T or F: An autoimmune response always translates to an autoimmune disease.
False. An autoimmune response is defined as an immune response to self antigens. Yet an autoimmune response does not uniformly translate into an autoimmune disease. Two autoantibodies, antinuclear antibodies (ANA) and rheumatoid factor (RF), are each found in approximately 5% of the normal, healthy, young population. In the elderly the percentage of people with these autoantibodies increases to 10‐15%.
If an autoantibody does not routinely result in an autoimmune disease, what factors appear to play a role in some individuals where autoimmune disease does result from an autoimmune response? Autoimmune diseases are affected by genetic factors and environmental factors and their interaction.
Autoimmune reactions occur when the
immune system loses ____ ____.
What age range is most commonly affected by autoimmune diseases? What sex?
Autoimmune reactions occur when the
immune system lose self-tolerance.
• Affects 2-5% of population in developing countries.
• Common in 20-40 year olds.
• Most disorders affect females more than males.
Persistent ___ infections lead to hypersensitivity reactions.
What is the prototypical disease for this?
• Persistent microbial infections can result in hypersensitivity reactions.
• Can give rise to severe inflammation and result in granuloma formation.
– Tuberculosis is a prototypical disease
• In some instances, antibodies or T-cells may cross react to host tissue.
What are 4 mechanisms for autoreactivity?
• Molecular mimicry
– Polio or measles and myelin; heat shock proteins
- polio and measles have domains that are similar to myelin
• Release of sequestered antigens from
immunologically privileged sites
– Brain, eye (anterior chamber, lens), testes
- if something in immune privileged site escapes can evoke and immune response
• Polyclonal B cell Activation
– EBV, Gram(-) Bacteria (LPS)
- can get robust non-specific Ab response in EBV
• Upregulation of costimulation (B7)
Define each of the 4 types of hypersensitivity reactions. State what part of the immune system mediates the response.
Which of the hypersensitivity reactions are organ specific? Which are not?
- Type I (immediate): Immunoglobulin E (IgE) against common, generally harmless environmental substances.
- Type II (antibody mediated) :Immunoglobulins against cell surface and extracellular matrix antigens.
Type III (antibody mediated): Immunoglobulins against soluble antigens in the serum that, when complexed, form circulating immune complexes.
- Type IV (cell mediated): T lymphocytes that induce inflammation or directly kill target cells.
What kind of antibodies are directed against tissues in Type II hypersensitivity reactions? Which is the predominant Ab formed?
What tissues does it direct Ab against? It is tissue/organ specific or a more generalized reaction?
Explain the cellular/immune effects that occur in these types of hypersensitivity reactions.
What are the two types of Type II hypersensitivity reactions (just list)
• ORGAN SPECIFIC Autoimmunity
• Antibody Class: IgG, IgM
• Antigen Distribution: Specific Tissue,
– Can involve cell surface or the extracellular matrix
Autoantibodies (predominantly IgG) directed at cell surface and matrix antigens result in cellular damage either by complement activation or via the binding of fixed antibody or complement components to Fc or complement receptors on effector cells respectively. See attached pic and slide 15 of PP.
There are cytotoxic and non-cytotoxic type II hypersensitivity reactions.
Explain the difference between cytotoxic and non-cytotoxic Type II hypersensitivity reactions. Explain what occurs in each.
• Cytotoxic: Local complement activation,
-Antibody-dependent Cell-mediated cytotoxicity
• Non-cytotoxic: alteration of organ function by autoantibody
-(ADCC): involves PMN, NK Cells, Macrophages
What kind of type II hypersensitivity reactions (cytotoxic or non-cytotoxic) are the following diseases?
State the autoantigen and the clinical consequence of each.
autoimmune hemolytic anemia
autoimmune thromobobytopenic purpura
Acquired C1-INH deficiency
All are cytotoxic Type II hypersensitivity reactions except for pernicious anemia and acquired C1-INH deficiency (bc Abs are not directed against cell surface proteins or ECM)
attached is pg 21 of course notes
What are the symtoms/clinical presentation of Goodpasture's disease? Why do they occur?
What is the mechanism for damage to collagen in this disease? How does it contrast to the mechanism of damage in autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura?
Goodpasture's disease is a potentially rapidly fulminant disease where binding of autoantibody to Type IV collagen in glomerular basement membrane (GBM) leads to renal failure. Due to cross‐reactive epitopes on pulmonary basement membrane, anti‐ GBM autoantibodies can produce alveolar hemorrhage presenting as coughing up blood (hemoptysis). The classic clinical presentation of a patient with Goodpasture's is acute renal failure in a patient with hemoptysis.
