recognition response Flashcards
what regulates recognition and response
Recognition & response are regulated by
surface receptors and intracellular proteins
what do surface receptors on immune cells recognize
Surface receptors on immune cells recognize antigens (B & T cells) or
patterns (innate cells)
activation of the receptor induces a response in the cell (signal transduction)
how do receptors interact with ligands
through non covalent interactions
h bond
VDW hydrophobic interactions
ionic bond
how is the strength of an interaction quantified between a receptor and a ligand
the dissocaition constant kd
what does a high and low kd value mean
the lower the kd, the higher the affinity of interaction
Most enzyme ligand interactions: Kd range 10 -3 to 10 -5 M
Ab – Ag interactions: Kd as low as 10 -12 M
what is equilibrium analysis used for
to determine antibody affinity
affinity
interaction between one ligand and receptor
avidity
overall strength of all interactions during multivalent binding
what regulates key steps in receptors binding to antigens
Key steps are regulated by
phosphorylation of proteins to form
docking sites, activate enzymes, or
promote degradation/stabilization of
proteins
what does receptor clusering by multivalent Ags do
activates signal transduction
a) individual receptors bind a multivalent ligand and nycleate receptor cluster formation
b) multivalent ligand mediates cluster formation
what do membrane microdomains do
Membrane microdomains increase organization and efficiency of receptor activation/clustering
what is an example of a membrane mircodomain
lipid raft
what are to ways of changing the affinity of receptors for thier ligands
Combining different receptor sub-units can change the affinity of receptors for their ligand
Changing the level of
receptor on the cell
surface can also vary
the response of the
cell
what is a protein domain commonly shared by many receptors
Many receptors share a
common protein domain-
Immunoglobulin (Ig)
domain
what is the immunoglobulin domain and what is its structure
The Ig domain was first described in Antibodies, which is why it
was named “immunoglobulin domain”
The Ig domain is sandwich of 2 b sheets with loops connecting the anti-parallel b strands
how do B lymphocytes interact with antigens
via the B cell receptor
this consists of an Ab that recognizes the antigen and molecules inserted into the membrane that communicates with the inside of the cell (signal)
BCR and co-receptors
Co-receptors can accelerate or change the
signal sent through the BCR
how do T cells recognize antigens
The T cell receptor and co-receptors allow interaction of T cells with peptide Ag;
when the Ag is presented by APC
Molecules that communicate with
the inside of the cell (signal)
what do innate immune cells recognize
Innate immune cells recognize pathogen associated molecular patterns (PAMPs) via pattern recognition
receptors (PRR)
what are cytokines
Group of low-molecular weight regulatory proteins that function as the ʻmessengers of the immune systemʼ
what cells are cytokines
Includes:
* Interleukins (secreted by leukocytes & act on
other leukocytes)
* Monokines (secreted by monocytes &
macrophages)
* Lymphokines (secreted by lymphocytes)
* Chemokines: related but regulate cell migration
how do cytokines act
Cytokines act in autocrine, paracrine, or endocrine fashion
how much. cytokines is required to have an effect
Cytokine RECEPTORS have
very high affinity for the
cytokine, SO cytokines can
have biological effects at
picomolar amounts
pleiotropy
same cytokine acts on different cels to have different effects
redundancy
difffrent cytokines have the same effect on the same cell
synergy
effect is more than the sum of its parts
effect changes
antagonism
one cytokine prevents action of another cytokine
cascade induction
multiple target cells, multiple secreting cells
what do mutations to the IL-2Ry chain cause
X linked severe combined immunodefficiency (XSCID)
