Immunology Part 2

They are in the BONE MARROW which they leave to go to the SPLEEN

The white pulp of the lymphoid tissue

Follicles

They are involved in the immune response

Follicles called the GERMINAL CENTRE

They move towards the MANTLE ZONE

The MARGINAL ZONE

Some T cells, numerous macrophages

The PERIARTERIOLAR LYMPHOID SHEATH

Specialized stromal cells that are found in the follicle area that is furthest from the central arteriole

No! They do not derive from bone marrow precursors

Lymphoid and myeloid dendritic cells that derive from a common bone marrow derived precursor

In the T cell zone

Composes most of the spleen and is where most defective RBCs are filtered out

Chemoattractant cytokines that stimulate the migration of B, T, and dendritic cells and are crucial in inflammatory responses

CCL19 and CCL21

MIP-3beta

SLC (Secondary lymphoid cytokine)

Stromal cells in the T zone

Connective tissue of an organ, inflammatory cells are a type of stromal cell

Interdigating dendritic cells

A T-cell receptor expressed by T cells that is a receptor for the chemokines CCL19 and CCL21

CXCL13 or B-lymphocyte cytokine, BLC

Follicular dendritic cells

They migrate first to the T cell zone, followed by the B cell follicle

They express the chemokine receptor CXCR5 as well as CCR7 (although in much lower levels)

There are 80 x 10^6 and some do not mature to pre-B if there is a FAILURE TO MAKE A PRODUCTIVE HEAVY CHAIN rearranegment

35x 10^6

-Failure to make a productive light chain rearrangement
-tolerance induction: some B cells undergo clonal deletion if they are reactive to multivalent self-antigens

They are IgM high and IgD low

3 days

They are excluded from lymphoid follicles

Long-lived mature B cells that are already established in the periphery

Survival signals provided by the follicle

1-2 x 10^6 every day

1-2 months

They are IgM low and IgD high

They have immature B cells but fail to develop mature B cells

A signal through the BCR

The BCR repetoire of mature B cells is enriched for certain antigen specificities compared to the immature B cell population- meaning these cells were positive selected for survival

Cytokines and positive signals

The percentage of B cells in the spleen and lymph nodes that survive lowers dramatically

Survival signals

TNF family member BAFF

B-cell activating factor belonging to the TNF family

B1 cells and marginal zone cells

CD5+ B cells

They make their first appearance in fetal developmnt which occurs before the development of conventional B cells

CD5+, high IgM, low IgD

THey bind with low affinity to microbial and self-antigens and are very cross-reactive

Carbohydrate antigens (strongly)
Protein antigens (weakly)

B1 cells do not require T cell help but B2 cells do

Mostly in the peritoneal and pleural cavity fluid

They do NOT express CD5
Low IgM
High IgD

Carbohydrate or protein antigens

Mostly in the lymphoid organs

1)They are derived from a separate line of a unique precursor cell
2)They differentiate to the B1 or B2 phenotype from a cell precursor that gives rise to both

B1-from fetal liver cells
B2- from adult bone marrow

The BCR specificity

-low levels of CD5
-high levels of IgM
-little/no IgD
-low levels of CD23
-high levels of CD21

CD21 (or CR2) is a receptor for the C3 fragment of complement

Carbohydrate and protein antigens

In the marginal zone of the white pulp of the spleen

THey have restricted antigen specificities repertoire that is biased towards common bacterial antigens and self antigens
-They are thought to be possibly positively selected by certain self-antigens

A signal through the Notch1 receptor

The third pharyngeal pouch and the third branchial cleft

The thymic anlage

An underdeveloped thymus

It gets taken over by hematopoietic cells

Blood cells

T cell precursors, dendritic cells, and macrophages

They move to the thymus, where their T cell receptor genees undergo rearrangements

Those that recognize self MHC

Those that interact strongly with self-antigen

In the peripheral lymphoid organs when they encounter foreign antigens

They proliferate and eliminate infection

Just over the heart

In the outer cortical region of the thymus

Immature thymocytes and a few macrophages

On the inner side of the thymus

Mature thymocytes, dendritic cells, and macrophages

Precursors of bone marrow origin committed to become T cells

In the thymic stroma

Cortical and medullary epithelial cells

Before puberty

After puberty, the thymus starts to get smaller so there are less T cells made in adults

Immunity can last because there are long-lived T cells, and mature T cells can divide

The thymus cannot form properly

DiGeorge's syndrome

The condition is similar to mice that have a missing RAG protein. There is a mutation in a DNA dep protein kinase so DNA cannot join at the junctions between gene segments encoding the V region

recombination activating genes encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination.

It does not produced any of the co-receptors and these cells are called double-negative thymocytes

Gamma delta T cells or alpha beta T cells

-Gamma delta T cells are found in the minority and do NOT express CD4 or CD8<BR>-Alpha beta T cells are found in the majority

They give rise to double positive thymocytes

THey express the pre-TCR

Beta chain and a surrogate alpha chain

THey express a TCR and most die

Only T cells whose TCR can interact with self MHC will survive
They lose expression of either CD4 or CD8

They are exported to the periphery

only 5%

V, D, J rearrangement

At two separate locii:
Either alpha and beta or
Gamma and delta

When the gene rearrangements result in inframe DNA sequences that can be translated into a protein

NO.

