Researchers at Thomas Jefferson University and the University of Utah have discovered that antibiotics being studied for the treatment of cystic fibrosis (CF) and muscular dystrophy (MD) have the potential to initiate autoimmunity.
Every gene has a message at the end of its sequence that signals the translational machinery to stop (stop codon). Diseases like cystic fibrosis and muscular dystrophy can result from mutations that insert this stop codon into the middle of a gene causing the the resulting protein to be shortened. There are some antibiotics that have the ability to cause the cell’s translational machinery to ignore the stop codons, which means some antibiotics have the potential as a form of therapy for these diseases. The report demonstrates that this approach may come with the price of initiating autoimmunity.
Get more information about Cystic Fibrosis.
According to Laurence Eisenlohr, Ph.D., a professor in the department of Microbiology and Immunology at Thomas Jefferson University and co-lead investigator, “It’s worth thinking about this as a potential mechanism for autoimmunity.”
In autoimmunity, the immune system attacks normal components in different tissues of the body and/or brain. What causes the immune system to malfunction in some individuals and not others has been an enigma. Eisenlohr notes, “Often, the trigger happens years before the disease has been diagnosed.”
Eisenlohr and colleagues looked at a class of antibiotics that includes gentamicin. These antibiotics are unique in that they have the ability to induce cells to read through stop codons producing a longer protein product. This can save the translation of mutated genes that contain aberrant stop codons. However, when the translational machinery reads through normal codons, this may create abnormally elongated proteins. Pieces of these abnormal proteins can be presented to the immune system as a part of normal protein processing, where they could be detected by the immune system.
At least, that’s the theory.
Eisenlohr’s team decided to test this theory by using a gene that they knew would get presented to the immune system and added a stop codon in the middle of it. The modified gene was spliced into a mammalian cell line. Since a stop codon placed in the middle of a gene, shortens the gene, normal cells did not produce the protein. Researchers observed that gentamicin treated cells began expressing the protein on the cell surface.
A very low number of these proteins were produced and in fact too little to be detected by normal biochemical methods. However, T cells of the immune system are sensitive enough to pick up these small amounts. Researchers were able to demonstrate that the immune cells could detect the protein produced by the gentamicin-treated cells.
First author Elliot Goodenough at Thomas Jefferson University tested whether this process was active in normal cells that weren’t expressing an experimental gene. He exposed HeLa human cell line to gentamicin and then looked for novel peptides presented on the surface of these cells. Seventeen peptides were identified that hadn’t been characterized before in cells treated with gentamicin. He also demonstrated that the peptides were presentable to the immune system. Goodenough notes, “The results suggest that gentamicin can cause cells to display novel protein fragments to the immune system.” Eisenlohr adds, “what may be garbage biologically may be important immunologically.”
Eisenlohr notes that antigen presentation to the immune system doesn’t guarantee that it will activate the kind of immune response that initiates autoimmunity. However, because gentamicin is used to treat infections, “all of the right conditions are in place to potentially initiate autoimmunity.” Inflammation associated with bacterial infections provides a signal to immune cells that the peptides they encounter are dangerous. Thus, as gentamicin fights bacteria, it also causes normal cells to produce abnormal proteins that are presented to the immune system and have a potential of initiating an autoimmune response.
Eisenlohr goes on further to say, “A number of autoimmune diseases are thought to be triggered by infections. The results of this study suggest that certain antibiotics used to treat those infections may also contribute to that trigger.”
The next step is to look at population data to see if the use of gentamicin correlates with higher rates of autoimmunity. Testing should be done on whether the peptides generated during gentamicin therapy in diseases such as cystic fibrosis or muscular dystrophy actually cause autoimmunity in a mouse model of the disease.