Specific Defenses of the Host

The Immune response

The Immune SystemInnate (Nonspecific) Immunity Acquired

(Specific) Immunity

First line of defense (barriers at the body surface)

Second line defense

Third line of defense

•Skin•Mucous membranes•Secretions•Reflexes•Normal microbiota

•Inflammation•Phagocytes•Fever•Complement system•Interferon

•T cell lymphocytes•B cell lymphocytes•Antibodies

Acquired (specific) immunity

• The Acquired immune system recognizes foreign substances and develops a specific immune response against them.

• Substances that provoke an immune response are called Antigens (Ag).– Bacteria, viruses, fungi, protozoa, helminthes, and

cancerous cells are examples.

• The main type of cells of the Acquired immune system are lymphocytes.

Acquired (specific) immunity

• Humoral immunity– B-cells (B- lymphocytes)– Carried out by

Antibodies – Effective against

Extracellular antigens (antigens outside our cells like bacteria)

– MHC independant

• Cell mediated– T-cells (T-lymphocytes)– Carried out by Perforin– Effective against

Intracellular antigens (antigens inside cells i.e.… viruses)

– Cancer– Tissue transplant

rejection.– MHC dependant

Cell Mediated Response

T cytotoxic (Tc ) cells

T- cells

• Thymocyte (immature T-cells) are produced by the bone marrow.– Thymocytes are immature

and are unable to react with antigen

– They travel to the thymus where they are screened and mature into T-cells.

• Mature T cells must be able to distinguish between self and non-self.

Distinguishing self from non-self

Question

• How do T-cells recognize self cells (The cells that make up your body) from foreign cells?

• Answer: They bind to and analyze a protein marker found on all of your cells called the Major Histocompatability complex (MHC).

Major Histocompatability complex(MHC)

The MHC is a marker found on all of your cells. – It identifies your cells as

“self” to your immune system.

– The MHC also randomly picks up proteins from inside your cell and displays them on the outside to your immune system

• T-cells must be able to differentiate your MHC markers from others

Positive selection of Thymocytes in the thymus.

• Thymocytes that enter the thymus are self programed to die.

• The thymoctyes that are able to recognize the MHC and bind to it receive a signal that allows them to live.

• All thymocytes that are unable to bind to your MHC die.

Question

• How do your T-cells recognize unhealthy body cells harboring intercellular parasites from your normal healthy cells?

Answer:

• The bone marrow generates T- cells that collectively are able to recognize any possible protein in the context of your MHCs.

• The T-cells that bind to healthy normal self-proteins in the context of an MHC die in the thymus.

• Only T-cells that are able to bind to an MHC coupled

with a foreign protein are released out to the body.

• This is called Negative selection

• The MHC constantly samples proteins in the cytoplasm.

• The MHC displays these proteins to the immune system outside the cell.

• If the protein displayed is normal and are regularly found in the cell, the T-cells will not attack.

• If the protein in the MHC is foreign, (ie…viral protein) the T-cells will attack the cell.

Screening of T-cells

• In the thymus, Thymocytes undergo a double screening process.– Positive selection: Selects for thymoctes that have

receptors capable of binding self-MHC. These cells are given a positive stimulus which allow them to live.

• Thymocytes that fail positive selection die.

– Negative selection: selects against thymocytes that are able to bind self proteins presented by self-MHC.

• Thymocytes that have high affinity receptors for self proteins receive a negative stimulus that causes them to die.

Results of Positve and Negative Screening

• The T-cell repertoire in the body consists of T-cells which are only able to recognize foreign proteins in the context of self MHC.

• The Cell mediated response is MHC restricted

Turning on the Specific Immune Response

A job left to the Innate Immune system

Overview of Cell Mediated Response

• Antigen presenting cells (APC) ingest microbes and present the Antigens to a type of T-cell called a T-Helper cell (TH-cell).

• The TH-cell becomes activated and secretes a cytokine called interleukin 2.

• Interleukin 2 from the TH-cell, binds to T Tc-cell and has 2 effects.– 1. Activates Tc-cells causing them to produce

perforin molecules. These cells are now able to kill infected host cells.

– 2. Causes activated Tc-cells to proliferated and go through clonal expansion.

The non-specific or innate immune response turns on the specific immune response.

• APC (macrophages, dendritic cells and B cells) ingests a microbe.

• The microbe is processed into short antigenic fragments

• These fragments are combined with a MHC molecule inside the APC.

• The MHC /Ag complex is presented on the surface of the APC

MHC II /AG complex

Antigen Presenting Cell (APC)

T Helper cells

• The APC travels to the lymph node where it meets T-helper cells (TH-cells)

• A TH-cell with an appropriate receptor binds to the MHC II /Ag complex.– This is called the primary

signal

• The Primary signal causes receptors for interleukin 2 to be expressed on the surface of the TH-cell.

V

V

V

Interleukin 2 receptors (IL-2)

Co-stimulatory signal

• B7 protein on the APC binds to a CD28 receptor on the TH-cell.– This is called the

Costimulatory signal

• The costimulatroy signal induces the TH-cell to produce and secrete IL-2.

Interleukin 2

• The costimulatroy signal induces the TH-cell to produce and secrete IL-2.

• The IL-2 binds to IL-2 receptors on the TH-cell.

Clonal Expansion

• IL-2 causes the TH-cell to clone itself over and over.

• The TH-cell is now ready to activate a T-cytotoxic cell.

Activating Tc-cells

• T cytotoxic cells (Tc-cells) migrate into an area of infection by chemotaxis.

• A Tc-cell with an appropriate T-cell receptor binds to an MHC I /Ag complex.

• This binding stimulates the Tc-cell to produce receptors for IL-2

C

Infected Cell

TCR

MHC I /Ag

IL-2R

Differentiation of Tc-cells

• After the IL-2Rs are expressed on the outside of the Tc-cell the Tc-cell lets go of the infected body cell and migrates into lymph-nodes or other lymphatic tissues.

• If the Tc-cells in the lymphatic tissue finds an activated TH-cell and receives IL-2 it will proliferate into active T cytotoxic lymphocytes and memory cells.

Cell Mediated Cytolysis

IL-2

The MHC Question

• Why doesn’t activated Tc-cells bind to the APCs and kill them?

Answer to MHC Problem

• There are two different types or classes of MHCs: MHC I and MHC II

MHC I.

• This class is found on every nucleated cell of the body.

• Proteins and antigens bound to MHC I are always taken up from the pool of free floating proteins in the cytoplasm.

• Only T-cytotoxic cells are able to bind to this class of MHC.– Tc cells can only kill cells with MHC I.

MHC II

• This class is only found on the surface of APCs. • Antigens that are bound to this class of MHC are

always taken from phagolysomes.– This means that the cell is healthy

• Only T-Helper cells can bind to this class of MHC– TH-cells activate Tc- cells but never kill cells that they

interact with. Thus APCs are perserved.