Adv immunology 2024 11 mars Flashcards
The innate arm of the immune system constitutes the first line of defense against
pathogens. Several different immune cell types have the ability to ingulf pathogens by
phagocytosis.
a) Which receptors are typically involved in the initiation of phagocytosis? (1p)
The major receptor class is opsonin receptors which are Fc receptors that binds to antibodies IgG and complement receptors that binds to complement proteins such as C3b and C4b as they have marked them for phagocytosis and phagocyting cells binds to them and initiate phagocytosis.
But scavenger receptors that recognize LPS and PRRs such as Toll like recpeotrs and C-type lectin receptors activate immune responses and indirectly then leada to phagocytosis of pathogens.
The innate arm of the immune system constitutes the first line of defense against
pathogens. Several different immune cell types have the ability to ingulf pathogens by
phagocytosis. b) What are the major steps of the phagocytic process? (3p)
-Recognition and attachment:
-Engulfment
-Phagolysosome:
-Digestion:
-Exocytosis:
Ideally, the phagocytosed pathogen will be killed inside the phagocyte. Describe at
least 4 mechanisms that contribute to the killing of pathogens inside these cells. (2p)
- ROSs are produced and causes oxidative stress in microbial cells.
- NO produced by iNOS has antimicrobial effects
-Enzymes in the phagolysosome, such as lysozyme and proteases degrade microbial components. - pH Acidification: Acidification of the phagolysosome creates an inhospitable environment for pathogens.
Besides phagocytosis, innate immune cells can also mount inflammatory responses in
response to the recognition of pathogens. NLRP3 is an intracellular receptor that can
be activated by a large number of both endogenous danger-associated molecular
patterns (DAMPs) and pathogen associated molecular patterns (PAMPs)/microbeassociated molecular patterns (MAMPs). Please describe the events following the
activation of NLRP3 after exposure of a cell to a PAMP/DAMP.
First is the priming phase where for example TOLL like receptors or other PRRs signal in response to PAMP and DAMP. This leads to transcription of the NLRP3 gene and pro-inflammatory cytokines such as pro-IL1b and pro-IL18
Then activation happens after a second signal that could be ATP release causing a potassium efflux or ROS causing lysosomal rupture. This leads to conformational changes in the NLRP3 receptor causing it to oligomerize and form a large protein complex called NLRP3 inflammasome.
Then assembly of the inflammaosme happens through recruitment of different domains and pro-caspasase-1
The formed inflammasome triggers caspase-1 activation by cleaving it into it’s active form. Caspase-1 cleaves the pro-inflammatory cytokines into their active form (IL-1B and IL18) and also leads to pyroptosis.
The IL-1b and IL-18 gets secreted and promotes activation of neutrophils and macrophages to site of injury contributing to inflammation.
Pyroptosis is a programmed cell death characretsized by cell lysis which releases the inflammatory mediators.
a. For the activation of naïve T helper cells, three signals are required. Which are these
three signals? Motivate for each signal why it is important. (3p)
The activation steps of Th cells include TCR-MHC interaction where the TCR receptor binds to a compatible antigen on a MHC molecule, co-stimulation that happens between co-receptors CD28 on T-cell and B7 on APCs and cytokine signaling such as IL-12+IFN-g or TGFb-IL6 which allows for T-cell differentiation so the immune response is appropriate.
. Factors from antigen-presenting cells can shape the nature of the adaptive immune
response during the activation of Th cells. State which mediators that lead to the
polarization of naïve Th cells into the three main inflammatory Th subsets.
Th1 cells develop from IL-12 and IFN-gamma signals, Th2 cells require IL4 and Th17 TGF-B, IL-6 and IL-23.
For one of these three inflammatory Th subsets, describe which cytokines are released
by this subset, which cells are activated by these cytokines and how this ultimately
eradicates an infection. (2p)
Th1 cells secrete IFN-g and IL-2 and TFN-B activates macrophages which kills intracellular pathogens and cytotxic T cells.
During recent years, unconventional T cells have received more attention, and we have
started to understand the physiological roles of these cells and how they could be
involved in inflammatory conditions. What is the major difference between
conventional and unconventional T cells? (1p)
Unconventional T cells don’t need antigen presentation to be activated they can be activated by lipids, metabolites, etc
Immune complexes are soluble complexes of antibodies and antigens and they can bind to
Fc receptors. Immune complexes also have the ability to activate the complement system.
a. What is the normal role for immune complexes? (1p)
The normal role of IC is clearance of pathogens. The antibodies binds to antigens and the antibodies with their Fc receptors opsonize the antigens which enhances the ability to phagocytize them, it causes complement activation through the classical pathway that leads to generation of C3b which also enhanzes opsonization tagging the pathogen for phagocytosis and when transported to the liver the Kuppfer cells can then phagocytize and clear out the pathogens.
b. Describe two mechanisms by which IgG immune complexes together with
complement may result in harm to tissues. (4p)
When IC is deposited to tissues because it’s not soluble or when the antigen and antibody meet in the tissue and form an IC the classical pathway is activated leading to C3b protein and C5a that activated phagocytosis and chemoattractant for immune cells. This leads neutrophils and macrophages for the cite and as they try to phagocytoise and release pro-inflammatory cytokines, ROS, proteases etc it leads to tissue damage to to excessive inflammation.
