Imunto Flashcards
Regulation of lymphocyte responses prevents:
Responses against self (tolerance),
Tissue damage
Excessive lymphocyte activation during immune responses
Immune regulation is
control of the immune response to prevent inappropriate reactions
IR us required to
Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections;
Prevent inappropriate reactions against self antigens (“tolerance”).
autoimmunity
immune response against self (auto-) antigen = pathologic
Systemic or organ-specific
auto-immune diseases featires
Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
Fundamental problem
imbalance between immune activation and control;
Failure of control mechanisms
is the underlying cause autoimmune diseases;
autoimmunity results from
May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease);
causes
May be caused by T cells and antibodies;
chronic
because it is attacking self-antigen there is always more antigen to attack.
Allergy
chronic
Harmful immune responses to non-infectious antigens that cause tissue damage and disease
mediated by
1/2
Antibody (IgE) and mast cells – acute anaphylactic shock
2/2
Or T cells – delayed type hypersensitivity
Hypercytokinemia and Sepsis
causes
Too much immune response
Often in a positive feedback loop
Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level
3 phases of Cell mediated immunity
Induction Effector Memory 1. Cell infected DC collects material 2. MHC:peptide TCR interaction 3. Naïve T becomes effector 4. Effector cell sees MHC:Peptide on infected cell Performs function 5. Effector pool contracts to memory
Principal mechanism:
immune response eliminates antigen that initiated the response
=> First signal for lymphocyte activation is eliminated
Licensing a response – the 3 signal model
Antigen Recognition
Co-stimulation- protien protien interactiom on cell surface
Cytokine Release
all 3 cause t or b cell activation
Antigen
Responses against pathogens decline as the infection is eliminated
Apoptosis of lymphocytes that lose their survival signals (antigen, etc)
Memory cells are the survivors
Three possible outcomes of infections
Resolution: no tissue damage, returns to normal. Phagocytosis of debris by macrophages.
Repair: healing with scar tissue and regeneration. Fibroblasts and collagen synthesis.
Chronic inflammation: active inflammation and attempts to repair damage ongoing.
Tolerance
specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Significance
All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
restoring tolerance may be exploited to prevent
treat autoimmune and allergic diseases
Types of tolerance
Tolerance occurs at two time points:
Before the T or B cells ever enter the circulation (central)
Or once in the circulation (peripheral)
Central tolerance
destroy self-reactive T or B cells before they enter the circulation
why before
Lymphocytes that recognise self antigens are eliminated (deletion) or made harmless in the generative organs as part of the maturation process.
AIRE
AutoImmune REgulator
not all eptide made in thymus
yes
How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?
A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues
AIRE promotes self tolerance by allowing the thymic expression of genes from other tissues
mutations in aire results in
multi-organ autoimmunity
Peripheral tolerance
destroy or control any self reactive T or B cells which do enter the circulation
3 pathway if b
Antibody
Production
Memory
Affinity Maturation- self reactive b cell can be activated, recognise antigen change shape if antibody to bind on antigen
somatic hypermutation
, B cells can change specificity after leaving the bone marrow
good
as it improves antibody quality
Exposure to environmental antigens or self antigens
can make them less tolerance
how many Mechanisms of Peripheral tolerance
Normal T cell response Anergy Ignorance Deletion/ AICD Regulation
Naive T cells needs in order to become activated
need co-stimulatory signals
problem
Most cells lack co-stimulatory proteins and MHC class II
what happens if n t cell see without co stimulatory protuen
If a naive T cell sees its MHC/peptide ligand without appropriate co stimulatory protein it becomes anergic
whats anergic
unresposive, as actiavtion energy is too high
what happens if it sees it in the future
less likley to become activated
slower to respond
Conditions in anergic
+ Antigen
- Co-stimulation
Ignorance Conditions
- Antigen
- Co-stimulation
what happens
Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
not activating so can become anergic
happens where
Immunologically privileged sites e.g. eye, (brain)
where t cells don’t see the antigen
Compartmentalisation of cells and antigen controls interactions
if they never meet they can’t become active
Antigen Induced Cell Death (AICD) Conditions
+ Antigen
+ FasL
how does it work
Activation through the T-cell receptor can result in apoptosis
Treg (T regulatory cells) function
inhibit other T cells and other cells by cytokines
what do they do
inhibit t cell activation
inhibit t cell effector function
Secretion of immune-suppressive cytokines
inactivation of dendritic cells or responding lymphocytes
Treg express transcription factor
FoxP3
Mutation in FoxP3 leads to
severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
Treg main iL is what
IL-10 (master regulator) cytokine
features and functions
Key anti-inflammatory cytokine Multi-functional (pleiotropic) Acts on a range of cells Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFNγ Downregulates Macrophage functions Viral mimics
“Natural” regulatory T cells (nTreg) develop where
in thymus
function
Development (in thymus) requires recognition of self antigen during T cell maturation
prevent harmful reactions against self
Inducible regulatory T cells (iTreg)
develop from
Develop from mature CD4 T cells
function
Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus
May be generated in all immune responses, to limit collateral damage
Cytokines prgms
immune response
function
They can be inflammatory (increase the response)
Or anti-inflammatory (decrease the response)
Chemokines function
Chemokines drive movement around the body
Chemokine receptor profiles
change with activation state of the cells
how do cell follow
moves up chemokine gradient
T helper type defined by
transcription factors
Different antibody classes have different
constant regions.
T cells shape the antibody response
T cells cytokine drive Ig class switch