At the locus that contains the D gene segment (beta and gamma)

D joins J and then V joins DJ

The beta chain associates with an invariant surrogate alpha chain to form the pre-TCR

Produces signals that stop rearrangements at the gamma/delta locus and halts cellular division so that the cell is commited to the alpha beta lineage

They die by apoptosis

V joins J

The alpha chain couples to the beta chain and the cell expresses a TCR at the surface

Four

Kit and CD44 are expressed (not CD25)
-The alpha and beta chains are found in the germline configuration

The alpha chain of the IL-2 receptor

They do not undergo a DP stage and are exported after their DN stage when they are CD3+

Immunoglobulin and T cell receptor genes are said to be in the germline configuration in the DNA of germ cells and in all somatic cells in which somatic recombination has not occured

VDJ recmobination

Kid, CD44 and CD25 are expressed
-D and J (beta) rearrangement starts

DN2 cells become Kit(low) and CD44 (low).
V-> DJ (beta)rearrangement starts
A pre-TCR is formed

Cells with productive beta chain rearrangement pairs with a surrogate pre-T cell receptor alpha chain called pTalpha
-They lose expression of CD25, Kit and CD44

A rearranged beta chain with a pTalpha and CD3+

Causes the beta chain rearrangement to stop and rapid cell proliferation resulting in the loss of CD25

CD4 and CD8 are expressed and the cells become double positive thymocytes

Valpha->J alpha rearrangements starts and expression of TCR at low levels

Only when thymocytes express a TCR that is able to interact with self MHC

They will become either CD4 or CD8 single positive thymocytes

It is involved in signalling

Signalling

It is an adhesion molecule

It is involved in signalling

They are coreceptors

-Absence of D segments
-Rearrange only once after their partner receptor-chain gene has been expressed
-Multiple rearrangements of alpha chain are able to compensate for non-productive joins
-Many kinds of alpha chains can be made per T cell

Rearrangement of TCR alpha chain occurs until a selfpeptide MHC postively selects the receptor

Only one receptor can reecognize an antigen presented by a self MHC

80%

Yes, they usually contain a gamma chain that is out of frame

beta, gamma and delta

A productive rearrangement at both gamma and delta gene

Both a gamma delta T TCR and a pre-TCR tha thas a beta and pTalpha chain

B chain expression is turned off

The cell turns off gamma and delta chain expression. Beta chain rearrangement is inhibtied
Proliferation is stimulated, expression of CD4 and CD8 is induced and alpha chain rearrangement occurs

Gamma delta TCRS

Epidermis and dendritic epidermal T cells

T cells that are trapped between keratinocytes and look like dendritic cells

At the reproductive epithelium

All cells assemble the same V gamma and V delta regions

There is no TdT expressed in fetal T cells, and therefore there is no addition of N nucleotides

Vgamma5

Cgamma1

Vgamma6 (the most proximal gene)

In the reproductive tract

The same delta chain

The T cells are produced constantly

95% are alpha beta

Their receptors are more diverse because they have different V segments used, and also N nucleotides are added (due to expression of TdT)

A peptide presented by an MHC

A combination of MHC molecule and peptide

The generation of the mature T cell population whose repetoire is MHC restricted

A type of transfer that occurs when one MHC genotype is transfered to an irradiated mouse of a different MHC genotype

All hematopoietic cells are killed

Hematopoetic cells are transferred so the mouse can now generate progenitors and the recipient will now have T and B cells (before they were lost due to irradiation)

The original MHC genotype (because these cells that were not hematopoeitic stem cells are radioresistant)

That of the donor (because all of the recipient ones were wiped out by the radiation)

The expression of MHC molecules is co-dominant

Cells of bone marrow origin express both A and B (from the two alleles) and the rest express only one

In the mouse chimera experiment, T cells can respond to both, so the response is restricted to the type of MHC the recipient has

The thymic stroma

The thymic stroma determines the MHC restriction

Take a nude mouse (defect in thymus epithelium) and do a thymic graft with only MHCa genotype. The other cells are express both A and B type MHC, but only A is recognized, meaning that the stroma determines which MHC type the T cells will recognize

Inhibits rearrangement of endogenous alpha and beta chain genes
-T cells produced express apha/beta genes of the transgene

Only if the mouse thymic stromal cells also express MHCa

The double positive CD8+/CD4+ stage

Cell death in the thymus

The specificity of the TCR for self MHC

Only cells that will continue in the maturation process are the CD8+ T cells

Those expressing a co-receptor that binds the same MHC molecules as the TCR

CD8+ T cells and a few abnormal CD4+ cells

They have CD4+ T cells and a few abnormal CD8+ T cells

They have BARE LYMPHOCYTE SYNDROME

Engagement of both the TCR and the co-receptor with an MHC molecule

Lck signals are more effectively delivered when CD4 rather than CD8 is engaged as a co-receptor, resulting in either CD4 or CD8 lineage commitment

-The cells downregulate both CD4 and CD8
-They upregulate CD4
-Selection occurs at this stage

-There is a sustained signal mediated by Lck
-Induction of Th-POK TF
-Resulting in differentiation along CD4+ pathway
-Loss of CD8+ expression

CD4+ is not ligated, therefore there is no further signalling through Lck and no induction of Th-POK
-This results in differentiation along the CD8+ pathway and the loss of CD4+ expression

The cortical epithelial cells

Through the medulla and migrate to the cortex

DN4

At the cortico-medullary junction

In the medulla

They constitutively express BOTH MHCI and MHCII so they can mediate the expression of both T cell types

They are deleted in the thymus

Autoimmune regulator

Stromal cells in the medulla

An autoimmune disease called autoimmune polyglandular syndrome type I

T cells that recognize tissue specific self-antigens

Throughout T cell development

Thymic cortex, medulla

They are improtant in negative deletion of T cells that are too reactive to self-antigen

The T cells are not reactive to MHCb but the bone marrow derived dendritic cells and macrophages have induced tolerance to MHCb

They migrate to the peripheral organs

Only a small number of mature thymocytes are exported to the periphery (1-2x10^6 per day)

They need contact with self-peptide/MHC complexes to survive

On the lymphoid subset of interdigating dendritic cells in the T-cell zone of the lymphoid organ