It can also lead to the formation of MAC which creates pores in the endothelial cell membranes and also cause harm to tissues.
Janus kinase (JAK) inhibitors constitute a new class of immunomodulatory drugs for the
treatment of inflammatory conditions. The JAK inhibitors upadacitinib, baricitinib and
tofacitinib are used for the treatment of for example rheumatoid arthritis and psoriatic
arthritis in cases when TNF inhibitors are considered inappropriate or have lost their
efficacy.
Describe the general mechanism-of-action of JAK inhibitors on a cellular and molecular basis.
Which underlying inflammatory mechanisms are inhibited, and which potential detrimental
side effects require attention?
The general MoA of works like this:
1. Cytokines binds their respective receptors on the cell surface.
2. Receptor associated JAKs are activated.
3. The activated JAKs phosphorylate the receptor, creating docking sites for STAT proteins.
4. Phosphorylated STAT proteins (also phosphorylated by JAKs) bind the receptor and forms dimers that
translocate to the nucleus.
5. In the nucleus STAT dimers regulate gene expression of genes involved in inflammation and other immune
responses.
Inhibition:
-JAK inhibitors, such as , interfere with JAK activity, preventing
phosphorylation of STAT proteins
-By inhibiting JAKs, these drugs downregulate the production of pro-inflammatory cytokines and other mediators
involved in immune responses.
Side effects:
- JAK inhibitors can suppress the immune response, increasing the risk of infections. Especially herpes zoster.
- Changes in blood cell counts, including anemia, neutropenia, and lymphopenia, may occur.
-May elevate liver enzymes
- There is a potential increased risk of blood clots.
- Rare cases of gastrointestinal perforations have been reported.
Autoimmune reactions of the immune system are the underlying cause of autoimmune
diseases. There are several (physiological) mechanisms involved to prevent the development
of autoimmune disease.
a. Define and describe the basic principles of central and peripheral tolerance. (4p)
Central tolerance:
Definition: It’s the mechanism by which potentially self-reactive T cells and B cells are eliminated or rendered nonfunctional during their development in the thymus (T cells) or bone marrow (B cells).
Thymic selection: T cells undergo positive selection for recognition of self-antigens presented by thymic epithelial
cells. Those with strong reactivity to self-antigens undergo negative selection and are eliminated. (need to recognize
but not react(?)).
Bone marrow selection: B cells that strongly react to self-antigens during their development are eliminated or under
go BCR editing to reduce self-reactivity.
Peripheral tolerance:
Definition: Tolerance mechanism that occur in the periphery (outside thymus or bone marrow) t control and suppress
any remaining self-reactive lymphocytes that escaped the central tolerance.
Tregs: Suppress the immune responses and prevent autoimmunity by inhibiting the activation of autoreactive T cells.
Anergy (tolerance induction): Anergy refers to the functional inactivation of potentially self-reactive lymphocytes that
encounter self-antigens without co-stimulatory signals.
b. Give one example of an autoimmune disease and describe where in its pathogenesis
autoimmune mechanisms contribute to the disease. (2p)
In RA the body develops self antibodies so it fevelops a loss of tolerance to self antigens. This leads to Th cells recognizing MHC II molecules and activating and releasing pro-inflammatory molecules such as TNF-a, IL-1 and IL-6 contributing to inflammation in the joints. B cells also produce autoantibodies and this can form immune complexes and activate the complement system further contributing to inflammation and tissue damage.
The allergic reaction can be divided into an early and a late phase. Describe the immunological
mechanisms underlying these phases. Explain at the molecular and cellular level. (4p)
Early phase happens within minutes of exposure to the allergen where IgE antibodies cross links to mast cells and basophils and cause mast cell degranulaiton. This releases histamine, prostaglandins etc causing vasodilation and brhonchoconristriction.
Late phase the mast cell degrnaultion leads to chemotactic factors such as IL-5 and TNF-a that attracts eosinophils and neutrophils and TH2 cells that release IL-4, IL-5 and IL-13 which promotes B cell differentitation to IgE and recruitment and surrvival of eosinophils. This leads instead to chronic inflammation.
Immunological tolerance, for example in the gut, is crucial for homeostasis and dampens
unnecessary immune reactions to commensals. Homeostasis in the gut is maintained via
several different mechanisms, and one type of T helper (Th) cell dominates the immune
responses to commensals.
a. Which Th cell subtype dominates the immune responses to commensals in the gut?
How and where is this Th subtype induced? (2p)
Th17 cells dominate in the gut and is induced in gut asscoiated lymhpoid tissue which is preyers patches and mesenteric lymph nodes.
