Immunology 2 Flashcards
Immune system is confronted with a ___ number of antigen determinants
___ amino acids known to make up a protein antigenic determinant
Assume 20 amino acids are used randomly to make a protein determinant.
For a determinant of 5 amino acids, ___ = ____ antigens (determinants)
For a determinant of 6 amino acids, ___ = __ million antigens (determinants)
Immune system is confronted with a finite number of antigen determinants
5-6 amino acids known to make up a protein antigenic determinant
Assume 20 amino acids are used randomly to make a protein determinant.
For a determinant of 5 amino acids, 205 = 3,200,000 antigens (determinants)
For a determinant of 6 amino acids, 206 = 64 million antigens (determinants)
So, here is the challenge for the immune system:
- There are between 3,000,000 and 60,000,000 protein antigenic determinants in our world of antigens.
- Each determinant must be recognized by a ___ ____ molecule specific for that ___.
- Hence, there must be between 3,000,000 and 60,000,000 antibody specificities.
- Antibody molecules are coded for within the ___. However, the human genome has only ____-____ genes.
- Far too few genes to code for all of the antibody specificities.
- How is this achieved?
- A process of ___ ___ of a few ____ genes makes this possible.
So, here is the challenge for the immune system:
- There are between 3,000,000 and 60,000,000 protein antigenic determinants in our world of antigens.
- Each determinant must be recognized by a unique antibody molecule specific for that antigen.
- Hence, there must be between 3,000,000 and 60,000,000 antibody specificities.
- Antibody molecules are coded for within the genome. However, the human genome has only 25,000 - 50,000 genes.
- Far too few genes to code for all of the antibody specificities.
- How is this achieved?
- A process of random rearrangement of a few antibody genes makes this possible.
Here’s how it works
Ig gene rearrangement to make the LIGHT chain variable region
- ____ gene clusters – the ____gene group and the____gene group – code for the light chain variable protein.
- Take 1 gene from each cluster randomly
- What is not used is cut out
- The 2 genes are then coupled to the Constant Region
Ig gene rearrangement to make the HEAVY chain variable region
- ____gene clusters – the ____ gene group, the _____ gene group, and the____ gene group – code for the heavy chain variable protein.
- These are different gene clusters than light chain!
- ___ joins, _ is added
- All connected to ___ region (IgM)
Here’s how it works
Ig gene rearrangement to make the LIGHT chain variable region
Two gene clusters – the variable (V) gene group and the joining (J) gene group – code for the light chain variable protein.
Take 1 gene from each cluster randomly
What is not used is cut out
The 2 genes are then coupled to the Constant Region
Ig gene rearrangement to make the HEAVY chain variable region
Three gene clusters – the variable (V) gene group, the diversity (D) gene group, and the joining (J) gene group – code for the heavy chain variable protein.
These are different gene clusters than light chain!
DJ joins, V is added
All connected to constant region (IgM)
How to make all of the Ab specificities with a few genes
How many different gene combinations can be generated in the variable region. In other words, how many Ab specificities can be generated?
_______ total combinations using k or l light chain genes and heavy chain genes. We call this ____ _____
200 x 8,262 = 1,652,400 combinations using k light chain
116 x 8,262 = 958,392 combinations using l light chain
How to make all of the Ab specificities with a few genes
How many different gene combinations can be generated in the variable region. In other words, how many Ab specificities can be generated?
2,610,792 total combinations using k or l light chain genes and heavy chain genes. We call this Combinatorial Diversity
200 x 8,262 = 1,652,400 combinations using k light chain
116 x 8,262 = 958,392 combinations using l light chain
Four mechanisms are used to generate Ab diversity:
‘____ ____’– the random selection of V-J and V-D-J genes to make an Ab gene (~2,610,792 combinations).
Three additional mechanisms add to Ab diversity (not required to know these):
Random use of palindromic (P) nucleotides.
Random insertion of ‘N’ nucleotides.
Somatic Hypermutation.
Four mechanisms are used to generate Ab diversity:
‘Combinatorial Diversity’– the random selection of V-J and V-D-J genes to make an Ab gene (~2,610,792 combinations).
Three additional mechanisms add to Ab diversity (not required to know these):
Random use of palindromic (P) nucleotides.
