PAMPs, DAMPs, and Phagocyte Mobilization

PAMPs and DAMPs

• PAMPs are molecular structures that form patterns, including proteins and carbohydrates
• Patterns are conserved and found on microorganisms like bacteria, viruses, and fungi
• Innate immune cells use pathogen recognition receptors (PRRs) to recognize patterns
• Innate immune cells include macrophages, monocytes, neutrophils, NK cells, and dendritic cells
• Toll-Like Receptors (TLRs) are examples of PRRs
• PAMP-PRR binding triggers innate immunity responses like inflammation, fever, and phagocytosis

Phagocyte Mobilization

• A wound or infection causes an inflammatory reaction
• Inflammation is triggered at the infection site, leading to leukocytosis (leukocyte movement in blood vessels)
• Neutrophils cling to the blood vessel (capillary) wall through margination
• Margination makes the capillary leaky
• Neutrophils flatten and squeeze through capillary clefts, called diapedesis
• Neutrophils follow a chemical trail (chemotaxis) from the initial inflammatory process
• Neutrophils engulf pathogens and neutralize the infectious threat

Acute Inflammation Overview

• Tissue injury triggers the release of inflammatory chemicals and leukocytosis-inducing factors
• Arterioles dilate, increasing capillary permeability and causing local hyperemia
• Neutrophils, monocytes, and lymphocytes are drawn to the area via chemotaxis
• Leukocytosis causes increased white blood cells in the bloodstream
• Leukocytes migrate to the injured area and cling to capillary walls, known as margination
• Diapedesis occurs as leukocytes pass through capillary walls
• Fluid leaks from capillaries, forming exudate and causing local swelling
• Pain occurs
• Clotting proteins leak and wall off the area to prevent injury spread
• A fibrin patch forms for repair scaffolding
• Phagocytosis of pathogens and dead cells occurs
• Pus may form and is eventually cleared
• This process results in healing

Adaptive Defenses

• The adaptive immune system is a specific defensive system that eliminates pathogens or abnormal cells
• This system amplifies the inflammatory response and activates the complement system
• Must be primed by initial exposure to a foreign substance, which takes time

Characteristics of Adaptive Immunity

• Adaptive immunity is specific, recognizing and targeting specific antigens
• It is systemic, not restricted to the initial infection site
• It exhibits memory, launching a stronger attack on "known" (second or subsequent exposure) antigens

Two Main Branches of the Adaptive System

• Humoral (antibody-mediated) immunity
• Cellular (cell-mediated) immunity

Humoral Immunity (B cells)

• Antibodies are produced by lymphocytes to circulate freely in body fluids
• They temporarily bind to target cells to inactivate or mark them for destruction
• Humoral immunity has extracellular targets

Cellular Immunity (T cells)

• Lymphocytes act against target cells directly by killing infected cells
• They can act indirectly, by releasing chemicals to enhance inflammatory response
• Cellular immunity has cellular targets

Antigens

• Antigens are substances that mobilize adaptive defenses and provoke an immune response
• They are the targets of all adaptive immune responses
• Most are large, complex molecules not normally found in the body (nonself)

Characteristics of Antigens

• Can be a complete antigen or hapten (incomplete)
• Contain antigenic determinants (epitopes)
• Can be a self-antigen

Complete Antigens

• Have two important functional properties immunogenicity and reactivity
• they stimulate the proliferation of specific lymphocytes
• They react with activated lymphocytes and antibodies released by immunogenic reactions
• Examples include foreign proteins, polysaccharides, lipids, and nucleic acids
• Commonly found on foreign invaders such as pollen and microorganisms

Incomplete Antigens

• Also called haptens
• Involve small molecules, so they are not immunogenic by themselves
• Examples include peptides, nucleotides, and some hormones
• If a hapten attaches to the body's own proteins, it may become immunogenic
• The combination of protein and hapten is then seen as foreign
• The immune system attacks both the hapten and the body's own proteins
• Examples include poison ivy, animal dander, detergents, and cosmetics

Antigenic Determinants

• Parts of antigen that antibodies or lymphocyte receptors bind to
• Most naturally occurring antigens have numerous antigenic determinants
• These determinants mobilize different lymphocyte populations
• Form different kinds of antibodies against them
• Large, chemically simple molecules (plastics) have little or no immunogenicity

Self-Antigens: MHC Proteins

• All cells are covered with a variety of proteins
• These are not antigenic to self, but may be antigenic to others in transfusions or grafts
• MHC proteins are a group of glycoproteins
• Coded by genes of major histocompatibility complex (MHC) and unique to each individual
• MHC is a protein type on all cells that creates an individualized signature that is specific for each person
• They contain a groove that holds a piece of self-antigen or foreign antigen
• T lymphocytes can recognize only antigens presented on MHC proteins

Three Crucial Types of Cells

• Two types of lymphocytes: B and T lymphocytes
• Antigen-presenting cells (APCs)

Antigen-Presenting Cells (APCs)

• Do not respond to specific antigens
• Play essential auxiliary roles in immunity by introducing antigens to T cells to prompt learning
• Larger antigens can be presented to B cells
• B cells can act like APCs

Lymphocyte Origin

• Both B and T lymphocytes originate in red bone marrow

Lymphocyte Maturation

• Lymphocytes mature in primary lymphoid organs (bone marrow and thymus)
• Immunocompetence lymphocyte can recognize only one kind of antigen
• B and T cells display only one kind of receptor on surface
• Self-tolerance lymphocytes must be unresponsive to own antigens
• B cells mature in red bone marrow; the process of B cell maturation is not yet fully understood

