Microbio Module 7

Adaptive immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is the immunity that one develops throughout life.

Innate immunity refers to antigen-non-specific defense mechanisms that a host uses immediately or within several hours after exposure to almost any antigen. This is the immunity one is born with and is the initial response by the body to eliminate microbes.

Antigen: a substance that can interact with antibodies and antigen receptors on lymphocytes; or a portion of foreign object that is displayed on MHC-I or MCC-II.

Immunogen: An antigen recognized by the body as non-self and stimulates an adaptive immune response.

PAMP: “Pathogen-Associated Molecular Patterns”, are conserved microbial structures that are recognized by host cell pattern recognition receptors. This is used for innate immune response by cells such as phagocytes, and Natural Killer cells

B bacterial antagonism
I inflammation
P phagocytosis
A anatomical barriers
L leukocytes
M mechanical removal

F fever
C complement protein

Neutrophils, Basophils, Eosinophils, Monocytes, Lymphocytes

Neutrophils: The most abundant leukocytes (60%), important phagocytes, short lived, do not multiply.
Monocytes: (5%), important phagocytes, differentiate into macrophages when they leave the blood and enter the tissue.
Macrophages: Mature form of monocytes. Very important in phagocytosis and serve as APC in the adaptive immune responses. They produce cytokines that play numerous roles in body defense. (Several key functions: Kill microbes, infected cells, and tumour cells by phagocytosis).

Endocytic PRRs: Promotes phagocytosis
Signlaing PRRs: Promotes cytokine secretion

Cytokines: proteins produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune systems. Produced by all cells involved in innate and adaptive immunity, but especially by Th cells

Chemokines: Chemotactically attract leukocytes to sites of infection or injured cells.

Interferons (IFN): class of antiviral. Alpha, Beta and Gamma.
Alpha and Beta are produced by infected cells and stimulate non-infected cells to produce antiviral proteins (interfere viral replication)
Gamma is produced by lymphocytes and causes neutrophils to kill bacteria. Interferons induce uninfected cells to produce enzymes that degrade viral and cellular mRNA. This blocks viral protein synthesis, and kills the infected cell.

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. The cells involved in innate immune responses are designed to recognize a few highly conserved structures present in many different micro-organisms.

The major cells that make up the innate immune system are phagocytes (neutrophils, monocytes, macrophages) that release inflammatory mediators (basophils, mast cells, and eosinophils), and NK cells.

These cells recognize microbial structures called pathogen-associated molecular patterns (PAMPs) in order to activate the innate immune response.

Most defense cells have receptors for PAMPs so there is an immediate response against invading microbes.

PAMPs can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathway.

Smooth muscles around larger blood vessels contract.
Endothelial cells that make up the wall of the smaller blood vessels contract.
Diapedesis

Benefits of inflammation:
Plasma flows out of the blood into the tissue which contains clotting factors, antibodies, complement proteins, nutrients, lysozyme (kills microbes), and transferring (sequesters iron).

Leukocytes enter the tissue through diapedesis.

Fever is a beneficial systemic response because it increases the environmental temperature above the optimum growth temperature for many micro-organisms.

Acute Phase response is an innate body defense seen during acute illnesses and involves the increased production of blood proteins termed acute phase proteins.

+ve Acute Phase Proteins:C-reactive protein, Mannose-binding protein

-ve acute phase proteins: Albumin and Transferrin

Series of protein cascades that ultimately produce C3 convertase.

Purpose of CS is to carry out 6 beneficial innate defense functions:
Inflammation
Chemotaxis
Promote attachment of antigens to phagocytes
Cause lysis of G-ve bacteria
Activation of naive B-Lymphocytes
Remove harmful immune complexes from body


There are three pathways (Classical, Lectin and alternative).

The important complements are C3 and C5.
C3 is split into C3a and C3b by C3 convertase
C5 is split into C5a and C5b by C5 convertase

C3a stimulates inflammation
C3b enhances attachment to antigen
C5a is the most potent complement protein that triggers inflammation
C5b becomes a part of MAC (membrane attack complex which lyses G-ve bacteria and viruses)

The Classical Complement Pathway
Activated by antigen-antibody complexes

The Lectin Pathway
Activated by the interaction of microbial carbohydrates with mannose-binding proteins in the plasma and tissue fluids.