Random insertion of ‘N’ nucleotides.
Somatic Hypermutation.
Using less than ____ genes, it is possible to make all of the Ab specificities for every possible antigen.
Using less than 1,000 genes, it is possible to make all of the Ab specificities for every possible antigen.
Types of T Cells
- T helper (Th) cells
- Express the ___ surface marker
- Two main subcategories
- Th_ cells: activate and regulate ___ ___cells and ___ ____ immunity
- Th_ cells: activate and regulate __ cells and ____ immunity
- T cytotoxic (Tc) cells
- Express the ___ surface marker
- Involved in __ ___ ___ (CMI) and direct ___ ____ of virus or bacterial infected tissue cells
- Two major classes of T cell receptors (TCR): On Tc cells?
- ___ TCR heterodimer
- ___ TCR heterodimer
*
Types of T Cells
T helper (Th) cells
Express the CD4 surface marker
Two main subcategories
Th1 cells: activate and regulate cytotoxic T cells and cell-mediated immunity
Th2 cells: activate and regulate B cells and humoral immunity
T cytotoxic (Tc) cellsExpress the CD8 surface marker
Involved in cell-mediated immunity (CMI) and direct cytotoxic killing of virus or bacterial infected tissue cells
Two major classes of T cell receptors (TCR): On Tc cells?
αβ TCR heterodimer
γδ TCR heterodimer
The T cell receptor (TCR) vs. Ab (the B cell receptor).
The TCR is only expressed on the __ __ ___
Ab can be expressed on __ __ ___ or can be____ from B cells and plasma cells.
TCR consists of a ____ of _ and _ chain molecules.
The T cell receptor (TCR) vs. Ab (the B cell receptor).
The TCR is only expressed on the T cell membrane.
Ab can be expressed on B cell surface or can be secreted from B cells and plasma cells.
TCR consists of a heterodimer of α and β chain molecules.
Basic structure of a TCR molecule
_ chains and each have ___ Region and ___ region. The 2 chains are connected by ___ ___
Basic structure of a TCR molecule
2 chains and each have Variable Region and constant region. The 2 chains are connected by disulfide bond
In the ___, TCR α and β genes undergo ____ in a manner similar to ___ genes
Alpha Chain: A gene from TCR _ and _gene families are selected to form a rearranged α gene
Beta Chain: A gene from TCR _ _ _gene families are selected to form a rearranged β gene
In the thymus, TCR α and β genes undergo rearrangement in a manner similar to Ab genes
Alpha Chain: A gene from TCR V and J gene families are selected to form a rearranged α gene
Beta Chain: A gene from TCR V, D, J gene families are selected to form a rearranged β gene
What is the purpose of T cell maturation in the ___?
A T cell only recognizes__ ___ when it is present on the ____of our __ ___. (Wont recognize Ag if it floats passed it)
Importantly, T cells must not recognize our __ ___ as ‘___’.
T cell precursors become ‘___’ to distinguish __ from __ ___ in the thymus.
What is the purpose of T cell maturation in the thymus?
A T cell only recognizes foreign Ag when it is present on the surface of our own cells. (Wont recognize Ag if it floats passed it)
Importantly, T cells must not recognize our own cells as ‘foreign’.
T cell precursors become ‘educated’ to distinguish self from non-self in the thymus.
Two steps in thymus T cell education
___ ___ – The TCR on a new T cell is tested to make sure it has__ ___ for ___antigen. (Some but not strong)
___ ___ – The TCR on a new T cell is then tested to make sure it is not __ __ with ___antigen.
Two steps in thymus T cell education
Positive Selection – The TCR on a new T cell is tested to make sure it has weak affinity for self antigen. (Some but not strong)
Negative Selection – The TCR on a new T cell is then tested to make sure it is not over-reactive with self antigen.
Step-by-step guide to Positive and Negative T cell selection in the thymus
- T cell precursor from the ___ ___ goes to the ___
- TCR genes ____. TCR expressed on surface.
- New TCR tested for reactivity to ___
- ___ reactivity, T cell survives
- ___ reactivity, T cell dies
- New TCR tested for ___ ___ to self-antigen.
- T cells that pass these tests will be exported into the ____ and ___ ___ __.
