almost know (2) Flashcards

1
Q

L8- NETs in thrombosis, autoimmune, gout?

A

Thrombosis: NETs can form scaffolds within blood vessels, trapping circulating platelets. Proteases present on NETs can activate the coagulation cascade, contributing to blood vessel occlusion during thrombosis.
Autoimmune Diseases: NETs are a source of autoantigens. For instance, RNA released during NETosis can be recognized by autoantibodies in autoimmune diseases such as systemic lupus erythematosus (SLE). These immune complexes can further stimulate neutrophils to form more NETs, creating a feedback loop that exacerbates the disease.
Gout: In gout, urate crystals that accumulate in joints can induce NET formation. NET-associated proteins, such as elastase, may cleave pro-inflammatory cytokines and potentially modulate inflammation under certain conditions.

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2
Q

L8- HSC differentiate into what during Granulopoiesis?

A

Hematopoietic Stem Cells (HSCs):

Found in the bone marrow, these multipotent stem cells differentiate into all blood cell types.
Common Myeloid Progenitor (CMP):

HSCs give rise to CMPs, which are committed to producing myeloid lineage cells (e.g., granulocytes, monocytes, megakaryocytes, and erythrocytes).

CMPs further differentiate into GMPs (Granulocyte-Macrophage Progenitor ) , which are precursors for granulocytes and monocytes.

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3
Q

L8- neutrophil cross-talk?

A

Neutrophil Crosstalk and Interaction with Immune Cells
Neutrophils are the first responders to infection sites and play a crucial role in coordinating immune responses by instructing other immune cells.

Key Interactions:
Chemokine Signaling:

CXCL8 (IL-8): Binds to CXCR2, recruiting additional neutrophils to the site of infection.
CCL2: Recruits monocytes, which can differentiate into macrophages or dendritic cells.
CXCL12: Activates immune cells such as T cells, guiding their migration to infection sites.
Cytokine Secretion:

Neutrophils produce IL-1, IL-18, TNF, and IL-12, which are pro-inflammatory cytokines that activate T cells and amplify the immune response.
Antimicrobial Molecules with Secondary Functions:

Neutrophil granules contain antimicrobial peptides and proteases like LL-37, cathepsin G (CG), and azurocidin, which also act as chemoattractants, recruiting immune cells to infection sites.
Lipid Mediator Production:

Neutrophil stem cells produce lipid mediators, such as:
PGE2, LTB4: Promote inflammation.
Lipoxins, resolvins, and protectins: Mediate anti-inflammatory and resolution-phase responses.
B Cell Support:

Neutrophils produce factors like BAFF (B-cell activating factor) and APRIL, which promote B cell proliferation and antibody production.
Immune Suppression:

Reactive Oxygen Species (ROS): Can suppress immune responses by reducing cytokine production in other immune cells, exhibiting immunosuppressive effects.
Arginase: Depletes arginine, an amino acid essential for T cell proliferation, thus suppressing T cell responses.
Additional Roles of Neutrophils:
Recruitment and Activation: Mobilize monocytes, dendritic cells (DCs), and T cells to infection sites.
Antigen Presentation: Support antigen presentation functions, aiding dendritic cells and macrophages.
Macrophage Reprogramming: Facilitate macrophage reprogramming through efferocytosis (clearance of apoptotic cells).
B Cell Activation: Enhance B cell proliferation and antibody production, particularly in the spleen.
T Cell Modulation: Can either activate or suppress T cell responses depending on the context.

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4
Q

L8- Neuotrphil phagocytosis?

A

Phagocytosis by neutrophils
Sensing and Ingestion of
particles larger 0.5μm
* Phagosome maturation upon
sequential fusion with
granules - phagolysosome
* Delivery of antimicrobial
peptides, enzymes, chelators to phagosomal lumen
* enzymes can assemble in phagosomal membrane and cause Production of ROS and pump into phagosomal lumen
* pH regulation. Pump protons into phagosomal lumen. Make hostile environment for pathogen.
Phagocytic receptors insude phagocytosis. Opsonic receptors: recognise microbes that are opsonised, coated with complement proteins or antibodies.
Cr and fcyr can induce phagocytosis. Non opsonic receptors: prrs binding to pamps and c-type lectin receptors e.g: dectin-1 binds to fungal polysaccharides.

