destroy virally infected cells and unhealthy host cells (e.g., tumor cells) by recognizing changes in MHC Class I expression or antibody-coated cells (ADCC).

    • Chemical Defenses, featuring:

      • Hydrochloric acid (HCl) in the stomach, which maintains a low pH (around 1.5-3.5) inhospitable to many microbes.

      • Defensins: Small cationic peptides produced by neutrophils and epithelial cells (e.g., Paneth cells in the gut) that disrupt bacterial and fungal cell walls/membranes, leading to lysis.

      • Lysozyme: An enzyme found in tears, saliva, and phagocytes, which hydrolyzes peptidoglycan components of bacterial cell walls, particularly gram-positive bacteria.

      • The Complement System: A complex cascade of plasma proteins that, when activated, enhances immune responses by opsonizing pathogens, directly lysing cells (Membrane Attack Complex - MAC), and attracting phagocytes.

      • Interferons (IFNs): Type I interferons (IFN-\alpha, IFN-\beta) are signaling proteins released by virally infected leukocytes and other cells that induce an antiviral state in neighboring uninfected cells, enhancing viral resistance.

Adaptive Immunity

  • Develops to target specific microbial invaders and is characterized by its specificity, diversity, and immunological memory. It relies primarily on lymphocytes (T and B cells) and Antigen-Presenting Cells (APCs).

  • Produces memory cells after an initial exposure, allowing for more rapid, robust, and effective responses upon subsequent encounters with the same pathogen.

  • Key locations of lymphocyte activation and maturation:

    • Primary Lymphoid Organs: Sites where lymphocytes develop and mature to become immunocompetent.

      • Thymus: Critical for the maturation and selection of T cells.

      • Bone Marrow: Site of origin for all leukocytes and the primary site for the maturation and selection of B cells.

    • Secondary Lymphoid Organs: Sites where mature, naive lymphocytes encounter antigens, become activated, proliferate, and differentiate into effector cells.

      • Lymph Nodes: Filter lymph.

      • Spleen: Filters blood.

      • Mucosa-Associated Lymphoid Tissue (MALT): Includes widespread lymphoid tissues in the digestive, respiratory, and urogenital systems, crucial for immune surveillance at mucosal surfaces.

Structure of the Immune System

Lymphoid Organs
Primary Lymphoid Organs

  • Bone Marrow: The soft tissue within bones responsible for hematopoiesis (the production of all blood cells, including all leukocytes). It is the primary site of B cell origin and their subsequent maturation, including crucial selection processes.

  • Thymus: A bilobed organ located in the mediastinum, superior to the heart. It is the exclusive site for T cell development and maturation, where progenitor T cells (thymocytes) undergo rigorous selection processes to ensure they can recognize self-MHC and are not self-reactive.

Secondary Lymphoid Organs

  • Lymph Nodes: Small (typically 1-25mm) encapsulated, bean-shaped organs strategically located along lymphatic vessels throughout the body. They function as filters for lymph, trapping antigens and enabling interactions between APCs, T cells, and B cells, which leads to the initiation of adaptive immune responses. They possess distinct cortical (B cell rich), paracortical (T cell rich), and medullary regions.

  • Spleen: The largest secondary lymphoid organ, located in the upper-left abdomen. It functions as a filter for blood, removing old or damaged erythrocytes (red pulp) and serving as a major site for initiating immune responses against blood-borne pathogens (white pulp). It also produces antibodies and hosts a significant reservoir of monocytes.

  • MALT (Mucosa-Associated Lymphoid Tissue): A diverse collection of unencapsulated lymphoid tissues found beneath the epithelial linings of the digestive, respiratory, and urogenital tracts. MALT includes specific structures such as tonsils (pharyngeal, palatine, lingual), Peyer patches (in the ileum of the small intestine), and the appendix. MALT is crucial for immune surveillance and mounting responses directly at mucosal surfaces, often involving the production of secretory IgA.

Innate Immunity in Detail

  • Physical Barriers: Beyond skin and mucous membranes, these include the flow of urine, tears, saliva, and the movement of cilia, all of which help physically remove pathogens. The commensal microbiome also acts as a biological barrier by competing with pathogens for resources and space.

