[GRG] antibiotic may initiate autoimmune response- John Hopkins

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Cryptic MHC class I-binding peptides are revealed by aminoglycoside-
induced stop codon read-through into the 3′ UTR

Elliot Goodenougha,
Tara M. Robinsona,1,
Matthew B. Zooka,2,
Kevin M. Flaniganb,3,
John F. Atkinsc,d,
Michael T. Howardc,4, and
Laurence C. Eisenlohra,4,5

Abstract

Significance

Many genetic disorders, including Duchenne muscular dystrophy and
cystic fibrosis, are caused by a defective protein resulting from a
premature termination codon (PTC) in the mutant gene.
Aminoglycosides have been proposed as therapies for these disorders
because they increase the frequency of translational read-through
of PTCs, permitting expression of full-length protein. We consider
the possibility that this approach may prompt an autoimmune
response to HLA-presented epitopes encoded downstream of the PTC or
other stop codons. We demonstrate that gentamicin induces
immunologically relevant levels of an epitope derived from PTC read-
through. Furthermore, we identify multiple HLA class I-binding
peptides derived from read-through of conventional stop codons in
gentamicin-treated cells. These results substantiate the
possibility of immune autoreactivity from read-through therapies.

Abstract

Aminoglycosides have been proposed as therapies for genetic
disorders caused by nonsense mutations, because of their capacity
to enhance translational read-through of premature termination
codons (PTCs), thereby permitting expression of functional full-
length protein. However, a potential consequence of this strategy
is the development of an autoimmune response to HLA-presented
epitopes encoded downstream of the PTC or other stop codons. Using
a recombinant virus-expression system in tissue culture and in
mice, we demonstrate that gentamicin can induce expression and MHC
class I presentation of a model epitope encoded downstream of a PTC
at levels sufficient to activate CD8+ T cells. The degree of read-
through–derived peptide presentation varies with the sequence of
the stop codon and +1 nucleotide. Additionally, we applied a mass
spectrometry exploration of the HLA class I peptide repertoire of
gentamicin-treated cells and identified multiple peptides derived
from read-through of conventional stop codons. These results
substantiate the possibility of self-reactivity to cryptic epitopes
revealed by stop codon read-through therapies and potentially other
therapeutic approaches involving compounds that alter translational
fidelity.

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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