MICR 270 Module 3

Overall immune response

From the entrance of the pathogen in the body to its elimination

• Includes innate and adaptive immune response

Phases of adaptive immune response

1. Antigen recognition (antigen presentation)

   1. PAMPS are seen by antigen-presenting cells (APCs), such as dendritic cells and macrophages

   2. APCs present antigens to naïve T-cells via their surface MHC proteins

2. Lymphocyte activation

   1. series of cellular interactions/communication which lead to T-cell and B-cell differentiation and clonal expansion

      1. B-cells → Plasmocytes 

      2. T-cells → Helper T-cells or cytotoxic T-cells

3. Elimination of pathogens or non-self perceived antigens

   1. Most efficient defences are unleashed to destroy the pathogen

      1. Humoral Immunity: Plasmocytes produce antibodies that bind to extracellular pathogens.

      2. Cell-mediated Immunity: Cytotoxic T-cells destroy cells infected by intracellular pathogens or get activated by antigens presented by APCS

4. Apoptosis of immune cells (contraction)

   1. Once the pathogen is eliminated, the majority of activated lymphocytes undergo apoptosis, and the immune response gradually declines

5. Establishment of immunological memory

   1. The adaptive immune cells that don’t apoptose differentiate into memory cells

   2. Memory cells will proliferate quickly to generate a fast and robust immune response if re-exposed to the same antigen

Clonal expansion

Production of a large quantity of identical cells from the same original cell

Apoptosis

Programmed cell death that occurs in a way controlled by the cell itself, which generate almost no damage to the surrounding area

Major Histocompatibility complex (MHC)

molecules that display antigenic peptides on the surface of cells. 

• serves as a self-label, helping to identify self from non-self molecules

• MHC-antigen complex can be recognized by the TCR and its co-receptors (CD4 or CD8) to initiate an adaptive immune response to eliminate foreign antigens

What are the two classes of MHC?

• There are two classes of MHC that distinguish between different recognition patterns

  • MHC class I and MHC class II

Antigen-presenting cells (APCs)

Cells that function to present the antigens found inside the body to T-cells (because T-cells can’t recognize extracellular pathogens by themselves)

• APCs internalize pathogens (by phagocytosis or receptor-mediated endocytosis) and process them into peptides (antigens) which are displayed on their surface via an MHC class II to be recognized by T-cells

Professional APCs

the most efficient cells that both present antigens through MHC class II and express costimulatory signals to activate helper T-cells

• Include macrophage, B-cell, and dendritic cell

  • Dendritic cell is the best

Non-professional APCs

Can be induced to express MHC class II complexes or stimulatory molecules, but normally don’t (only in the case of a sustained inflammatory responses)

• Include fibroblasts and glial cells

Receptor-mediated endocytosis

An endocytic process in which a cell absorbs external material by invagination of the plasma membrane. This process relies on receptors specific for the material being absorbed.

What are the two pathways which lead to the formation of an effective peptide:MHC signalling complex?

1. Endogenous pathway

2. Exogenous pathway

Endogenous pathway

Forms peptide:MHC class I complex (recognized by CD8+ cytotoxic T-cells)

• allows the cell to process self or foreign intracellular particles and present them at the cell surface in order to be recognized by T-cell receptors on cytotoxic T-cells

Steps of endogenous pathway

1. Proteins produced within the cell are broken into fragments (antigens)

2. Antigens are transported to rough ER and combine with class I MHC

3. antigen:MHC class I complex is transported to Golgi, then the cell membrane for display

Exogenous pathway

Forms peptide:MHC class II complex (recognized by CD4+ helper T-cells)

Steps of exogenous pathway

1. Antigen engulfment: Foregin antigen recognized by PRRs is engulfed by an APC by endocytosis forming an endosome.

2. Proteolytic processing: Foreign antigens inside the endosome are broken down into fragments 

3. Formation of antigen:MHC complex: vesicle containing the foreign fragments fuses with vesicle containing MHC molecules (originating from the ER via the Golgi), forming MHC-antigen complexes

4. Cell-surface expression: MHC-antigen complex is transported to the plasma membrane, for display on the surface of the cell

5. Recognition by helper T-cell: T-cell receptor on the surface of a helper T-cell binds to MHC-antigen complex on the surface of the APC, which will initiate adaptive immunity

Proteolytic processing

proteases cleave one or more bonds in a target protein to modify its activity (activation, inhibition, or destruction of activity)

B-cell receptor (BCR)

composed of a membrane-bound antibody and signal transduction molecules (ITAMs). 