A signal important for survival of T lymphocytes in peripheral lymphoid organs

1) Highly specific recognition of foreign antigens with potent mechanisms for pathogen elimination
2) A vast universe of distinct antigenic specificities
3)The capacity to display immunological memory
4) Tolerance to self antigens

Once we recognize a given antigen and generate an inflammatory response against it, the immune system has engineereed within it the genetic and cellular capacity to retain memory.
-Consequently, if one is rechallenged with the same antigen then the response will be alot swifter with a possible greater capacity to eliminate the threat

-In order to have the capacity for specificity
-To have memory for the case of reinfection
-Have a system that is capable of fine tuning itself

The dose or the route of ingestion of the pathogen

The strength of a given response to a particular antigen

-The timing and stength of the signal that goes into the particular lymphocyte
-How the lymphocyte integrates the incoming signal into a response

Efficiency of the reponse

Isotype switching often requires optimal T cell signalling

They are inflammatory

It evaluates the external and internal environment. If there are alot of extracellular pathogens, it would be better o have an antibody mediated response, however if there are intracellular pathogens or tumor cells, the antibody response would most likely be inefficient

The microenvironment and the quality of the signals that are going through the T cell receptor and accessory proteins

Cell mediated immunity

Humoral immunity

They are helping B cells to undergo isotype switching as well as to secrete their antibodies to caot and neutralize extracellular pathogens

Interferon production

A wide variety of cells in response to infection by a virus

Activating APCs, enabling them to undergo metabolic activities that allow them to try and wipe out the intracellular pathogen (virus)

CD8 Cytotoxic T cells, CD4 Th1, CD4 Th2, and CD4 Th17

Most of the time (but not ALL the time) the role of these lymphocytes are to suppress/regulate/fine tine the immune response

It has no experience with an antigen

It has a state of functional competency

It provides the recall capacity for immune responses

Dendritic, macrophages, B cells

Antigen processing and presentation

The thymus and bone marrow

The lymph nodes and spleen

The anatomical locations of the immune system that enables migrating/trafficking lymphocytes to potentially encounter a potential antigen that is or is not a threat

Via the blood through the area of the endothelium known as the high endothelial venules (HEV)

In the lymph node cortical region

They enter an area with a variety of T cells

2-3 times

It searches for APCs that present the correct antigen

They are retained and permitted to survive

The T cells leave via the cortical sinuses to return to the blood and continute to another lymphnode

Dendritic cells

Programming of cell division, resulting in an increase in activated T cells

THey acquire an effector function

THey are no longer attached to dendritic cells and also leave the lymph node to go to the tissues

They are molecules on the leukocytes that mediate the initial rolling event on the HEVs

Another name for L-selectin

It is the primary anchor that enables cells that are travelling quite rapidly to attach themselves to the HEV, slowing down the cell

Integrins

LFA-1

Diapedesis: movement of leukocytes out of the circulatory system to the infected tissue

Increases its permeability

Extracellular proteins of the endothelium of venules that bind surface homing receptors of T cells

Sulfated sialyl Lewis
-CD34
-GlyCAM-1
-MAdCAM-1

CD-34 and GlyCAM-1

MAdCAM-1

Upon Ag encounter

The T cell can migrate away from the lymph nodes and remain in the tissue

T-cell activation

That we have a memory cell

It has a role to play in the types of signals that are transmitted down from the dendritic cell to the T cell

-Selectins
-Addressins
-Integrins
-Ig Superfamily

An integrin that interacts with intracellular adhesion molecules

ICAM-1, ICAM2, ICAM3

Mac-1

DC-SIGN (a cell surface protein found on the surface of dendritic cells)

Activated vessels, lymphocytes, and dendritic cells

Resting vessels

Naive T cells

THe level of inflammation and activation

To specifically navigate to environments with a certain level of activation

VCAM-1

On activated endothelium

VLA-4 (Very Late Antigen-4)

They lose the expression of L-selectin but gain the expression of VLA-4

The Heme contains Iron which it uses to attract an oxygen molecule.

ICAM-3 is expressed not on the APCS or endothelium but on the T cell itself

Part of the immunoglobulin superfamily of molecules

CD-58(LFA-3) in humans, CD48 in mice

Heterodimers of alpha and beta chains

Alpha1
Beta 2 chains

Adhesion molecules in the lamina propria that express receptors for beta7 and alpha4 found in LPAM-1

The lamina propria is a thin layer of loose connective tissue which lies beneath the epithelium and together with the epithelium constitutes the mucosa.

L-selectin

VCAM-1 is upregulated on activating endothelium, while in resting endothelium, it is largely MAdCAM-1

They both have the same alpha-4, but differ in that VLA-4 has beta 1, and LPAM-1 has beta7

Allows the thymocytes to move away from the lymph nodes and go to the tissue where the danger is

Through a low affinity LFA-1/ICAM-1 interaction (NO TCR MHCII interaction yet)

Through the low affinity interaction between the LFA1/ICAM-1

Results in a conformational change

An increased affinity for its ligand (ICAM-1) resulting in an increased strength and duraction of APC/T cell contact

In the alpha component

The interaction between LFA-1 and ICAM-1 would be lost, leading to a loss in T cell activation

LFA-1
L-Selectin
CCR7

Sulfated sialyl-lewisx moieties on the vascular addressins CD34 and GlyCAM-1

A chemokine receptor

CCL21

L-selectin to either glyCAM-1 or CD34

Initiation of the rolling mechanism of the leukocyte

By binding to soluble chemokines SLC (CCL21)