Step-by-step guide to Positive and Negative T cell selection in the thymus
- T cell precursor from the bone marrow goes to the thymus.
- TCR genes rearranged. TCR expressed on surface.
- New TCR tested for reactivity to self.
- Mild reactivity, T cell survives
- No reactivity, T cell dies
- New TCR tested for over-reactivity to self-antigen.
- T cells that pass these tests will be exported into the c irculation and secondary lymphoid tissue
*
- T cells that pass these tests will be exported into the c irculation and secondary lymphoid tissue
γδ T cells: A second class of T cells found mostly in ____tissues
- Most T cells in the circulation express ___ TCR
- A second class of T cells designated γδ T cells use a ___ consisting of a heterodimeric protein made from γ and δ genes.
- Located in___ and ____(___) tissues.
- ~__% of all T cells in the gut and reproductive tract are γδ T cells.
- The proportion in oral mucosa is___
- ____ in most secondary lymphoid tissues (~___% of splenic T cells are γδ).
- What you find is spleen is representative of blood bc blood filters thru it
- May be an evolutionarily ___ form of _ cells (??).
- Often regarded as part of the ___ immune system.
- ___ in the same way as αβ TCR
γδ T cells: A second class of T cells found mostly in mucosal tissues
Most T cells in the circulation express αβ TCR
A second class of T cells designated γδ T cells use a TCR consisting of a heterodimeric protein made from γ and δ genes.
Located in mucosal and epidermal (skin) tissues.
~50% of all T cells in the gut and reproductive tract are γδ T cells.
The proportion in oral mucosa is unclear.
Rare in most secondary lymphoid tissues (~3-5% of splenic T cells are γδ).
What you find is spleen is representative of blood bc blood filters thru it
May be an evolutionarily ancient form of T cells (??).
Often regarded as part of the innate immune system.
Develop in the same way as αβ TCR
γδ T cells
Function of γδ T cells is ___ ___ ____
May be ___ and ___ _____ ___ cells.
Some γδ T cells in the ___ produce ___ ___ ___ involved in ____ ___.
γδ T cells
Function of γδ T cells is not fully known.
May be recognize and destroy damaged body cells.
Some γδ T cells in the skin produce epidermal growth factors involved in tissue repair.
Remember, T cells recognize Ag only when it is associated with a self tissue cell.
This inherently focuses the T cell response onto___ ___ (virus, bacteria, some fungi) and some ___cells.
Protein Ags must be ‘____’, i.e., ____ into ___ (peptides) by an ___ ___ ____ for recognition by a ___ or ___
Antigen-Presenting Cells are:
Major histocompatibility complex (MHC) molecules ____ ____ to T cells.
They exist on the ___
Remember, T cells recognize Ag only when it is associated with a self tissue cell.
This inherently focuses the T cell response onto infected cells (virus, bacteria, some fungi) and some cancer cells.
Protein Ags must be ‘processed’, i.e., chopped into fragments (peptides) by an antigen presenting cell (APC) for recognition by a T helper cell (Th) or a cytotoxic T cell (Tc).
Antigen-Presenting Cells are:
Macrophages
Dendritic cells
Langerhans cells
(B cells)
Major histocompatibility complex (MHC) molecules present antigen to T cells.
They exist on the APC
Structural Arrangement of MHC-I and MHC-II Molecules
___and ___are anchored in the cell membrane.
MHC-I is a ____ of a single protein chain (_ chain) coupled to _- ____(not part of MHC-I).
MHC-II is a___ (_ and _ chains) joined by ___ ____
They take a piece of the ___ ____ and ___ it ___ so the T cell can see it
Structural Arrangement of MHC-I and MHC-II Molecules
MHC-I and MHC-II are anchored in the cell membrane.
MHC-I is a monomer of a single protein chain (α chain) coupled to β2- microglobulin (not part of MHC-I).
MHC-II is a heterodimer (α and β chains) joined by disulfide bonds.
