Immune System Chapter 1 Overview

The Immune System: An Overview

• The immune system provides constant surveillance of the human body, maintaining a balanced state of health by effectively eliminating infectious agents and controlling malignancies.
• The immune system has evolved to interact with the environment to protect against harmful invaders, while also tolerating the naturally occurring microbiome.
• The chief function of the immune system is to discriminate between self and non-self.

Innate and Adaptive Immunity

• The immune system is divided into two major functional categories: innate and adaptive immunity.
• Innate immunity provides the first line of defense against infectious diseases, with mechanisms that exist from birth and include physical and biochemical barriers.
• Innate immune components are particularly powerful at limiting infections, but once an infection is established, adaptive immunity is required to combat the specific organism.
• Adaptive immunity is responsible for specific recognition of foreign antigenic substances, with lymphocytes recognizing unique shapes associated with foreign antigens.

Key Elements of Innate and Acquired Immune Responses

• Innate immunity:
  • Rapid response (minutes to hours)
  • Polymorphonuclear leukocytes and phagocytes
  • Preformed effectors with limited variability
  • Pattern recognition molecules
  • Soluble activators
  • Proinflammatory mediators
  • Nonspecific
  • No memory, no increase in response to secondary exposure
• Adaptive immunity:
  • Slow response (days to weeks)
  • B cells and T cells
  • Highly selective specificities to foreign agents
  • Memory, maturation of secondary response to re-exposure

Anatomy of the Immune System

• The immune system is a network of protective barriers, organs, cells, and molecules.
• Primary lymphoid organs (e.g., bone marrow, thymus) are sites where lymphoid cells are generated and differentiate.
• Secondary lymphoid organs (e.g., spleen, lymph nodes) are sites where antigen-driven proliferation and maturation of lymphocytes occur.
• Lymphoid organs are connected via the lymphatic system, which allows for the circulation of lymphocytes and antigens.

Cells of the Immune System

• Leukocytes are white blood cells that play a functional role in either innate or adaptive responses.
• Myeloid cells:
  • Include neutrophils, monocytes, macrophages, and dendritic cells
  • Involved in innate immunity and provide immediate protection against pathogens
• Lymphoid cells:
  • Include B lymphocytes, T lymphocytes, NKT cells, and NK cells
  • Involved in adaptive immunity and provide specific recognition of foreign antigens

Myeloid Cells

• Neutrophils:
  • Highly adherent, motile, and phagocytic
  • First cells recruited to acute inflammatory sites
  • Engulf and devour pathogens using granular enzymes and toxic molecules
• Eosinophils:
  • Specialized molecules stored as granules
  • Defend against large multicellular parasites
• Basophils and mast cells:
  • Produce cytokines that help defend against parasites
  • Involved in allergic inflammation### Immune System Components
• Basophils and mast cells have surface receptors for specific antibodies, releasing histamine and vascular mediators when cell-bound antibodies recognize allergens
• Macrophages are involved in phagocytosis and intracellular killing of microorganisms, and can reside in tissues for long periods
• Macrophages are highly adherent, motile, and phagocytic, and regulate other immune cells, such as T lymphocytes
• There are different subsets of macrophages, including M1 and M2, which secrete different mediators and are involved in different functions, such as bacterial control and wound healing

Dendritic Cells (DCs)

• DCs provide a critical link between innate and adaptive immunity by interacting with T cells
• DCs originate from cell precursors and have a unique function in delivering strong signals for the development of memory responses
• DCs recognize foreign agents through specific receptors and have the ability to guide the specificity and magnitude of subsequent immune responses

Antigen Presentation

• Macrophages and DCs are known as antigen-presenting cells (APCs)
• APCs destroy pathogens and then present pieces of the pathogen to T lymphocytes, mediating a connection with the adaptive immune response
• The pathogen is digested inside the presenting cell, and small fragments are shown on the cell surface for recognition by adaptive lymphocytes

Lymphocytes

• Lymphoid cells provide efficient, specific, and long-lasting immunity against microbes and pathogens
• Lymphocytes respond to infectious invasion only after myeloid cells have begun their work
• B lymphocytes secrete antibodies, while T lymphocytes operate in a supervising role to mediate cellular and humoral immunity
• Natural Killer (NK) cells are critical in defense against viral agents

Antigen Receptors

• The B-cell antigen receptor is the surface immunoglobulin, which has unique regions to bind specific antigenic shapes
• B-cell activation occurs when the receptor encounters the antigen, leading to a morphological change and the production of antibodies
• T lymphocytes have a surface receptor, the T-cell receptor (TCR), which is structurally similar to the antibody and recognizes specific pieces of the antigen

Cluster of Differentiation (CD)

• The CD designation refers to proteins found on the surface of cells
• Each unique surface molecule is assigned a different number, allowing cell phenotypes to be identified
• CD molecules may be specific for just one cell or cell lineage, or they may not

