Introduction to Human Immune System

Overview of the Immune System

• Organs, tissues, cells, and molecules form the immune system.
• It protects against microorganisms, eliminates toxins, and destroys tumor cells by generating immune responses.

Immune Response Steps

• Threats are identified.
• An attack is initiated.
• Pathogens are eliminated.
• Mechanisms for future encounters are developed.
• The process takes up to 10 days.
• Chronic inflammation arises when the immune system targets its own tissues or when a pathogen persists.

Two Main Branches of the Immune System

• Innate immune response
  • Non-specific cells distinguish invaders from human cells, but not among different invaders.
  • Functions rapidly, within minutes to hours.
  • Causes fevers.
  • Lacks immunologic memory.
  • Chemical barriers include lysozyme in tears and low pH in the stomach.
  • Physical barriers include epithelium in the skin and gut, plus cilia in the airways.
• Adaptive immune response
  • Highly specific to each invader.
  • Cells possess receptors that differentiate pathogens by unique components, known as antigens.
  • Recognizes almost an infinite number of specific antigens.
  • Relies on cell priming or activation, which can take weeks.
  • Advantage of immunologic memory.
  • Activated cells undergo clonal expansion, proliferating greatly during subsequent encounters.
  • Most clonally expanded cells undergo clonal deletion and die after the pathogen is destroyed.
  • Some cells survive as memory cells, ready to expand if the pathogen reappears.

White Blood Cells (Leukocytes) and Hematopoiesis

• The immune system's soldiers consist of white blood cells.
• Hematopoiesis forms white blood cells, red blood cells, and platelets.
• Primarily occurs in bone marrow.
• Begins with a multi-potent hematopoietic stem cell capable of developing into varied cell types.
• Some cells become myeloid progenitor cells, and others become lymphoid progenitor cells.

Myeloid Progenitor Cells and Myeloid Cells

• Myeloid progenitor cells develop into myeloid cells:
  • Neutrophils
  • Eosinophils
  • Basophils
  • Mast cells
  • Dendritic cells
  • Macrophages
  • Monocytes
• All are part of the innate immune response.
• Present in blood and tissues.
• Neutrophils, eosinophils, and basophils are granulocytes because they contain granules in their cytoplasm.
• Neutrophils are also known as polymorphonuclear cells (PMNs) because their nuclei have multiple lobes.

Neutrophils

• Bone marrow produces many cells, especially neutrophils, during an immune response; these cells use phagocytosis to engulf pathogens within a phagosome.
• Neutrophils use the following to destroy pathogens:
  • Cytoplasmic granules
    • Cytoplasmic granules merge with the phagosome, creating a phagolysosome.
    • Granules contain molecules that lower the pH of the phagolysosome, killing roughly 2% of pathogens.
  • Oxidative burst
    • Neutrophils generate highly reactive oxygen species like hydrogen peroxide.
    • These molecules degrade proteins and nucleic acids inside phagolysosomes.

Eosinophils and Basophils

• Eosinophils and basophils are far less common compared to neutrophils.
• Both contain granules possessing histamine and other pro-inflammatory molecules.
• Eosinophils stain pink with eosin dye.
• Best known for combating large helminth parasites by releasing molecules that perforate their outer layers.
• Also involved in allergic reactions like atopic dermatitis and allergic rhinitis.
• Eosinophils degranulate, releasing enzymes and proteins that cause an inflammatory reaction.
• Basophils stain blue with hematoxylin dye.
• Basophils are non-phagocytic.
• They are important for initiating allergic responses.

Mast Cells, Monocytes, Macrophages, and Dendritic Cells

• Mast cells reside in tissues, not in the bloodstream.
• Mast cells closely resemble basophils.
• Mast cells are non-phagocytic and participate in allergic responses.
• Monocytes, macrophages, and dendritic cells are phagocytic.
• They engulf pathogens, present antigens, and secrete cytokines to attract other immune cells.
• Monocytes circulate in the blood.
• Some monocytes enter tissues and differentiate into macrophages, which remain there.
• Dendritic cells are the main antigen-presenting cells.
• Usually located at sites exposed to external antigens, such as the skin epithelium or gastrointestinal mucosa.

Dendritic Cells Role as Antigen Presenters

• Immature dendritic cells excel at phagocytosis.
• When a dendritic cell phagocytoses a pathogen, it matures.
• They break down the pathogen into short amino acid chains after destroying it.
• Dendritic cells travel through the lymph to the nearest lymph node.
• They perform antigen presentation, displaying amino acid chains (antigens) to T-cells.
• Antigen presentation connects the innate and adaptive immune systems.
• Presenting cells include:
  • Dendritic cells
  • Macrophages
  • Monocytes
• Dendritic cells are the best antigen presenters.
• The only cells residing where pathogens enter via epithelia (skin, gut, airways) and capable of moving from these tissues to lymph nodes where T-cells circulate.