  • Phagocytosis: A fundamental innate immune process carried out primarily by neutrophils and macrophages. It involves: chemotaxis (migration towards chemical signals from pathogens or damaged tissue), adherence (binding to pathogens, often enhanced by opsonins), ingestion (engulfment into a phagosome), and digestion (fusion with lysosomes to form a phagolysosome, where enzymes, reactive oxygen species, and reactive nitrogen species degrade the pathogen).

  • Cytokines and Chemokines: These signaling molecules mediate and regulate immune responses. Key pro-inflammatory cytokines include IL-1, TNF-\alpha, and IL-6, which induce systemic effects like fever and acute phase protein production. Chemokines are a subset of cytokines that act as chemoattractants, guiding immune cells to sites of inflammation or infection.

  • Special Cells:

    • Natural Killer (NK) Cells: A type of innate lymphoid cell that identifies and attacks virus-infected and tumor cells primarily by recognizing the absence of MHC Class I molecules (the "missing self" hypothesis) or by specific activating receptors. They induce apoptosis in target cells through the release of perforin (forms pores in the target cell membrane) and granzymes (induce apoptosis).

  • Antimicrobial Chemicals: In addition to HCl, defensins, lysozyme, complement, and interferons, other antimicrobial peptides (e.g., cathelicidins) and various enzymes (e.g., lactoferrin, transferrin which sequester iron) contribute to limiting microbial growth.

Adaptive Immunity in Detail

Key Components
Lymphocytes

  • B Cells: Lymphocytes identified by the presence of a B Cell Receptor (BCR) on their surface (a membrane-bound antibody molecule). Upon activation, generally involving specific antigen binding and help from T helper cells, B cells differentiate into plasma cells (antibody-secreting factories) and memory B cells.

  • T Cells: Lymphocytes that recognize antigens presented on Major Histocompatibility Complex (MHC) molecules by APCs. They include:

    • Helper T Cells (CD4+): Primarily recognize antigens on MHC Class II molecules and secrete cytokines that orchestrate and assist in the activation and differentiation of other immune cells, including B cells, cytotoxic T cells, and macrophages.

    • Cytotoxic T Cells (CD8+): Primarily recognize antigens on MHC Class I molecules and directly kill infected host cells or tumor cells.

    • Regulatory T Cells (Tregs): Essential for maintaining immune tolerance and suppressing excessive or self-reactive immune responses, thereby preventing autoimmune diseases.

  • Antigen-Presenting Cells (APCs): Specialized cells that capture, process, and present antigens to T cells. The most potent APCs are dendritic cells, but macrophages and B cells also function as APCs. They express high levels of MHC Class II molecules and co-stimulatory molecules necessary for T cell activation.

Antigen Presentation

  • MHC Class I Molecules: Found on the surface of all nucleated cells (except red blood cells). They primarily present endogenous peptides (peptides derived from proteins synthesized within the cell, often indicating viral infection or tumor presence) to CD8+ Cytotoxic T Cells.

  • MHC Class II Molecules: Primarily present on professional APCs (dendritic cells, macrophages, B cells). They display exogenous peptides (peptides derived from proteins taken up from the extracellular environment, such as by phagocytosis) to CD4+ Helper T Cells.

B Cells and Antibodies

  • Antibody Structure: Also known as immunoglobulins (Ig), antibodies are Y-shaped glycoproteins composed of four polypeptide chains: two identical heavy (H) chains and two identical light (L) chains, linked together by disulfide bonds. Each chain has a variable region (which forms the antigen-binding site, conferring specificity) and a constant region (which mediates effector functions).

  • Classes of Antibodies (Isotypes): Determined by differences in their heavy chain constant regions, each class has distinct functions and locations:

    • IgG: The most abundant antibody in serum (approx. \%75-80). It is the only antibody that can cross the placenta, providing passive immunity to fetuses. Functions include opsonization, neutralization of toxins and viruses, and activation of the classical complement pathway.

    • IgA: Found predominantly in secretions (saliva, tears, mucus, breast milk) as a dimer. It protects mucosal surfaces from pathogens by preventing adherence and colonization.

    • IgM: The first antibody produced during a primary immune response, typically found as a pentamer in serum and a monomer on B cell surfaces (as a BCR). It is highly effective in activating the classical complement pathway due to its multiple binding sites and is excellent at agglutination.

    • IgE: Present in very low concentrations in serum. Primarily involved in allergic reactions (by binding to mast cells and basophils, triggering histamine release upon antigen encounter) and defense against parasitic infections.