Inflammatory Response

• The inflammatory response is the coordinated effort of cells and blood components to elicit a response to infection
• Innate immune mechanisms provide the first line of defense against infectious disease
• The inflammatory response is triggered by the detection of microorganisms, leading to a signaling cascade and the activation of cell types that are adept at controlling infection

Cardinal Signs of Inflammation

• Redness occurs due to changes in localized blood flow (vasodilation)
• Swelling comes from the influx of fluid and cells from blood vessels to tissue
• Heat is caused by increased blood arriving to areas of damage
• Pain results from edema (fluid accumulation), which increases pressure on local nerves surrounding the damaged site

Initiation of the Inflammatory Response

• The skin provides an effective mechanical barrier against microorganisms
• Breach of the inflammatory barrier triggers an immediate cascade
• Release of lipids from cellular membranes leads to the production of signaling molecules, which exert effects on blood vessels
• Breakdown of cell membranes produces arachidonic acid, which has effects on cyclooxygenase and lipoxygenase activity, producing prostaglandins and leukotrienes### Pathogen Recognition and Cytokine Signaling
• Phagocytes have unique receptors that recognize microbial components, bind bacterial carbohydrates, and induce phagocytosis
• Recognition occurs through:
  • Mannose receptors
  • Scavenger receptors
  • Toll-like receptors (TLRs)
  • Pathogen-associated molecular patterns (PAMPs)
• Recognition triggers a proinflammatory response, activating gene regulation and releasing cytokines

Cytokines

• Small chemical mediators that allow cells to communicate with each other
• Regulate development and behavior of immune effector cells
• Facilitate cross-talk at low concentrations (10^-10 to 10^-15 M)
• Short-lived and bind to cell surface receptors
• May act alone or in concert with one another synergistically
• Exert multiple actions on multiple different cell types, with overlapping and redundant functions
• Also known as lymphokines, produced by cells of the lymphoid lineage
• Some cytokines function as growth factors for specific cell subsets

Danger-Associated Molecular Patterns (DAMPs)

• Subset of molecules that can trigger an immune response
• Released from injured tissue, includes components from the nucleus, cytosol, and mitochondria
• Jump-start an immune response in the absence of PAMPs

Feedback and Adaptation

• Cell-to-cell contact allows for direct delivery of cytokines and mediators
• Enables functional lymphocyte development in the immediate area
• Systemic communication via cytokines and chemokines directs cells and organs to respond to tissue damage

Chemokines

• Special subclass of chemical mediators that attract cells to the area of inflammation
• Assist in leukocyte migration into tissue (diapedesis)
• Synthesized by a wide variety of cell types

Inflammatory Response

• Initiation of the proinflammatory response is extremely potent to limit the spread of microorganisms
• Full clearance of the infectious agent typically requires adaptive immune components
• The inflammatory response culminates in the draining of fluid, cells, and antigens to local lymph nodes

B Lymphocytes and Antibodies

• B lymphocytes produce antibodies, which are responsible for humoral immunity
• Antibodies are glycoproteins consisting of two heavy chains and two light chains
• The structure of antibodies confers multiple cellular processes, mediated by variable and constant region domains
• Antibodies are capable of binding to a nearly limitless number of specific antigens

Antibody Structure

• Consists of two heavy chains and two light chains
• Held together by interchain disulfide bonds
• Enzymatic cleavage of the disulfide bonds results in two fragments: Fc and Fab2
• The Fab2 portion is responsible for antigen binding, while the Fc region confers specific biological properties

Immunoglobulin Isotypes

• Five unique heavy chains are defined by differences in amino acid sequences
• Labeled according to Greek letter designations: alpha, gamma, mu, epsilon, and delta
• Each heavy chain pairs with one of two light chains (kappa or lambda) to form a specific antibody isotype
• Properties of each isotype are summarized in Table 3.1

Development and Selection of Mature B Cells

• B-cell development involves V(D)J recombination of heavy-chain genes
• Successful rearrangement results in a pre-B receptor, which inhibits further rearrangement of heavy-chain genes
• Immature B cells are tested for autoreactivity, and cells that react with self-antigens are removed from the cell repertoire
• Mature B cells that show no reactivity with self-antigens migrate to peripheral lymph tissues

Activation and Differentiation of B Cells

• Mature B cells in the periphery respond to antigen, which depends on the type of epitope recognized
• Signaling through nearby membrane receptors (CD19 and CD21) is required
• B cells specific for protein antigens require help from CD4+ T cells
• Interaction with T cells drives isotype switching, resulting in the generation of plasma cells
• Isotype switching is the process by which the antigen specificity of the antibody remains the same, but the heavy-chain gene locus is excised and replaced with another heavy-chain gene constant domain

How We Defend Against Infectious Agents

• The human host has a delicate balance between normal commensal flora and the ability to distinguish specific agents that are harmful to daily living
• The immune system balances responses to its normal microbiome with the need to control and eliminate infectious agents that cause disease
• Major immune defense mechanisms against pathogens include:
  • Physical barriers
  • Cellular recognition of pathogenic motifs
  • Adaptive responses directed towards specific foreign antigens