Autoimmunity Flashcards
Autoimmune diseases operate by what types of hypersensitivity?
- Type II - cytotoxic
- Type III - immune complex
- Type IV - T-cell mediated/delayed
What causes autoimmunity?
- Developmental regulation disfunction
- Genetics
- Environment
NO ONE FACTOR CAN CAUSE AUTOIMMUNITY
Mutations in what gene(s) is the most common genetic determinant of autoimmunity?
HLA - MHCI and MHCII
11% of caucasian people have the HLA-A1-B8-DQ2-DR3 haplotype, which is more likely to _______
bind self-antigen, thus predisposing them to autoimmunity
What are the 3 “immune-privileged” sites of the human body?
- Corneas
- Brain
- Testes
What is the only autoimmune disease that is more common in men than women?
Ankylosing spondylitis
What is the normal function of the autoimmune regulator (AIRE) gene?
Production of self-antigen to aide in negative selection
What is autoimmune polyglandular disease (APD)?
- Autoimmune response against many endocrine glands
- hypoparathyroidism
- adrenal failure
- ovarian failure
- type I diabetes
- candidiasis
- enamel hypoplasia
- nail dystrophy
What are the mechanisms that contribute to central tolerance? (3)
- Negative selection of B cells in the bone marrow
- Expression of tissue-specific proteins in the thymus so that they participate in negative selection of T-cells (AIRE)
- Negative selection of T-cells in the thymus
What are the mechanisms that contribute to peripheral tolerance? (3)
- Exclusion of lymphocytes from immune-privileged sites
- Induction of anergy in autoreactive B and T cells that reach the peripheral circulation
- Suppression of autoimmune responses by regulatory T-cells
Mutation of the X-linked FoxP3 gene causes a rare immunodeficiency that principally affects boys, called _______
immune dysregulation, polyendocrineopathy, enteropathy, X-linked disease (IPEX)
Children with IPEX have normal levels of _____ cells and elevated levels of ______ cells
- CD25 T-reg cells
- TH17 cells
How does IPEX present clinically?
- Enteritis → chronic diarrhea
- Type 1 diabetes
- Eczema
- Failure to thrive
- Do not survive past 1 y/o
_____ tolerance is negative selection during lymphocyte development, occurring in primary lymphoid organs
Central tolerance
_____ tolerance refers to anergy or suppression of auto-reactive cells; occurring in secondary lymphoid organs
Peripheral tolerance
True or false, peripheral tolerance only occurs after infection occurs.
True
What is the consequence of a T-cell failing to receive a co-stimulatory signal from B7 on APCs?
Anergy
Binding of pathogen to self-protein results in _____
pathogen creating a unique epitope for autoimmunity to occur
How can disruption of cell tissue or barrier result in autoimmunity?
Unregulated release of cellular contents (self-antigen) can activate nontolerized lymphocytes
What is molecular mimicry?
Pathogen antigen resembles host antigen, which triggers production of cross-reactive antibodies or T-cells
How do superantigens elicit an autoimmune reaction?
Stabilization of the MHC-TCR complex without the need for a co-stimulatory signal, thus activating potential auto-reactive T-cells
Describe the Bystander effect in regard to B and T cells.
Self-reactive B/T cells receive second signal for activation from nearby cells
Grave’s disease is associated with mutations in what gene?
HLA-DR3
Describe the mechanism of Grave’s disease
Auto-IgG are generated against TSH receptor, however these antibodies are agonistic so they cause activation of the receptor and cause chronic overproduction of T3 and T4
What are the symptoms of Grave’s disease?
-
Hyperthyroid
- heat intolerance
- nervousness
- irritability
- weight loss
- bulging eyes
- enlarged thyroid
Grave’s disease can be treated with drugs that inhibit uptake of _____
Iodine
True or false. If someone with Grave’s disease was pregnant, they cannot transfer the disease to their child.
False. IgG cross the placenta so the newborn will suffer the disease until the IgG is cleared
Describe the mechanism of myasthenia gravis
Auto-IgG against acetylcholine receptors are antagonistic and marks them for endocytosis and degradation
Describe the clinical presentation of myasthenia gravis in its early and late stages
- Early - drooping eyelids (ptosis); double vision (diplopia)
- Late - weakening of chest muscles; impaired breathing
How do pyridostigmine and azathioprine work to treat myasthenia gravis?
Inhibits the breakdown of acetylcholine
What are the differences between warm antibody types and cold antibody types in autoimmune hemolytic anemia?
- Warm - IgG against RhD
- Cold - IgM against glycophorin (I antigen)
- only produced in individuals that live in cold climates (advised to move)
Infection by _______ produces a mimicry response by cross-reacting with the I antigen on hemoglobin.
Mycoplasma pneumonia
Describe the mechanism by which Rheumatic fever is triggered.
- IgG against Streptococcus pyogenes cross-reacts with heart myosin, joints, and kidneys
- Occurs weeks after infection
Describe the mechanism by which Goodpasture’s syndrome develops
- Auto-IgG against Type IV collagen against the glomerulus basement membrane
- Triggers complement cascade leading to inflammatory damage
How does Goodpasture’s syndrome present clinically?
- Glomerulonephritis
- Pneumonitis (in smokers)
- Pulmonary hemorrhage (in smokers)
How is Goodpasture’s syndrome treated?
Plasma exchange
Rheumatoid arthritis is associated with mutations in what gene?
HLA-DR4
Describe the two possible mechanisms by which Rheumatoid arthritis develops.
- Deposition of immune complexes in the joints (rheumatoid factor)
- Abs directed against citrullinated epitopes of self-proteins (peptidyl arginine deaminases); citrulline is a non-human amino acid
What exactly is rheumatoid factor?
Auto-IgG directed against the Fc region of other IgG
How do adalimumab and rituximab treat rheumatoid arthritis?
- Adalimumab - antibodies against TNF-α
- Rituximab - antibodies against CD20
In Systemic Lupus Erythematosus (SLE), how are antinuclear antibodies generated?
- UV radiation induces apoptosis and alteration of DNA structure
- CD4 T-cells specific for self nucleosomal antigens produced
In SLE, where do immune complexes deposit? (4) Consequences?
- Kidneys → glomerulonephritis
- Joints → arthritis
- Blood vessels → vasculitis
- Skin → rash
How is SLE treated?
- NSAIDs
- Immunosuppressants
- Biologics
______ is caused by a CD4 TH1 response against a variety of thyroid antigens, leading to an infiltration of lymphocytes that destroy normal architecture and impairs thyroid function
Hashimoto’s thyroiditis
How does cell architecture change in Hashimoto’s thyroiditis?
Thyroid becomes organized like lymphatic tissue
How is Hashimoto’s thyroiditis treated?
Replacement thyroid hormone therapy
Mutations in ______ confer susceptibility to type I diabetes, whereas ____ confers resistance and overrides the former.
- DR4
- DQ6
Infections by _____ can induce type I diabetes by cross-reacting with insulin, glutamate decarboxylase, or protein components of β-islet cells, mediated by CD8+ T-cells
- Coxsackie (A&B) virus
- Echovirus
Describe the mechanism by which celiac disease develops
- TH1 cells release inflammatory cytokines
- Macrophages activated
- More cytokines and ROS
- Destruction of intestinal epithelial cells
