Type II Immunology Flashcards
Type I immunopathology
What antibody is most seen in this immunopathology?
Of the helper T cells, which one is often seen along with with the mentioned Ig?
-Symptoms or pathology due to IgE antibody.
Since the type of B-cell-helper Tfh cell that drives switching to IgE is closely related to the Th2 cell, Th2 - mediated events are often seen along with those caused by IgE.
Type II immunopathology
This one is mediated by _____, ______, or ______ antobodies that cause harm to self (autoantibodies).
Pathology due to IgG, IgM, or IgA antibody causing harm to self.
In most cases this refers to autoantibodies.
In the original Gell and Coombs classification, Type V was separate; but it is now folded into Type II, as it involves autoreactive antibody against surface receptors which happen to stimulate (rather than damage) the cell.
This form of immunopathology is due to the actions of antibodies directed against a specific target tissue or cell; so it is one of the forms of autoimmunity.
Type III immunopathology
Where are the immune complexes trapped in the body?
When this immunopathology becomes chronic, what cell mediated immunity does it become?
Type III: Pathology caused by the formation of immune complexes which are trapped in the **basement membranes of blood vessels and activate complement, leading to vasculitic inflammation.
When Type III is chronic, T cell - mediated immunity tends to become increasingly important as part of the disease.
Chronic Frustrated immune response:
This is not part of the ori ginal classification; JJC made up the name.
- It refers to conditions in which the body is using the adaptive immune response to try to get rid of antigens that it never can.
- These include things like normal gut flora (as in Crohn disease), skin flora (psoriasis), chemicals (as in chronic beryllium disease), or foods (gluten in celiac disease). In CFIR the antigen can be neither disposed of nor effectively walled off.
MECHANISMS OF TISSUE DAMAGE
Mention the three ways of tissue damage:
If for some reason people start making antibody against their own cells, it’s possible that the destructive power of the immune system could be unleashed.
Individual cells might be lysed by complement; tissues might be damaged by complement - induced inflammation. These mechanisms are exactly the ones we are already familiar with from, say, bacterial immunity.
Tissues can be damaged by ►lysis (red cells in autoimmune hemolytic anemia), by ►phagocytosis (platelets in autoimmune thrombocytopenic purpura, ATP) or by ►release of neutrophils ’ lysosomal enzymes and reactive oxygen species (demonstrated in myasthenia gravis, and in Goodpa sture disease).
Mechanisms of tissue damage:
Stimulatory hypersensitivity
What is a good example?
What type of Ig?
“Stimulatory hypersensitivity.” If the autoantibody happens to be directed against a cell-surface receptor, it may behave as an agonist, mimicking whatever hormone or factor normally works at that receptor.
►The best example of this is an autoantibody found in the blood of most patients with hyperthyroidism. It is IgG against the TSH (thyroid - stimulating hormone) receptor on thyroid cells; when it binds to these receptors, it mimics TSH and causes the cell to secre te thyroid hormones. Of course, the normal feedback controls won’t work in this case, so the result is ►hyperthyroidism, known as Graves disease .
Neutralization
How are human proteins affected?
What is an example of an importnat lymphokine neutralized?
How do patients appear in this case?
Just as a toxin is neutralized if an antitoxic antibody binds it, a human protein may be inactivated by an autoantibody.
Neutralizing anti-interferon (IFN) - γ autoantibodies have been described, most often in adults in Southeast Asia; they are typically associated with disseminated non-tuberculosis my cobacteria.
The most severely affected patients have had multiple infections. Because Th1 cells work largely by releasing IFN - γ , they are ineffective, and the patients appear to be immunodeficient, although the real etiology is the autoimmunity.
What is Myasthenia Gravis?
Antibodies to what are made in myasthenia gravis?
The antibody to the ______ subunit of the AChR does the damage via the ______ and _________.
What gene is responsible to make the AChR alpla subunit?
What are some of the treatments?
It is a disease of progressive muscle weakness, because patients are making antibody to the acetylcholine receptor (AChR)
►The antibody to the alpha subunit of the AChR does the real damage, which is complement - and neutrophil - mediated.
- We know how the antibody gets made in at least some patients: The thymic transcription factor Aire ( see T cells) drives the thymic expression of CHRNA1, the gene for the AChR alpha subunit.
- Two kindreds were found to have an allele of the CHRNA1 promoter that does not interact with Aire, so the protein is not expressed in patient s ’ thymuses, and Th clones reactive with the AChR are not deleted by negative selection.
- Tfh are therefore available to help B cells make antibody to the receptor. In the majority of patients the thymus becomes abnormal, with hyperplasia and even, sometimes, the appearance of germinal centers. Perhaps Th against the AChR attack that antigen on the surface of intr athymic muscle cells, leading to chronic inflammation.
In such patients, thymectomy often yields dramatic improvement. Treatment may include immunosuppression, neostigmine - related drugs to increase the effectiveness of residual Ach, and IVI g for its systemic anti - inflammatory action .
Goodpasture syndrome
Autoantibodies are made against _______ and ________ basement membranes. Why?