T-Cells and Antigen Presentation

• Only T-cells with receptors that match the antigen's specific shape will activate.
• T-cells require antigen presentation on the major histocompatibility complex (MHC).
• The antigen-presenting cell loads the antigen onto an MHC molecule for display to T-cells.

Lymphocytes: B-Cells, T-Cells, and Natural Killer Cells

• Lymphocytes:
  • B-cells
  • T-cells
  • Natural killer cells
• B and T-cells are part of the adaptive immune response.
• Natural killer cells belong to the innate immune system.
• B-cells and natural killer cells mature in the bone marrow.
• Some lymphoid progenitor cells move to the thymus to develop into T-cells.
• All lymphocytes can move in and out of tissue and the bloodstream.
• Natural killer cells are large lymphocytes containing granules.
• Target cells infected with intracellular organisms (like viruses) and cancer cells.
• Natural killer cells release cytotoxic granules to kill target cells.
• Granules contain molecules that create pores in the target cell membrane and induce apoptosis.

B-Cells and Humoral Immunity

• B-cells possess a surface receptor that binds only to antigens of a specific shape.
• B-cells do not require antigen presentation on an MHC molecule; they can directly bind antigens.
• B-cells can internalize, degrade, and present antigens to T-cells.
• B-cells load the antigen onto an MHC molecule called MHCII and display it to T-cells.
• T-cell activation aids B-cell maturation into a plasma cell.
• Plasma cells secrete numerous antibodies or immunoglobulins.
• Antibodies share the same antigen specificity as their parent B-cell.
• Antibodies travel through the plasma, attaching to pathogens and marking them for destruction.
• This is humoral immunity, because antibodies are not bound to cells and float freely in the blood.

T-Cells and Cell-Mediated Immunity

• T-cells are the final lymphocyte type.
• T-cells handle cell-mediated immunity.
• T-cells are antigen-specific.
• They cannot secrete their antigen receptor.
• A naive T-cell can be activated or primed by antigen-presenting cells, most often dendritic cells, to become a mature T-cell.
• Main Types of T-Cells
  • CD4+ T-cells
    • Also known as helper cells.
    • Secrete cytokines, coordinating macrophages and B-cells.
    • Can only recognize antigens presented on an MHCII molecule.
  • CD8+ T-cells
    • Called cytotoxic T-cells.
    • Destroy target cells like natural killer cells.
    • CD8+ T-cells specifically kill cells presenting an antigen on an MHCI molecule.
    • Natural killer cells are less specific in their targets.

Complete Immune Response to a Bacterial Pathogen in the Lungs

• Inhaled bacteria bypass nose hairs and cilia in the airways to penetrate the lung epithelium.
• Bacteria multiply in lung tissue.
• Resident macrophages in the lung tissue ingest bacteria and release cytokines.
• Cytokines initiate inflammation by increasing blood vessel leakiness and attracting eosinophils, basophils, and mast cells.
• Amplification of inflammation occurs.
• Neutrophils enter the tissue from the blood to join the defense.
• Natural killer cells help eliminate infected cells if the pathogen is a virus.
• All of the above are components of the innate immune response.
• Immature dendritic cells under the epithelium digest pathogens and relocate from lung tissue to a nearby lymph node.
• They present processed antigen on an MHCII protein to a naive T-cell.
• The dendritic cell bridges the innate and adaptive immune responses.
• Bacteria may directly enter a lymph node without dendritic cell assistance if the infection spreads.
• In this case, B-cells might phagocytose the bacteria and present it to a naive CD4+ T-cell.
• Regardless, if the antigen fits the T-cell, the T-cell differentiates and undergoes clonal expansion.
• Differentiated CD4+ T-cells release cytokines, inducing B-cells to differentiate into plasma cells.
• Plasma cells secrete antibodies that will enter the lymph and bloodstream.
• Antibodies tag pathogens, facilitating phagocyte consumption.
• Some cytokines activate macrophages to eliminate ingested bacteria that the macrophage cannot kill alone.
• If a virus replicates within infected cells, CD8+ T-cells will kill infected cells expressing the viral antigen on MHCI.
• Most B and T-cells die off as the invading pathogen diminishes.
• A few become memory B and T-cells, remaining for potential future encounters.