Autoimmunity Flashcards
What defines autoimmunity?
- Generation of adaptive immune cell receptor diversity comes with the danger of producing cells that are able to strongly bind SELF
- If these SELF-specific T or B cells which recognize autoantigens are not checked, then the result is autoimmunity
- Leads to serious tissue/organ damage and possibly death if not treated
*Autoimmune disorders are an adaptive response, not innate
What are 3 examples of autoimmune disorders?
- Rheumatoid arthritis → autoreactive lymphocytes reacting to Ag to the joints
- Systemic lupus erythematosus → auto-ab generated to DNA are deposited in the kidney
- Graves’ disease → Auto-Ab against thyroid hormone receptor, too much thyroid hormone
Which of the following is an autoimmune disorder?
1. Antibodies generated against cellular DNA leading to kidney failure
2. Chronic production of IL1-beta leading to intermittent fever
3. Macrophages located in plaques contributing to tissue damage in heart disease (atherosclerosis)
Answer: 1. Antibodies generated against cellular DNA leading to kidney failure
What experiment first showed autoimmunity?
Auto-ab bind to RBC upon cold exposure → activate complement → RBC get lysed
What defines immunological tolerance vs self-tolerance? What defines breaking tolerance?
A state of functional unresponsiveness for a particular antigen
- Cells are not there or cells are there but not responding
Breaking Tolerance → making the immune system responsive to an antigen
Breaking Tolerance to self-antigen → Autoimmunity
Tolerance is an active process and tolerance to self is an essential feature of the immune system
Self-tolerance protects an individual from potentially self- reactive lymphocytes
What defines central tolerance?
Deletion of the T- and B-cell clones before the cells are allowed to mature if they possess receptors that recognize self Ags with greater than a threshold affinity.
- Clonal deletion during lymphocyte development
What defines peripheral tolerance? What are 3 mechanisms?
Deletion or rendering anergic lymphocytes that possess receptors reacting with self Ags.
Self is detected:
1. Suppression by regulatory T cells
2. Anergy
3. Activation induced cell death
Self not detected or not accessible:
1. Ignorance
What are different levels of tolerance?
- Individual choice → at level of individual cells
- Committee governance → interaction between other cells (with DCs)
- Governance by police → Specific reg cells that shut down autoreactive processes (Tregs)
What antigens are presented in the thymus to educate T cells? How is tolerance to peripheral tissue-specific antigens (TSA) achieved?
- Self-proteins are presented → membrane channels, house keeping proteins involved in cell division/maintenance (this is limited to cells and genes that can be expressed in the thymus)
Achieving tolerance to peripheral tissue-specific antigens (TSAs) → TSA expression in mTECs:
2. AIRE: autoimmune regulator
What is AIRE? What is the effect of lack of AIRE?
Autoimmune Regulator expressed in mTECs
- A crucial transcriptional regulator which can promote the expression of thousands of TSAs
Lack of AIRE causes autoimmune polyglandular syndrome type 1 (APS-1) → autosomal recessive disease in humans
Taking self-reactive T cell from mouse that has APS-1 → you would transfer autoimmunity if you transfer that T cell
Autoimmune component = cell intrinsic
*Expression of Aire is specific to medullary region (where they undergo negative selection as developping, can generate lots of self-proteins in the thymus that would not normally be made
What are mimetic cells?
Mimetic cells are specialized mTECs that present tissue-restricted antigens
Mimicking peripheral cell counterparts of other epithelium
What is T cell fate defined by?
T cell fate in the thymus is determined by the strength of the signal transmitted by the T cell receptor (avidity/affinity)
Big number of T cells generated are fltered out because they don’t recognize peptide:MHC (death by neglect = majority!!) → After selection ~ 5% of T cells you make a making it out of the thymus
Does central tolerance get rid of all self-reactive T cells? Descrive the experiment.
What was thought was that was that negative selection efficiently deletes self-reactive T cells and peripheral tolerance mechanisms regulate only a small number of T cells
Actually, negative selection is very incomplete and many T cells escape deletion
Experiment: CD8 T cells recognizing a Y chromosome specific antigen (SMCY, self for males, foreign for women) is only 3x greater in women than in men.
- A large fraction (1/3) of SMCY-specific CD8 T cells are not deleted in men
How does central tolerance involve in the case of B cells?
Immature B cells expressing an autoreactive receptor recognizing a multivalent self antigen can undergo receptor editing
IgM cross-linking results in IgM downregulation, RAG re-expression and light-chain gene rearrangement
B cells remaining autoreactive undergo clonal deletion
What conditions induce anergy in T cells?
T cell receptor binding to peptide-MHC on a cell that does not express the co-stimulatory factor B7, results in a long-lasting non-responsive state called anergy
Once anergic, no cell division upon antigen stimulation + costim (even when full signal)
This is dependent on the way DCs were activated (if fully activated or not)
What experiment showed the existence of Tregs?
- Take CD25+ and CD25- T cells from a WT mouse
*Nude mice don’t have a thymus
Inject in group 1 of nude mice → CD25- T cells → autoimmunity
Inject in group 2 of nude mice → CD25+ and CD25- T cells → healthy
Showed that there was a subset of CD25+ T cells that where required for self-tolerance
What transcription factor defines Tregs?
What do these cells develop from?
FoxP3
FoxP3+ Tregs develop from CD4 T cells that have a higher reactivity for self antigen than conventional T cells
What is the effect of a mutation in FoxP3?
Give an example of syndrome.
Mutations in FoxP3 cause a human disease with aggressive and lethal lymphoproliferative syndrome characterised by multisystem autoimmunity
IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome
What are the different mechanisms of action of T regs to suppress effector T cells responses?
