Immunology I: Functions and Characteristics of the Immune System

Immunology Overview

• Immunology is a complex field that involves multiple functions, including protection from microbial pathogens, protection from foreign cells, detection of damaged tissue, and facilitation of regeneration or repair.
• The immune system has many components, including cells derived from the bone marrow, lymphatic tissues, and molecular signals and effectors.
• Immunology also deals with various disorders, such as allergy, autoimmune disease, acute and chronic inflammatory states, and bystander damage.

Immune Response

• The immune response involves recognizing foreign molecules, microbes, or cells, destroying them, and communicating between these two activities.
• The immune system has two major functional divisions: innate immunity (the "1st line of defense") and adaptive immunity (activated when innate defenses are breached).
• Innate immunity features cellular and molecular effectors that are less specific and genetically hard-wired, while adaptive immunity features highly specific and genetically changeable effectors.

Adaptive vs. Innate Immune Response

• Response time: Innate immunity responds within hours to days, while adaptive immunity responds within days to weeks.
• Memory: Adaptive immunity has memory, while innate immunity does not.
• Specificity: Adaptive immunity is highly specific, while innate immunity recognizes patterns.

Specificity - Adaptive Immunity

• Specificity involves recognition of a foreign molecule by high-affinity binding to a receptor.
• Receptors are generated by genetic recombination and can increase in affinity over time.
• Antigens are substances that can bind to a receptor, while immunogens are substances that can generate an adaptive immune response.
• Epitopes are the molecular entities that bind to a receptor, and haptens are substances that can bind to an antibody but cannot generate an immune response.

Hallmarks of Adaptive Immunity

• Diversity: The vertebrate immune system can recognize ~10^16 distinct antigens through a diverse set of recognition molecules (receptors) on immune cells.
• Clonal Selection Theory: Each lymphocyte bears a single type of receptor with a unique specificity, and receptor binding is required for cell activation.
• Memory: Exposure to an antigen increases the ability to respond to the same or closely related antigen following re-exposure, resulting in faster, larger, and qualitatively different secondary immune responses.

B Cell Receptor

• Naïve B cells express Ab on their surface, which can be activated to secrete Abs into the blood.
• B cell receptors have variable and constant regions, with the variable regions being "shuffled" and able to bind to antigen.
• Antigens can be bound by many different antibodies, recognizing different epitopes.

T Cell Receptor

• T cell receptors are structurally similar to the Fab portion of an Ab, with two chains (alpha and beta) each having a variable and constant region.
• T cell receptors are best at recognizing protein antigens and only recognize antigen through close communication with molecules on other cells (antigen presentation).
• T cell receptors are never secreted and always stay attached to the membrane.

Cells and Tissues of the Immune System

• Myeloid cells include granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages, and dendritic cells.
• Lymphoid cells include T cells, B cells, and NK cells.
• Primary lymphoid tissue includes the bone marrow and thymus, while secondary lymphoid tissue includes lymph nodes, spleen, and lymphoid organs.

Myeloid Progenitor Cells

• Monocytes/macrophages are phagocytic, present antigens to T cells, and produce soluble messengers that help orchestrate immune responses.
• Dendritic cells are resident in tissues, recognize infection, and transport antigens to lymphoid organs to present to T cells.
• Granulocytes (neutrophils, eosinophils, basophils) are involved in defense against infection and play a role in hypersensitivity responses.
• Mast cells reside in connective tissues, orchestrate hypersensitivity responses, and are important in mucosal immune responses.

