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GPCR signal cascades

GPCR signal cascades

0: resting stage, 1: ligand binding, 2: conformational change, 3: GTP bound Ga dissociates, 4: Ga as a GTPase converts Ga-GTP to Ga-GDP, 5: reassembly of heterotrimeric G protein

GPCR on vs off

GTP bound to G protein is active (on), GDP bound to G protein is inactive (off)

RTK components

extracellular domain w ligand binding site, hydrophobic transmembrane alpha helix, cytosolic segment w domain w protein kinase activity, C-terminal w tyrosine residues that the receptor's own kinase phosphorylates

RTK activation

activated by extracellular growth, differentiation factors, or metabolic regulators

SH2 domains

~100 amino acids, conserved binding pocket that accommodates a phosphorylated tyrosine residue. mediate a large number of phosphorylation-dependent protein-protein interactions

JAK-STAT signaling

Janus kinase (JAK) signal transducer, activator of transcription (STAT) pathway, regulated by post-translational modifications

IFNγ signaling

IFNγ: cytokine produced by immune cells, signals through its receptor which activates JAK-STAT1 pathway to induce expression of classical interferon-stimulated genes

Rapamycin

binds a prolyl-isomerase (FKBP12) to form complex that broadly inhibits cell growth and proliferation, targets mTOR kinase in mammals

FK505/tacrolimus

binds to FK binding proteins, inhibits calcineurin - t cells express low levels so they are sensitive

Caspase

protease enzymes essential in programmed cell death - cysteine in active site cleaves target protein after Asp residue - produced as a zymogen

inflammasome activation

multimeric protein complexes, assemble in the cytosol after sensing PAMPs or DAMPs

inflammasome activity

activate inflammatory caspases, cysteine-dependent aspartate-directed proteases

cysteine-dependent aspartate-directed proteases

promote maturation of IL1B and IL18 cytokines and induce pyroptosis (lytic cell death)

inflammasome structure

consist of sensor PRRs, an adaptor ASC, and an effector pro-caspase-1

central tolerance

developing lymphocytes encounter self-antigens in generative/central lymphoid organs

peripheral tolerance

mature lymphocytes encounter self-antigens in peripheral/secondary lymphoid organs/tissues

T cell anergy

when T cells recognize antigens without co-stimulation and lose their ability to transmit activating signals, or after recognition of self antigens when inhibitor receptors of the CD28 family are used

inhibitory receptors of the CD28 family

CTLA-4 or PD-1

CTLA-4

CD152, inhibitory for T cell activation, controlled by regulation of its surface expression, binds to same ligans as CD28

PD-1

programmed death-1, higher affinity for B7 than CD28,

multiple sclerosis

demyelination of neurons due to CNS antigen T cells activated in periphery reencountering antigen in brain (when unknown inflammation trigger causes blood-brain barrier to become locally permeable to leukocytes)

voltage-gated ion channels

Na+, K+, Ca2+

ligand-gated ion channels

nicotinic acetylcholine receptors, AMPA/NMDA/kainate types of glutamate receptors, GAbAA receptors, GLycine receptors

Ca2+ channels

increases in cytosolic/organellar Ca2+ concentrations in lymphocytes control functions such as metabolism, proliferation, differentation, antibody/cytokine secretion, and cytotoxicity

second messengers

small non-protein molecules that pass along a signal initated by the binding of a ligand (first messenger) to its receptor

second messenger transmit information by:

a change in their concentration

classes of secondary messengers

cyclic nucleotides (cAMP, cGMP...), metal ions (Ca2+), membrane lipid derivatives (IP3, DAG) nitric oxide/carbon monoxide

ITAMs

immunoreceptor tyrosine-based activation motifs - cytoplasmic region of the T cell receptor - signalling is activated by tyrosine phosphorylation of the ITAM

apoptosis morphologic characteristics

cell is shrunken w condensed cytoplasm, membrane blebbing, apoptotic bodies (cell disassembly into membrane-enclosed vesicles)

intrinsic apoptosis pathway

mitochondria mediated - mitochondrial outer membrane permeabilization, cytochrome C released from mitochrondria, apoptosome assembly, procaspase 9 cleaved into caspase 9, procaspase 3 cleaved into caspase 3

extrinisc apoptosis pathway

death receptor mediated - activated by extracellular ligands binding to cell-surface death receptors

autophagic cell death

large scale autophagic vacuolization of the cytoplasm, induced/inhibited by autophagy inhibitors/inducers (tat-beclin 1 - a cell penetrating autophagy-inducing peptide)

necrosis

cell death as a consequence of extreme physicochemical stress - heath, osmotic shock, mechanical stress, freeze-thawing

necrotic cell death pathways

necroptosis, ferroptosis, pyroptosis

necroptosis

Necroptosis-inducing complex (necrosome); RIPk1, RIPk3, MLKL phosphorylated, MLKL forms channels that induces influx of ions and causes cell to burst

ferroptosis

increased levels of intracellular reactive oxygen species

pyroptosis

activation of inflammatory caspases, release of IL1B or IL18

kinase

mediate transfer of phosphate onto a protein

phosphatase

remove phosphate group from a protein or target

adaptor proteins

membrane-anchored or cytoplasmic proteins with several signaling modules that serve to link two proteins together