Lymphocyte Seeding

• Immunocompetent B and T cells not exposed to an antigen are called naive.
• Naive lymphocytes are exported from primary lymphoid organs to "seed" secondary lymphoid organs
• Secondary lymphoid organs include (lymph nodes, spleen, etc.)
• This process increases chances of encountering antigen

Lymphocyte Antigen Encounter

• Naive lymphocyte's first encounter with an antigen triggers lymphocyte to develop further
• A lymphocyte is selected to differentiate into an active cell by binding to its specific antigen
• Referred to as clonal selection
• With the correct signals, lymphocytes will complete their differentiation into active cells
• The correct signals refer to genetic recombination needed for T and B cells to recognize an antigen

Lymphocyte Proliferation and Differentiation

• Once selected and activated, lymphocyte proliferates forming clones
• Most clones become effector cells that fight infections
• The remaining clones become memory cells that respond quickly the next time an antigen is encountered
• B and T memory cells and effector T cells circulate continuously

Antigen Receptor Diversity

• Genes, not antigens, determine which foreign substances the immune system will recognize
• Variety of immune cell receptors are result of acquired genetic knowledge of microbes
• Approximately 25,000 different genes code for up to a billion different types of lymphocyte antigen receptors
• Numerous receptors result in multiple combinations
• Gives rise to different T and B cell populations

Dendritic Cells

• Found in connective tissues and epidermis
• Act as boundary tissue mobile sentinels
• They phagocytize pathogens that enter tissues
• Dendritic cells enter lymphatics to present antigens to T cells in lymph node
• Most effective known antigen presenter
• They are the key link between innate and adaptive immunity

Macrophages

• Widely distributed in connective tissues and lymphoid organs
• Present antigens to T cells, which activates them
• Activated macrophages are voracious phagocytic killers that trigger powerful inflammatory responses and recruit additional defenses

B Lymphocytes

• Do not activate naive T cells
• Internalize the antigen and process it (into peptides) to make it part of the B cell membrane signature (MHC)
• This signature can be presented on the B cell MHC signature to T helper cells
• T helper cells help in their own activation (i.e., T cell activation)

Humoral Immune Response

• The B cell encounters a target antigen, it provokes a humoral immune response
• Antibodies specific for that particular antigen are then produced
• B cells are activated when antigens bind to surface receptors cross-linking them
• Receptor-mediated endocytosis of cross-linked antigen-receptor complexes results in proliferation and differentiation of the B cell into effector cells
• Most clone cells become plasma cells, antibody-secreting effector cells
• Antibodies secrete specific antibodies at 2000 molecules per second for 4 to 5 days and then die
• Antibodies circulate in blood or lymph, binding to free antigens, marking them for destruction by innate or other adaptive mechanisms

Clone Cells Become Memory Cells

• Provide immunological memory
• Mount an immediate response to future exposures of the same antigen

Primary Immune Response

• Involves cell proliferation and differentiation upon exposure to antigen for the first time
• The lag period lasts 3 to 6 days
• Peak levels of plasma antibody are reached in 10 days
• Then declines

Secondary Immune Response

• Re-exposure to antigen gives faster, more prolonged, more effective response
• Sensitized memory cells provide immunological memory
• Respond within hours, not days
• Antibody levels peak in 2 to 3 days at much higher levels
• Antibodies bind with greater affinity
• Antibody level can remain high for weeks to months

Antibodies Classes

• IgM is the first immunoglobulin class secreted by plasma cells during the primary response
• It readily fixes and activates complement
• It exists in monomer and pentamer forms
• The pentamer circulates in blood plasma
• IgA the dimer, referred to as secretory IgA, found in body secretions
• It helps stop pathogens from attaching to epithelial cell surfaces
• IgD found on the B cell surface that functions as a B cell antigen receptor
• IgG the most abundant antibody in plasma accounting for 75-85% of circulating antibodies
• It protects against bacteria, viruses, and toxins circulating in blood and lymph and crosses the placenta to confer passive immunity
• IgE stem end binds to mast cells or basophils and is secreted by plasma cells in the skin.
• Antigen binding triggers cells to release histamine and other inflammation chemicals
• Only traces of IgE are found in plasma

Antibody Targets and Functions

• Antibodies do not destroy antigens, they inactivate and tag them
• They form antigen-antibody (immune) complexes
• Defensive mechanisms include neutralization, agglutination, precipitation, and complement fixation

Antibody Action - Neutralization

• It is the simplest, most important defensive mechanism, where antibodies block specific sites on viruses or bacterial exotoxins
• This prevents antigens from binding to receptors on tissue cells
• Antigen-antibody complexes undergo phagocytosis

Antibody Action - Agglutination

• Antibodies can be directed to the same determinant on two different antigens at the same time
• The two-armed antibody has a variable region capable of binding to one antigen
• This allows for antigen-antibody complexes become cross-linked into large lattice like clumps
• This process is referred to as agglutination
• Clumping makes it easier for phagocytes to find and engulf pathogens
• This disables pathogens from action

Antibody Action - Precipitation

• Soluble molecules are cross-linked into complexes
• Complexes precipitate out of solution
• Precipitated complexes are easier for phagocytes to engulf

Antibody Action - Complement Fixation

• A primary antibody defense
• Several antibodies bound close together on same antigen
• This causes complement-binding sites on stem regions to become aligned
• This triggers complement fixation, cell lysis, and other complement functions such as inflammatory response amplification, opsonization