• BCRs recognize and bind to extracellular pathogens or toxins directly

T-cell receptor (TCR)

formed of a membrane-bound antigen-specific molecule and signal transduction molecules (CD3 and ITAMs).

• TCRs in association with a co-receptor (CD4 or CD8) recognize and bind to peptide:MHC complex

CD4 vs CD8 and MHC Classes

• CD4 co-receptors are expressed on helper T-cells, which recognize peptide: MHC class II complex.

• CD8 co-receptors are expressed on cytotoxic T-cells, which recognize peptide: MHC class I complex

How does the immune system communicate?

• Components of the immune system communicate between themselves using specific cell surface receptors found on immune cells and a cytokine network

  • Lymphocyte activation involves many interactions with other immune cells

Cytokine networks

coordinate appropriate immune responses and modulate the balance between humoral and cell-mediated immunity

T-cell dependent activation of B-cells

interaction between a T-cell and a B-cell that involves the exchange of activation signals to produce plasmocytes and memory B-cells for humoral immunity

Thymus-independent antigens

antigens that can induce the production of antibodies by B-cells without the presence of a T-cell (but the majority are thymus dependent and do require a T-cell)

What are the steps of the signalling pathway for T-cell-dependent activation of B-cells?

1. Peptide MHC-Class II complex

2. Signal 1: TCR - Peptide:MHC class II complex

3. Expression of co-stimulatory molecules

4. Signal 2: co-stimulation (B7:CD28 and CD40:CD40L)

5. Signal 3: cytokines

6. Outcome of the 3 signals

Step 1 of signaling: peptide:MHC Class II complex

when an antigen binding to the BCR does not produce enough signal to activate the cell, the antigen is internalized by receptor mediated endocytosis and displayed as an MHC on the membrane

Step 2 of signaling: signal 1 TCR - Peptide:MHC class II complex:

The specific TCR complex and CD4 co-receptor on the T-cell recognizes and binds to the peptide:MHC class II complex 

Step 3 of signaling: expression of co-stimulatory molecules

Signal 1 (TCR- peptide:MHC complex II) induces the expression of CD40L on the cell surface of the helper T-cell.

Step 4 of signaling: Signal 2: co-stimulation (B7:CD28 and CD40:CD40L)

CD40L and CD28 expressed on the T-cell, bind to CD40 and B7 (respectively) expressed on the B-cell, inducing a costimulatory signal in both cells.

Step 5 of signaling: Signal 3: cytokines

The activated helper T-cell secretes cytokines which bind to their associated cytokine receptor located on both cells (a paracrine and an autocrine effect).

Step 6 of signaling: outcome of the 3 signals

The combination of these 3 signals stimulate the proliferation and differentiation of B-cells into plasma cells and memory B-cells, forming the humoral immune response against the specific antigen

Immune synapse

structure formed by the interaction between a T-cell and an APC, consisting of signal molecules and adhesions proteins

• Often arranged into SMACs

Supra molecular activating clusters (SMACs)

‘bullseye’ of three rings depicting three different cell clusters with similar functions

• Includes cSMAC, pSMAC, and dSMAC

central SMAC/c SMAC

Signal molecules: contains the molecules responsible for signaling between the two cells (TCR and peptide:MHC molecules)

peripheral SMAC/p SMAC

Adhesion molecules: contains adhesion proteins (integrins and cytoskeletal linker proteins) responsible for keeping cells in contact long enough for signals to propagate

distal SMAC/d SMAC

Signal regulation molecules: consists of proteins with large extracellular domains that are responsible for helping regulate signal transduction

Function of immune synapse

1. Primary goal of the immune synapse is the effective activation of the T-cell

2. The synapse holds signal proteins together to form stronger connections, which give enough time for the right amount of signals to be produced.

