Essay writing (2) Flashcards
cancer essay
1. definition of cancer
2. pd-1?
3. how is ctla-4 used?
4. what cancers are ICB used in?
5. PEP
6. introducing innate system extra reading?
7. L19 link?
- Cancer encompasses a diverse range of diseases characterized by heterogeneity in location, genetic mutations, and clinical behavior. It generally results from the uncontrolled proliferation of cells originating from a single transformed progenitor cell.
- PD-1 requires transcriptional activation.
Mechanisms for why the ligands are overexpressed in cancer: cancer cells have oncogenic protein pathways which are activated e.g: akt. When tumour cell has oncogenic signalling, pd-L1 is expressed at very higher levels. Called innate resistance or intrinsic resistance:
Intrinsic resistance refers to the constitutive expression of PD-1 ligands because of genetic alterations or activation of oncogenic pathways in cancer cells.
Constitutive expression of PD-1 ligands - amplification of chromosome 9p24.1 in Hodgkin’s lymphoma which encodes PD-L1, PD-L2 and JAK2.
EBV viral infection is another mechanism of PD-L1 overexpression in the lymphomas.
Alternativley: adaptive resistance. T cell recognises signal 1 and secrete ifn-y which is taken up by tumour cell, triggers stats signalling that elavates pd-L1.
Adaptive resistance refers to the induction of tumour PD-L1 expression in response to cytokine IFN-γ secreted by proximal T cells.
Adaptation of tumor cells upon sensing an inflammatory immune/T cell response.
Inhibition of T cells also mediated by PD-L1+ myeloid cells or DCs in the tumour microenvironment
3. CTLA-4 is essential for controlling clonal expansion of T cells, ensuring that immune responses are self-limiting. By blocking excessive T cell proliferation, it helps prevent chronic inflammation and autoimmunity, both of which can result from unchecked immune activation.
4. Anti-PD-1 antibody ICB immunotherapy (with nivolumab) has substantial clinical activity against melanoma and lymphoma patients.
T cell-mediated lysis (tumour kill)
5. phosphoenolpyruvate- INTERMEDIATE
6. Although the adaptive immune response is central to tumour immunity, innate immune cells, such as tumour-associated macrophages, also contribute by creating a pro-tumour environment through chronic inflammation and angiogenesis.
7. HPV vaccines and Provenge
PD-1 wider reading?
PD-1 inhibitory function depends on the ITSM phosphotyrosine, which preferentially recruits SHP-2 phosphatase, resulting in downregulation of downstream signaling9,10,11 (Chemnitz et al. 2004)
inteferon function?
a
Interferon-γ (T cells, NK cells)
* Induces macrophage activation
* Promotes Th1 differentiation
* Upregulates APC capacity (MHC I and II expression)
Interferon α (leukocyte) and interferon β (fibroblast)
* Prevents viral replication
* Increases MHC class I expression
Cytokine storm
Immune response is normally controlled by feedback mechanisms.
Yes, what you’ve described is largely about a cytokine storm, but it can be refined a bit to better capture the underlying mechanisms. Here’s a more polished version:
A cytokine storm occurs when the immune system’s feedback mechanisms fail, leading to an excessive, uncontrolled immune response. This results in the release of a large number of pro-inflammatory cytokines and other immune mediators—more than 150 in some cases. The overproduction of these mediators can trigger widespread inflammation, causing symptoms such as high fever, swelling, redness, extreme fatigue, and nausea.
Cytokine storms can arise in both infectious and non-infectious diseases, and have been observed in conditions like graft-versus-host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, and infections like Ebola, avian influenza, and COVID-19. In these cases, the immune system becomes hyperactivated, leading to tissue damage and, in severe instances, organ failure.
cytokine chains + disease?
Cytokine receptors frequents share subunits
a common chain involved in specifying ligand specificity and a more shared signalling chain/
e.g: IL-4 alpha chain shared by both IL-4R AND IL-13R
X-linked severe combined
immunodeficiency (X-SCID).
* x-linked recessive trait - mutated IL2-Rg
chain.
* IL-2Rg shared between receptors for IL-
2, IL-4, IL-7, IL-9, IL-15 and IL-21.
* Isolation in a “bubble” was an early
prophylactic treatment.
* BM transplant – standard treatment.
neutrophil essay
1. extravasation process
2. development?
3. when is band released?
