The immune system is neat and organized

Why do we have an immune system?

What is foreign and what is self?

Cell necrosis and cell apoptosis

Where is the immune system exactly located?

Who happened first, the doctor or the illness?

Microbes are two types and too smart

Defense against small extracellular pathogens

Lysozyme, phagocytes, complement

Inflammation

Defense against large extracellular pathogens

Complement, eosinophils

Defense against intracellular pathogens

Interferon, Natural killer cells

Empirical recognition of pathogens

Recognition of pathogens and killing of pathogens

Upgrade of recognition and killing of the immune system to higher levels of sophistication

The immune system is neat and organized

Why do we have an immune system?

What is foreign and what is self?

Cell necrosis and cell apoptosis

Where is the immune system exactly located?

Who happened first, the doctor or the illness?

Microbes are two types and too smart

Defense against small extracellular pathogens

Lysozyme, phagocytes, complement

Inflammation

Defense against large extracellular pathogens

Complement, eosinophils

Defense against intracellular pathogens

Interferon, Natural killer cells

Empirical recognition of pathogens

Recognition of pathogens and killing of pathogens

Upgrade of recognition and killing of the immune system to higher levels of sophistication

The immune system is neat and organized

Why do we have an immune system?

What is foreign and what is self?

Cell necrosis and cell apoptosis

Where is the immune system exactly located?

Who happened first, the doctor or the illness?

Microbes are two types and too smart

Defense against small extracellular pathogens

Lysozyme, phagocytes, complement

Inflammation

Defense against large extracellular pathogens

Complement, eosinophils

Defense against intracellular pathogens

Interferon, Natural killer cells

Empirical recognition of pathogens

Recognition of pathogens and killing of pathogens

Upgrade of recognition and killing of the immune system to higher levels of sophistication

The indication for the evolution of the specific immune system:

First: After having been dealing with pathogens rather empirically, the immune system decided to deal with them very specifically and constructed huge numbers of different specific receptors for the large numbers of different possibly invading pathogens. Receptors for extracellular pathogens were produced by the B-cell system (B-cell receptors or antibodies) and receptors for intracellular pathogens were produced by the T-cell system (T-cell receptors).

Second: In addition, a new option was added that was not present in the older immune system. That was the ‘memory’ function.

The appearance of the B-cell system and the T-cell system

The evolution of the function of memory

The indication for the evolution of the specific immune system:

First: After having been dealing with pathogens rather empirically, the immune system decided to deal with them very specifically and constructed huge numbers of different specific receptors for the large numbers of different possibly invading pathogens. Receptors for extracellular pathogens were produced by the B-cell system (B-cell receptors or antibodies) and receptors for intracellular pathogens were produced by the T-cell system (T-cell receptors).

Second: In addition, a new option was added that was not present in the older immune system. That was the ‘memory’ function.

The appearance of the B-cell system and the T-cell system

The evolution of the function of memory

What are the 3 orange circles:

1. Monoclonal lymphoid cells: implications 

The immune response is polyclonal as the invading organisms are poly-antigenic

2. Large number of lymphoid cells: implications

1. How can a large number of receptors be produced from only a limited set of genes?

GENE REARRANGEMENT

2. How can the body accommodate this enormous number of cells bearing the different receptors?

CLONAL SELECTION AND CLONAL EXPANSION

3. If there is only a limited number of lymphocytes at any one time available for recognizing a particular antigen, and bearing in mind that lymphoid cells are mono-specific, how then can the opportunity be made for a larger number of mono-specific lymphocytes to come in contact with an antigen that has entered the body?

HOMING OF LYMPHOCYTES TO SECONDARY LYMPHOID ORGANS

4. OK, now lymphocytes came to get acquainted with bad antigens at lymphoid clubs. However, the major site of injury is our there in some tissue somewhere in the body. How can the selected clones of lymphocytes come to go selectively to the sites where the antigen is damaging the tissues?

ADHESION MOLECULES AND CHEMOTAXIS

3. Two additional functions of ‘MEMORY’

Finding ways to:

Bind antigens more efficiently: SOMATIC HYPERMUTATION

Eliminate antigen more efficiently: IMMUNOGLOBULIN CLASS SWITCH

What are the 3 orange circles:

1. Monoclonal lymphoid cells: implications 

The immune response is polyclonal as the invading organisms are poly-antigenic

2. Large number of lymphoid cells: implications

1. How can a large number of receptors be produced from only a limited set of genes?

GENE REARRANGEMENT

2. How can the body accommodate this enormous number of cells bearing the different receptors?

CLONAL SELECTION AND CLONAL EXPANSION

3. If there is only a limited number of lymphocytes at any one time available for recognizing a particular antigen, and bearing in mind that lymphoid cells are mono-specific, how then can the opportunity be made for a larger number of mono-specific lymphocytes to come in contact with an antigen that has entered the body?

