Tolerance and Autoimmunity Flashcards
What is self tolerance?
Immune system is unresponsive to self cell components
What is the different in tolerance between T and B cells?
T cells tolerize earlier, to a higher threshold of activation, and last longer than B cells.
Where does central tolerance occur? What are the mechanisms?
In primary lymphoid organs, during the selection process of immune cells.
Clonal deletion, clonal anergy, and receptor editing in B cells (light chain)
What is clonal anergy? How can this be reversed?
When cells are unresponsive but not deleted. Can be reversed via IL-2, which upregulates CD28
What are the mechanisms of peripheral tolerance? Where does it happen?
Taking place in secondary lymphoid organs
- Clonal deletion
- Clonal anergy
How does clonal deletion occur?
3 ways:
- Activation-induced cell death
- Superantigens (1/2 are very similar)
- Apoptosis via Fas-FasL interaction
How do cells become anergized?
Cells receive TCR stimulation without costimulation via CD28/B7
What cytokines do Th1 cells produce?
IFNgamma and TNF alpha
IFNy inhibits Th2 functions
What cytokines do Th2 cells produce?
IL-4, IL-13 (induce b cells), IL-5 (eosinophils), IL-10 (anti-inflammatory)
IL-4 is antiinflammatory and inhibits Th1
What is the function of Treg cells and what cytokines do they produce?
Suppress activation of immune response via production of TGFb and/or IL-10
What are natural Tregs?
Cells generated in thymus based on intermediate affinity for self-MHC. Upregulate the Foxp3 transcription factor, and highly express CD4 and CD25 (beta chain of IL-2 receptor)
What is an induced Treg? How are they made?
An antigen-specific Treg produced in the periphery.
How is a FoxP3+ induced Treg made?
They are originally CD25-, but are induced by TGFb in the absence of IL6 (would make Th17), and begin secreting TGFb
What is a Th3 cell?
A FoxP3- Treg found mostly in the mucosal immune system. They produce IL-4 and IL-10(like Th2), but also make TGFb.
Thus, not all Treg cells utilize one particular marker.
How are immune-priviledged sites generally treated? Use testes as an example?
The tissues are tolerized.
Testes stromal cells express FasL, and can apoptose any immune cells entering the tissue.
How does maternal placenta not interact with fetus?
They are tolerant to eachother, since paternal MHC could cross-react
Give one example of autoimmunity being a good thing for RBC clearance?
IgG autoantibodies can bind senescent cell antigen and clear aged RBCs.
During what regenerative process has T cell autoimmunity been shown to play a role?
Neural regeneration following injury
What is an autoimmune disease?
Pathologic condition resulting from failure of tolerance mechanism to self antigens.
Can result from a defect in innate OR adaptive immunity
What types of immune responses are associated with organ specific vs systemic?
Organ specific: cellular
Systemic: humoral
What are two classes of genes which can affect one’s genetic predisposition to autoimmune disease?
- MHC association - can be a predictive marker for relative risk
- Non-MHC genes - including AIRE and FasL
What are some environmental factors influencing autoimmune disease development?
Geography - MS disease risk decreased towards equator
Infection
Anatomical injury - immune-privileged sites lose tolerance due to trauma
Hormonal - females more susceptible
Exposure to drugs, radiation, and toxins - i.e. SLE and UV light
How does molecular mimicry play into infection causing autoimmune disease?
If the antigen used to clear the infection looks alot like a self antigen, T cell tolerance might be lost and the immune system could begin attacking self.
I.e. Coxackie virus B4 and IDDM
What are two ways in which immune mechanisms can fail to cause autoimmune disease?
- Complement over-activation can cause cellular damage due to inflammation
- Treg cells fail to regulate disease manifestation
What is the autoimmune disease with highest prevalence?
Graves’ disease, followed closely by rheumatoid arthritis
What is the genetic association with myasthenia gravis?
HLA-DR3
What is the mechanism of pathogenesis of MG? Give the disease classifications
Systemic, antibody-mediated, inhibitory antibodies
B cell disease which causes auto-antibodies to Ach receptors at neuromuscular junction, causing muscle fatiguability / weakness
What do many MG patients have concurrently with muscle weakness?
Thymoma (hypertrophy of thymus)
How is MG treated?
Ach-ase inhibitors and immunosuppressants
What is the genetic association with graves’ disease? What are some symptoms?
HLA-DR3 in whites (like MG)
Asians - HLA Bw35 and 36
All symptoms of elevated T3/T4, can cause proptosis and goiter
What is the mechanism of pathogenesis of GD? Give the disease classifications
Organ specific, antibody-mediated, stimulatory antibodies
Antibodies are made to TSH receptors, greatly elevating T3/T4 levels, especially in females. TSH will be low by negative feedback.
Can GD effect a fetus?
