almost know (3) Flashcards
L14- Regulation and tolerance?
Central tolerance (thymus) is not effective 100%
(Self-Ag specific cells are detectable in healthy and diseased individuals’ peripheral
blood)
Cells in the periphery (blood, tissues) can control the activation of the immune system:
peripheral tolerance.
dual roles of immune regulation and tolerance in determining the outcome of immune responses. Effective regulation ensures a balanced immune response, facilitating clearance of infections or tumors while preventing excessive inflammation. Dysregulation, however, can lead to chronic inflammation and autoimmunity, where the immune system mistakenly attacks healthy tissues. On the other hand, immune tolerance mechanisms, which suppress overactive immune responses, are essential for preventing allergies, maintaining tolerance to self-antigens, and ensuring graft tolerance in organ transplantation. However, excessive tolerance can also allow undesirable outcomes, such as chronic infections persisting due to immune evasion or tumor growth due to insufficient immune responses. Thus, the balance between regulation and tolerance is critical for both protective immunity and preventing immune-mediated damage.
In autoimmunity: there is a high ratio of inflammatory immune cells to treg cells.
In healthy there is a balance between them.
In cancer there is a high ratio of treg to inflammatory immune cells.
Biology of immune checkpoint PD-1 in health (normal immune homeostasis)
PD-1 ( programmed cell death 1) is absent on resting naïve and memory T cells and is expressed upon TCR engagement.
In contrast to CTLA-4, PD-1 expression on the surface of activated T cells requires transcriptional activation, and thus is delayed (6–12 hr after activation).
PD-1 engagement can also activate the inhibitory phosphatase PP2A. PD-1 engagement directly inhibits TCR-mediated effector functions.
`PD-1 has important physiologic role in restraining collateral tissue damage during T cell responses to infection. Prevent t cells from being overactivated.
The 2 ligands for PD-1 are PD-L1 and PD-L2 .
PD-L1 is induced on activated hematopoietic cells by cytokine IFN-γ
PD-L2 expressed on DCs and some macrophages
Same for ctla-4 either cd8 or cd26.
L20- How do tumour cells exploit PD-1?
a
Immune checkpoint receptors (PD-1, CTLA-4) and their ligands (PD-L1/2) are upregulated in cancer
PD-1 ligands (PD-L1, PD-L2) are upregulated in cancer
PD-1 receptor is highly expressed on T cells from cancer patients (TILs) – chronic stimulation by tumour antigens (Ags) drives “T cell exhaustion”
Co-option of the immune checkpoint network (ligands and receptors) is a central process by which tumours resist elimination by endogenous tumor-specific T cells
In healthy tissues- pdl-1 normally expressed at relatively low levels on dendritic cells?
So increased expression= more pd-1 engaged with the ligand. Interacts much more readily. Ligands can be expressed by tumour themselves or by dendritic cells. Drives immune suppression as if t cell interacts with cancer=suppressed more readily by cancer cells.
In addition, tumor infiltrating lymphocytes (TILs) (CD8+ CTLs) commonly express heightened/increased levels of PD-1 and are thought to be “T cell exhausted” due to chronic stimulation by tumour antigens.
Exhaustion or anergy of PD-1+ T cells is a form of inactivation in which the cell remains alive but cannot be activated to execute an immune response. Anergy is a reversible state.
T cell exhaustion- suppressed, not activated or functioning well. T cells no longer kill cancer cells effectivley.
L12- B cell activation?
detail?
a
In a T-dependent B cell response, two signals are required for B cell activation:
Signal 1: Interaction between the B cell receptor (BCR) and the antigen.
Signal 2: Provided by the interaction between CD40 on the B cell and CD40L (CD154) on the T cell.
CD40: A receptor on the surface of B cells.
CD40L (CD154): A ligand (binding partner) on the surface of activated T cells.
The binding (ligatory = interaction) of CD40 on the B cell with CD40L on the T cell delivers a crucial signal that ensures the B cell fully activates.
