Tolerance And Autoimmunity Flashcards
What is the normal response of an immune cell recognizing a microbe?
Proliferation and differentiation –> immune response
What are the 3 mechanisms of self-tolerance when a self-antigen is recognized by an immune cell?
Anergy
Apoptosis
Change in specificity/receptor editing (B cells only)
Define anergy
Functional unresponsiveness
What is the difference between central and peripheral tolerance?
Central refers to developing lymphocytes (in primary lymphoid organs)
Peripheral refers to mature lymphocytes present in peripheral tissues
Where does central tolerance for T cells develop?
Thymus
Negative selection for T cells occurs in the presence of _______, which stimulates the expression of peripheral “tissue-restricted” self antigens in the thymus
AIRE
[autoimmune regulatory protein]
What does a defect in AIRE lead to?
Autoimmune polyendocrinopathy
What is the result of weak recognition of class I or class II HLAs + peptide lead to in the thymus?
Positive selection
What two conditions lead to negative selection and apoptosis during T cell development?
No recognition of MHC + peptide
Strong recognition of MHC + peptide
How is the formation of regulatory T cells an outcome of central tolerance?
Thymocytes with a LOW affinity for self antigen become T cells (CD4 or CD8)
Thymocytes with an INTERMEDIATE affinity for self antigen become T regulatory cells (CD25)
[those with high affinity undergo negative selection]
FOXP3 T cells upregulate what CD marker?
CD25
What might the loss of FOXP3 in mice lead to?
Widespread autoimmunity
Treg cells account for approx. what percentage of circulating CD4+ T cells?
5-10%
What is the general mechanism of peripheral T cell tolerance in preventing autoimmunity?
Upregulation and binding of CTLA-4 promotes T cell anergy
Peripheral T cell tolerance relies on the concept of two-signal activation of T cells. What is the first signal?
TCR binding to HLA:peptide complex
Peripheral T cell tolerance relies on the concept of two-signal activation of T cells. What is the second signal?
Binding of the costimulatory protein B7 (APC) to CD28 (T cell)
Describe the expression of B7 on APCs in the absence of infection or inflammation
B7 expression will be low or absent on APCs in the absence of infection/inflammation
Which binds B7 with higher affinity, CD28 or CTLA-4?
CTLA-4
Describe the expression of CTLA-4 on APCs in the absence of infection or inflammation
Expression will be upregulated and CTLA-4 will preferentially bind B7, leading to anergy
What are the 3 mechanisms of central B cell tolerance?
Receptor editing –> non-self reactive B cell
Apoptosis –> deletion
Reduced receptor expression and signaling –> anergy
What are the 3 mechanisms of peripheral B cell tolerance?
Functional inactivation –> anergy
Apoptosis –> deletion
Inhibitory receptors –> regulation by inhibitory receptors
Are tolerogenic self antigens present in generative organs?
Yes (some self-antigens): high concentrations induce negative selection and regulatory T cells (central tolerance)
Are immunogenic foreign antigens present in generative organs?
No: microbial antigens are concentrated in peripheral lymphoid organs
Will tolerogenic self-antigens be presented with second signals like co-stimulation?
No: deficiency of second signals may lead to T cell anergy or apoptosis
Will immunogenic foreign antigens be presented with second signals like co-stimulation?
Yes; second signals promote lymphocyte survival and activation
Describe the persistence of tolerogenic self-antigens
Long-lived (throughout life); prolonged TCR engagement may induce anergy and apoptosis
Describe the persistence of immunogenic foreign antigens
Usually short lived; immune response eliminates antigen
What are the 3 primary factors that contribute to autoimmune disease?
Genes (HLA haplotypes)
Infections
Environmental factors (UV radiation, chemicals, etc.)
T/F: the principle factors in the development of autoimmunity are inheritance of susceptibility genes and environmental triggers
True
The 3 general effector mechanisms of autoimmunity:
immune __________
Circulating ____________
___________ T lymphocytes
Complexes
Autoantibodies
Autoreactive
T/F: Self antigens are often easily identified in cases of autoimmune diseases
False; self antigens are often not identified which hinders our understanding of autoimmune disease
Some of the other factors that hinder our understanding of autoimmune disease include that they are heterogenous, ____________, and clinical manifestation is prolonged and ___________ after initiation
Multifactorial
Variable
What determines the type of tissue injury in autoimmune disease?
Type of tissue injury is determined by the DOMINANT immune response
Are autoimmune diseases organ-specific or systemic?
Can be both!
What makes an autoimmune disease a chronic condition?
Chronicity is due to many amplification loops
[normal response to Ag allows a small number of Ag-specific cells to increase their numbers, when response is against same self-Ag, the SAME amplification mechanism exacerbates and prolongs injury]
What makes an autoimmune disease persistent and progressive?
Epitope spreading
[response against one self-Ag causes damage that leads to the release of other Ags; T cells will react against the epitopes found on newly released Ags]
Autoimmune diseases run in families with variations between populations, typically involving HLAs. Which allotypes are primarily involved?
HLA class II allotypes
Which autoimmune disease is associated with an environmentally acquired infection?
Rheumatic fever
Which autoimmune disease is related to physical trauma?
Sympathetic ophthalmia
Which autoimmune disease is considered drug-induced?
SLE
T/F: pathology of autoimmune diseases is mediated by cell-mediated immunity only
False; can be mediated by humoral or cell-mediated immunity
T cell help is often necessary for autoantibody formation
What is the sex distribution of common autoimmune conditions like Hashimotos, Sjogrens, Addisons, RA, etc.?
Predominantly female
What is one theory as to why females tend to develop more autoimmune conditions, especially in middle age?