    • IgD: Primarily acts as a receptor on naive B cells (as a monomer), playing a role in B cell activation, though its exact functions are less well understood compared to other isotypes.

Mechanisms of Antibody Action

  • Neutralization: Antibodies bind directly to pathogens (e.g., viruses, bacteria) or their toxins, preventing them from adhering to host cells, entering cells, or exerting their toxic effects.

  • Agglutination: Antibodies, with their multiple binding sites, can cross-link multiple pathogen particles, clumping them together. This makes them easier targets for phagocytic cells to engulf and clear.

  • Opsonization: Antibodies (especially IgG), by coating the surface of pathogens, act as "tags." Phagocytic cells (such as macrophages and neutrophils) have Fc receptors that bind to the Fc (constant) region of the antibody, enhancing the efficiency of phagocytosis.

  • Complement Activation: Antigen-antibody complexes (especially involving IgM or IgG) can initiate the classical pathway of the complement system. This cascade leads to the formation of the Membrane Attack Complex (MAC), which directly lyses target cells, and also generates components that opsonize pathogens and recruit inflammatory cells.

  • Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): Antibodies can bind to target cells (e.g., infected cells, tumor cells). The Fc region of these antibodies is then recognized by Fc receptors on immune effector cells, such as NK cells, which subsequently kill the target cell.

Cellular Components of the Immune System

T Cells

  • T cell activation is a complex process requiring at least two signals: Signal 1 involves the specific binding of the T cell receptor (TCR) to an antigen-MHC complex on an APC. Signal 2 provides co-stimulation, typically through interaction between CD28 on the T cell and B7 molecules (CD80/CD86) on the APC. Without co-stimulation, T cells may become anergic (unresponsive).

  • Types of T cells and functions:

    • Helper T Cells (CD4+): Key orchestrators of adaptive immunity. Subtypes of helper T cells include:

      • Th1 cells: Primarily produce IFN-\gamma and IL-2, promoting cell-mediated immunity against intracellular pathogens and activating macrophages.

      • Th2 cells: Primarily produce IL-4, IL-5 and IL-13, promoting humoral immunity, B cell antibody production (especially IgE), and responses against helminth parasites and allergens.

      • Th17 cells: Primarily produce IL-17 and IL-22, crucial for defense against extracellular bacteria and fungi, also implicated in autoimmune diseases.

    • Cytotoxic T Cells (CD8+): Recognize and directly kill host cells that are infected with intracellular pathogens (e.g., viruses) or transformed into tumor cells. They achieve this primarily by releasing perforin and granzymes, which induce apoptosis in the target cell, or by engaging Fas/FasL pathways.

    • Regulatory T Cells (Tregs): Characterized by the expression of the transcription factor FoxP3. They play a critical role in maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammation by suppressing the activity of other immune cells through various mechanisms, including cytokine release (e.g., TGF-\beta, IL-10) and direct cell-cell contact.

B Cells

  • B Cells are activated through several mechanisms: T-dependent activation generally involves antigen binding to the BCR (Signal 1) and subsequent co-stimulation and cytokine help from activated T helper cells (CD4+). T-independent activation can occur for certain antigens (e.g., repeating polysaccharide units) that can directly activate B cells without T cell help.

  • Upon activation, B cells undergo clonal expansion (rapid proliferation) and differentiate into: plasma cells (short-lived, highly active antibody-secreting cells) and memory B cells (long-lived cells that can mount a faster and stronger response upon re-exposure to the same antigen). Further maturation includes isotype switching (changing the class of antibody produced) and somatic hypermutation leading to affinity maturation (producing antibodies with higher affinity for the antigen).

Thymus and T Cell Selection

  • T cell development in the thymus involves rigorous positive and negative selection processes, ensuring that mature T cells are both useful and safe:

    • Positive Selection: Occurs in the thymic cortex. Only thymocytes whose TCRs can weakly recognize and bind to self-MHC molecules (either Class I or Class II) presented by cortical thymic epithelial cells receive survival signals. Those that fail to bind undergo apoptosis, ensuring MHC restriction.

    • Negative Selection: Occurs primarily at the cortico-medullary junction. Thymocytes whose TCRs bind too strongly to self-peptide-MHC complexes presented by medullary thymic epithelial cells or dendritic cells undergo apoptosis. This eliminates potentially self-reactive T cells, ensuring self-tolerance. The AIRE (Autoimmune Regulator) gene is crucial in medullary thymic epithelial cells as it promotes the expression of many peripheral self-antigens, extending the repertoire of self-antigens for negative selection.