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5
Q

L9- Thymocyte values in one day?

A

In a healthy person: 5x10^7 new thymocytes everyday. Total remains at 2x10^8
1x10^6 exit everyday.

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6
Q

L10- Effector stage of lytic synapse?

A

In the effector stage, key steps include actin reorganization and
accumulation (F-actin polymerisation), receptor clustering,
polarization of the microtubule-organizing centre (MTOC) and
lytic granules, leading to lytic-granule fusion with the plasma
membrane.
in common with cd8, the centrosome moves from back to synapse contact site to deliver cytolytic molecules.
* Actin reorganization (formation of F-actin networks from G-actin-WASP-dependent)
* Receptor clustering, lipid-raft aggregation, further activation signalling and lytic-granule
redistribution
* Polarization of lytic granules to the synapse (lytic granules aggregate around the MTOC and
the MTOC begins to polarise towards the immunological synapse)
* Targeted F-actin disassembly (to create a conduit through which the lytic-granules gain
access to the plasma membrane)
* Lytic granule approximation to the membrane (target cell) and fusion

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7
Q

L10- ADCC?

A

CD16 (FcγRIIIA),
which is a low-affinity receptor for IgG antibodies - Antibody-
Dependent Cell-mediated/or Cellular Cytotoxicity (ADCC)
Antibody molecules have highly
variable antigen-binding ends,
and on the opposite end, they
have an invariant portion, called
the Fc region, that interacts with
various other molecules in the
immune system

CD16 binds to the Fc regions of IgG1 and IgG3 antibodies.
During an infection, the adaptive immune system produces IgG1 and
IgG3 antibodies that bind to microbial antigens expressed on the
surface of infected cells, and CD16 on NK cells can bind to the Fc
regions of these antibodies. As a result, CD16 generates activating
signals, through its associated signalling partners, and the NK cells kill
the infected cells that have been coated with antibody molecules. This
process is called ADCC; it is an effector function of adaptive immunity

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8
Q

NK inhibitory receptors?

A

NK cell Inhibitory Receptors e.g: CD94, NKG2A (HLA-E displaying class 1 peptides) or KIRa (ligand: HLA-C) recognize class I
MHC molecules expressed on all healthy
nucleated cells in the body.
* NK cells use different types of receptors than CD8+ T cells to recognize
class I MHC molecules
* NK receptors respond to recognition of class I MHC molecules by
inhibiting NK activation
* Normal cells express class I MHC molecules, and many viruses and
other causes of cell stress lead to a loss of cell surface expression of
class I MHC
* Thus, NK cells interpret the presence of class I MHC molecules as
markers of normal, healthy self, and their absence is an indication of
infection or damage.

NK cells will be inhibited by healthy cells
In contrast, NK cells are likely to receive activating signals from infected or
damaged cells through activating receptors.
The net result will be activation of the NK cells to secrete cytokines and to
kill the infected or stressed cell.
This ability of NK cells to become activated by host cells that lack class I
MHC has been called “recognition of missing self”
The largest group of NK inhibitory receptors belong to the same KIR
family that also includes activating receptors, discussed earlier
Inhibitory KIRs bind a variety of different class I MHC molecules
Other inhibitory receptors are lectins, such as the CD94/NKG2A
heterodimer, which recognizes a class I MHC molecule called HLA-E.

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9
Q

L11- RAG activity?

A

what mediates gene segment recombination?

a
The joining mechanism for recombining gene segments during V(D)J recombination is initiated by the enzymes RAG1 and RAG2 (Recombination Activating Genes 1 and 2). These proteins recognize recombination signal sequences (RSS) flanking the V, D, and J gene segments and bring the segments together to facilitate recombination.

