The Immune System

The Anatomy of the Immune System

• A fundamental difference between the immune system and other body systems: many of the cells involved in the immune response are highly motile.
  • They use the blood vessels and lymphatic vessels to move into and out of organized lymphoid tissue and to reach the site of an infection.

Location and Development of Immune Cells

• The skin and mucosal outer surfaces provide a first line of defense.
• All immune cells are generated from multipotent hematopoietic stem cells in the bone marrow.
• Immune cells mature within the bone marrow and are released into the blood circulation to enter tissues.
• Cells of the innate response are found throughout the body:
  • Macrophages
  • Mast cells in connective and mucosal tissues
  • NK cells in many locations
  • Neutrophils recruited to sites of infection
• Lymphocytes of the adaptive immunity:
  • B-cells become fully mature within the bone marrow.
  • T-cells must travel from the bone marrow to the thymus to reach full maturity.
• The bone marrow and thymus are the primary lymphoid tissues.
• Figure 6.1 (reference to primary vs. secondary lymphoid tissue organization).

The Skin Immune System

• The skin provides a strong physical barrier via keratinocytes.

• Keratinocytes express recognition receptors, including:

  • Toll-like receptors (TLRs)
  • NOD-like receptors (NLRs)
  • RIG-I-like receptors
  • C-type lectins

• These receptors trigger keratinocytes to produce microbicidal compounds such as:

  • β-defensins
  • Cytokines

• The epidermis contains resident Langerhans cells and both αβ and γδ T-cells.

• Langerhans cells can promote Th17 responses against extracellular pathogens.

• The underlying dermis contains dendritic cells, macrophages, T-cells (αβ and γδ), NK cells, and mast cells.

• There is continuous migration of leukocytes into the dermis from blood vessels.

• See Figure 6.2 for structural context.

Lymphatic Organs: Primary and Secondary

• Primary lymphatic organs:
  • Red bone marrow
  • Thymus
  • Site where T and B cells become immunocompetent (able to recognize and respond to antigens)
• Secondary lymphatic organs:
  • Lymph nodes
  • Tonsils
  • Spleen
  • Immunocompetent cells populate these tissues

Red Bone Marrow

• Involved in hematopoiesis and immunity.
• Structure: soft, loosely organized, highly vascular material.
• As blood cells mature, they move through reticular and endothelial cells to enter sinusoids and flow away in the bloodstream.
• Sinusoids drain into veins, leaving bone.

Bone Marrow: Antibody Synthesis and Plasma Cells

• Major site of antibody synthesis.
• B-cells mature in the bone marrow from hematopoietic stem cells.
• The generation of antibody responses is maintained by bone marrow dendritic cells secreting a cytokine (unspecified in the transcript).
• The bone marrow is the major residence of long-lived plasma cells.

Mucosal Immunity

• Most pathogens enter via mucosal surfaces (ingestion, inhalation, sexual transmission).
• The gastrointestinal, respiratory, and genitourinary tracts are guarded by immune cells present in the lamina propria (connective tissue).
• Many lymphocytes are organized into mucosa-associated lymphoid tissue (MALT) with well-formed follicles.
• Figure 6.4 (reference).

Mucosal Immunity: MALT and Inductive Structures

• In humans, MALT includes:
  • Lingual, palatine, and pharyngeal tonsils
  • Peyer’s patches of the small intestine
  • Appendix
• M cells are specialized antigen-transporting cells with short, irregular microvilli on their apical surface.
• M cells endocytose antigens, which are carried to the basal surface where they are exocytosed to lymphocytes, dendritic cells, and macrophages.

Tonsils

• Guard against ingested or inhaled pathogens.
• Covered with epithelium.
• Have deep pits called tonsillar crypts lined with lymphatic nodules.
• Part of MALT (mucosa-associated lymphoid tissue).
• Clinical note: tonsillitis and tonsillectomy.

Thymus

• Bilobed organ that undergoes involution with age.
• Structure includes cortex and medulla populated by T lymphocytes (thymocytes).
• Dendritic cells, macrophages, and epithelial cells populate the thymic lobules.
• T cells mature here; arrival at the medulla via blood; migrate to cortex; move to blood-exposed medulla for maturation.
• After ~$3\ weeks$, blood carries T-cells away from the medulla.
• Fibrous capsule forms trabeculae (septa) that divide the gland into lobes.