It increases its affinity for its cognate ligand ICAM-1

CCs and CXLs

CXL12 and CCL21

HEV's, Lymphoid tissue stromal cells, activated dendritic cells

Migration of the T cells through the HEV's into the lymph node cortex

A G-protein coupled signal through its receptor CCR7

There is a loss of CCR7 expression

To leave the lymph node compartment and influx the necessary non-lymphoid tissue so that inflammation can occur

It acts in conjunction with the loss of L selectin and the acquisition of VLA-4

Activated cells and some memory cells

Central memory cells
Effector memory cells

To engage themselves upon subsequent reactivation

TO remain dormant or to reside in lymph nodes for the purpose of self-renewal

To ensure that memory cells are still there

Naive cells and a portion of central memory cells

It is a cell that has the capacity to recognize antigen but that hasn't been exposed to the corresponding antigen by the APCs. They actively circulate through the lymphoid tissue

They change their phenotype (protein expression)

How that cell will localize and function

It is instructed to proliferate, undergoing clonal expansion

Certain T cell lines were not able to proliferate if the APC was not in some way stimulated itself

B7 binds to CD28

B7 is a molecule on the APC

A molecule that is constitutively expressed on T cells

When the T cell is activated, B7 molecules are upregulated, enabling it to be ligated to CD28, resulting in the 2nd signal

To produce IL-2 (interleukin-2)

It is a growth factor and a critical autocrine signal for driving cellular proliferation

IL-2 receptor genes

T reg cells

5-10%

They are anti-inflammatory, immunosuppressors

The Ig superfamily

B71 (CD80)
B72 (CD86)

The same APC

They become anergic (nonresponsive) or tolerant

They can recognize the antigen but they cannot proliferate since signal 1 is not sufficient to induce proteins in the Il-2 pathway

Activation, cell cycle progression, proliferation, survival, etc...

-Either they are 2 independent pathways, or if signal 2 somehow enable signal 1 to act in a different way

NO

No, even if the T cell were to detach and see a dendritic cell, and even in the context of co-stimulation, it will not be able toa ctivate

If the bacteria is present in the environment of an APC presenting non-bacterial proteins, it can provide the signal for the induction of B7, engaging CD28 on the T cells and breaking tolerance

Through complement, or pattern recognition of LPS by TLR-4

The APCS arent providing the necessary costimulation to the T cell, and therefore B7 is not induced and CD28 wont be engaged

Enhances the immune response to an antigen (increases the activation of the T cell)

It has 3 subunits

It only has two subunit structures: the beta and gamma chain

It is largely intracellular a its role is more for signal transduction rather than IL-2 binding

The alpha subunit is expressed

CD25

TO give the receptor high affinity binding to IL-2

It chaperones IL-2 to the gamma and beta chains allowing the signalling to increase
-Can also make T cell secrete IL-2

It blocks IL-2 production

Transplant patients to suppress the anti-graft responses

It blocks signalling through the IL-2R

THe CD40 and CD40L pathways

Constitutively expressed on APCs

After signal 1 is delivered, the T cell upregulates CD40L

-Upregulation of CD28 in T cell
-Activation of CD4+ or CD8+

Short clonal expansion upon immunization with antigen (signal 2 is required for proliferation!)

Plasma cells

1) Antigen binding to BCR
2) Second signal depending on antigen type

1) BCR transmits intracellular signal required for gene transcription in order to differentiate
2) Antigens are taken up and degraded and presented by MHC II molecules

Thymus dependent antigen
Thymus independent antigen

Help from a CD4+ cell

-There is an interaction between CD40L on the T cell and CD40 on the B cell
-T cells can also secrete cytokines that bind to receptors on B cells

Usually proteins

The delivery of an antigen by itself onto receptors other than the BCR

Microbial constituents

Bacterial polysaccharides

B cell can only be activated by helper T cells that respond to the same antigen

No- they do not need to be the same, just linked (for instance, different portions of the same antigen)

For instance, in viral infections a B cell might recognize the viral coat but present proteins from instide the viral particle to the T cell
-In this case, the antigen is considered to be the WHOLE virus

Meningitis

The body has a weak response against the TI bacterial polysaccharide. If the polysaccharide is linked to the tetanus toxoid, which we are already strongly immune against
-B cells specific for the polysaccharide will recognize the vaccine and will internalize it and present the tetanus toxoid portion to T cells, which will stimulate the B cells to produce antibodies against the polysaccharide (which they are specific for)

CD154

IL4, 5, 6

This is necessary for the proliferation of B cells

B-cell differentiation

A co-stimulatory molecule that binds to B7-RP on B cells that is required for B cell proliferation and differentiation in response to TD antigens

The isotype of the heavy-chain constant C domain

IgM, IgG3, IgG1, IgG2b, IgG2a, IgE and IgA

The association of the heavy chain C domain with a heavy chain V domain to form a full antibody during an immune response.

CD40L and cytokines when there is positive reactions between B and T cells

They have abnormally high levels of IgM

X-linked hyper IgM syndrome

Since CD40L is involved in isotype switching, they have difficulty in this process and since IgM is the first antibody produced, there is alot of it produced since no switching occurs

IgG1 and IgE

IgG3 and IgG2a

They do so by stimulating the production of mRNA transcripts from the switch recombination sites

The 5' end of each heavy chain C domain except before IgD

No!!!