This process involves:

Formation of hairpin loops:
The DNA is cut at the RSS, and the free ends of the DNA form hairpin loops to maintain genome integrity (to avoid open free DNA).

Opening the hairpins:
The hairpins are then opened at random points by enzymes, introducing junctional diversity. This imprecision at the site of joining results in diversity in the final recombined gene sequence.

Adding palindromic (P) nucleotides:
When the hairpins are opened, the DNA ends often form overhangs, creating a palindromic sequence (P nucleotides) as they fold back on themselves.

Adding or removing nucleotides:
To create a blunt end for joining, nucleotides may be removed from the overhangs, or additional random nucleotides (N nucleotides) are inserted into the gap by the enzyme Terminal deoxynucleotidyl transferase (TdT). N nucleotide addition is entirely random and significantly enhances diversity.

Imprecise joining:
The imprecise nature of this process—where hairpins are opened, and nucleotides are added or removed—creates further variability and is a key contributor to junctional diversity.

Combinatorial diversity:
This mechanism works alongside the random combination of V, D, and J segments (combinatorial diversity) to generate a vast repertoire of antibodies or T cell receptors.

easier explanation:
1. What is V(D)J recombination?
This is a process where B cells and T cells create a huge variety of antibodies (for B cells) or T-cell receptors (for T cells) to recognize many different pathogens.
It achieves this by rearranging specific segments of DNA called V (Variable), D (Diversity), and J (Joining) segments.
2. Role of RAG1 and RAG2
RAG1 and RAG2 are special enzymes that cut DNA at specific places called Recombination Signal Sequences (RSS) next to the V, D, and J segments.
These enzymes bring one V segment, one D segment, and one J segment close together for recombination.
3. Formation of Hairpin Loops
After RAG enzymes cut the DNA, the free ends of the DNA fold into hairpin loops.
Why? This helps protect the DNA from breaking apart completely.
4. Opening the Hairpins
Another enzyme comes in and opens the hairpins at random spots.
This is important because the randomness creates diversity in the resulting DNA sequence.
5. Adding Palindromic (P) Nucleotides
When the hairpins are opened, the ends of the DNA sometimes form small sequences that read the same forward and backward (like “GAAG” or “CAGC”).
These are called P nucleotides and are created naturally as the DNA folds back on itself.
6. Adding or Removing Extra Nucleotides
An enzyme called Terminal deoxynucleotidyl transferase (TdT) can:
Add random nucleotides (N nucleotides) to the open ends.
Remove existing nucleotides if needed to make the DNA ends blunt.
This randomness is called junctional diversity and is another way the immune system generates variety.
7. Joining the DNA
The DNA ends are then joined together to form a complete V-D-J segment.
The joining isn’t perfect—it’s imprecise, but this imprecision adds even more variety to the final antibody or receptor.
8. Combinatorial Diversity
On top of the randomness of junctional diversity, the immune system can mix and match different V, D, and J segments to create an enormous number of combinations.

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10
Q

L11- Pre B chain receptor function?

A

The newly formed heavy chain gene is tested for functionality - ability to be expressed and bind to surrogate light chain receptor.
* Pre-BCR signals back into the cell causing:
- 1. The 5 and VpreB to be no longer expressed.
- 2. Pre-B cells proliferate
- 3. Heavy chain rearrangement is stopped (allelic
exclusion)
- 4. Light chain rearrangement started
* The newly formed heavy chain gene is tested for
functionality by it’s ability to be expressed and
bind to surrogate light chain receptor.
* There is only a 1/3 chance that VDJ
rearrangement will be in frame and functional.
* BUT …There are 2 alleles so 2 chances for
rearrangement
* If Heavy chain rearrangement is NON-Functional
2nd allele can be rearranged
he best quality Pre-B cell receptors are
expressed at a higher level on the pre-B cell
surface and therefore send back stronger
signals.
* This results in more proliferation
* The best quality pre-BCR out-proliferates
the others.

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