The Alternative Complement Pathway
Activated by C3b binding to microbial surfaces and to antibody molecules.

1. C3b enhances attachment of antigens to antibody (opsonisation)
2. Activates the alternative complement pathway by binding to the microbial surface and Antibody molecules

Antigen-specific defense mechanisms
Take several days to become protective and act on specific antigen.
Involves lymphocytes, and macrophages and the immunity develops throughout life.

Specificity – as a result of lymphocyte receptor repertoires
- Diversity – as a result of lymphocyte receptor repertoires
- Immunologic Memory – improves upon repeated exposure to a given infection.
- Discrimination of self and non-self - to prevent autoimmune tissue damage

Positive selection: During the development if T-lymphocytes bind weakly to MHC antigen they are allowed to survive.
Negative selection: Elimination of any self-reactive (strong attachment to MHC antigens) B- and T-lymphocytes during its development

Anamnestic response is “memory”.
After the first exposure and its clonal selection and expansion against the antigen, the body keeps a large number of the antigen specific antibodies to fight against the same antigen in the future

Both B and T-cell receptors are unique to a single type of antigen.
BCRs are actually surface immunoglobin (sIg). It can attach directly to an epitope.
TCRs are either CD4+ (T4 lymphocytes or Th cells) or CD8+ (T8 lymphocytes or CTL cells). It requires epitopes on MHC to attach.

In adaptive immunity the body recognizes an antigen as foreign when epitopes of that antigen bind to a B- or T-cell receptor that has a shape complementary to the epitope.

B-cell receptors bind directly to epitopes on peptide, protein, polysaccharide, nucleic acid and lipid antigens.
However, TCR of T4- and T8-cells can only recognize epitopes from MHC.

T8 cells looks for MHC-I on cells. All cells in the host cell should contain MHC to avoid destruction by T8 cells. Foreign particles which does not have MHC-I or infected cells with epitope on MHC-I are destroyed

Clonal selection – when antigen binds to the B-cell receptor the B-cell is stimulated, and the antigen has “selected” this B-cell.

Clonal expansion – Once stimulated, the B-cell proliferates and makes lots of copies of itself, or clones.

MHC-1 molecules are made by all nucleated cells and bind epitopes from endogenous antigens to enable recognition by T8-cells (CTLs). So basically it is present on the surface of all cells of the body to protect it from T8-cells. If the cell is infected with a foreign particle, an epitope of the antigen is displayed on MHC-1 so T8-cells can destroy it.

Endogenous antigens are found within the cytosol such as viral proteins, proteins produced from the replication of intracellular bacteria, proteins that have escaped into the cytosol from the phagosome of phagocytes, tumor antigens produced by cancer cells.

MHC-II molecules are made primarily by antigen-presenting cells (APC). Remember APCs are macrophages and B-lymphocytes. They bind epitopes from exogenous (outer) antigens to enable recognition by T4-lymphocytes. Exogenous antigens enter from outside the body such as bacteria, fungi, protozoa, and free viruses and are taken up by APC by phagocytosis.

Naïve B-Lymphocytes:

B-lymphocytes are activated (become effector lymphocytes) when the following two things happen: 1. It recognizes a specific antigen, engulfs it and displays epitope on its MHC II.
2. The matching T4 helper cell (Th2) attaches to the B-cell.

Once activated it proliferates (makes lots of copies of itself) and becomes:
Plasma cells producing lots of Ab for that antigen
Memory B cells for future


Naïve T-Lymphocytes:

APC macrophage engulfs and displays the epitope on its MHC II molecule.
T helper cell unique to the epitope attaches to the MHC II molecule of the APC.
It is then activated and produce cytokines that promotes the activity of macrophages and Cytotoxic T cells.

APC macrophage engulfs and displays the epitope on its MHC II molecule.
T helper cell unique to the epitope attaches to the MHC II molecule of the APC.
It is then activated and produce cytokines that promotes the activity of macrophages and Cytotoxic T cells.