The Innate and Adaptive Immune Response

Immune System Overview

• The immune system comprises organs, cells, and molecules which work to protect against microorganisms, like viruses and bacteria, by generating an immune response
• It has two main branches: the innate and adaptive immune responses

Innate Immune Response

• Cells involved are non-specific, distinguishing invaders generally from human cells
• Responses are rapid
• There is no immunological memory
• The response to a pathogen is identical each time

Adaptive Immune Response

• This response is specific to viruses and bacteria
• Cells use receptors to differentiate pathogens by their unique antigens to recognize an infinite number of specific antigens and mount specific responses against each
• It relies on cell activation to differentiate into the appropriate type of fighter to kill a pathogen
• Activation can take a few weeks
• There is immunological memory
• Subsequent exposures elicit stronger, faster responses

White Blood Cells

• There are two types of white blood cells: myeloid cells and lymphocytes
• Myeloid cells are a part of the Innate response; they include basophils, eosinophils, neutrophils, and macrophages (monocytes)
• Phagocytic cells bind to pathogens, internalize them in a phagosome, which fuses with lysosomes to destroy the pathogen
• Neutrophils, macrophages, and dendritic cells are phagocytic and release cytokines

Neutrophils

• Neutrophils primary job is to ingest pathogens, known as phagocytosis, and destroy them
• During phagocytosis a pathogen is put in a Phagosome
• Neutrophils employ granules and oxidative bursts as methods of destruction
• Granules from the cytoplasm fuse with the phagosome to form a phagolysosome, lowering the pH inside and killing approximately 2% of pathogens
• Oxidative bursts involve the production of highly reactive oxygen species such as hydrogen peroxide, destroying proteins and nucleic acids within the phagolysosomes to eliminate the pathogen

Dendritic Cells

• Dendritic cells are derived from monocytes
• They ingest pathogens and present the antigens to other immune cells, primarily T cells, acting as antigen-presenting cells
• Found in sites in contact with external antigens, such as skin and GI mucosa
• Process: Phagocytose a pathogen, destroys it, breaks its protein into short antigens, moves to nearest lymph node and presents antigen to T cells, connecting to adaptive immune system
• Dendritic cells are the only cells that travel from skin/GI mucosa to lymph nodes, where T cells circulate

Antigen-Presenting Cells

• T cells can only recognize antigen if presented on a Major Histocompatibility Complex (MHC)
• Antigen-presenting cells load the antigen on an MHC molecule and display it to T cells, triggering binding if a T cells recognizes the antigen

Lymphocytes

• These include B cells, T cells, and natural killer cells
• B and T cells mediate the adaptive immune response
• Natural killer cells mediate the innate immune response
• Maturation Site
  • B cells and natural killercells mature in bone marrow
  • T cells mature in the thymus

Natural Killer Cells

• Target intracellular organisms, such as viruses, and tumor cells
• Natural killer cells kill cells via cytotoxic granules and apoptosis
• They release cytotoxic granules that punch holes in the target cell's membrane
• Release molecules that get inside the cell and cause the target cell to undergo apoptosis

B Cells

• Transform into plasma cells and make antibodies by locating a corresponding antigen and presenting it to a T cell, which triggers the transformation
• Antigen-presenting cells, presenting to T cells
• B cells are specific
• Receptors bind only to antigens that "match"
• Binds to antigen directly and does not need antigens to be presented on an MHC molecule
• Binds to an antigen on the surface of pathogen, internalizes antigen, degrades it, and loads it on an MHC molecule to present to T cells, leading to T cell activation and B-cell maturation into a plasma cell that secretes antibodies against that pathogen
• Antibodies have same antigen specificity as the B cell they come from
• Antibodies circulate in plasma and attach to pathogens, tagging them for destruction
• This process involves Humoral Immunity, where antibodies float freely in the blood

T Cells

• There are two types: T-helper cells, which assist other immune cells, and cytotoxic T cells, which kill pathogens
• T cells mature and work when antigen-presenting cells present antigens to them
• Mediates cell-mediated immunity
• It is also antigen-specific
• Naive T cells become Mature T cells by attaching to antigen-presenting cells (usually dendritic cells)
• Two main types of T cells: CD4 and CD8
  • CD4 = helper cells
  • CD8 = cytotoxic T cells
• CD4 cells recognize antigens presented on MHC II molecules and secrete cytokines to coordinate actions of the immune system
• CD8 recognize antigens presented on MHC 1 molecules and kill target cells that carry the specific antigen