HOMING OF LYMPHOCYTES TO SECONDARY LYMPHOID ORGANS

4. OK, now lymphocytes came to get acquainted with bad antigens at lymphoid clubs. However, the major site of injury is our there in some tissue somewhere in the body. How can the selected clones of lymphocytes come to go selectively to the sites where the antigen is damaging the tissues?

ADHESION MOLECULES AND CHEMOTAXIS

3. Two additional functions of ‘MEMORY’

Finding ways to:

Bind antigens more efficiently: SOMATIC HYPERMUTATION

Eliminate antigen more efficiently: IMMUNOGLOBULIN CLASS SWITCH

SIX ISSUES TO DEAL WITH

TWO NEW TRICK BY PATHOGENS

THE FOUR ISSUES IN THE REFINEMENT PROCESS OF THE SPECIFIC SYSTEM:

ONE

IF B CELLS CAN RECOGNIZE EXTRACELLULAR PATHOGENS JUST BECAUSE THEY ARE EXTRACELLULAR (THAT IS, THEY ARE FACE TO FACE), HOW THEN CAN T-CELLS RECOGNIZE INTRACELLULAR PATHOGENS THAT ARE HIDING INSIDE THE CELLS?

Solution: All cells in your body are constantly presenting on their surfaces samples of proteins they are synthesizing.

TWO

WHAT IF THE B-CELL RECEPTOR RECOGNIZES THE EXTERIORIZED INTRACELLULAR ANTIGENS OR IF THE T-CELL RECEPTOR RECOGNIZED THE EXTRACELLULAR ANTIGENS?

Solution: B cells were made in such a way as to recognize repeating units of peptides and T cells recognize individual peptides only.

THREE

NOW THE TCR RECOGNIZES SIMPLE PEPTIDES ONLY AND WILL NOT GET CONFUSED WHEN FACING EXTRA-CEULLULAR UNPROCESSED PROTEINS.

BUT WHAT IF YOU GET: A SINGLE AMINO ACID CHAIN IN THE CIRCULATION OR ADSORBED ON THE SURFACE OF A CELL TEMPORARILY

Solution: A guide: the MHC

FOUR

SELF-SPECIFIC ANTIGEN RECEPTORS

Solution: A reference cell: the T helper cell.

There are two types of T-helper cells: Th1 for cell-mediated immune responses (as cytotoxicity by cytotoxic T cells against virally-infected cells) and Th2 for humoral (extracellular) immune responses (as antibody responses to extracellular pathogens). 

TWO NEW TRICKS BY PATHOGENS:

ONE: A NEW TRICK BY EXTRACELLULAR PATHOGENS: some extracellular pathogens changed their minds and became intracellular pathogens in macrophages.

Solution: The immune response, in turn, shifted from an extra to an intracellular defense strategy.

TWO: A NEW TRICK BY INTRACELLULAR PATHOGENS: down regulation of the MHC I and the role of natural killer cells in filling that gap

Solution: Natural killer cells would kill any cell in the body that does not have the MHC I on its surface

SIX ISSUES TO DEAL WITH

TWO NEW TRICK BY PATHOGENS

THE FOUR ISSUES IN THE REFINEMENT PROCESS OF THE SPECIFIC SYSTEM:

ONE

IF B CELLS CAN RECOGNIZE EXTRACELLULAR PATHOGENS JUST BECAUSE THEY ARE EXTRACELLULAR (THAT IS, THEY ARE FACE TO FACE), HOW THEN CAN T-CELLS RECOGNIZE INTRACELLULAR PATHOGENS THAT ARE HIDING INSIDE THE CELLS?

Solution: All cells in your body are constantly presenting on their surfaces samples of proteins they are synthesizing.

TWO

WHAT IF THE B-CELL RECEPTOR RECOGNIZES THE EXTERIORIZED INTRACELLULAR ANTIGENS OR IF THE T-CELL RECEPTOR RECOGNIZED THE EXTRACELLULAR ANTIGENS?

Solution: B cells were made in such a way as to recognize repeating units of peptides and T cells recognize individual peptides only.

THREE

NOW THE TCR RECOGNIZES SIMPLE PEPTIDES ONLY AND WILL NOT GET CONFUSED WHEN FACING EXTRA-CEULLULAR UNPROCESSED PROTEINS.

BUT WHAT IF YOU GET: A SINGLE AMINO ACID CHAIN IN THE CIRCULATION OR ADSORBED ON THE SURFACE OF A CELL TEMPORARILY

Solution: A guide: the MHC

FOUR

SELF-SPECIFIC ANTIGEN RECEPTORS

Solution: A reference cell: the T helper cell.