  • Unguided or incorrect (non-specific, high-affinity self-reactive) TCR binding ultimately leads to apoptosis, a process critical for preventing autoimmune conditions.

Lymph Nodes

Structure and Function

  • Lymph nodes are encapsulated with a distinct internal architecture:

    • Cortex: Contains lymphoid follicles, which are primarily B cell zones. Upon activation, B cells can form germinal centers within these follicles, sites of intense B cell proliferation, differentiation, isotype switching, and affinity maturation.

    • Paracortex: The region between the cortex and medulla, predominantly a T cell zone, housing many T cells and dendritic cells that migrate from tissues.

    • Medulla: Contains medullary cords (plasma cells, macrophages) and medullary sinuses (lymphatic channels).

  • High endothelial venules (HEVs), found in the paracortex, are specialized blood vessels with cuboidal endothelial cells that express specific adhesion molecules, allowing naive lymphocytes to extravasate (leave the bloodstream) and enter the lymph node.

  • Lymph flows into the node via afferent lymphatic vessels, percolates through the sinuses, interacts with antigen-presenting cells and lymphocytes, and exits via efferent lymphatic vessels. This filtration process efficiently traps antigens, facilitating the necessary interactions for B and T cell activation and the initiation of adaptive immune responses.

Spleen

  • The spleen consists of two main functional areas:

    • White Pulp: Rich in lymphocytes and organized around central arterioles. It contains periarteriolar lymphoid sheaths (PALS), which are T cell-rich zones, and lymphoid follicles (containing germinal centers), which are B cell-rich zones. The marginal zone surrounds the white pulp and contains specialized B cells and macrophages, serving as a critical area for antigen presentation and initial immune responses.

    • Red Pulp: Constitutes most of the splenic volume and is primarily involved in filtering blood. It contains numerous macrophages that remove old, damaged, or senescent erythrocytes, and stores platelets. The architecture of the red pulp, with its intricate network of sinusoids and splenic cords (of Billroth), allows for efficient blood filtration.

  • Stave cells are specific endothelial cells lining the splenic sinusoids in the red pulp. Their arrangement creates narrow slits through which blood cells must pass. Healthy, flexible red blood cells can navigate these slits, while old, rigid cells are trapped and subsequently phagocytosed by macrophages.

Clinical Applications

  • The study of the immune system has profound clinical implications:

    • Autoimmune Diseases: Occur when the immune system loses its ability to distinguish between self and non-self antigens, leading to an attack on the body's own tissues. Examples include Type 1 Diabetes (T cells attack pancreatic eta--cells), Rheumatoid Arthritis (immune attack on joints), Multiple Sclerosis (immune attack on myelin in the CNS), and Systemic Lupus Erythematosus (autoantibodies against various self-antigens). Mechanisms often involve molecular mimicry, genetic predisposition, and environmental triggers.

    • Immunocompromised Patients: Individuals with reduced or dysfunctional immune systems are highly susceptible to infections (opportunistic infections) and certain cancers. Causes include HIV/AIDS (attacking CD4+ T cells), chemotherapy (suppressing bone marrow activity), genetic immunodeficiencies (e.g., SCID), long-term use of immunosuppressants (e.g., for organ transplantation or autoimmune conditions), and severe malnutrition. Management often involves prophylactic antibiotics, immunoglobulin therapy, or hematopoietic stem cell transplantation.

    • Vaccination: A cornerstone of preventive medicine, relying on the principle of adaptive immune memory. Vaccines introduce inactivated pathogens, attenuated live pathogens, or specific pathogen components to induce a primary immune response, generating memory cells without causing disease, thus providing protection against future infections.

    • Transplantation Immunology: Involves understanding and managing immune responses to transplanted organs or tissues, as the recipient's immune system may recognize the graft as foreign, leading to rejection. Immunosuppressive drugs are used to prevent this, but they also increase the risk of infection and cancer.

Conclusion

  • A comprehensive understanding of the immune system's intricate structure and sophisticated functionality allows for deep insight into disease mechanisms, the development of diagnostic tools, and the design of novel therapeutic approaches. The coordinated action of immune cells and lymphoid organs forms a complex and dynamic network critical for the body’s defense systems, constantly adapting to protect against a myriad of threats.