Switching to IgG2b and IgA

R-loops

Regions of DNA that form bubble-like structures

AID, APE1, and UNG

They cause ss nicks in the DNA on both strands

It recognizes the ds nicks and induces double strand break repair

Two switch regions (ex: miu and epsilon) to join together

The intervening sequences are excised, resulting in the selected constant region being acjacent to the VDJ region

-All isotype switching is productive
-It does not use RAG enzymes
-It occurs when a mature B cell encounters a foreign antigen, not during B cell development
-It is not random

All switch regions are located within introns, so no frameshift mutation can result

Its directed by signals by helper T cells

1x10^4 - 1x10^6

1x10^8-1x10^12

In follicles

Paracortical area

PALS (Periarteriolar Lymphoid Sheath)

T cell area

Trapped at the border of the B cell zone and the T cell zone

It expresses adhesion molecules and chemokine receptors

Stimulates B cell proliferation

A few B cells and their cognate T cells migrate a tthe border of the T cell area and red pulp where they proliferate even more

5 days after infection with an antigen that has not been previously encountered

Plasmablasts

Cells that have begun to secrete antibodies and are still dividing

They can stop dividing and die, or differentiate into short-lived plasma cells that secrete antibodies

They will travel to the follicle and form a germinal center

Sites of rapid B cell proliferation and differentiation

Rapidly, every 6-8 hours

They reduce their expression of surface antibodies

Centroblasts

Centroblasts proliferate to form this in the germinal zcenter

Centroblasts reduce their rate of division and start re-expressing high levels of surface antibodies

To the zone rich in follicular dendritic cells

The light zone of the germinal center

The B cells that were in the follicle before the development of the germinal center and are not involved in the immune response are displaced to the periphery of the germinal center to form this

A gradual increase in the affinity of antibodies for the antigen

Somatic hypermutation
Clonal selection of B cells

DNA point mutations in the immunoglobulin V region genes

Somatic hypermutation has produced antibodies with high affinity for antigen

In the germinal center

Dividing centroblasts

At a high rate - 1 bp/1000 per cell division

1bp/10^10

On the surface of the progeny of the centroblasts: centrocytes

-No longer recognize antigen
-Bind antigen with a lower affinity than previously
-Bind antigen with a higher affinity than previously

They stay bound to antigen and associate w/ appropriate T cells
-The high affinity increases the cels chance of interacting with T cell and thus for proliferation and survival

-Ag:Ab:complement complexes
and Ag:Ab complexes bound to the Fc portion of Igs and to the complement receptor on the surface of the FDC

B-lymphocyte induced maturation protein-1

-Controls the differentiation of plasmablasts
-Represses transcription of genes needed for B cell proliferation, class switching, and affinity maturation

The ability to present Ag

Plasma cells have low surface Igs but secrete Abs at high levels

Their ability to bind antigen exposed on FDC

Some in the bone marrow, others in the red pulp

They express surface Ig but do not secrete antibody at a high rate
-They have the same changes as their precursors (rearrangements, mutations, isotypes, etc..)

TI-1 and TI-2 (They activate B cells by different mechanisms)

It would induce the proliferation and differentiation of B cells in the absence of specific antigen binding to surface Ig

The fact that many different clones of B cells can divide in the presence of a high concentration of TI-1 antigens, regardless of their surface Ig specificity

Polyclonal B-cell mitogens (polyclonal activators)

Something that induces proliferation

Only B cells specific for the TI-1 molecules are activated

They do not induce affinity maturation or memory B cells that require T cell help

LPS

Bacterial cell wall and capsular polysaccharides that are highly repetitive structures

Only mature B cells

They are inactivated by repeittive epitopes

Most of their B cells are immature. B1 cells and marginal zone B cells are good responders to TI-2 antigens

5 years

Most TI-2 responses, because they accumulate with age (do not recirculate)

To cause extensive aggregation of the BCR

Sufficient signal transduction to induce proliferation and IgM secretion by B cells

A TNF cytokine that is secreted by dendritic cells when the cells are thought to bind Ag though innate receptors

Increase Ab production against TI-2 Ag, induced isotype switching

Helping the ingestion and destruction of the pathogens (opsonization) (dendritic cells have receptors for Abs that are bound to antigen)
-presentation of bacterial peptides with MHC
-stimualting T cell response

-Production of antibodies
-Prevent spreading of intracellular pathogens
-Destroy extracellular microorganisms

Antibodies prevent viruses entering the cell by binding to the pathogen and preventing their binding to specific molecules on the surface of cells

By coating the pathogen, Abs can facilitate the uptaking and destruction of the pathogen by phagocytic cells that express receptors that recognize the Fc portion of the Abs

Enhancement of opsonization and complement can destroy pathogens by forming pores in the membranes

Because pathogens can enter the body by different routes

IgM

Low

It has high avidity because it forms a pentamer and therefore has 10 Ag binding sites

The sum of the total strengths of binding of two molecules or cells to one another at multiple sites

Affinity is the strength of binding of one site on a moelcule to its ligand
Avidity is the sum of the total strengths (so all of the IgMs together in the pentamer)

It is alot larger

IN the blood and lymph

So they can diffuse easily from the blood to the tissues

The complement cascade

Monomer

Monomer

Dimer

High

IgG

Opsonization and activation of the complement cascade

In secretions (the mucus of the intestinal and respiratory tracts)

Neutralization, and lesser in opsonization and activation of complement

At low levels in the blood and ECF (main is IgG)

Receptors on mast cells

Beneath the skin and mucosa and along blood vessels in the connective tissue

Activation of mast cells

Mediators that function in expulsion of the pathogen

They cause coughing, sneezing and vomiting that result in the mechanical expulsion of the pathogen

When the IgA in its dimeric form binds through its Fc portion to the poly-Ig receptor present on the basolateral surfaces of the epithelium, resulting itn its internalization and transport in vesicles to the luminal side of the epithelial cell

The poly-Ig receptor is cleaevd and its extracellular portion remains attached to the Fc portion of the IgA

The secretory component

Gut, respiratory epithelium, lactating breast, salivary glands, tear glands

Protection of epithelial surfaces from infectious agents through neutralization

Prevents attachment of bacteria, virus or toxins to epithelial cells

It is secreted in the breast millk and transferred to the gut of the newborn infacnt where it provides protection from newly encountered bacteria

