17: Autoimmunity Flashcards
Autoimmunity
Immune response directed at “self” antigens/tissues
What are the effectors of autoimmune responses?
Autoantibodies and autoimmune T cells
The classes of autoimmune disease are defined by _______.
The immunological effector that causes the disease
T or F: Autoimmune diseases are usually mediated by IgE antibodies.
F: Nevaaaaaa
What goes wrong in the immune system that causes autoimmune disease?
The negative selection process that removes self-reactive B cells and T cells from the lymphocyte repertoire breaks down
Type II autoimmune diseases are caused by __________.
Antibodies specific for components of cell surfaces or the ECM
What are 5 mechanisms that contribute to immunological self-tolerance?
- Negative selection in bone marrow and thymus
- Expression of tissue-specific proteins in the thymus
- No lymphocyte access to some tissues
- Suppression of autoimmune responses by regulatory T cells
- Induction of anergy in auto reactive B and T cells
What causes autoimmune hemolytic anemia?
IgG and IgM antibodies specific for surface antigens of erythrocytes
What happens in autoimmune hemolytic anemia?
- Activation of the classical complement pathway, and MAC destroys the RBCs
- Bound Ab and C3b mediate clearance of RBCs from circulation by phagocytes in the spleen
- Destruction of RBCs –> anemia
What test is used to confirm autoimmune hemolytic anemia?
Direct Coomb’s hemagglutination test
Patients that have autoimmune responses directed at surface antigens of neutrophils suffer from _______.
Neutropenia
What is a common treatment for patients that suffer from chronic autoimmunity to blood cells?
Splenectomy (removal of the spleen reduces the rate of blood cell destruction)
What is Goodpasture’s syndrome?
People make antibodies specific for type IV collagen (part of the basement membrane). These antibodies become deposited along the renal glomeruli and renal tubules, eliciting inflammatory responses.
What is the treatment for Goodpasture’s syndrome?
Plasma exchange to remove self-reactive Abs and immunosuppressive drug treatment to prevent production of new Abs
How much kidney failure can be attributed to damage caused by the immune system?
25%
What is Autoimmune (Idiopathic) Thrombocytopenic Purpura?
IgG-mediated inhibition of an enzyme responsible for cleavage of von Wildebrand factor (vWF). vWF normally links platelets and blood vessels with clots
What organs does autoimmune thrombocytopenic purpura effect/what are the symptoms?
Affects kidneys, blood vessels, liver, and brain. Symptoms: thrombocytopenia, bruising, neurological symptoms, microangioplastic hemolytic anemia
Treatment for Autoimmune Thrombocytopenic Purpura
Plasmapheresis (exchange transfusion) with plasma from healthy donors, Rutiximab, RhoGam, steroids
What happens in scleroderma?
Inflammatory destruction of vascular endothelial cells of arterioles and smooth muscle cells, and replacement with collagen and other fibrous materials
Symptoms of scleroderma?
Localized or systemic skin thickening; hard, smooth ivory colored areas of hardened skin
T or F: Rheumatoid factor is required for scleroderma.
F
What tests ID scleroderma?
Presence of ANAs, anti-topoisomerase Abs, and anti-centromere Abs
What is the treatment for scleroderma?
No known cure; patient-specific treatments include drugs that increase blood flow to extremities
What causes acute rheumatic fever?
Antibodies produced during response to bacterial infection cross-react with self-antigens of the human heart
What does acute rheumatic fever have to do with molecular mimicry?
Streptococcal cell-wall components are similar to the constituents of health heart tissue, so antibodies raised as a component of protective response against the bacterium are detrimental to the host
T or F: Acute rheumatic fever can lead to heart valve scarring and myocarditis.
T
What are symptoms of acute rheumatic fever?
Chest pain, fever, weakness, fatigue, and joint pain
T or F: In acute rheumatic fever, B cells can’t be fully activated so no immunological memory results.
T
What are examples of Type II autoimmune diseases?
Autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, Goodpasture’s syndrome, scleroderma, acute rheumatic fever, pemphigus vulgaris, Grave’s disease, and myasthenia gravis
What is pemphigus vulgarism?
An autoimmune condition mediated by IgG specific for 2 proteins (desmoglein 1 and 3) that results in loss of cohesion in keratinocytes in the epidermis
What are symptoms of pemphigus vulgaris?
Painful chronic blistering of skin
How do you diagnose pemphigus vulgaris?
Punch biopsy of lesion followed by immunofluorescent staining
What is the treatment for pemphigus vulgaris?
Corticosteroids and other anti-inflammatory drugs, rituximab
What are 4 autoimmune diseases of the thyroid gland?
- Hashimoto’s thyroiditis
- Grave’s disease
- Subacute thyroiditis
- Idiopathic hypothyroidism
What are autoimmune diseases of the pancreas?
Type I and Type II diabetes
What is an autoimmune disease of the adrenal gland?
Addison’s disease
What causes Grave’s disease?
Antibodies that bind to the TSH receptor and mimic binding of TSH to the receptor. This results in overproduction of thyroid hormone.
Symptoms of Grave’s disease
Heat intolerance, nervousness, irritability, warm moist skin, weight loss, thyroid enlargement, bulging eye syndrome, characteristic stare
In Grave’s disease, the autoimmune response is biased towards _________.
A TH2 response
What is the treatment for Grave’s disease?
Drug therapy to reduce thyroid function or removal/destruction of the thyroid
T or F: Ab causing Grave’s disease can be transported across the placenta to the developing fetus, so that newborns will suffer from symptoms of the disease.
T
What is myasthenia gravis?
An autoimmune disease in which signaling from nerve to muscle across the neuromuscular junction is impaired
What is the mechanism for myasthenia gravis?
Autoantibodies specific for Ach receptors on muscle cells bind to the receptors, inducing their endocytosis and degradation in the lysosomes. Loss of receptors leaves muscles less sensitive to neuronal stimulation
Treatment for myasthenia gravis
- Immunosuppressive drugs to prevent formation of autoantibodies
- Pyridostigmine to inhibit cholinesterase (which degrades Ach) so that Ach can compete for receptor binding
What is commonly the first symptom you see in myasthenia gravis?
Facial muscle weakness (eye drooping, etc)
What is subacute bacterial endocarditis?
IgG-mediated inflammation of the endocardium initiated by antibodies that bind to microorganisms that have colonized damaged heart valves
T or F: Typically patients will only develop subacute bacterial endocarditis if they have already suffered damage to their heart valves.
T
What cells mediate inflammation in subacute bacterial endocarditis?
Phagocytes that recognize opsonized bacteria and anaphylatoxins produced as part of the complement cascade
What are examples of type III autoimmune diseases?
Subacute bacterial endocarditis, mixed essential cryoglobinemia, SLE
What is mixed essential cryoglobuinemia?
A disease characterized by the production of cryoglobulins(immunoglobulins that become insoluble at reduced temperature)
Cryoglobulins are most-often produced by patients that have ________.
A B cell proliferative disorder such as multiple myeloma or Waldenstrom macroglobulinemia
Which autoimmune disease commonly occurs after hepatitis C infection?
Mixed essential cryoglobulinemia
What do cryoglobulins bind to?
Fc regions of antibody molecules
What are the symptoms of mixed essential cryoglobulinemia?
Meltzer’s triad: purpura, arthralgia, myalgia
What is Guillain Barre Syndrome (GBS)?
A disease mediated by IgG specific for gangliosides (components of nerves) that mediate an acute inflammatory demyelinating polyneuropathy (AIDP)
How does Guillain Barre Syndrome usually come about?
There’s an infection and the immune response made against the pathogen cross-reacts with gangliosides (The biggest infection that leads to GBS symptoms is Campylobacter jejuni)
What are symptoms of Guillain Barre Syndrome?