Initial reaction made through interaction of mhc molecule and tcr that upregulates expression of cf40 on the b cell, t cell already activated so expressing cd40 ligand. Strimulates b cell proliferation and differentiation. Stimulates isotype switching and somatic hypermutation.
T-idenpendentType I:
Type I antigens are specialized antigens that are strong signaling molecules, often referred to as polyclonal activators ( activate multiple B cells).
These antigens are recognized through Pattern Recognition Receptors (PRRs) (to recognise PAMPS) such as TLR-4 (Toll-like Receptor 4), which are part of the innate immune system giving second signal.
B cells receive two signals:
Signal 1: The antigen binds directly to the B cell receptor (BCR).
T-Independent Type II:
Triggered by large repeating molecules (eg
H. influenzae b).
These repetitive structures cluster B cell receptors (BCRs) together, generating a strong Signal 1 for activation. Bind multiple BCRs on the cell
surface causing cross linking
and activation.
Only a single signal is required to activate B cells, leading to the production of IgM-positive plasma cells.
Unlike T-dependent responses, this pathway does not support secondary diversification activities, such as:
Isotype switching (e.g., switching from IgM to IgG).
Somatic hypermutation (improving antibody quality).
Exception:
If the same antigen is also present on cancer cells, it can activate dendritic cells, which release a cytokine called BAFF (B cell Activating Factor).
BAFF acts as a second signal, allowing:
The production of IgM plasma cells.
Class switching to other antibody types (e.g., IgG or IgA).
Diversification activities, enhancing the antibody response.
L12- Somatic hypermutation?
Somatic hypermutation: Occurs after B cells recognize an antigen and receive T-cell help in T-dependent responses.
It happens in the germinal centers of secondary lymphoid organs (e.g., lymph nodes, spleen). recognised pathogen antigen, b cells expand and diversify and produce antibodies.
some diversified cells are maintained in immune system and retain memory. Within the expanded pool of clones, each b cell has the same vdj recombination makeup?
During that proliferation process, undergo somatic hypermutation and can induce point mutations in the v d and j segments. This occurs due to the action of AID. ( As cells divide the Ig gene is mutated (Activation
induced Cytidine deaminase – AID)
* Mutation occurs in the DARK ZONE)
within that clone of cells that has expanded through proliferated, diff cells diff mutations at diff points in its variable region genes. Slightly diff capacity to recognise same antigen. Random process. Mutations can increase or decrease ability.
Selection stage is important as immune system wants to select the b cell with improved affinity for antigen. Takes place in the light zone. Proliferared b cells move into light zone, have their bcr tested by competing for follicular Dendritic cells and a small no. follicular th cells. If b cell selection it can re enter dark zone and undergo further rounds of mutations. So cycle between them. So most successful cloness go back to dark zone. So get constant improvement of affinity. Together that process is called affinity maturation (increasing ab affinity).
So somatic hypermutation is the act of inducing mutations into the variable region genes. That are tested for affinity.
Driven by specific chemokines present in those 2 areas. Cxcl12 in dark zone cxcl13 in light zone.
L12- Neutralisation by AB?
+ opsonisation by AB?
viruses bind to receptor on cell and internalised and release genetic material to infect cell and undergo replication. Antibodies block molecules on virus surface that allow it to interact with receptors on target cell. In hiv: binds to gp120 and blocks interaction with cd4, blocks virus entering cell.
Neutralising Ab against tetanus toxin (vaccination with inactive toxoid)
prevents binding to neurons.
Neutralising Ab against SARS-CoV-2 block Spike protein binding ACE2
receptors on cells
all other activities require other cells from innate immune system. Here the antibody coats bacteria via ab portion variable region. Fc region is exposed and interacts with fc receptors on cells e.g: phagocytic cells and bind to antibody and in turn bind to the thing the antibody is bound to. Increases efficiency of pathogen clearance and stimulates efficiency of antigen presentation. So adaptive influences activity of innate immune system- cross talk.