Maternal IgG

Across the placenta directly into the bloodstream of the fetus

Due to the IgG transport protein in the placenta called FcRn

2 FcRn proteins bind to a single IgG, and they bind to the Fc portion of the IgG

To regulate the level of IgG in serum and other body fluids

Proteins that are secreted by bacteria, and are common disease causing molecules

-They bind to receptors through a binding domain on a polypeptide chain
-They carry out their toxin function by another polypeptide chain

By binding to the receptor binding domain, thus preventing the toxin from entering the cell and thus acting as a neutralizing antibody

IgG

They diffuse easily in ECF and have high affinity

IgA

At the mucosal surfaces of the body

High affinity IgA and IgG

They bind to viral receptors and block binding of a virus to host cell surface receptors or they block the subsequent entry of the virus

Cell surface molecules of bacteria that enable them to bind to the surface of host cells, and this adherence is critical for the bacterium to cause disease

An adhesin of Neisseria gonorrhoeae

The bacteria can adhere to the epithelial cells of the urinary and reproductive tract

By the classical pathway

Antibodies bound to the surface of the pathogen bind C1q

IgM and IgG

Six globular heads joined to a common stem by long filaments

Each globular head can bind to 1 Fc domain

2

No. The pentameric IgM has a planar conformaiton that does not bind C1q

When the IgM binds to the pathogen surface, this changes its conformation and exposes the binding sites for C1q heads

Small soluble antigens form Ab:Ag complexes

Through activation of complement

The binding of C4b and C3b to these complexes

They are transported by erythrocytes

C3b (bound to complex) binds to the CR1 on the erythrocytes

Macrophages bearing receptors for bound complement components and the Fc portion of the Abs remove the complexes from the RBCs for degradation

On the basement membrane of small blood vessels

Renal glomerulus

On the basement membrane of small blood vessels

Renal glomerulus

Blood is filtered to make urine

The renal podocytes

It is an autoimmune disease caused by excessive levels of immune complexes that accumulate on the renal podocytes

Kidney failure

A family of receptors that bind to the Fc portion of Abs

An antibody of one isotype or closely related isotypes

The alpha chain

The gamma chain

The zeta chain of the TCR

The alpha and gamma chains are fused into a single chain receptor
-It bind IgG1

They are a single chain receptor that contain an ITIM motif
They both bind IgG1

An immunoreceptor tyrosine-based inhibition motif is a conserved sequence of amino acids that is found in the cytoplasmic tails of many inhibitory receptors of the immune system. After ITIM-possessing inhibitory receptors interact with their ligand, their ITIM motif becomes phosphorylated by enzymes of the Src of kinases, allowing them to recruite other enzymes such as the phosphotyrosine phosphatases SHP-1 and SHP-2, or the inositol-phosphatase called SHIP. These phosphatases decrease the activation of molecules involved in cell signaling

They need to be cross-linked

Antigen bound antibodies (not free)

Bacteria coated with IgG and complement are more readily ingested

IgM

It can activate complement, which can interact with complement receptors

Macrophages and neutrophils

Eosinophils

They release toxic contents directly onto the parasite

NK cells can kill virally infected host cells by binding antibodies

FcgammaRIII

IgG1 and IgG3

This triggers the release of cytoplasmic granules containing perforin and granzymes

They are found in the vascularized connective tissue just beneath the body epithelial surfaces (gastrointestinal tract, respiratory tracts, dermis)

Histamine

Making local blood vessels more permeable, resulting in the influx of polymorphonuclear leukocytes, macrophages, eosinophils, and lymphocytes

FcgammaRIII
FcepsilonRI

Basophils and eosinophils

Free IgG has a low affinity for Fcgamma receptors, but Free IgE has a high effinity for FcepsilonRI

Mast cells are usually found associated with IgE

When the bound IgE is cross-linked by multivalent Ag

Recruitment of effectors
Flow of lymph to regional lymphnodes
Trigger muscle contraction leading to physical expulsion of pathogens

CTLA-4

When B7/CD-28 signals, CTLA-4 is upregulated

It resembles CD-28 and competes for binding to B7. It has a higher affinity for B7 (20x) and therefore as CTL-4 increases, there is a shift towards preferential binding of B7 to CTLA-4

Autoreactive T cells and any activated cells

Inducible co-stimulators

Only in activated T cells (not naive)

ICOS-L

Activated dendritic cells, monocytes and B-cells

CD-28

IL-10

A cytokine that is immunomodulatory and immunosuppressive

OX40, CD30, 4-IBB, CD27

On CD8+ T cells

Through APC:
1)CD4 activates APCS through CD40/CD40L pathway
2)CD4 cells produce IL-2
3)4-IBB on the T cell, 4-IBBL on the APC

The APC can activate the CD8+ T cell (that has the 4-BB molecule) to increase Il-2 produciton, as well as differentiation and proliferation

Super Molecular Activating - it is formed of the proteins in the contact area between the T cell and the APC

LFA molecules are in a dense core surrounded by TCR and costimulatory molecules

pSMAC (peripheral SMAC)

The central SMAC

THe actin cytoskeleton is rearranged, and the dense core of the LFA is shifted to the outside and the TCR goes to the inside

LFA1/ICAM-1

TCR, CD4, CD8, CD28, and CD2

L-selectin, TCR and LFA-1, CD4

LFA-1

TCR, L-selectin

VLA-4 and CD-44

A receptor for HA, part of the Extracellular matrix

T cell is given another capacity to leave towards non-lymphoid sites

A Cell-surface molecules on CD4 cells

RA and RO

A naive T cell is CD45RA+ and CD45 RO-

Upon activation, the isoform of CD45 expression changes, by alternative splicing of the RNA transcript of the CD45 gene, so that activated T cells express the CD45RO isoform and are now CD45RA-

There are more activated T cells, thus the individual saw a sufficient number of antigens

Mast cells, Mononuclear phagocytes, but not T cells

It binds to S1PR on naive T cels, and regulates T cell movement in the lymph nodes and spleen and their chemotaxis in non-immune tissues

S1PR is downregulatd.

