Immune tolerance Flashcards
What is the definition of immune regulation?
Control of the immune response to prevent inappropriate reactions
What can decreased immune function lead to?
Leads to removal of unwanted cells or pathogens
Immunocompromised patients (AIDs, leukaemia, genetic diseases)
Opportunistic infections
Cancer (cells evade apoptosis)
What can increased immune response (hypersensitivity) be caused by?
Infection Environmental factors Genetic factors (family Hx) Female predisposition Hygiene hypothesis theory
What are some examples of diseases caused by an increased immune function?
Rheumatoid arthritis
Type 1 diabetes
Systemic lupus erythematosus SLE
Psoriasis
What is immune regulation required for?
Avoiding excessive lymphocyte action and tissue damage during normal protective responses against infection
Prevent inappropriate reactions against self-antigens
What are complications of an exaggerated immune response?
Sepsis- immune cells entering the wrong part of the body and causing organ dysfunction
this can be caused by…
hypercytokinaemia (cytokine storm) where there are so many cytokines produced that it leads to organ dysfunction
Direct organ damage - Type 1 diabetes, Hashimoto’s thyroiditis
Fatal damage to tissues - multiple sclerosis, ALS
What are the three signals that a T cell needs to be activated?
Antigen to which it is specific
Co-stimulation via receptors on the APC
Cytokines to be released
Define auto-immunity?
immune response against self antigen - pathologic
aka immune-mediated inflammatory diseases
What is tolerance in immunity?
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
What two levels can tolerance occur at?
Before lymphocytes enter circulation - central tolerance
After lymphocytes enter circulation - peripheral tolerance
What is the mechanism for autoimmune diseases?
Immune response against self antigens (autoimmunity) or microbial agents (crohns disease)
Immune response is inappropriately directed or controlled; mechanisms of injury are the same
What are the three possible outcomes to inflammation?
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 repair attempts ongoing
Where does central tolerance occur?
Thymus for T cells and bone marrow for B cells
How does central B cell tolerance occurs?
Immature B cells express IgM antibodies on cell membranes
If these immature B cells bind to stromal cells in the bone marrow they are auto reactive and undergo apoptosis
What are the 3 steps to central T cell tolerance?
Useless - Doesn’t bind to any self-MHC at all; Death by neglect (apoptosis)
Dangerous - Binds to self-MHC too strongly; Apoptosis triggered - negative selection
Useful - Binds to self-MHC weakly → Signal to survive - positive selection
Give the steps of cell-mediated immunity
Induction - Cell infected DC collects material
MHC-peptide TCR interaction
Effector- Naïve T cell becomes effector
Effector cell sees MHC-peptide on infected cell performs function
Memory - Effector pool contracts to memory
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What is AIRE and why is it needed?
Transcription factor which allows the thymus to express antigens found on cells not found in the thymus
T cells need to be exposed to antigens from all cells in the body however not all are present in the thymus
What can mutations in the AIRE gene lead to?
Severe systemic autoimmune disease called autoimmune multiendocrinopathy type 1
What is the role of peripheral tolerance?
Picks up any self-reactive B and T cells that escape central tolerance or regulate changed immune responses
This is especially important for B cells which undergo somatic hypermaturation
What is affinity maturation?
When B cells are stimulated they divide- expansion
During this transcription they are prone to errors, some antibodies are made with a higher affinity to antigen and others with less
Higher affinity ones survive and the B cell antibodies will have a stronger response to the pathogen
How can affinity maturation lead to autoimmunity?
Some environmental antigens and antigens that pathogens have are similar to self antigens
Self reactive B cells can be activated by the matured antibody recognising the antigen and changing the shape of the antibody to better bind to it
What can cause infective endocarditis?
Anti-streptococcus progenies antibodies can cross react with heart muscle and cause infective endocarditis
Name the four mechanisms of peripheral tolerance?
Anergy
Ignorance
Deletion/AICD
Regulation
What is anergy?