Innate Immune Response to a Pathogen

• Bacteria encounters a macrophage*, ingests bacteria, and then releases cytokines
• Released Cytokines
  • Makes blood vessels leaky
  • Attract eosinophils, basophils, and mast cells to the area where the macrophage encountered the bacteria
• Neutrophils from the blood arrive, phagocytize the pathogens and destroy them
• Immature dendritic cells digest pathogens in tissues and travel to the lymph node, present the antigen on an MHC II protein to a naive T cell and it attaches

Adaptive Immune Response to a Pathogen

• Bacteria directly enter lymph nodes and encounter B cells
  • When it encounters a B-cell that is specific to that pathogen, the B cell phagocytose the bacteria and presents it to naive CD4+ T cell
• Viruses live in cytoplasm of the body, they are called host cells
  • Infected "host" cells express the antigen of the virus (that is in the cell) on an MHC I molecule, which the cytotoxic T cells recognize and attaches to it to kill the infected cell
• T cell undergoes differentiation and clonal expansion
  • CD4+ T cells turn around and make the presenting B cells change into plasma cells and secrete antibodies

MHC I and MHC II Molecules

• T cells can only bind antigens that are displayed on a Major Histocompatibility Complex (MHC) molecule and are found on the surface of a cell
• MHC molecules, also called human leukocyte antigens (HLA), ensure that T cells recognize and react to antigens

Location of MHC Molecules

• MHC class I molecules are on all nucleated cells in the body (except RBCs)
• MHC class II molecules are only on antigen presenting cells, like macrophages, dendritic cells, and B cells

MHC Class I Molecules

• Has an Alpha chain with three domains (alpha 1, alpha 2, and alpha 3)
• Transmembrane regions anchors the MHC class I molecule onto the cell surface and Beta-2-microglobulin chain links to the alpha chain
• This molecule present antigens to Cytotoxic T-Cells and Natural Killer Cells, which will then destroy the host cell and the pathogen within
• Peptide is displayed on the outside of the cell, allowing Cytotoxic T cells and Natural Killer Cells to attach to the antigen in the MHC I molecule.

MHC Class II Molecules

• Only found in Antigen-Presenting Cells that ingest an organism and put the antigen into the MHC Molecule
• They only present to T-helper cells (CD4+ cells)
• Has an alpha and beta chain, where both chains penetrate the cell membrane
• Groove binds larger peptides comprised of 14-20 amino acids

T-Cell Activation

• Helper T-cells and Cytotoxic T-cells express two groups of molecules on their cell surface, CD3 and either CD4 or CD8, respectively
• CD3 complex binds to the antigen in the MHC Molecule and the MHC Molecule itself, while CD4 or CD8 molecules also bind to the MHC Molecule to secure the interaction
• Cytotoxic T-cells (CD8+ T-cell) kills cells that are infected or have cancer
• Helper T-cells (CD4+ T-cell) helps B-cells turn into Plasma Cells

T Cell Activation

• Begins with naive T cells that get activated and differentiate into effector T cells
• Cytokines present around the cell determine the type of T cell it will become
• Structure includes the the CD3 complex (Antigen Binding Site and MHC Binding Site) and CD4/CD8 molecules

Activation of T Cells Requirements

• Requires 2 Signals
• T Cell Receptor binds the antigen (on the MHC complex)
  • A signal goes down the CD3 Complex AND CD4 or CD8 molecule
• Co-Stimulation
  • Ligand CD 28 on T cell binds with B7 molecule on the antigen-presenting cell
• CD28 structure on the surface of the T cell binds to B7, a structure on the antigen-presenting cell
• If a T cell binds to an antigen but CD28 does not happen, the T cell will NOT activate = Anergy

Immune Synapse

• T cell receptor is bound to antigen + CD4/CD8 bound to MHC + B7 is bound to CD 28 THE ABOVE T-CELL IS NEWLY ACTIVATED

Helper T-Cell Clonal Expansion

Is done through IL-2 (a cytokine) and the IL-2 Receptor. How?

• Activated T-helper cell starts making IL-2 and upregulates its IL-2 receptor and the alpha component of the IL-2 receptor
• Production: Activated T helper cell begins making lots of IL-2, which then bind to active T cells, causing autocrine stimulation. This in turn causes the Activated T-helper cell starts to rapidly undergo cell division (clonal expansion)