Immunology: Phagocytes and Natural Killer Cells

Phagocytes

• Macrophages are large, phagocytic cells that develop from monocytes.
  • Free macrophages wander through tissue spaces, e.g., alveolar macrophages in the lungs.
  • Fixed macrophages reside permanently in specific organs, e.g., Kupffer cells in the liver and microglia in the brain.
• Neutrophils become phagocytic when encountering infectious material in tissues

Natural Killer Cells

• Natural Killer (NK) cells are large granular lymphocytes that are NOT phagocytic.
• They target cells lacking "self" cell-surface receptors (MHC).
• NK cells directly contact target cells and induce:
  • Apoptosis (programmed cell death) in cancer and virus-infected cells.
  • Secretion of potent chemicals that enhance the inflammatory response.

Inflammation

• Inflammation is the tissue response to injury, clearing the area of pathogens, dead cells, and debris.
• It's triggered by:
  • Physical trauma
  • Intense heat
  • Irritating chemicals
  • Infection by bacteria, viruses, and fungi.
• Beneficial effects of inflammation:
  • Prevents the spread of damaging agents
  • Disposes of cell debris and pathogens
  • Alerts the adaptive immune system
  • Sets the stage for tissue repair

Inflammatory Response: Phagocyte Mobilization

• Leukocytosis: increased production and release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells.
• Margination: neutrophils adhere to the walls of capillaries in the inflamed area, facilitated by cell adhesion molecules (CAMs).
• Diapedesis/Emigration: neutrophils squeeze between capillary cells to enter the inflamed tissue.
• Chemotaxis: inflammatory chemicals (chemotactic agents) attract neutrophils to the site of injury.

Antimicrobial Proteins: Interferons

• Interferons (IFNs) are proteins released by virus-infected cells, activating neighboring cells to produce antiviral proteins, blocking viral reproduction.
• IFNs are non-specific and act against viruses.

Antimicrobial Proteins: Complement System

• Complement is a group of 20 plasma proteins (C1-C9, factors B, D, and P, plus regulatory proteins).
• Functions of the complement system:
  • Amplifies the inflammatory response
  • Promotes phagocytosis
  • Kills bacteria and certain cells through cell lysis (membrane attack complex)
  • Enhances both innate and adaptive defenses.

Fever

• Fever is a systemic response to invading microorganisms.
• Pyrogens (released from leukocytes and macrophages) reset the body's thermostat upward, causing a rise in body temperature.
• Benefits of moderate fever:
  • Sequesters iron and zinc (needed by microorganisms) in the liver and spleen.
  • Increases metabolic rate, speeding up tissue repair.

The Adaptive Immune System

• The adaptive immune system is a specific defense system with two arms:
  • Humoral immunity (antibody-mediated): Antibodies target extracellular antigens.
  • Cellular immunity (cell-mediated): T lymphocytes directly attack target cells.
• Functions of the adaptive immune system:
  • Protects against infectious agents and abnormal body cells.
  • Amplifies the inflammatory response.

T-Cell Maturation and Selection

• Positive selection: T cells capable of binding to self-MHC proteins are selected for survival.
• Negative selection: T cells binding to self-antigens displayed by MHC proteins undergo apoptosis, ensuring self-tolerance.

B-Cells

• B-cells mature in the red bone marrow.
• Self-reactive B cells:
  • Are eliminated by apoptosis (clonal deletion).
  • Undergo receptor editing (receptor rearrangement).
  • Are inactivated (anergy) if they escape the bone marrow.

Antigen-Presenting Cells (APCs)

• APCs engulf antigens and present fragments to T cells, activating naive T cells.
• Three major types of APCs:
  • Dendritic cells (in connective tissues and epidermis).
  • Macrophages (in connective tissues and lymphoid organs).
  • B cells (present antigens to T helper cells).

Humoral Immune Response

• Antigen challenge: The first encounter between an antigen and a naive immunocompetent lymphocyte, usually in the spleen or lymph node.
• B cell activation: When antigens bind to B cell surface receptors, the activated B cell clones itself.
  • Plasma cells: Produce antibodies.
  • Memory B cells: Remain for future encounters with the antigen.

Immunological Memory

• Primary immune response: Occurs upon first exposure to an antigen.
  • Lag period: 3-6 days.
  • Peak antibody levels: 10 days.
  • Antibody levels decline.
• Secondary immune response: Occurs upon re-exposure to the same antigen.
  • Response: Faster, more prolonged, and more effective.
  • Peak antibody levels: 2-3 days.

Humoral Immunity: Active vs. Passive

• Active humoral immunity: B cells encounter antigens and produce specific antibodies.
  • Naturally acquired: Response to an infection.
  • Artificially acquired: Response to a vaccine.
• Passive immunity: Protection from antibodies acquired from another source.
  • Naturally acquired: Antibodies transferred from mother to fetus (placenta) or infant (breast milk).
  • Artificially acquired: Injection of serum (e.g., gamma globulin).

Antibody Types

• Antibodies (immunoglobulins, Igs) are proteins secreted by B cells in response to antigen.
• Antibody functions:
  • Neutralization: Block the binding of antigens to cells.
  • Agglutination: Clump antigens together, making them easier to phagocytize.
  • Precipitation: Form complexes with soluble antigens that can be phagocytized.
  • Complement activation: triggers cell lysis; amplifies the inflammatory response, promotes opsonization (marking pathogens for phagocytosis).

Cellular Immune Response

• Cellular immunity consists of T lymphocytes that directly attack target cells or regulate the immune response.
• Two major types of T cells:
  • CD4 cells: Become helper T cells (TH) when activated.
  • CD8 cells: Become cytotoxic T cells (TC) when activated, destroying cells with foreign antigens.
• Other T cell types: Regulatory T cells (Treg) and memory T cells.

MHC Proteins and T-Cell Activation

• Major histocompatibility complex (MHC) proteins present antigens on the cell surface, alerting the immune system.
• Two types of MHC proteins:
  • Class I MHC: Found on all nucleated cells (except red blood cells).
  • Class II MHC: Found on APCs (dendritic cells, macrophages, and B cells).
• T-cell activation:
  • CD4 cells: Bind to MHC class II on APCs, becoming TH cells.
  • CD8 cells: Activated by antigen fragments linked to MHC class I on APCs, becoming TC cells.

Roles of Helper T (TH) and Cytotoxic T (TC) Cells

• TH cells:
  • Play a central role in the adaptive immune response.
  • Help activate T and B cells.
  • Induce T and B cell proliferation.
  • Activate macrophages and recruit other immune cells.
• TC cells:
  • Directly attack and kill other cells.
  • Circulate in blood, lymph, and lymphoid organs.
  • Target: Virus-infected cells, cells with intracellular bacteria or parasites, cancer cells, foreign cells (transfusions or transplants).

TC Cell and NK Cell Lethal Mechanism

• TC cells and NK cells release: perforins and granzymes by exocytosis.
  • Perforins: Create pores in target cells.
  • Granzymes: Enter through pores and stimulate apoptosis.

Regulatory T (Treg) Cells

• Suppress the immune response through direct contact or by secreting inhibitory cytokines (IL-10 and TGF-β).
• Important in preventing autoimmune reactions.