What signs and symptoms do patients with goodpasture syndrome present with?
This uncommon condition involves formation of autoantibodies to lung and kidney basement membranes (BM) (which are the collagenous non-living connective tissue framework upon which the endothelial cells of capillaries sit).
►There is an epitope on the antigen (Type IV collagen) shared between the BM’s of these two organs; other organs are not involved. The patients have persistent glomerulonephritis, and former or current smokers risk pneumonitis with pulmonary hemorrhages.
–>This was the first human autoimmune disease in which the antibody was proved to cause the condition: kidneys were removed from a patient who had died of Goodpasture, the antibody eluted from them (low pH breaks antigen - antibody bonds), purified, and injected into a chimpanzee , who came down rapidly with typical Goodpasture syndrome.
In Goodpasture the antibody is directed against the basement membrane, not trapped as clumps, so the staining by immunofluorescence is sharp and ‘linear,’ not ‘lumpy - bumpy’ as it is in Type III, immune complex conditions.
Dressler Syndrome
How does this disease manifests?
Most people who have a heart attack will make some autoantibody which reacts with heart. This seems to do them no harm.
Dressler syndrome manifests as persistent cardiac pain, fever, malaise, and pericardial effusion seen after heart attack (and more commonly after heart surgery) which is directly related to an immune response to pericardial or myocardial antigens. A better name might be post - cardiac injury syndrome.
Treated with anti-inflammatory agents, it usually gets better as the heart heals.
Rheumatic Heart Disease
Happens due to _____ of group A streptococcus M-protein antigen and laminin in endothelias heart cells.
Which cells does most of the damage?
It refers to heart disease occurring shortly after a streptococcal infection, for example a ‘strep throat.’
There is very good evidence that it is due to ►cross - reaction between a Group A Streptococcus M-protein antigen and a structure on the heart’s endothelial lining, probably laminin on heart valves, followed by neutrophil - mediated tissue destruction.
Rheumatic fever is the same disease with more widespread manifestations, including in the skin and CNS. These are classic Type II conditions. (Poststreptococcal glomerulonephritis , on the other hand, is the Type III immunopathology, due to complexes between antibody and strep antigens trapped in the kidney.)
AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ATP)
Autoantibodies are made for________.
What is a possible treatment?
Until recently this was called idiopathic thrombocytopenic purpura. ***These patients have bleeding abnormalities due to destruction of platelets (thrombocytes) by autoantibody.
►The platelets are opsonized and their destruction, mainly in the spleen, is rapid.
Platelets are needed, of course, for blood clotting. (Treatment: ***suppress the immune system and/or ***remove the spleen.
ATP is often seen in young healthy people some weeks after a viral infection; in older people, in association with many other autoantibodies; and in people treated with certain drugs; all of which might suggest to you, when you’ve read through these notes, the sorts of processes that could be going on.
AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA )
What drugs can induce AIHA at least temporarily?
Like ATP, this may follow a viral infection, or be associated with an other autoimmune syndrome, or cancer.
►Many drugs, such as penicillin, methyldopa, chlorpromazine and quinidine, can induce AIHA, usually temporarily.
In the rare condition paroxysmal cold hemoglobinuria (PCH), the patient experiences hemolysis after exposure to cold. It is due to an autoantibody which only binds to red cells at about 15 C .
Graves and Hashimoto’s Thyroid disease
What is the leading cause of hypothyroidism?
In Hashimoto the antigens include________ and _________.
Pathological process if inflammatory and destructive with both _____ and _____ involvement.
Grave’s as mentioned above, involves ‘stimulatory autoimmunity’ to the TSH receptor on thyroid cells. It is the leading cause of hyperthyroidism.
The leading cause of hypothyroidism , also autoimmune, is Hashimoto disease. But in Hashimoto the antigens include thyroglobulin (the molecule in which iodine is stored) and thyroid peroxidase, and the pathological process is inflammatory and destructive (with both antibody and T cells involved).
There is so much overlap between the conditions that some geneticists and endocrinologists refer to them together as AITD, autoimmune thyroid disease.
***Graves disease can frequently morph into Hashimoto.
About 75% of the risk for these conditions is estimated to be genetic; they occur in perhaps 5% of the population in western countries ; there are 1.5 million people with Hashimoto in the US. Five out of 6 of those are female, as is the case in most of the autoimmune diseases. We know this is an estrogen effect, and it’ s related to the observation that female immune systems are typically “stronger” than those of males.
ETIOLOGY: MECHANISMS OF LOSS OF TOLERANCE
Hybrid (foreign + self) antigen formation
Mechanisms of loss of tolerance:
Innocent bystander
A common mechanism, in which there is damage to normal tissue which happens to be associated with or infected by the antigen, which is truly foreign. Imagine a drug adhered to your red blood cells, and you made antibody against the drug. What would get lysed by complement — the drug? No, the poor innocent red cell.
Mechanism of loss of tolerance:
Release of a sequestered antigen
Diagnosis
The hallmark test is_______
What is the difference between the direct and indirect immunofluorecense test?