4. efferocytosis and g-csf role?
a
Extravasation to reach the site of infection:
When endothelial cell activated e.g: through cytokines it upregulates regulation of P and E selectins. psgl-1 which bind to L-selectin on the nutrophil (also known as cd-62l). Interaction is loose, selectin bonds prone and break easily leads to rolling of neutrophil along the endothelium. Rolling can form membrane protrusions? Due to Selectin binding = intracellular signalling activated. Leads to clustering of integrin receptors: Lfa-1 and mac-1 bind to icam on endothelial cells, cause stop of cell, firm adhesion. Cytoskeleton rearranged. Cell forms lamellipodum. Cell Penetrates between gap junction of endothelial cells squeezes through blood vessel into tissue, secretory vesicles are mobalised. Neutrophils release enzymes to break the extracellular matrix and so can move into the tissue (transmigration) and move along a chemotaxic gradient.
Neutrophils recruitment is fast and tightly regulated. Neutrophil swarm as they arrive fast at site of infection.
- promyelocyte and granulocyte macrophage progenitor (GMP)
- Band shape- last immature progenitor. But can be released prematureley during acute infection/inflammation e.g: sepsis, cancer, autoimmune disease.
- “This suppresses IL-23, a cytokine required for Th17 survival and expansion”: This is correct, but you should clarify that efferocytosis also plays a role in resolving inflammation to prevent tissue damage.
“G-CSF levels reduce”: G-CSF reduction is important in controlling neutrophil production, so this point is accurate. But you may want to mention that G-CSF is primarily involved in promoting the production of neutrophils during infections and inflammation.
neutrophil nets and disease?
Tissue damage, e.g. NET histones toxic to epithelial
and endothelial cells;
Impaired wound healing
Sepsis, Infection, Autoimmunity
Diabetes
Vaso-occlusion, scaffold for platelets, coagulation Deep vein thrombosis, Cancer, Sepsis
NETs expose endogenous danger signals triggering
inflammation (DNA, histones, cytoplasmic proteins,
antimicrobials e.g. LL37)
Atherosclerosis, Systemic lupus
erythematosus SLE, Liver
Ischemia/Reperfusion Injury, Cancer
Source of self antigens Rheumatoid arthritis, SLE, ANCA
vasculitis
Lung inflammation
Increased sputum viscosity
Tobacco smoke-induced chronic inflammation
Covid-19
Cystic fibrosis
COPD
Anti-inflammatory properties: NET-associated
proteases degrade pro-inflammatory cytokines
MSU-crystal induced Gou
tumour evasion strategies?
- Tumor Cells Avoiding T Cell Recognition: Tumor cells can evade T cell recognition through several mechanisms that reduce immunogenicity. These include the absence of peptide-MHC ligand interactions, which are essential for T cell recognition, as well as the lack of adhesion molecules and costimulatory molecules. Without these key signals, the tumor cells fail to effectively interact with T cells, preventing proper immune activation and reducing the likelihood of immune surveillance and attack. e.g: CD28, LFA-1
- tumour treated as self antigen. tumour antigens taken up and presented by apcs in absence of co-stimulation tolerarize t cells. This lack of co-stimulation prevents full T cell activation, leading to immune tolerance and allowing the tumor to evade immune attack.
- Antigenic modulation occurs when antibodies targeting tumor cell-surface antigens bind to these antigens, triggering endocytosis and degradation of the antigen. This process can lead to the immune selection of tumor variants that have lost the targeted antigen, allowing these antigen-loss variants to escape immune detection and continue growing.
- tumour-induced immune supression: TGF-BETA secreted by tumour cell inhibits t cells directly and cause induction of treg.
- tumour-induced privledged site: factors secreted by tumour cells create a physical barrier to the immune system.
neutrophil cross-talk with t cells?
a
Neutrophil elestase can cleave and deactivate inflammatory cytokines like il-1beta or And il-6 and il-2. Arginase depletion and ros suppress t cell function. Neutrophilexpress immune checkpoint inhibitors like pdl-1 that bind to pd-1 on t cell. Activating: cscl-12 and il-12 activate and recruit t cells. Present mhc 1 and 2 so can present antigens to t cells. Net in disease? Can be recognised by prr and activate t cells.
t cell double negative stages?