The exiting of the T cell allowing proliferation and differentiation. A few days later, the S1PR is re-expressed, allowing the effector cell to go to the non-immune tissue

A "coctail" of inflammatory cytokines

IL-1, IL-6, IL-12

Through downregulation of the 1st + 2nd by CTLA-4, which are required for APC to provide sgnal 3

TLR-4

TLR-9

-Dendritic cells
-Macrophages
-B cells

Dendritic cells

Macropinocytosis

Large amounts of extracellular fluid are taken up into an intracellular vesicle, allowing alot of antigen to be taken up from the surroundings

They may prresent peptides from their phagocytosed foreign material

They take up antigen that binds to their BCR and may present via MHC class II if induced

After infection

In the peripheral tissue

MHC Class I/II, LFA, ICAM-1, DEC 205, DC-SIGN

Immature dendritic cells are better at uptake and presentation
Mature dendritic cells function more to co-stimulate effector cells

In the lymphoid tissue

MHC I/II, LFA, DC SIGN, ICAM-2, B7 1 and 2, CCR7

DEC 205

It is important for DC homing to cortical regions of the lymph node

Plasmacytoid have only MHC II, B7 and TLR-7/9
They are important in innate sensing and in anti-viral responses

Plasmacytoid have a preferential capacity to secrete Alpha/beta interferon

Immature DCs

Via TLRS, PAMP activates and induces CCR7 expression. CCR7 will direct the migration of dendritic cells into the lymphoid tissue and augment the necessary co-stimulation, leading to maturation of the DC in the cortical tissue of the spleen/lymph node

The cytokine environment

IL-12 and IFN gamma

Il-4

IL-2 and IFN-Gamma

-Produce cytokines for activating CD8+ cytotoxicity
-Delayed hypersensitivity
-activate macrophage APCs
-stimulate B cells to produce opsonizing IgG

IL-4,5,13 and Il-10

Provide essential help to Ag-specific B cells resulting in B cell activation and IgA, IgE, and IgG formation
-Found in asthma and allergic responses due to prominent eosinophil responses

Dendritic cells

T-cells, but can also come from basophils

Inhibit TH2 differentiation by counteracting the effects of IL-4 (also activates macrophages in concert with IFN gamma produced by CD8 and NK cells)

Stat1 and Stat4

Stat3

Through the presence of TGF-beta1 and IL-6

Transforming growth factor beta 1

TH17 cells produce Il-17

It is important for the recruitment of immune cells to inflammatory sites

Extracellular pathogens

-Autoimmune disorders such as multiple sclerosis
-Gut associated pathologies

IL-21 and IL-23

Sustains the transcription faror RORgammaT

RAR-related orphan receptor gamma T

TR1/TH3 cells

They are important in the gut immunology and the mucosal associated lymphoid tissues (MALT). For instance in tolerating foreign antigens, or in tolerating commensal bacteria

Sometimes, the release of IFN-gamma by TH1 cells is needed to establish antibody production (of IgG3 and Ig2A

THe dominance of a cell type determines the nature of the response

Neutrophil recruitment

IL-17, secreted by Th17 cells, is a primary neutrophil recruiter

They produce Il-10, which regulates Th1 cells

IL-3, TNF-alpha, and granulocyte macrophage colony stimulating factor (GM-CSF)

Granulocyte-macrophage colony stimulating factor

Support production of granulocytes, myeloid cells, and dendritic cells

All cells of the blood lineage except lymphocytes

Inhibitory, but can have immunostimulatory effects in the form of antibody production (for instance of IgG2b and IgA

IgA and IgG2b

Some TH1 cells can produce IL-17, and some TH17 cells can produce IFN-gamma

Th2 cells suppresses Th1 responses by IL-10 acting on APCS to suppress co-stimulation of HLA-B71 and HLA-B72

It can directly inhibit its proliferation and it can also inhibit the activity of the TF GATA3

By Il-4 and IFN-gamma inhibition of the TF RORgammaT

Through activity of CD40L on the T cell surface and the secretion of IFN-gamma by the T cell

IFN-gamma will act on the infected macrophage to enable it to secrete the necessary oxygen radicals and nitric oxide as well as the cytokine TNF-alpha

TNF-alpha acts in an autocrine manner, directly triggering its own receptor on the macrophage surface.
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By TH1 cells

It activates the intracellular killing mechanisms
-It increases the magnitude of the Ag presentation

Sensitizes the APC

When TH1 cells try and activate macrophages, and the bacteria tries to inhibit the TH1 response

Inner- multinucleated giant cells
Outside of core: Epithelioid cells
Periphery: Ring of immune cells (T cells)

Through Fas ligand and LT-alpha

The proliferation of other antigen-specific cells

The differentiation of stem cells and proginetors in the bone marrow

They activate the endothelium to induce macrophage binding and exit from the blood vessel

A chemokine produced by TH1 cells that is important for the accumulation of the immune cells at the site of infection

THey condition the B cell to produce the immunoglobulin

CD40L/CD40 interaction

It helps determine whether the cytotoxic cell should perform its function, ie. it determines whether or not the target cell is infected

It will bind via LFA-1 to the target cell

MHC class I presentation will then occur, then T cell receptor signalling and co-stimulation

on account of, because of

It perforates and creates channels in the target cells through which products like granzymes can navigate through