They take a piece of the antigenic peptide and hold it out so the T cell can see it
Gene Nomenclature of the MHC Complex – also referred to as ___ ___ ___ (HLA)
- Class II:
- Regions
- __
- __
- ___
- Gene Products
- _____
- ____
- ____
- Regions
- Class I:
- Regions
- _
- _
- _
- Gene Products
- Regions
Gene Nomenclature of the MHC Complex – also referred to as Human Leukocyte Antigen (HLA)
Class II:
Regions
DP
DQ
DR
Gene Products
DP αβ
DQ αβ
DR αβ
Class I:
Regions
B
C
A
Gene Products
HLA-B
HLA-C
HLA-A
Numbers of MHC Class-I and Class-II genes (alleles) in the human population
Multiple alleles for each ___, each ___ of dimer, ___ class
Numbers of MHC Class-I and Class-II genes (alleles) in the human population
Multiple alleles for each region, each subunit of dimer, each class
Example of MHC molecules on an APC
___ MHC molecules are expressed, __ from each parent.
Because these will___ from person to person, the difficulty and complexity of successful __ __ is obvious.
Example of MHC molecules on an APC
12 MHC molecules are expressed, 6 from each parent.
Because these will differ from person to person, the difficulty and complexity of successful tissue grafting is obvious.
Tissue Distribution of MHC-I and MHC-II Molecules
Note that ____molecules are expressed on almost all cells in the body (except ___), whereas ____ molecules are mostly restricted to cells of the ____ ___.
Tissue Distribution of MHC-I and MHC-II Molecules
Note that MHC-I molecules are expressed on almost all cells in the body (except RBCs), whereas MHC-II molecules are mostly restricted to cells of the immune system.
Foreign antigen inside an APC or a tissue cell of the body is____and pieces are displayed to T cells by MHC
Foreign antigen inside an APC or a tissue cell of the body is digested and pieces are displayed to T cells by MHC
Processed Ag peptides are wedged into the ___ of the ___ molecules
Processed Ag peptides are wedged into the top of the MHC molecules
T Cell Superantigens: ____, usually of ____origin, that activate many ___ ___ of _ cells independent of the __ __ ___ by sticking to both the __ and the ___ molecule.
__ ___of T cells to become___ ____
Not binding to TCR in___ ___ ____
Rapid __-___ activation of ___ T cells results in the release of large amounts of ___ ___.
If in the circulation, it causes:
___ ___
Sudden___ in blood pressure
____
T Cell Superantigens: Molecules, usually of bacterial origin, that activate many different types of T cells independent of the T cell specificity by sticking to both the TCR and the MHC molecule.
Large numbers of T cells to become simultaneously activated.
Not binding to TCR in antigen reacting portion
Rapid non-specific activation of many T cells results in the release of large amounts of proinflammatory cytokines.
If in the circulation, it causes:
Vascular collapse
Sudden drop in blood pressure
Shock
Cell-Mediated Immunity (CMI)
- Types of cells:
- ____ ___ ___ (CTLs), i.e., CD8+ T cells
- Direct ___ of ___ or ____ cells such as tumor cells.
- _____
- ___ and ___ of infectious ___, and also by destruction of ___ ___
- __ ___ ___
- Described in this lecture. ____ of infected cells or tumor cells.
- CMI is the primary mechanism responsible for ___ ___ ____ (separate lecture).
- Is the mechanism behind ___ ___ _____ in contact dermatitis or ___ ___ skin tests (separate lecture).
*
- ____ ___ ___ (CTLs), i.e., CD8+ T cells
Cell-Mediated Immunity (CMI)
Types of cells:Cytotoxic T cells (CTLs), i.e., CD8+ T cells
Direct killing of infected or diseased cells such as tumor cells.
Macrophages
Ingestion and destruction of infectious agents, and also by destruction of infected cells.
Natural killer (NK) cells.
Described in this lecture. Killing of infected cells or tumor cells.
CMI is the primary mechanism responsible for graft transplant rejection (separate lecture).
Is the mechanism behind delayed-type hypersensitivity (DTH) in contact dermatitis or positive TB skin tests (separate lecture).
Steps in the Destruction of a Tissue Cell by a Cytotoxic T cell (CD8+ T cell)
- The CTL recognizes ___ on a ___ ___ cell using the ___
- The CTL releases ___-____ material into the tissue cell.
- The tissue __ ___
- CTL will ___ and start over again against another target cell.