maturation stages: The first stage is termed the double negative (DN) stage because thymocytes in this stage lack the CD4 or CD8 co-receptors. The double negative stage can be broken down even further into four successive developmental subsets based on the cell surface expression of the CD117, CD44, and CD25 receptors [1]. Therefore the double negative subsets are as follows: DN1 (CD117+CD44+CD25−), DN2 (CD117+,CD44+,CD25+) DN3 (CD117lo/−,CD44−,CD25+), and DN4 (CD117−,CD44−,CD25−) [Fig. 1]. DN1 cells are not yet committed T cell precursors since they have been shown to be able to develop into other thymus-derived lineages such as dendritic cells and natural killer cells. Transition to the DN2 subset occurs when DN1 cells begin expressing CD25. Transition from DN1 to DN2 also triggers the developmental program leading to a diverse T cell receptor (TCR) repertoire. This is accomplished by distinct α and β TCR chains along with their variable region encoded by several variable (V), joining (J), and diversity (D) gene segments. Besides expressing CD25, the DN2 subset contains joined D and J segments of T cell receptor β chain (TCRβ). The DN2 subset progresses to the DN3 subset by joining of the V gene segment to the DJ segments of the TCRβ chain and losing expression of CD117 and CD44. In order to continue to the DN4 subset, the DN3 subsets must express a functional TCRβ chain and a pre-TCRα chain on the cell surface, a process known as β-selection.
death by neglect?
failiure to be stimulated by apcs. . Therefore 95% of new thymocytes die.
Peptides recognised/presented are mhc and self antigen peptides In thymus. so if recognise self peptides too much, not released in the periphery as can cause autoimmune diseases.
what is allelic exclusion?
Allelic exclusion occurs when the pre-BCR signals to stop further rearrangement of the heavy chain on the second allele, ensuring that only one functional heavy chain is expressed in each B cell. If the first chromosome fails to produce a functional heavy chain, the B cell will attempt to rearrange the second chromosome. If both attempts fail, the B cell dies by apoptosis.
Rearrangement proceeds on one allele first,
recombination of the second allele is blocked.
* If this is unsuccessful the second allele rearranges
* If this is unsuccessful the cell dies
* This process is called Allelic Exclusion
negative selection?
If heavy chain and light chain rearrange successfully then there is immature b cell. Over half original cells have died due to rearrangement process failure. Random process: can recognise self or other antigens.
At this transition the B cell has a complete BCR on the
surface and is tested for self-reactivity.
* If the BCR recognises antigens in the bone marrow it does
not progress to the immature B cell stage
Death: apoptosis, strong self recognition
Anergy: weak self-recognition, alive but non responsive. b cell still released from bone marrow. Could under certain conditions be reactivated.
Receptor editing: cells edit ig genes to alter antigen specificity. It can go back into the process and rearrange the remaining gene segments. Occurs in the light chain. The self reactive cells re-express rag1/2 and repeat light chain rearrangement.
attenuated vaccines?
1st gen: Effective vaccines are composed of intact microbes that are treated in such
a way that they are attenuated OR killed, so they no longer cause disease,
while retaining their immunogenicity
Advantage of attenuated microbial vaccines is that they elicit all the innate and
adaptive immune responses (both humoral and T cell mediated)
However, the inactivated (killed) bacterial vaccines generally induce limited
protection and are effective for only short periods
Live, attenuated viral vaccines are usually more effective e.g. polio, measles,
and yellow fever.
Early approach for producing attenuated viruses was repeated passage in cell
culture
More recently, temperature-sensitive and gene deletion mutants have been
generated
Viral vaccines often induce long-lasting specific immunity, so immunisation of
children is sufficient for lifelong protection
So good cus they activate innate and adaptive-memory b and t cells produced. The innactibated killed are not as potent, limited protection, do not have long lasting effects.
Learn examples of pathogens associated with vacines
Attenuated: formed in lab through repeat passage in cell culture.
In live-attenuated
vaccines, like the
measles, mumps, and
rubella shot, weakened
viruses incorporate their
genetic instructions into
host cells, causing the
body to churn out viral
copies that elicit
antibody and CD4 and
CD8 T cell response
Purified antigen (subunit) vaccines (more)
Bacterial polysaccharide antigen vaccines
are used against pneumococcus
and Haemophilus influenzae
However, polysaccharides are T-independent
antigens, they tend to elicit low-affinity
antibody responses and are poorly
immunogenic in infants (who do not mount strong T
cell-independent antibody responses)
High-affinity antibody responses may be
generated against polysaccharide antigens
even in infants by coupling the
polysaccharides to proteins to
form conjugate vaccines: weak prufiied antigen given in combination with strong antigen to help immune response like a carrier protein. Used when bacterial polysaccharide antigen. Help t cell response, enable th to enable antibody production. These types do not gen cd8 responses but cd4. So not good for viruses as they often presented through mhc class 1 pathway so mhc class 1 aka cd8 needed.
These conjugate vaccines elicit helper T cells.
to simulate germinal centre GC reactions,
which would not occur with simple
polysaccharide vaccine
