Download Type II and Type III Immunopathology: Antibody-Mediated Autoimmune Diseases and more Study notes Acting in PDF only on Docsity!
TYPE II IMMUNOPATHOLOGY
TYPE II. 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, as we’ve seen, may also be due to self-reactive antibodies, but the manifestation there is immune complex-based rather than specific tissue damage. T cell- mediated autoimmunity is referred to as Type IV immunopathology. As we’ve said before, these conditions are often mixed.
We’ll first discuss how antibodies damage or otherwise affect cells, and give some examples, before getting to ways the immune system might go wrong in this way.
TYPE II PATHOGENIC MECHANISMS
1. Complement-mediated damage. In the disease myasthenia gravis antibody is made to the acetylcholine receptor at the neuromuscular junction’s motor end plate, the excitable region of muscle fiber plasma membrane where action potentials are triggered. This antibody may block transmission from nerve to muscle, or increase receptor turnover, but even more important is the ►destruction of the endplate by complement/phagocyte mediated mechanisms.
These 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 the phagocytes’ lysosomal enzymes and reactive oxygen species (probable in myasthenia gravis, and in Goodpasture’s disease, see below).
2. “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 LATS (long-acting thyroid stimulator), found in the blood of most patients with hyperthyroidism. It is IgG antibody to the TSH (thyroid- stimulating hormone) receptor on thyroid cells; when it binds to these receptors, it mimics TSH and causes the cell to secrete thyroid hormones. Of course, the normal feedback controls won’t work in this case, so the result is ►hyperthyroidism, or Graves’ disease.
Some people have ‘inappropriate’ tachycardia , a fast heart rate without cardiac abnormalities. About half have been shown to have autoantibodies to the β-adrenergic receptor, which are stimulatory, like epinephrine; the effect can be reversed by the beta blocker propranolol. Most of the autoantibody-positive patients are women, as is often the case in autoimmunity^1.
SOME ILLUSTRATIVE CONDITIONS
MYASTHENIA GRAVIS. A disease of progressive muscle weakness. ►Patients make pathogenic antibodies to the ACh receptor (AChR). Damage is mediated by complement and
(^1) Chiale PA, et al. 2006. Inappropriate sinus tachycardia may be related to an immunologic disorder involving
cardiac beta adrenergic receptors. Heart Rhythm 3:1182-6.
neutrophils. A recent study 2 shows that the thymic transcription factor Aire ( see T cells) drives the thymic expression of CHRNA1 , the gene for the AChR alpha subunit. Two families were described in which there is an allele of the CHRNA1 promoter that cannot 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. They 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. It could be that Th against the AChR attack that antigen on the surface of intrathymic muscle cells, leading to chronic inflammation and abnormal development of lymphoid tissue which makes AChR antibody. In such patients, thymectomy often yields dramatic improvement.
GOODPASTURE’S DISEASE. 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’s, the antibody eluted from them (low pH breaks antigen-antibody bonds), purified, and injected into a chimpanzee, who came down rapidly with typical Goodpasture’s syndrome. In Goodpasture’s 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.
Type II, linear: Goodpasture’s Type III, lumpy-bumpy: Lupus
(^2) Giraud, M. et al. 2007. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in
thymus. Nature 448: 934-937.
Blood flow
YY YY Y YY Y Y Y Y Y
Y Y Y Y Y Y Y Y YY YY
Y
Endothelial cell
basement membrane
antibody
immune complex formation near sun-damaged, DNA-releasing skin cells. In the US the incidence of SLE is 1/3500; it is lowest in people of European origin.
In the following group of diseases, both autoantibodies and autoreactive T cells are implicated in the pathogenesis, so they are mixed Type II and Type IV mechanisms. Sometimes, as we’ve already seen, Type III is also involved.
RHEUMATOID ARTHRITIS. This is probably the most common autoimmune disease, affecting more than 1 in 100 Americans. It is the ‘inflammatory arthritis.’ (Osteoarthritis, the ‘degenerative arthritis,’ where the joints wear out, is even more common.) RA affects women more than men, and usually attacks the smaller joints, especially those of the fingers, first. The initial evidence that it was autoimmune came with the discovery of rheumatoid factor (RF), which can be detected by adding the patient’s serum to microscopic beads coated with normal human IgG. RF makes the beads agglutinate; ►it is IgM anti-IgG! It is a useful biomarker, but may not actually cause much joint damage. There are other antibodies involved, as well as T cells, so the pathogenesis is complex (and the etiology is unknown). Although it’s been difficult to identify a pathogenic antibody (unlike the case in lupus), nevertheless RA can respond extremely well to rituximab, a monoclonal antibody against the CD20 on the surface of B cells, which effectively depletes them from the body.
Several groups have conducted genome-wide single nucleotide polymorphism screens of RA patients, and the loci identified are interesting: HLA-DRB1 (one of the β chain genes of HLA-DR, associated of course with antigen presentation, in this case maybe autoantigen;) PTPN22 (a tyrosine phosphatase involved in T cell signaling;) C5 (the 5 th^ component of complement;) TRAF (a modifier of signal transduction through proinflammatory TNF receptors;) and PADI4 (a deiminase that converts arginine in proteins to citrulline.) This last is intriguing, since antibodies to citrullinated peptides seem to be absolutely specific to RA, though their role in pathology is not known. Most of the pathogenesis of RA seems to be due to T cells.