Immune Response Overview

• The immune system has two major functional divisions: innate immunity and adaptive immunity.
• Innate immunity is the "1st line of defense" and features cellular and molecular effectors that are:
  • Less specific, recognizing a range of targets
  • Genetically "hard-wired", with cells and molecular effectors that don't change during the lifespan of the organism
• Adaptive immunity is activated when innate defenses are breached and features cellular and molecular effectors that are:
  • Highly specific, recognizing particular targets
  • Genetically "changeable", with cells and molecular effectors that change their germline DNA to produce unique receptors/effectors during the lifespan of the organism

Characteristics of Innate and Adaptive Immune Responses

• Response time: Innate immunity responds within hours to days, while adaptive immunity responds within days to weeks
• Memory: Adaptive immunity has memory, whereas innate immunity does not
• Specificity: Adaptive immunity is highly specific, recognizing particular targets, whereas innate immunity recognizes patterns
• Diversity: Adaptive immunity has an extremely large number of entities that can be recognized and neutralized/destroyed, whereas innate immunity has a limited repertoire

Adaptive Immunity

• Specificity: Recognition of a foreign molecule by high-affinity binding to a receptor
• Receptors are generated by genetic recombination (gene shuffling) of particular portions of the receptor
• Antigens: Substances that can bind to a receptor of the adaptive immune system, including B-cell and T-cell receptors
• Immunogens: Substances that can generate an adaptive immune response
• Epitopes: The molecular entity that binds to the receptor, with different antibody affinities
• Haptens: Substances that can bind to an antibody, but cannot generate an immune response

Hallmarks of Adaptive Immunity

• Diversity: The vertebrate immune system can recognize ~10^16 distinct antigens through randomly "shuffling" portions of genes for lymphocyte receptors and selecting receptors that are functional and do not recognize self
• Specificity: Each lymphocyte bears a single type of receptor with a unique specificity, and receptor binding is required for cell activation
• Clonal selection theory: Activated lymphocytes bear receptors of identical specificity as the parent cell, and those lymphocytes bearing receptors for self molecules are destroyed at an early stage

B-Cell Receptors

• Naïve B cells express Ab on their surface, where they are called B-cell receptors
• Once activated, B cells secrete Abs into the blood (aka immunoglobulins – Igs)
• B-cell receptors are composed of light chains and heavy chains, with variable and constant regions
• Variable regions are the portions that are "shuffled" and that can bind to antigen
• Some antigens can be bound by many different antibodies, recognizing different epitopes on the same antigen

T-Cell Receptors

• Structurally similar to the Fab portion of an Ab
• Composed of two chains: alpha and beta, with variable and constant regions
• Best at recognizing protein antigens
• T-cell receptors are never secreted, always staying attached to the membrane
• Recognize antigen by close communication with molecules on other cells, known as antigen presentation

Memory

• Exposure of the adaptive immune system to an antigen increases its ability to respond to the same or closely related antigen following re-exposure
• Secondary immune responses are generally faster, larger, and qualitatively different, involving relatively high-affinity B-cell receptors
• Memory can be explained by the clonal selection theory, where activated lymphocytes bear receptors of identical specificity as the parent cell

Hallmarks of Adaptive and Innate Immunity

• Self-limiting: Both adaptive and innate immune responses are transient, with tightly regulated and controlled immune responses
• Self/non-self discrimination: The immune system must distinguish self from non-self, with immune responses to self resulting in autoimmunity, and immunological unresponsiveness to self being tolerance

Cells and Tissues of the Immune System

• Myeloid cells: Include granulocytes, monocytes, macrophages, and dendritic cells
• Lymphoid cells: Include B cells, T cells, and natural killer cells
• Primary lymphoid tissue: Includes bone marrow and thymus, where lymphocytes are generated and mature
• Secondary lymphoid tissue: Includes lymph nodes, spleen, and MALT, where adaptive immune responses are initiated

Primary Lymphoid Organs

• Bone marrow: Where B cells and T cells are generated
• Thymus: Where T cells mature

Secondary Lymphoid Organs

• Lymph nodes: Collect extracellular fluid and return it to the blood, with antigen-trapping and B/T cell interactions
• Spleen: A "filter for blood" that collects blood-borne antigens, destroys aged RBCs, and produces large quantities of antibodies
• MALT: Includes gut- and bronchial-associated lymphoid tissues, which collect Ag from mucosal surfaces and have specialized lymphoid tissue at the body's "wet" surfaces