Symmetrical weakness of lower limbs that RAPIDLY ascends to upper limbs and face, difficulty swallowing and breathing, drooling once muscle weakness ascends to the face, and partial paralysis often occurs
Treatment for Guillain Barre Syndrome
Plasma exchange with immunosuppressive drug treatment
What’s Miller-Fisher Syndrome?
A rare variant of GBS that is pretty similar except that the paralysis develops in a descending fashion (instead of ascending like in GBS).
Wegener’s Granulomatosis is mediated by ____________, and the most common determinant is _________.
Mediated by anti-neutrophil cytoplasmic antibodies (ANCAs); most common determinant is proteinase-3
What happens in Wegener’s Granulomatosis?
- ANCAs bind to neutrophils, which activates them.
- Neutrophils upregulate adhesion molecule expression, allowing them to bind to vascular endothelial cells
- They then degranulate causing vasculitis
How does Wegener’s Granulomatosis usually come about?
Onset usually follows bacterial or viral infection, and response to pathogen elicits production of IgG that cross reacts with neutrophil determinants
What parts of the body does Wegener’s Granulomatosis affect?
1.Upper airway
2.Airways
3.Kidney
4.Arthritis
5.Skin
6.Nervous system
Look at Miller’s handout for exact symptoms… there were too many!
Treatment for Wegener’s Granulomatosis
Plasma exchange with anti-inflammatory drug treatment
What is systemic lupus erythematosus (SLE) caused by?
Autoantibodies specific for many intracellular macromolecules present in all cells in the body
What is often the first symptom that is noticed in lupus?
Arthritis
How does lupus work?
Autoantibodies bind to cell surface components and initiate inflammation, which leads to tissue destruction. Damaged cells released soluble macromolecules and immune complexes are deposited in blood vessels, kidneys, and joints.
T or F: Lupus is a progressive disease.
T: the autoimmune responses that cause SLE mature over time, and the disease gets progressively worse.
Experiments in mice suggest that ______ may be the key to the development of SLE.
Breakdown of T cell tolerance
How is lupus treated?
With anti-inflammatory drugs
What is the main consequence of subacute bacterial endocarditis?
Glomerulonephritis
What is the main consequence of mixed essential cryoglobulinemia?
Systemic vasculitis
What are the main consequences of SLE?
Glomerulonephritis, vasculitis, arthritis
What is Insulin-Dependent Diabetes Mellitus?
An autoimmune disease that results in destruction of insulin-producing cells in the pancreas
What are the effectors of insulin-dependent diabetes mellitus?
CTLs with specificity for an unknown component of Beta cells in the islets of Langerhans
Treatment for insulin-dependent diabetes mellitus
Daily injections of pig/bovine insulin (except human recombinant insulin is used in people that have hypersensitivity to pig/bovine insulin)
What are examples of type IV autoimmune diseases?
IDDM, rheumatoid arthritis, multiple sclerosis, Sjogrens syndrome
What is rheumatoid arthritis?
An inflammatory disease of the joints that is initiated by autoreactive T cells and features the production of IgG, IgM, and IgA specific for the Fc region of antibody molecules
T or F: Rheumatoid factor is required for rheumatoid arthritis but not for Sjogren’s.
F: Rheumatoid factor not required for either!
IgM, IgG, and IgA autoantibodies specific for the Fc regions of human IgG molecules are referred to as _________.
Rheumatoid factor
In all patients with rheumatoid arthritis, affected joints have an infiltrate that includes ________.
CD4 and CD8 T cells, B cells, plasma cells, neutrophils, and macrophages
What is the treatment for rheumatoid arthritis?
Combo of physiotherapy and various immunosuppressive and anti-inflammatory drugs (i.e. TNF-alpha blockers)
What is one of the primary mediators of inflammation observed in rheumatoid arthritis patients?
TNF-alpha
What role do B cells play in rheumatoid arthritis?