T cell encounters antigen without co-stimulation (context is different to normal inflammation)
Most cells lack costimulatory proteins and MHCII
The naive T cells become anergic and are less like to induce a response even if later antigen with co-stimulation is encountered
What is ignorance in peripheral tolerance?
either…
T cell encounters antigen in amounts lower than the threshold response level eventually becoming anergic or undergoing apoptosis
Naive T cells, that could potentially be self-reactive are kept out of important “immunoprivileged sites” ie eye and Brain by
- anatomical barrier preventing migration (compartmentalisation)
- Anti-inflammatory cytokines and apoptotic signals
What is deletion/antigen induced cell death in tolerance?
antigen presenting cell promotes T cell apoptosis by sending out a signal in the presence of antigen
This is often induced by the Fas ligand FasL/CD95
Reduces amount of self reactive T cells
How does regulation occur in peripheral tolerance?
Carried out by regulatory T cells - CD4 Treg cells
Formed in the thymus, bind to self antigen but do not kill them
Start up regulating transcription factor FoxP3 which helps them mature into Treg cells
What are some of the mechanisms of action of Treg cells?
- Inhibition of dendritic cells
- Secretion of immunosuppressive cytokines
- suppresses endothelial cell activation by reducing their adhesion
- modulate cholesterol metabolism
- Inhibition of macrophage inflammation
- inhibition of inflammatory T cells
What can a mutation in FoxP3 lead to?
It is an important transcription factor
without it you can develop a severe and fatal autoimmune disorder - immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome
What called scurfy In mice?
mutations in FoxP3
What is IL-10 and what does it do?
Key anti-inflammatory cytokine - blocks pro-inflammatory cytokine synthesis ie TNF, IL-6, IL-8 and IFN-γ
Downregulates macrophage functions
Viral mimics this to escape the immune system
Where are nTreg cells produced and what do they do?
Natural Treg cells, development in thymus requires recognition of self antigen during T cell maturation
Resides in peripheral tissues to prevent harmful reactions against self
What are iTreg cells and what do they do?
Develop from mature CD4 T cells that are exposed to antigen in the periphery, no role for the thymus
May be generated in all immune responses to limit collateral damage
Why do Tregs only exist in mammals?
Important in pregnancy as mother is exposed to cells in the foetus with different MHCI receptors so immune response must be prevented
What do T regs reflect?
The Th subsets (type of T cell) seen in T effectors
What are the main 3 functions of T reg cells?
1. Release indolamine 2.3 dioxygenase to inhibit APC receptor expression This limits: - ability to present antigens - Co-stimulation - Survival signals
- Release anti-inflammatory cytokines IL10, IL35 and TGF-β
this leads to
- blocking of production of pro-inflammatory cytokines
- stimulation of expression of inhibitory ligands on APC’s, this means cells that come into contact become inactivated - Express IL2 and adenosine receptors that mop up inflammatory cytokines to prevent response in other immune cells
What are the 5 different subtypes of CD4 T helper cells?
Tfh - pro-antibody Th17: control bacteria/fungal infection Th1: Boost cellular immune response Th2: Anti-multicellular organisms Treg (Th0): Anti-inflammatory
What do Tfh cells do?
Help shape the antibody response by activating naive cells to become plasma cells
- B cell internalises antigen and presents on MHCII to Tfh
- Co-stimulatory binding CD40 TO CD40L activates B cell
- Co-stimulatory binding CD28 to B7 activates T cell
The Tfh then starts secreting IL-21 that amplifies B cell activation
What do cytokines do and give some examples?
Program the immune response by focusing it for the right kind of response
Can be inflammatory or anti-inflammatory
INF-γ, IL-2, IL-1
What do chemokines do and give some examples?
Drive movement around the body
Send stuff to the right place, chemokine receptor profile changes with activation state of the cell
What determines with type of antibodies are produced?
Different T helper cells secrete different types of interleukins
This determines the type of antibodies produced
Explain how T cells influence the fc region of the antibody?
T cells produce cytokines
Cytokines programme B-cells to make different classes of antibodies
The cytokines associated with the different T helper subclasses go from T cells to B ells
B cells then activate a family of gene transcription or gene editing meaning they either drop in or out of the different constant regions