- Secretion of immuno-suppressive cytokines
ex: TGFbeta - Metabolic disruption
- CD25 receptor on Tregs have high affinity with IL-2 → Mop-up IL-2 which is critical for survival of effector T cells, expansion and division → T cells undergo cell death without iL-2
- CD39 and CD73 are exonuclease → generate adenosine → act on receptor to dampen effector T cells phenotype (immunosuppressive effect)
- Inhibition of dendritic cell maturation and function
- Through CTLA-4-4:CD80/86 → DC produce IDO → immunosuppressive cytokine
*CTLA-4 on Tregs - Cytolysis
- Release of Granzyme A or B to lyse and kill effector T cells
Where are Tregs found in the lymph nodes?
In the deep t cell zone, colocalized with other T cells
What is involved in activation-induced cell death as a mechanism of peripheral tolerance?
Following clonal expansion of effector T cells when pathogen is cleared, effector cells undergo apoptosis and only a small pool of memory T cells remains
Activation induced Fas/FasL expression (both expressed by T cells) → Autocrine and paracrine apoptosis
What is ALPS?
(Autoimmune Lymphoproliferative Syndrome)
Autosomal dominant disorder where defect in T cell receptor induced apoptosis leads to non-malignant T cell division
*problem in peripheral activation induced cell death
Unchecked cell division can result from stimulation by self or foreign antigens
What does ignorance imply as a mechanism of peripheral tolerance?
Antigens that are not accessible or presented to T cells induce neither tolerance nor activation = T cells are ignorant
Antigens to which this applies in particular are those that are in immunologically privileged sites**
If the ignorant T cells are activated elsewhere, then the sequestered autoantigens could become targets of autoimmune attack – eg. multiple sclerosis
What are different immunologically privileged sites?
- Brain
- Eye
- Testis
- Uterus (fetus)
*These organs doo not have antigen cells in them and peptides from these organs are not presented in the thymus so they would be recognized as non-self
What is sypathetic ophthalmia?
It is an example where ignorance is maintained only until there is damage to an immunologically privileged site
- Trauma to 1 eye result in the release of sequestered intraocular protein antigens
- Released intraoccular antigen is carried to lymph nodes and activates T cells
- Effector T cells return via bloodstream and encounter antigen in both eyes
*If not treated, both eyes will be damaged → complete loss of vision
What is autoimmunity the result of?
What factors are involved?
It is the result of a combination of multiple factors coming together.
- Genetic susceptibility
- Environmental triggers such as infections
- Breakdown in neural tolerance mechanisms
*Does not occur as the result of only 1 factor
Where is multiple sclerosis mostly present world-wide?
High prevalence in Canada and North of the US + Northern Europe
What are 2 ways in which Autoimmunity is multifactorial?
- Takes multiple factors to trigger it (genetic + environmental)
- Although some autoimmune diseases have traditionally been thought to be mediated by B cells or T cells, it is important to consider that all aspects of the immune system have a role to play.
How is the full immune system involved in autoimmunity although it is only caused by an imbalance in the adaptative immune response?
Give an example.
Ex: Systemic Lupus Erythematosus
Type 1 IFN plays a critical role…
Genetic susceptibility:
1. Antigen presentation (HLA-DR)
2. IFN/TLR signaling
3. TNF/NF-kB signaling
4. T cell signaling
5. B cell signaling
6. Immune complex clearance
etc.
Envrionmental/endogenous triggers lead to DCs releasing more IFN-a → monocytes, autoreactive Cd4 T cells, autoreactive CD8 T cells, B cells, etc.
- TLR receptors recognize it
- Plaque formation through Ab-Ag complexes
etc.
What are the 2 main classifications of autoimmune diseases?
*For clinical purposes
- Organ-specific autoimmune diseases
- Type 1 diabetes mellitus
- Goodpasture’s syndrome
- Multiple sclerosis
- Graves’ disease - Systemic autoimmune diseases
- Rheumatoid arthritis
- Scleroderma
- SLE
In systemicautoimmune diseases multiple organs are affected and have a tendency to become chronic, because the autoantigens cannot be cleared from the body.
What characterizes type 1 diabetes as an autoimmune disease?
Specific destruction of the β-cell producing insulin in the pancreatic islets of Langerhans.
- Other cells in the islets are not destroyed
Studies in the NOD mouse model of type I diabetes have shown that peptides from insulin itself are recognized by the CD8 T cells (Tc).
- These studies confirm that insulin is the autoantigen.
*Glucagon and somatostatin are still produced by alpha and delta cells, but no insulin can be made
What characterizes multiple sclerosis as an autoimmune disease?
Multiple sclerosis is an example of a T-cell mediated chronic neurological disease that is caused by the destructive immune response against several brain Ags like:
- myelin basic protein
- proteolipid protein
- myelin oligodendrocyte glycoprotein
- Unkown trugger sets up initial focus of inflammation in brain and blood-brain barrier becomes locally permeable to leukocytes and blood proteins
- T cells specific for CNS antigen and activated is peripheral lymphoid tissues reencounter antigen presented on microglia or DC in brain
- Inflammatory reaction in brain due to mast-cell activation, complement activation, Abs and cytokines
- Demyelination of neurons
Which cells are specifically involved in MS response?
Th1/Th17 CD4+ T cells
What characterizes rheumatoid arthritis as an autoimmune disease?
Rheumatoid arthritis is a chronic disease characterized by inflammation of the synovium (thin lining of a joint).
- As the disease progresses, the inflamed synovium invades and damages the cartilage followed by erosion of the bone.
- Patients suffer from chronic pain, loss of function and disability.
- Matrix metalloproteinases (MMPs) → attacks tissues which activates bone-destroying osteoclasts resulting in joint destruction