It has been recently discovered that infusion of monoclonal Ab with specificity for CD20 bind to B cells and serve as a trigger for ADCC by NK cells
T or F: It’s not clear whether rheumatoid arthritis is mediated by primarily T cells, B cells, or both.
T
What is multiple sclerosis?
An autoimmune disease caused by an immune response directed at the myelin sheath of nerve cells that causes sclerotic plaques of demyelinated tissue in the white matter of the CNS
What are symptoms of multiple sclerosis?
Motor weakness, impaired vision, lack of coordination, spasticity
T or F: Multiple sclerosis is typically a very progressive disease.
F: highly variable progression
What cells are responsible for the demyelination experienced in MS? How so?
Activated TH1 CD4 effector cells, which are enriched in the blood and cerebrospinal fluid. They produce IFN-gamma that activates macrophages in sclerotic plaques, which release proteases and cytokines responsible for demyelination
What are the autoantigens of MS?
Structural proteins of myelin (myelin basic protein, proteolipid protein, or myeloid oligodendrocyte glycoprotein)
Treatment for multiple sclerosis
High doses of immunosuppressive drugs and subcutaneous injections of IFN-B1 (which reduces the incidence of disease attacks)
What is experimental allergic encephalomyelitis?
The animal model for MS – inbred strain of mice immunized with myelin basic protein emulsified in Freund’s complete adjuvant produce myelin-specific immune responses that attack the CNS of the animal
What is Sjogren’s syndrome?
A systemic T cell-mediated autoimmune disease that attacks exocrine glands that produce tears and saliva
What is the second most common of the rheumatic diseases?
Sjorgren’s syndrome
What is a known autoantigen for Sjogren’s syndrome?
alpha-Fodrin
Symptoms of Sjogren’s syndrome
Dry eyes and dry mouth, sometimes skin, nose, and vaginal dryness
How do you diagnose Sjogren’s?
Depends on a combo of several tests:
- Blood tests for ANA and Rheumatoid factor
- Schirmer test for tear production
- Salivary gland function test
- Lip biopsy (can reveal lymphocytes clustered around salivary glands)
- Ultrasound of the salivary glands
What is the simplest confirmatory test for Sjorgrens?
Ultrasound of the salivary glands
Treatment for Sjogrens
Moisture replacement with artificial tears, wearing goggles, punctual plugs, drug therapies to reduce inflammation or stimulate salivation
What is the diagnostic lab test for MS?
Look for the presence of oligoclonal bands of IgG in cerebrospinal fluid – found in 85% of MS patients
What is APECED/APD?
A disease that results from the absence of AIRE (AIRE normally induces expression of tissue-specific proteins in the thymus, so when these proteins are not expressed, negative selection of T cells is impaired)
How does APECED typically present?
Starting in childhood, B cell and T cell responses develop against peripheral tissues, so there are usually disorders of multiple organs/tissues
What is the most important genetic factor for IDDM?
HLA haplotype
Autoimmune diseases are more likely to affect those that express a particular ______.
HLA allotype
People that develop Goodpasture’s typically develop ________ too.
Pulmonary hemorrhage
How is smoking related to autoimmune diseases?
Smoking damages the alveoli, which causes a lack of tissue integrity, thus allowing access of autoantibodies to the basement membranes in the alveoli. These antibodies initiate inflammation that eventually results in hemorrhage.
What’s an example of an immunologically privileged site?
Anterior chamber of the eye – contains special proteins involved in vision
What is sympathetic ophthalmia?
If an eye is damaged by trauma, eye proteins can drain to lymph nodes and be processed/presented to naive T cells. IF autoimmune response develops, CTLs will attack and destroy tissue in either eye.
Why don’t corneal transplants require MHC haplotype matching?
After grafting, the corneal antigens will remain sequestered in the eye
What is molecular mimicry?
Organisms produce proteins that are very similar to self-proteins or contain antigens that closely mimic self components
What’s an example of an autoimmune disease that involves molecular mimicry?
Rheumatoid fever