Mechanism for action: Inflammation and tissue injury due to release of neutrophil enzymes, ROS onto the collagen (because collagen is to large to phagocytose).
The mechanism of damage in autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura is Ab and complement mediated phagocytosis (see slide 22 of PP).
What is the cause for hemolytic disease of the newborn? What is the most severe form?
How can it be prevented? How does this treatment work?
Hemolytic disease of the newborn: Another important clinical example of Type II cytotoxic hypersensitivity is hemolytic disease of the newborn, also known (in its severest form) as erythroblastosis fetalis. This disease in the fetus is due to the transport of IgG across the placenta specific for one of the red blood cell antigens; the most serious problems are incompatibilities between mother and fetus in the Rhesus (Rh) protein antigens (RhD). About 85% of people are Rh+. If a pregnant woman is Rh‐ and the father is Rh+, there is a chance that the fetus will also be Rh+.
This situation will pose no problem in the first pregnancy, as the mother's immune system will not usually encounter fetal red blood cell antigens until placental separation at the time of birth. At that time, however, Rh+ fetal red blood cells will enter the maternal circulation, and stimulate a T dependent immune response, resulting eventually in the generation of memory B cells capable of producing IgG antibody against RhD. In a subsequent pregnancy with another Rh+ fetus, this maternal IgG can be transported across the placenta, react with fetal Rh+ red cells, and produce hemolytic disease.
Hemolytic disease of the newborn can be prevented by treating the Rh‐ mother with RhoGAM, a preparation of human anti‐RhD IgG antibody, at 28 weeks of gestation and again within 24 hours after birth. This antibody effectively eliminates the fetal Rh positive red cells before they can generate RhD specific memory B cells in the mother.
Are the following diseases cytotoxic or non-cytoxic type II hypersensitvity reactions?
State the target antigen, mechanism of disease, and clinical consequences of each.
Insulin resistant DM
Grave's disease, myasthenia gravis, IDDM, and hypoglycemia are all non-cytoxic. Rheumatic fever is cytotoxic.
see slide 34 of notes for info on rheumatic fever
Note the difference in effect of Ab binding to TSH receptors in Graves disease vs Ab binding to AChRs in myasthenia gravis
What is Hashimoto's thyroiditis? Abs to what structures is found in this disease? What are the symptoms of this disease?
What is the cause of dysfunction in this disease?
Autoantibodies may be found in some degree but play no apparent role in the pathogenesis of disease.
Hashimoto's thyroiditis: Autoantibodies to thyroglobulin and thyroperoxidase are routinely found in patients with autoimmune thyroiditis (Hashimoto's thyroiditis). Patients have progressive loss of thyroid function and eventually become hypothyroid. Although these autoantibodies are found in this disease, there is no evidence to suggest that they have any role in the pathogenesis of disease. Cellular mediated immune injury (Type IV Hypersensitivity) is the cause of dysfunction in this disease.
What is Type III hypersensitivity due to?
What parts of the immune system are involved?
What do clinical symptoms depend on?
What serum levels are routinely evaluated in Type III hypersensitivity? Why?
Where are commonly affected areas?
Type III hypersensitivity is due to circulating immune complexes of antigen and antibody that deposit in blood vessel walls and connective tissue. When these complexes are in relative antigen excess (i.e. the immune complexes are small and are not rapidly cleared) and contain antibody isotypes that bind and activate complement, these immune complexes can cause disease via complement activation. Therefore, immune complex mediated diseases result in complement consumption and subsequently hypocomplementemia.
• Complexes containing cationic (positive charged) antigens bind to the negatively charged basement membrane.
• Once deposited, activate complement system.
• Leads to destruction of surrounding tissue.
• Clinical symptoms depend on location of immune complex, not where they were generated.
• Affected areas often include:
• Renal glomeruli and other capillary beds
• Synovial fluid
• NON organ-specific Autoimmunity
• Antibody Class: IgG, IgM
• Antigen Distribution: Systemic involvement with multiple tissues affected
• Damage: Systemic complement activation;
– Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells
– Macrophage -frustrated phagocytosis in attempt to
remove deposited immune complexes
Serum C3 and C4 complement levels are routinely followed clinically to evaluate complement activation. Levels of both components are decreased in immune complex mediated diseases. A CH50 quantitation, an assay used to evaluate the functional integrity of the entire classical complement pathway, is also reduced due to consumption of classical pathway components. This is distinct from type II autoimmune diseases where serum complement consumption does not occur (i.e. complement levels are normal in Type II autoimmune diseases).