Air pollution, and especially smoking, is an important RA risk factor. It is known to increase the citrullination of proteins in the lung.
HASHIMOTO’S THYROIDITIS. An inflammatory disease of the thyroid in which there is very good evidence for both T and B cell immunity to various thyroid antigens, including thyroglobulin. The antibodies to thyroid antigens are destructive, not stimulatory. Histologically the thyroid is infiltrated by T cells. It may be that T cell damage releases normally sequestered antigens, to which antibodies are made, worsening the condition. The result is hypothyroidism.
OTHER DISEASES. There are often autoantibodies found in conditions that are known to be T cell-mediated; this indicated that immunity may be generally dysregulated. In celiac disease, there is an antibody to tissue transglutaminase that is very useful for diagnosis, and in Type 1 (childhood) diabetes several antibodies to islet-associated antigens are seen which provide prognostic information; but in neither of these conditions are they thought to be pathogenic, so diabetes is considered under Type IV immunopathology, and celiac under Chronic Frustrated Immune Responses.
MECHANISMS. We don’t know in most cases what causes a breakdown of the body’s ‘horror autotoxicus’ rule 3 ; here are seven possible mechanisms. You could probably think up others.
(^3) Paul Ehrlich (1854-1915) believed the immune system would be horrified to harm the body; maybe it is, but it
does so anyway.
Y
Y
Y Y
Anti-self B cell
B cell binds
plus foreign epitope
self
It then ingests and digests.
Foreign epitope is presented to Tfh on Class II MHC.
Tfh secretes cytokines.
B cell is activated, secretes antibody to self
44
4
1
1
3 3
2
2
5
5
Tfh
- Emergence of a forbidden clone. A clone might somehow escape the normal clonal abortion mechanism, and mature so that encounters with antigen immunize it. This seems to be probable in at least some cases of myasthenia gravis.
- Illicit help. Suppose you had anti-self B cells that hadn’t been aborted. They would not necessarily get you into trouble if the self antigens were T-dependent, and you did not have antiself T helper cells. This actually seems to be the case for most antigens. But: suppose that a foreign antigen were to couple to the self antigen. ►The anti-self B cell could bind and ingest self, and carry the foreign antigen along with it. Then foreign epitopes might be presented to a Tfh cell on the B cell’s Class II MHC. The B cell would have received all necessary signals and become activated. Then it would make its antibody, against self.
ASK YOURSELF: Can you see how this mechanism is very similar to what goes on when you use a conjugate carbohydrate-protein vaccine?
- Cross-reaction between a foreign antigen and a self antigen. We’ve been talking about this one since the beginning. Undoubtedly important, and it would become more so if only we could identify the antigens that get things started. By the time the patient develops clinical symptoms, the triggering antigen may be long gone, with the process being maintained by autoimmune responses to normally-sequestered antigens released from damaged cells.
- Release of a sequestered antigen. Note that in the special case of sequestered antigens, the antigen cannot get out into the general system, and therefore is not normally immunogenic, ►but if an immune response does get initiated, then the response can usually get into the place where the antigen was sequestered. Example: some adult men who get mumps end up sterile. The virus breaks down the blood/testis barrier, allowing immunization to sperm antigens. Because these are not yet expressed in children, some sperm-reactive B and T cells never got aborted.
►There is a phenomenon in autoimmunity called ‘epitope spreading.’ Early in the disease antibodies are made to just one or two epitopes of some ‘self’ protein. With time, more epitopes, and more proteins are involved. Does tissue damage gradually reveal more sequestered antigens?
- Passive antibody. In a child with hemolytic disease of the newborn ( see Immunohematology); in a patient getting a mismatched transfusion; in a child of a mother with myasthenia gravis or SLE. A rare child of a lupus mother may be born with heart block due to cross-reactive antibodies.
Learning objectives for
Type II Immunopathology and Regulation
- Describe the molecular and cellular details of the immunologic mechanisms by which tissue damage occurs in a Type II (‘cytotoxic antibody’) reaction.
- Give an example of a Type II mechanism disease of muscle, kidney, heart, red cells, platelets, thyroid, and pancreatic islets.
- Describe the fluorescent antibody tests which would allow you to make the diagnosis of Goodpasture's Syndrome, given: patient's kidney biopsy, normal kidney biopsy, patient's serum, and fluoresceinated goat antisera to human IgG and complement.
- Distinguish between the ‘lumpy-bumpy’ and ‘linear’ immunofluorescent patterns in terms of the most probable immunopathologies they represent.
- Describe how you could tell, using fluorescent antibodies and biopsies of patient's kidney, if Type II or Type III immunopathology was involved. Name the antibodies you would use and the fluorescent patterns you would see.
- Given patient's serum, fluorescent antibody to human immunoglobulins, and slices of normal kidney, describe how you could tell if the patient's glomerulonephritis was due to Goodpasture's disease or SLE.
- Describe how antibody-mediated tissue damage could result from: The innocent bystander phenomenon. Cross-reaction of a foreign antigen with self. Coupling self antigen with a foreign antigenic ‘carrier’. Exposure of a sequestered antigen.
- Identify ‘Rheumatoid Factor’ and describe its molecular nature.
- Describe the Type II mechanism of Graves’ Disease.
- Discuss how the Aire gene is involved in preventing autoimmune disease.