3. The synapse leads to the reorganization of structures inside the T-cell, directing the release of cytokines close to the target cell.

4. The synapse regulates lymphocyte activation

Cytokines

chemical messengers secreted by immune cells that play a key role in cell-to-cell communication

What are the types of cytokines?

1. Chemokines

2. Interleukins (IL)

3. Interferons (IFN)

4. Tumor necrosis factor (TNF)

5. Growth factors

Chemokines

1. Induce chemotaxis

2. Call in cells to the region of infection or injury

3. Play a key role in:

   1. Inflammation; wound healing

   2. Cell-mediated and humoral immune responses

   3. Hematopoiesis

Interleukins

1. Contain over ten subfamilies (IL-1, IL-2, IL-4, IL-12, etc.)

2. Regulate immune and inflammatory responses

3. Primarily affect the proliferation and differentiation of various hematopoietic and immune cells

Interferons (IFN)

1. The most common and well-known interferon molecules are IFN-α, IFN-β, and IFN-γ

2. Induce an antiviral state - inhibit the replication process of viruses

3. Help regulate immune responses

Tumor necrosis factor (TNF)

1. The most common and well-known are TNF-α and TNF-β

2. Involved in systemic inflammation (septic shock)

3. Involved in tumor regression

4. Can cause apoptosis (cell death)

Growth factors

1. Stimulate growth, proliferation, healing, cellular differentiation

2. Regulate a variety of cellular processes such as immune response

Chemotaxis

the movement of an immune cell in direction of an elevated concentration of chemoattractant molecules, such as chemokines.

Septic shock

A serious medical condition associated with a significant drop in blood pressure that can lead to respiratory or heart failure, and death

Immunological memory

ability of lymphocytes to respond more efficiently with a greater and faster immune response to reinfection by a previously encountered antigen

• occurs when there is a second encounter with an antigen, that induces a heightened state of immune reactivity

• mediated by memory B-cells

Memory B-cells vs Naive B-cells

• Memory B-cells differentiate from naive B-cells and display the same antibody as their parent cell

• Memory B-cells have a longer lifespan than naive B-cells

• Memory B-cells can differentiate immediately into plasma cells, making the immune response more efficient than naive B-cells

Natural passive immunity

1. Acquired by the fetus or newborn from the mother

2. Placental transfer of antibodies during pregnancy or breastfeeding

3. Short-lived immunity (~6 months)

4. No immunological memory for the recipient

Artificial passive immunity

1. Acquired by injection of serum containing antibodies

2. Immunity is temporary

3. No immunological memory for the recipient

Natural active immunity

1. Acquired through infection by a pathogen, possibly leading to symptoms/a disease state

2. Development of innate and adaptive immune responses

3. Immunological memory has a significant chance of being developed

Artificial active immunity

1. Acquired through vaccination

2. Development of innate and adaptive immune responses

3. Normally, no symptoms/disease states are present

4. Immunological memory has a significant chance of being developed

Serum

Fluid portion of the blood, which is free of cells and clotting factors

Serology

serological analysis involves the diagnostic evaluation of blood serum to test for the presence of a host antibody response against a foreign particle/pathogen

Chicken pox/shingles case study

• 95% of the population shows serological evidence of having chicken pox due to the varicella-zoster virus (VZV) vaccine

  • Even if you did not actually have chicken-pox, the VZV vaccine produces antibodies in our systems

• Chicken pox remains in the immune system in latency (inactive state) after infection

  • Shingles is the reactivation of the latent virus in the immune system causing painful rashes

  • There is a vaccine for shingles (can reduce risk up to 90%)