Lymph Nodes

• Very numerous: about $450$ in a young adult.
• Functions:
  • Cleanse the lymph
  • Act as a site of T and B cell activation
• Anatomy:
  • Divided into cortex and medulla
  • Follicle (nodule) with germinal centers contains B cells that differentiate into plasma cells
  • Resident macrophages line subcapsular and medullary sinuses and engulf larger antigens
• Clinical notes:
  • Lymphadenitis: swollen, painful node in response to foreign antigen
  • Lymphadenopathy: collective term for all lymph node diseases
  • Metastasis: cancer cells from a primary tumor lodge in nearby lymph nodes

Peyer’s Patches (Gut-Associated Lymphoid Tissue)

• Part of MALT; clusters of lymphoid follicles in the wall of the distal small intestine and appendix.
• Structure includes lymphoid nodules and crypts.

Peyer’s Patches: Induction of Immune Responses in the Gut

• Pathogen uptake by M-cells activates lymphocytes.
• Activated lymphocytes travel via lymph to mesenteric lymph nodes where further activation and proliferation may occur.
• Activated T-cells assist IgA-forming B-cells and plasma cells.

Spleen

• Largest lymphatic organ.
• Two types of tissue:
  • Red pulp: sinuses filled with erythrocytes
  • White pulp: lymphocytes and macrophages
• Macrophages remove aged blood, bacteria, and debris; recycle components such as iron and hemoglobin.

Organized Lymphoid Tissue and Immune Communication

• Immunological communication between organized lymphoid tissues and the rest of the body is maintained by a pool of recirculating lymphocytes.

Immunity: Three Lines of Defense

• First line of defense: skin and mucous membranes.
• Second line of defense: innate defense mechanisms
  • Leukocytes and macrophages
  • Antimicrobial proteins
  • Natural killer (NK) cells
  • Inflammation and fever
• Third line of defense: adaptive immunity, specific
  • Defeats a pathogen and leaves the body with memory to respond faster in the future.

Interaction Map: Immunity Pathways (Overview)

• External environment ↔ Skin & Membranes ↔ Innate immunity mechanisms
• Innate defense activates Adaptive immunity via sentinel cells (e.g., dendritic cells)
• Cytokine/chemokine signaling facilitates interplay between innate and adaptive immunity
• Pathogens trigger a progression from physical and physiological barriers to antibody- and cell-based pathogen destruction
• Key pathway nodes include:
  • Physical barriers
  • Physiological barriers (pH, antimicrobial enzymes, etc.)
  • Macrophage activation
  • Cytokine/chemokine signaling
  • Complement system
  • B-cell activation and antibody production
  • T-cell activation and cytotoxic activity

Lymphatic Cells and Their Roles

• Neutrophils: phagocytic cells involved in early defense.
• Lymphocytes (B cells and T cells): mature in the respective primary organs and mount highly specific immune responses to antigens.
• Natural Killer (NK) cells: large lymphocytes that kill bacteria, virus-infected host cells, and cancerous cells.
  • Release perforin to form pores in targets.
  • Release granzymes to reprogram cells for apoptosis.

Lymphatic Cells: Macrophages, Dendritic Cells, and Reticular Cells

• Macrophages:
  • Phagocytic cells that develop from monocytes.
  • Antigen-presenting cells (APCs) displaying antigenic fragments to T cells.
• Dendritic cells:
  • Highly branched and mobile; concentrated in the epidermis and mucous membranes.
  • Phagocytose pathogens and function as another APC.
• Reticular cells:
  • Branched stationary cells; contribute to the stroma of a lymphatic organ

Lymphatic Tissues

• Diffuse lymphoid tissue: simplest form; reticular connective tissue with lymphocytes and macrophages found in all organs.
• Most abundant in body passages open to the exterior (MALT) and Peyer’s patches of the ileum.
• Lymphatic nodules (follicles): masses of lymphocytes and macrophages.
• These tissues come and go with infection; some are more permanent and form lymph nodes.