Yes, IgG antibodies to TSH receptors can pass through placenta, but baby can be treated with anti-anti-TSH
Why class of disease is systemic lupus erythematosus (SLE) and what is the general mechanism?
Systemic, antibody-mediated, immune-complexes (Type 3 hypersensitivity)
Autoantibodies to many different things, including DNA, histones, RBCs and other cells in serum
Who is most affected by SLE and what HLA groups are most susceptible?
Women and black people
DR2, DR3
What are some diagnostic places where immune complexes are deposited in SLE?
Skin - patients are sensitive to UV - butterfly rashes
Joints - non-erosive arthritis
Kidney - causes glomerulonephritis
How do we know T cells are involved in SLE?
IgG antibodies are high affinity
What are the most common antibodies in SLE?
Anti-nuclear antibodies, i.e. anti ds-DNA and anti-snRNP
What subset of B cells is most overactive in SLE?
CD5+ B cells.
What is the treatment for SLE?
Kidney dialysis and immunosuppressants like cyclophosphamide
What class of disease is rheumatoid arthritis?
Systemic / organ-specific (bone), antibodies and T-cell mediated
What HLA genotypes are associated with RA?
HLA DR-1 and DR-4 associated with 70% of cases
What are the diagnostic features of RA?
Morning stiffness in joints, swelling around three or more joints.
Swelling of proximal IP MP or wrist joints, OR systemic arthritis, subcutaneous nodules, and a positive RF test (rheumatoid factor)
How is rheumatoid factor related to RA?
RF is an IgM antibody directed against Fc portion of IgG, forming immune complexes and depositing in joints. However, it is not specific for RA as it is present in other diseases, and 30% of RA patients do not have this
What does RA primarily effect?
Peripheral synovial joints with antibodies which may be involved in the normal immune response
How are T cells involved in RA?
Primarily Th17 and Th1 cells produce IFNy and IL-17 to cause inflammation and activate synovial macrophages + fibroblasts. Antigens include type 2 collagen of cartilage (non-fibril forming), proteoglycans and heat shock proteins.
What is a pannus?
Organized mass of cells that grow in joint space, including fibroblasts, macrophages, mast cells, and stellar cells due to inflammation recruitment
What are treatments for RA?
NSAIDs, monoclonal Abs for B cell markers CD20, immunosuppressants, and corticosteroids among others
What class of disease is hashimoto’s thyroiditis?
Organ-specific, T cell mediated, antibodies secondary
What HLA classes are related to HT?
HLA-DR3 and DR5
What are the diagnostic features of HT? Symptoms?
High TRH and TSH, low T3 and T4, circulating anti-thyroglobulin and anti-thyroid peroxidase antibodies
Dry skin, brittle hair / nails, weight gain, myxedema, depression and fatigue
What autoantibodies are involved in HT?
Antibodies against thyroid peroxidase and thyroglobulin - destroying thyroid gland
How are T cells involved in HT?
CD4 T cells activate macrophages
CD8 T cells cause destruction of thyroid follicular cells
What is the onset of IDDM? What processes cause this? Which sex gets this more?
Early, sudden onset in adolesence
Initially, autoantibodies to pancreatic beta cells
Later, cytotoxic T cells kill the beta cells.
NO gender bias
Which HLA types are at highest risk for IDDM?
HLA DR3/DR4 - includes 50% of IDDM patients. 95% of whites will have at least 1 of these
What is the primary antigen for which IDDM antibodies are directed?
Glutamic acid decarboxylase
What is thought to trigger IDDM antibodies?
Viral infection / molecular mimicry. Congenital rubella infection is for sure linked to it, others inconclusive
What class of disease is IDDM in?
Organspecific, T-cell mediated since ultimately CD8 T cells will kill the beta cells.
CD4 T cells also produce IL-1, IL-6, and IFNa to increase inflammation
What genetic marker is associated with MS? What sex is more affected?
HLA-DR2
females are more affected, especially white people
What are autoantigens against in MS?
Myelin sheath components:
Myelin basic protein (MBP)
Proteolipid protein (PLP)
Myelin oligodendrocyte glycoprotein (MOG)
What type of disease is MS?
Organ specific, T-cell mediated
How do T cells mediate the MS progression?
Th1 cells secrete IFNy, stimulating IgG response
Th17 cells cause inflammation via IL-17
What is diagnostic of MS? What are symptoms?
Oligoclonal IgG bands in CSF
Plaques in white matter of brain on MRI
Symptoms:
Paralysis, incontinence, vision problems, ataxia, problems with speech or swallowing
What is the treatment of MS?
Beta interferons - regulate the T cells, inhibit T cell activation and entering of CNS
Copaxone - which resembles myelin basic protein
Monoclonal antibodies to integrins on T cells - natalizumab.