- IL-2 is essential for activation of T
cells - Patients have no T or NK cell
activity - Worse than expected if just T
cells affected
why is the gamma subunit so widely used
Unexpected severity of IL-2Rγ-deficiency
explained by common use of γ subunit
how do cytokine receptors change gene expression
Cytokine receptors communicate with the nucleus via a signal transduction
pathway to change gene expression and influence cell fate & activity
JAK
janus kinase
STAT
signal transducer and activator of transcription
what are some functions of specific cytokines
pyrogens (fever causing)
pro inflammatory
anti inflammatory
anti viral
chemokines
pygogens
Pyrogens (fever-causing): IL-1, IL-6 and TNF-alpha
pro inflammatory cytokines
- Pro-inflammatory: IL-1, IFN-γ, and TNF-alpha
anti inflammatory cytokines
- Anti-inflammatory: TGF-β
anti viral cytokines
Anti-viral: IFN-γ, IFN-α/β
chemokine cytokines
Chemokines: IL-8 attracts neutrophils, MIP-1alpha and MIP-1beta attract monocytes & NK cells
what controlls extravasation
chemokines
what are the steps of extravasation
rolling
activation
arrest/ adhesion
transednothelial migration
-integrins are necessary for adhesion
how do cytokines affect chemokine receptors
Cytokines can cause upregulation of chemokine re
what are two types of anti inflammatory agens
antibody based therapies
corticosteroids
antibody based therapies
blocking antibodies that bind integrins or other adhesion molecules
* kidney transplantation
* autoimmune diseases: crohn’s, MS, Rheumatoid arthritis
corticosteroids
- Interact with steroid hormones
- Decrease # of circulating leukocytes
- lysis of lymphocytes
- circulation of lymphocytes
- Inhibit secretion of almost all cytokines
- block NF-κB activation (transcription factor) = reduced IL-1 secretion
- inhibit T cell, macrophage, and neutrophil activation
how are cytokines related to hematopoesis
they regulate hematopoesis
G-CSF and GM-CSF are
used to treat
chemotherapy patients
and bone marrow
recipients.
what are cytokine related diseases
septic shock/ sepsis
cytokine storm
cancers
autoimmunity and other immune based diseases
septic shock/ sepsis
- Endotoxins produced by gram negative bacteria stimulate DCs and
macrophages via TLRs to overproduce IL-1 and TNF-α - Superantigens
- Trauma leading to ischemia (lack of blood blow); sterile inflammation
- neutralize TNF-α with an antibody
- neutralize IL-1 with soluble IL-1 receptor antagonist (IL-1Ra)
cytokine storm
influenza, SARS, COVID-19: positive feedback
activates too many immune cells; healthy immune system
* “Exacerbated lung inflammation due to cytokine dysregulation is the
underlying cause of respiratory failure in SARS-CoV-2-infected
individuals” Ramasamy and Subbian 2021
cancers (cytokine related)
- HTLV (human T cell leukemia virus): IL-2
- myelomas, cardiac myxoma cells, cervical cancer, bladder cancer: IL-6
- enhance proliferation
- autocrine
- Hodgkin’s lymphoma: IL-5
autoimmunity and other immyune based diseases
- SLE (lupus): IL-10
cytokine based therapies
cytokine inhibitors/ antagonists
reversing cellular deficiencies
treatment of immunodeficiencies
treatment of T cell leukemia and trasnplant patients
cytokine inhibitors and antagonists
*TNF inhibitors, IL-1Ra for RA /chronic inflammation
*IL-2R as clinical marker for chronic T cell activation
reversing cellular deficienceies
G-CSF and GM-CSF to escalate the rate of reconstitution
following chemotherapy or bone marrow transplantation
treatmnet of immunodeficiencies
*G-CSF for x-linked agammaglobulinemia,
*IL-2 for SCID; IFN-γ for leukocyte adhesion deficiencies
*IL-2 antibody stabilizes recombinant (injected) IL-2 in the circulation (paradox)
treatment of T cell leukemia and transplant patients
- Blocking antibodies to prevent T cell activation by IL-2
- Conjugate toxin to cytokine analogue to target TH cells
that express abnormally high amounts of CD25 (IL-2γ
chain)
destructino of activated Th cells or supression of T h cell proliferation and Tc cell activation