Estrogen may be protective, so when estrogen levels decline during menopause, women develop autoimmune conditions more easily
Which autoimmune condition is a 90% female diagnosis?
Systemic Lupus Erythematosus
HLA-B27 carries a 90% relative risk of developing what autoimmune disease?
Ankylosing spondylitis
RA is an autoimmune disease associated with which MHC allele?
HLA-DR4
Type I DM is associated with which MHC allele?
HLA-DR3/DR4
Pemphigus vulgaris is associated with what MHC allele?
HLA-DR4
Ankylosing spondylitis is associated with which MHC allele?
HLA-B27
PTPN22 is a gene that codes for enzyme __________ ___________, this is abnormal in the autoimmune conditions RA, T1D, and autoimmune thyroid conditions
Tyrosine phosphatase
The _______ gene is implicated in autoimmune disease like T1D and RA due to impaired inhibitory checkpoint and regulatory T cell function
CTLA4
A single gene defect in _______ leads to autoimmune polyendocrine syndrome (APS-1) due to defective elimination of self-reactive T cells
AIRE
_________ is a gene necessary for thymic expression of self-proteins and is associate with autoimmune diseases like diabetes, adrenal, and parathyroid diseases
AIRE
A single-gene defect in _______ leads to immune dysregulation, polyendocrinopathy, enteropathy, and widespread autoimmunity
FOXP3
A single-gene defect in ______ leads to splenomegaly, lymphadenopathy, and adrenal autoimmune disease due to defective apoptosis of self-reactive T and B cells in the periphery
FAS
Streptococcus pyogenes is able to form autoantibodies that attack cardiac tissue in people with certain HLAs. By what mechanism is it able to do this?
Molecular mimicry
[group A strep –> rheumatic fever (carditis, polyarthritis)]
Chlamydia trachomatis associated with HLA-B27 leads to what potential consequence?
Reiter’s syndrome (arthritis)
Shigella flexneri, Salmonella typhimurium, Salmonella enteritidis, Yersinia enterocolitica, and Campylobacter jejuni in the setting of HLA-B27 may lead to what potential consequence?
Reactive arthritis
Borrelia burgdorferi in association with HLA-DR2, DR4 may lead to what potential consequence?
Chronic arthritis in Lyme disease
Coxsackie A virus, Coxsackie B virus, echoviruses, or rubella in association with HLA-DQ2, HLA-DQ8, or DR4 may lead to what potential consequence?
IDDM
The TSH receptor interacting with and agonist antibody leads to hyperthyroidism in what disease?
Grave’s disease
The ACh receptor being acted on by an antagonist antibody leading to progressive muscle weakness leads to what syndrome?
Myesthenia gravis
The insulin receptor being acted on by an antagonist with the consequence of hyperglycemia and ketoacidosis occurs in the setting of what disease?
Insulin-resistant diabetes
The insulin receptor being acted on by an agonist antibody with the result of hypoglycemia occurs in the setting of what syndrome?
Hypoglycemia
Name the antigen, antibody classification, and consequence for the following syndrome:
Grave’s disease
Ag: TSH receptor
Antibody: Agonist
Consequence: Hyperthyroidism
Name the antigen, antibody classification, and consequence for the following syndrome:
Myasthenia gravis
Ag: ACh receptor
Antibody: Antagonist
Consequence: Progressive muscle weakness
Name the antigen, antibody classification, and consequence for the following syndrome:
Insulin-resistant diabetes
Ag: Insulin receptor
Ab: Antagonist
Consequence: Hyperglycemia, ketoacidosis
Name the antigen, antibody classification, and consequence for the following syndrome:
Hypoglycemia
Ag: Insulin receptor
Ab: Agonist
Consequence: Hypoglycemia
What is the prototypic immune complex disease causing defective apoptotic process leading to increased nucleic acid Ags available to stimulate an immune response and auto-antibody production?
SLE
What disease is characterized by inflammation of the synovium wherein Th17 and Th1 cytokine release sustains the inflammatory response and there is auto-Ab production including Rheumatoid factor?
RA
What are the auto-antibodies associated with rheumatoid arthritis specifically targeting?
The auto-antibodies (IgM) are against the Fc portion of IgG
In the setting of RA, you can find all immune mediators in the ________ space, and in advanced cases even including establishment of _________ and ________ _______ (tertiary lymphocyte tissue)
Synovial
Follicles
Germinal centers
________ is a pleiotropic cytokine with widespread roles in inflammation and host defense.
Agents directed against this cytokine were the first to develop and are currently approved and in use. They are typically _________ antibody-based.
TNF-a
Monoclonal
The ________ monoclonal Ab decreases T cell autocrine response to IL-2
Anti-CD25
The ________ monoclonal Ab blocks B7 frfom binding CD28 and promotes anergy
Anti-CTLA-4
The ________ monoclonal Ab targets mature naive B cells for deletion
Anti-CD20
What type of monoclonal Ab prevents T cells from infiltrating tissues?
Abs for adhesion molecules/chemokine receptors
________ is an autoimmune condition involving ________ mutations, leading to loss of function of Treg cells and uninhibited T cell activation.
IPEX
FOXP3
What are the most common symptoms of IPEX?
Intractable diarrhea leading to failure to thrive
Autoimmune diabetes type I, developing in infancy
[diarrhea is due to widespread inflammation of the gut, including colitis, resulting in villous atrophy]
What would you expect for serum Abs in a patient with IPEX?
Normal serum levels of Abs, except for elevated IgE, but the mechanism for hyper-IgE is unclear
Hyper-IgE results in what symptom in IPEX patients?
Dermatitis