List examples of type III hypersensitivity reactions.
System lupus erythematosus
Infections: post-streptococcal glomerulonephritis,
chronic active hepatitis, HIV, lepromatous
What is serum sickness due to? What are the clinicopathological manifestations?
Describe why serum sickness is observed when a certain substance is administered to reduce risk of graft vs host rejection.
Serum Sickness: Clinically immune complex mediated disease may be seen in various instances. In transplantation immune suppression to reduce the risk of graft rejection requires administration of immunosuppressive agents. One such agent is anti‐ lymphocyte globulin (ALG). ALG is comprised of equine anti‐human lymphocyte antibodies produced by the horse after human lymphocytes have been infused into the horse.
Administration of this heterologous preparation results in the production of ALG‐anti‐ALG immune complexes 7 ‐ 10 days after the initiation of infusion in the transplant recipient. The resulting disease is an example of serum sickness: patients will develop fever, arthralgias, glomerulonephritis, and vasculitis due to the production of anti‐equine ALG‐ALG immune complexes and complement activation. Similar findings may be noted if murine monoclonal antibodies (e.g. anti‐CD3) are repeatedly injected to suppress cellular immune function.
What sex is more affected? What age range?
Antibodies against what are formed in SLE? Abs against what molecules or structures is the most characteristic of SLE?
What two autoantibodies are diagnostic of SLE? What is the approximate amount of cases of SLE that these Abs are detected in?
What are the clinicopathological manifestations?
Systemic lupus erythematosus (SLE) is the prototypical Type III autoimmune disease. The 9:1 female:male ratio between 15‐45 years of age and 2:1 ratio on either side of this age range, strongly suggests that estrogen influences human SLE. Diagnosis depends upon appropriate clinical signs and symptoms and laboratory data.
From these criteria one can get a sense that as opposed to organ specific autoimmune diseases, SLE can involve multiple organs or tissues. Skin (malar rash, discoid rash, photosensitivity), mucosal membranes (oral ulcers), joints, central and peripheral nervous system, hematologic system, and renal systems are frequently involved. More subtle findings in the heart, liver, and spleen are common.
Patients with SLE frequently have multiple autoantibodies (against DNA, nucleoproteins, others). Two autoantibodies are essentially diagnostic of SLE, anti‐dsDNA and anti‐Sm (against snRNPs, involved in RNA splicing). Although diagnostic, these are found only in 40% and 30% of patients, respectively. Patients with high titers of anti‐dsDNA are at increased risk of developing renal disease yet the association is not absolute.
Autoantibodies may be directed at RBC, WBC, or platelets resulting in autoimmune cytopenia.
Autoantibodies may also be directed at other epitopes. One example is autoantibodies to phospholipids (resulting in false positive VDRL titers and circulating anticoagulants).
Autoantibodies reacting with nuclear components are most characteristic of SLE and can be detected in 95% of patients with SLE. These antinuclear antibodies (ANA) are detected using fluorescent microscopy.
What most closely predicts the outcome of SLE?
What is the lupus band test? Approximately what percentage of pts have a positive lupus band test?
Prognostically, the severity of renal disease, if present, predicts most closely the outcome of SLE. It is important to remember that SLE encompasses a wide spectrum of disease ranging from mild symptoms (e.g. malar rash, arthralgias, and detection of autoantibodies) to severe disease (e.g. rapidly progressive renal failure and diffuse arthritis).
The detection of circulating immune complexes in serum also correlate with increasing disease activity. In biopsied tissue the demonstration of antibody and complement using immunofluorescent techniques suggests immune complex deposition and complement activation.
A classic example of tissue deposition is in skin where at the dermal‐epidermal junction, immunoglobulin and complement are detected. This is called the lupus band test and is present in 60% of patients with SLE. Likewise, deposition of immunoglobulin and complement are routinely found by immunofluorescent microscopy in immune complex mediated kidney disease in SLE.
What is the arthus reaction?
Arthus reaction (definition 1):
a rare, severe, immediate nonatopic hypersensitivity reaction to the injection of a foreign substance, that usually is not irritating but in certain individuals is antigenic. The reaction is thought to involve the formation of an antigen-antibody complex that activates complement. Acute local inflammation, usually in the skin and marked by edema, hemorrhage, and necrosis, occurs at the site of injection.
a local antibody-mediated hypersensitivity reaction in which antibody-antigen complexes which fix complement are deposited in the walls of small vessels causing acute inflammation with an infiltration of neutrophils. Characteristic of type III hypersensitivity reactions.