Steps in the Destruction of a Tissue Cell by a Cytotoxic T cell (CD8+ T cell)
- The CTL recognizes Ag on a diseased tissue cell using the TCR.
- The CTL releases tissue-destroying material into the tissue cell.
- The tissue cell dies.
- CTL will recycle and start over again against another target cell.
5.
T cell activation – Costimulation
TCR binds to ____expressed on cell surface by an ___ molecule (referred to as ___ ___).
Signal one alone leads to ___ or even ___ T cell activation.
If a specialized molecule (a costimulation molecule referred to as___ ___) is engaged on the T cell, the T cell becomes___ ____
Costimulation –> ___ ____T cell response.
T cell activation – Costimulation
TCR binds to antigen expressed on cell surface by an MHC molecule (referred to as signal one).
Signal one alone leads to minimal or even no T cell activation.
If a specialized molecule (a costimulation molecule referred to as signal two) is engaged on the T cell, the T cell becomes fully activated.
Costimulation ® extremely strong T cell response.
Process of T cell costimulation
Some T cell costimulation molecules:
_____
Each binds to a specific molecule (____) on the ____ (___ for ___).
Process of T cell costimulation
Some T cell costimulation molecules:
CD28
CD278
CD43
CD137
Each binds to a specific molecule (ligand) on the APC (B7 for CD28).
T cell expansion/contraction phases
When T cell comes in contact with antigen you will ____ the number of those cells (by ___)
That’s the ____ phase
Some time after that you get____phase
Number of T cells ___
Usually occurs once ___ is ___
T cell expansion/contraction phases
When T cell comes in contact with antigen you will increase the number of those cells (by proliferation)
That’s the expansion phase
Sometime after that you get contraction phase
Number of T cells Decreases
Usually occurs once Ag is gone
CTLA-4: a __ cell molecule used to move T cells into the ___ ____
After a period of activation, T cells begin to express ___
CTLA-4 has ____ binding affinity for ___ than ___
Signal Two is ____; the T cell __ ___ and moves into the ‘____’ phase.
CTLA-4: a T cell molecule used to move T cells into the contraction phase
After a period of activation, T cells begin to express CTLA-4.
CTLA-4 has higher binding affinity for B7 than CD28.
Signal Two is removed; the T cell shuts down and moves into the ‘contraction’ phase.
In cancer, the T cell response is frequently turned off ____
Is there a way to keep T cells ___ and ___ cancer growth?
This radical approach does not rely on ____ therapies to block cancer cell growth and proliferation.
____ is currently being used to treat ____, some ___ cancers, ___ cancer, and ___ cancer.
They made an __ to the ____ molecule.
Will block___cells from going into____ phase, not just cancer T cells
In cancer, the T cell response is frequently turned off prematurely
Is there a way to keep T cells activated and stop cancer growth?
This radical approach does not rely on toxic therapies to block cancer cell growth and proliferation.
Ipilimumab is currently being used to treat melanomas, some lung cancers, bladder cancer, and prostate cancer.
They made an Ab to the CTLA4 molecule.
Will block all cells from going into contraction phase, not just cancer T cells
Natural Killer (NK) Cells
____ lymphocytes that do not have a standard type of____ and have ___ ____ ___, limited ____
Make up only about ___% of the total circulating ____ population.
They function primarily to___ ___-infected cells and ____ cells.
Natural Killer (NK) Cells
Cytolytic lymphocytes that do not have a standard type of TCR and have no immunological memory, limited specificity.
Make up only about 5-15 % of the total circulating lymphocyte population.
They function primarily to destroy virus-infected cells and cancer cells.
The NK two receptor system
They have an ____ receptor and a ___ Receptor
These are pretty ____ in different NK cells
How NK cells work:
If ___ activation and inhibitory receptors are engaged, cell is ___
If only ____ receptor is engaged, cell is ____
The NK two receptor system
They have an activation receptor and a Inhibitory Receptor
These are pretty similar in different NK cells
How NK cells work:
If both activation and inhibitory receptors are engaged, cell is spared.
If only activation receptor is engaged, cell is killed.
NK Cells in virus infection
After Viral infection
Get production of ___
Then get ___ cells
___ take longer to be brought into the response