They enable the activation of apoptosis

It has anti-microbial actions, can induce apoptosis

BID and an inactive form of caspase 3: pro-caspase 3

They TRUNCATE BID, leading to disruption of mitochondrial activity, activation of caspase 3, and intiating cleaving events of the target cell DNA to target the cell for apoptosis

It can activate them

Production of large amounts of IFN-gamma

development of TH1 cells, which can act on dendritic cell to wipe out microbe

They can secrete IL-4 which supports the development of TH2 cells

The dendritic cell produces TGF-beta 1, and little IL-6, CD4 T cells produce FoxP3, resulting in a regular pheontype

T reg cells can suppress any of the two primary helper cells

Dendritic cells produce IL-6, which in conjunction with TGF-beta1, results in
-RORgammaT expression
-Synthesis of IL-17
-Neutrophil recruitment
(Therefore shifts to TH17 response)

There must be a release of immunosuppression to enable the system to counteract the infection
-This is done by deactivating Treg cells

Through the action of cytokines IL-12 and IL-18

NO- they could target related epitopes

Inflammation can spread in an antigen non-specific way and therefore must be controlled

Fas ligand, and TNF-alpha/beta

Fas and TNFR-1 respectively

They have cytoplasmic death domains, resulting in programmed cell death

Activated lymphocytes

T cell develops in the periphery
T cell develops endogenously in the thymus

It is made in the thymus, moves to the periphery, makes contact with the APC and becomes an effector cell

Post thymically or peripherally induced regulatory cells- nTregs

A FoxP3 cell so that it can control the T helper response

THymically derived, naturally occuring regulatory cell - iTregs

They are immunosuppresive in the thymus (born immunosuppresive)

Il-2 receptor alpha chain

1-10%

They cannot make their own IL-2 unless provided, which only when provided can they be activated

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Scurvy is related to immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Through deleting FoxP3, then there is no development of the regulatory cells, resulting in autoimmunity/uncontrolled immunity

1-silent
2-Acute
3-Chronic

The pathogen enters the host but doesn't affect the immune response
The pathogen creates its home

Parasite numbers decrease due to the increasing size of the granuloma

The granuloma size plateaus, and the infection is not completely cleared. For the rest of the persons life, the a small number of parasites still lives

Yes- we have life long immunity and are completely resistant to it

In Il-10 FoxP3 cells, there is increased susceptibility to infection, but a complete resistance to secondary infeciton
In IFN-gamma producing T cells, there is an increased resistance to primary infection, but a high susceptibility to secondary infection

After the threshold of activation in which the infection is established

There is the initial phase of slow increase to the threshold of activation, but then the infection becomes completely uncontrollable

During the initial phase, the innate system is capable of contolling the infection

It is an essential protein that is required for innate signalling through TLRs

IL-12 and IFN-gamma levels are not high enough

-It discriminates between self and non self
-It is specific for donor tissue antigens
-It induces specific immune memory

-Graft from one body part to another
-In between genetically identical twins
-Between inbred partners

Males express a unique Hy antigen, that the females do not and therefore it is 'non-self"

Unrelated grafts
Fraternal twins

Isografts (or autografts) are always accepted

Allografts (or homografts) are always rejected

Yes

No

Major Histocompatibility Complex

6

Complement proteins, tumor necrosis factor, minor blood groups

A,B,C

Polymorphic and presents antigenic peptides derived from foreign material

E, F, G

Monomorphic, and have limited antigen presenting ability

MHC I are 8-12 aa long
MHC II are 12-18 aa long

Chromosome 15

The same as MHC, chromosome 6

In the groove- this is where the peptide binds

6- each set of haploid genes encodes 3 MHC antigens

B cell smIgR receptors can bind to whole antiegns
T cells can only bind to antigens on MHC

B cells look outside of soluble proteins
T cells look at amino acids that come from any part of the molecule

The Th cells of the recipient
They will activate if the MHC antigen is NOT the same!

If thymidine uptake increases, this means that the T cells are proliferating and thus are responding to the graft

1-10%

There is a poor proliferative response, and some activation of cytotoxicity

There is a strong proliferative response and no cytotoxic response

When they have the same MHC as the donor

A mouse of a different MHC type

There are self-proteins from the donor that are recognized as foreign

Endogenous: viral, parasitic and cancer

Exogenous: bacterial, funal and parasitic

Low affinity to autologous MHC/ self peptide and high affinity to non-self
High affinity to allogenic MHC antigens

Low affinity to autologous MHC/peptide

If the MHCs arent compatibile, the overall affinity is low
If the MHC does not have an affinity for the peptide being presented, the affinity is low
However, sometimes, the MHC has high affinity for the MHC and this results in a response

MHC dominant binding is stronger than than epitope binding

Macrophages can process and present foreign MHC

MHC II+ donor B cells or macrophages

Travel from the graft to regional lymph node where they activate T cells and TH cells

Using complement and specific antibodies that cause the lysis of MHC allele positive cells

By trypan blue, which shows the number of viable cells
Ethimidium bromide stains dead cells

Using Multiplex PCR with many allele specific primers

Th cells

Reduces Il-2 or blocks IL-2 response

Used to target proliferating cells

The IL-2 response

Attacks cells going from Go to G1

Eye, brain, testis, uterus, hamster cheek pouch

They do not reach the regional lymph nodes and fail to activate a strong immune response

TGF-beta

Transferring from an immunocompetent host to an immunocompromised patient

The T cells of the host will react to the host cells as foreign and kill them

Donor stem cells can be rejected by T and NK cells

-Match donor and recipient MHC I/II
-Deplete graft APCs or neutralize donor MHC-II with anti-MHCII antibodies
-Deplete recipient T/Th cells w/ anti-CD4 or CD8 antibodies
-Suppress cytokine function (ex Cyclosporin A)
-Induce tolerance to MHC at birth