Co-receptors

CD4 and CD8, engagement with the T cell receptor enhances phosphorylation of ITAMs

Src family PTKs

Eg Lck and Fyn, close proximity to ITAMs?

the CRAC channel

calcium release-activated channel

CD28

used by naive T cells as a co-stimulatory receptor - enhances antigen receptor signals that induce transcription factor activation and PI3K activation (therefore ensuring T cell activation)

CD40

used by naive B cells as a co-stimulatory receptor - enhances antigen receptor signals that induce transcription factor activation and PI3K activation (therefore ensuring B cell activation)

B7 family

expressed mainly on specialized APC such as dendritic cells

MAPK cascade

made up of Raf, MEK, and ERK - mitogen-activated protein kinase - turned on by activated PTKs - MAPKs phosphorylate and activate transcription factors that induce new gene expression

DISC

death-induced signaling complex - formed by the extrinisc apoptosis pathway

Bcl2 family

regulates mitochondrial outer membrane integrity in the intrinisic apoptosis pathway - have one or more Bcl2 homology (BH) regions

Autoimmunity

the immune response to self as a result of the breakdown in self-tolerance. presence of antibodies (by B cells) and T cells directed against normal components of a person

molecular mimicry

cross reacting antigens - similar structures shared by molecules from dissimilar genes or protein products - eg a foreign antigen that resembles a self antigen. Eg: streptococcal M protein and heart muscles

Treg in self-tolerance

can suppress self-reactive lymphocytes that recognize antigens different from those that the Treg cell recognizes - aka regulatory tolerance

True or false: Autoimmunity is the immune response to self, which is a result of a breakdown in immune tolerance (self-tolerance).

true

True or false: Autoantibodies are produced by autoreactive T cells.

false

True or false: Autoreactive or self-reactive lymphocytes are generated by our own immune system

true

True or false: Since autoreactive lymphocytes will be eliminated by central tolerance mechanisms, there are no autoreactive lymphocytes that enter peripheral tissues.

false

True or false: Apoptosis is an uncontrolled cell death process

false

True or false: Apoptosis is associated with the release of DAMPs

false

True or false: Apoptosis is caspase-dependent programmed cell death

true

True or false: Necrosis is caspase-independent cell death

false

True or false: Pyroptosis is a form of cell death that is associated with the release of pro-inflammatory cytokines upon cell rupture due to caspase 1 activation

true

True or false: NLRP3 signaling leads to NFkB-independent generation of pro-inflammatory cytokines and cell death through formation of a multi-protein complex known as the inflammasome.

true

In multiple sclerosis (MS), autoreactive T cells attack ________ (A) Mast cell (B) Microglia (C) Myelin sheath (D) BBB (blood-brain barrier)

(C) Myelin sheath

"What tissues, organs, or body systems can be affected by autoimmune diseases? (A) Skin (B) Joints (C) Thyroid (D) All of the above"

(D) All of the above

Which of the following is correct regarding where B and T cells mature just prior to traveling to lymph nodes? (A) B cells mature in the thymus; T cells mature in the thyroid gland (B) B cells mature in the bone marrow; T cells mature in the thymus (C) B cells mature in the thyroid gland; T cells mature in the pancreas (D) B cells mature in the pancreas; T cells mature in the bone marrow

(B) B cells mature in the bone marrow; T cells mature in the thymus

"Which of the following transcription factor is specific for Treg cells: (A) T-bet (B) RORrt (C) GATA-3 (D) FoxP3"

(D) FoxP3

Choose the correct sequence of events for G-protein coupled receptor (GPCR) activation: I. GTP-bound Gα dissociates from the ligand-bind GPCR, releasing Gα-GTP and Gβγ to trigger their respective effector proteins II. The intrinsic GTPase activity of Gα converts Gα-GTP to Gα-GDP III. A conformational change of the GPCR induced by ligand binding, which creates a binding pocket for Gα IV. Reassembly of heterotrimeric G protein

(A) IV - III - II - I (B) III - II - I - IV (C) III - I - II - IV (D) I - II - IV - III "

(C) III - I - II - IV