* Antibody recognises pathogen coat proteins
* Binds phagocytic cells via Fc receptors
* Phagocytes engulf and destroy pathogen in vesicles
* Aids APC presentation of pathogen proteins – Innate/adaptive overlap.
L12- IgM + IgD?
IgM: The first immunoglobulin that B cells
produce (with IgD). First constant
regions downstream of VDJ.
The Fc region enables the molecules to
form pentamers (with J chain) and intra
chain disulphide bonds
Very good at forming immune
complexes.
BUT too large to diffuse into tissues or
cross the placenta.
Very efficient at activating complement
through the classical activation pathway.
IgM Immune complexes
Pentamer has 10 possible
binding sites – high Avidity
BUT low affinity (has not
undergone somatic
hypermutation and
selected)
IgD:
a
Possible regulatory function but not sure. Only other isotype of igm that is independent of class switching, purely transcription driven event.
* Membrane-bound form of Immunoglobulin
on Naïve B cells (B cells early in
development before they see antigen)
* Function still not well understood.
* C lies immediately downstream of C.
IgD is formed by alternative splicing (NOT
class switching) of a transcript transcribed
from V region.
L12- IgG + IgA?
IgG: dimerised or pentermarised, small so good at entering tissues. 4 constant regions encode diff igG isotypes
IgG is the main antibody secreted in the blood
ONLY produced after B cell activation & class
switching.
It is very good at opsonisation.
Pathogens coated in IgG also become targets for
killing by Natural killer cells – ADCC.
Very good tissue entry & crosses placenta
There are 4 subclasses: IgG1,IgG2 IgG3 & IgG4
(humans)
IgA is the mucosal antibody – produced by
B cells at mucosal surfaces and
secreted into breast milk
It is actively secreted across mucosal
surfaces - Stabilised by secretory
component.
It can form a dimer via J chain.
– helps protect it from enzymatic breakdown
(such as occurs in the gut), but generally
exists in monomeric form in the plasma
There are two Subtypes (IgA1, IgA2)
Antibodies that give infant first antibodies along with igG.
L12- IgE?
Important in defence against parasitic infection.
Binds to the surface of Mast cells via it’s Fc receptor
(FcRI) – even in the absence of antigen (primed for
immediate activation).
Antigen cross-linking of IgE on Mast cells causes
degranulation. Kills helminth but causes immediate
symptoms of asthma/allergy.
Usually low in concentration (in serum), but higher in
cases of allergy – especially immediate
hypersensitivity
Has very high affinity so binds even in absence of antigen. Therefore allergic response is so rapid as mast cells and basophils are coated with igE. High local concentrations.
Therefore diff isotopes have diff effector abilities and distributions in the body.
L13- Controlling colonal expansion?
Control of clonal expansion
- Effector cell proliferation needs to be controlled
- Upon activation, CD4+ T cells also express co-inhibitory
receptors: CTLA-4
Reostat for Ag levels:
- B7 expression in APC depends
on Ag concentration
- CTLA-4 affinity for B7»_space;> CD28
Cdtla-4 has lots more affinity for B7 so CD28 unable to bind and delivers a negative signal and send the cell to cell cycle arrest.
If the number of B7 molecules on the surface on the APC is low then CTLA-4 sends the negative signal.
CTLA-4 is an immune checkpoint receptor expressed on activated T cells.
It competes with CD28 for binding to B7 molecules.
CD28 provides a co-stimulatory signal for T cell activation.
CTLA-4, however, delivers an inhibitory signal, dampening T cell activation.
The ability of CTLA-4 to inhibit T cell responses under conditions of low B7 expression is crucial for maintaining immune homeostasis and preventing overactivation, especially in scenarios like chronic inflammation or autoimmunity.
However, it can also be exploited by tumors to suppress anti-tumor immunity, which is why CTLA-4 inhibitors (e.g., ipilimumab) are used in cancer immunotherapy.
This is dependent on level of antigen
Clonal contraction: 90-95% effector
cells die. The surviving cells will form
the memory population