There are two types of T-helper cells: Th1 for cell-mediated immune responses (as cytotoxicity by cytotoxic T cells against virally-infected cells) and Th2 for humoral (extracellular) immune responses (as antibody responses to extracellular pathogens). 

TWO NEW TRICKS BY PATHOGENS:

ONE: A NEW TRICK BY EXTRACELLULAR PATHOGENS: some extracellular pathogens changed their minds and became intracellular pathogens in macrophages.

Solution: The immune response, in turn, shifted from an extra to an intracellular defense strategy.

TWO: A NEW TRICK BY INTRACELLULAR PATHOGENS: down regulation of the MHC I and the role of natural killer cells in filling that gap

Solution: Natural killer cells would kill any cell in the body that does not have the MHC I on its surface

SIX ISSUES TO DEAL WITH

TWO NEW TRICK BY PATHOGENS

THE FOUR ISSUES IN THE REFINEMENT PROCESS OF THE SPECIFIC SYSTEM:

ONE

IF B CELLS CAN RECOGNIZE EXTRACELLULAR PATHOGENS JUST BECAUSE THEY ARE EXTRACELLULAR (THAT IS, THEY ARE FACE TO FACE), HOW THEN CAN T-CELLS RECOGNIZE INTRACELLULAR PATHOGENS THAT ARE HIDING INSIDE THE CELLS?

Solution: All cells in your body are constantly presenting on their surfaces samples of proteins they are synthesizing.

TWO

WHAT IF THE B-CELL RECEPTOR RECOGNIZES THE EXTERIORIZED INTRACELLULAR ANTIGENS OR IF THE T-CELL RECEPTOR RECOGNIZED THE EXTRACELLULAR ANTIGENS?

Solution: B cells were made in such a way as to recognize repeating units of peptides and T cells recognize individual peptides only.

THREE

NOW THE TCR RECOGNIZES SIMPLE PEPTIDES ONLY AND WILL NOT GET CONFUSED WHEN FACING EXTRA-CEULLULAR UNPROCESSED PROTEINS.

BUT WHAT IF YOU GET: A SINGLE AMINO ACID CHAIN IN THE CIRCULATION OR ADSORBED ON THE SURFACE OF A CELL TEMPORARILY

Solution: A guide: the MHC

FOUR

SELF-SPECIFIC ANTIGEN RECEPTORS

Solution: A reference cell: the T helper cell.

There are two types of T-helper cells: Th1 for cell-mediated immune responses (as cytotoxicity by cytotoxic T cells against virally-infected cells) and Th2 for humoral (extracellular) immune responses (as antibody responses to extracellular pathogens). 

TWO NEW TRICKS BY PATHOGENS:

ONE: A NEW TRICK BY EXTRACELLULAR PATHOGENS: some extracellular pathogens changed their minds and became intracellular pathogens in macrophages.

Solution: The immune response, in turn, shifted from an extra to an intracellular defense strategy.

TWO: A NEW TRICK BY INTRACELLULAR PATHOGENS: down regulation of the MHC I and the role of natural killer cells in filling that gap

Solution: Natural killer cells would kill any cell in the body that does not have the MHC I on its surface

Various GO SIGNALS require different HELP

How the innate immune system paves the way for the specific immune responses?

Types of helper T cells

FIVE ISSUES TO DISCUSS:

Issue number 1:

The MHC is an opinionated protein

It does not present all peptides coming out of the antigen presenting pathway: selective in terms of quantity

It does not present, from the limited number it chooses, any peptide randomly: selective in terms of quality.

Issue number 2:

MHC and disease

If your MHC misses binding important peptides that would eliminate a given pathogen, you are more susceptible to infection with that pathogen.

If your MHC keeps on binding a certain self-peptide and it happens that the T-helper cell gives a “help” signal instead of “non-help” to the B or T cell presenting the peptide, then you are more susceptible to an autoimmune disease where the auto-antigen is that peptide.

Issue number 3:

Why our MHC is opinionated:

Because (1) In terms of quantity: this saves a lot of energy that would have been consumed in presenting virtually any peptide coming out of the antigen presenting pathway, (2) In terms of quality: if offered humans living today, the asset of benefiting from the many years of experience of their ancestors as they struggled against pathogens and autoimmune diseases

Issue number 4:

How many MHCs do you have?

Two MHCs from class I and two MHCs from class II and more…..

Issue number 5:

How can one MHC molecule bind and present a fairly large number of peptides at a time when the B- or T-cell receptors can each bind only one single peptide.