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TB or Not TB: That is Our Question
The role of Interleukin-12 Receptor in The Immune System and Preventing Tuberculosis
Grafton SMART Team: Megan Alascio, Lelaina Evans, Mariah Fox, Grace George, Brandon Itson-Zoske and Brendon Konon
Advisors: Dan Goetz and Fran Grant
Mentors: Richard Robinson, Ph.D. and Halli Miller, M.S., Department of Microbiology and Molecular Genetics, Medical College of Wisconsin
Abstract
According to the National Network for Immunization, the first tuberculosis(TB) vaccine was given in 1921 and has been administered to over 4 billion people. Unfortunately, the vaccine is not as effective as it once was because tuberculosis is becoming
increasingly resistant to antibiotic treatments. As a result, new methods of treating and/or preventing this disease are underway. One method that could be used to prevent tuberculosis is to study the Interleukin-12 Receptor (IL-12R) an essential protein in
initiating the immune response. When a pathogen invades the host, T-helper cells send signals to initiate an attack against the pathogen. IL-12, a cytokine, binds to IL-12R, which can signal macrophage activation to mount an attack against the invading
pathogen. Some people have a mutated IL-12R which causes the patient to be infected by a similar disease to TB upon vaccination with BCG which contains live bacteria. IL-12 is a heterodimer with two glycoprotein subunits, p40 and p35, that are bound to
the IL-12R via two disulfide bonds. If the IL-12R is mutated, the IL-12 will not bind properly to IL-12R, and the helper T cell's immune response to destroy the TB cell will not commence. Although IL12R has not yet been crystallized, the Grafton SMART
Team (Students Modeling A Research Topic) modeled gp130, a homolog of IL12R, using 3D printing technology. Ser 122 and Trp142 are highlighted on our model because this is where gp130 binds to IL-6, the homolog of IL-12.
Tuberculosis
Introduction to Interleukin-12
Tuberculosis (TB) is a bacterial disease caused
by Mycobacterium tuberculosis (picture to the
right), which is primarily located inside the
lungs. The lungs are responsible for the intake
and outtake of molecules in the air that are
vital for human survival. It is because of this fact that the
bacterium can easily escape and be readily available for the next
unsuspecting host. Symptoms include: body weakness, loss
of weight, chest pains, fever, or night sweats.
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The white mass indicated by
the red arrow on this X-ray
of a lung shows a granuloma,
which is a host cell’s immune
response and the clumping of
M. tuberculosis bacteria.
To prevent people from getting tuberculosis, a vaccine is
administered. In theory, since the vaccination has a small
portion of tubercle bacillus, a person should replicate T cells
into memory T cells so they can fight off TB; however, if
there is mutation on IL-12R, then the person is infected with
this disease. This occurs when there is a mutation in the IL-12
receptor site, which is a protein found in the membrane of a T
cell. The mutation hinders the ability of the IL-12 cytokine to
bind with the receptor site. The IL-12 cytokine is secreted by
a macrophage when the bacteria invades the lung tissue of a
human. Then IL-12 will attach to gp130 which will cause the
production of antibodies in order to help fight this bacterium.
Cell Response Without IL-12 Receptor
The Importance of the IL12RB1 Receptor
When the signal is made, the normal reaction is the release
of IL-12, a cytokine. IL-12 is then supposed to attach to
IL12RB1 receptor. When this does not happen, the
bacterium does not get neutralized, and can multiply
exponentially. (pictured below)
•The first lung (lung A) is from a genetically normal mouse.
•The second lung (lung B) is from a mouse that lacks IL12RB1
•It can be derived that the IL12RB1 receptor is vital to the prevention
of M. tuberculosis from spreading rapidly.
Model of Interleukin-6 and gp 130
http://www.exploremedicinetv.com
The Cell’s Normal Response
A physical model of Interleukin-6 may prove helpful in the study
of TB, as it gives a three dimensional reference for researchers. A
model designed by the Grafton SMART Team includes interleukin6 and glycoprotein 130. Highlighting the amino acids Ser122 and
Trp142 gives an insight into how binding may occur and possibly
where the problem lies.
Statistics on Tuberculosis
•2nd to HIV/ AIDS as the greatest worldwide killer due to a single
infectious agent.
•Having AIDS will make a host more susceptible to TB.
•Between the years 1990 and 2011, the tuberculosis death rate has
gone down 41% from years previous to 1990.
•There is a multi-drug resistant form of TB, called MDR-TB.
•According to 2011 data:
•1.4 million people died from this disease in 2011.
•There are 8.7 million people infected with TB.
•Below is a map of the world that includes the general
number of tuberculosis infections in each country.
Model specifications:
•Struts are colored white.
•Hydrogen bonds are colored alice blue.
•Glycoprotein-130 is colored midnight blue.
•Interleukin-06 is colored maroon.
•Amino acid Tryptophan-142 is colored lime.
•Amino acid Serine-122 is colored yellow.
1. When a pathogen such as M. tuberculosis binds to the surface of an antigen-presenting cell, the cell is engulfed and degraded.
2. The combination of the degradation of the pathogen and the binding of a specific helper T cell promotes the secretion of IL12 cytokines by the antigen-presenting cell.
3. These released cytokines bind to the IL-12 receptor on a helper T cell, and the cell proliferates.
4. Both the antigen-presenting cell and the helper T cell continue to release IL-12 cytokines as the activated helper T cell
activates B cells that are later cloned into memory B cells to degrade the same type of pathogen.
www.who.org
References:
Boulanger J., Chow, Brevnova E., Garcia K. (2003). Hexameric structure and assembly of the interleukin-6/il-6 gamma-receptor/gp130 complex. Science, 2101-2104. Retrieved from
www.sciencemag.org
Vosse, Lichtenauer-Kaligis, Dissel, Ottenhoff. (2003). Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for il-12 and il-23 receptor structure
and function. 54, 817-827.
Chua, Chizzonite, Desai, Truitt, Nunes, Minettie, Warrier, Presky, Lavine, Gately, Gubler. (1994). Expression cloning of a human il-12 receptor component. Journal of Immunology, 128136.
The SMART Team Program (Students Modeling A Research Topic) is funded by a grant from NIH-SEPA 1R25OD010505-01 from NIH-CTSA UL1RR031973.
Conclusion
Through studying gp130, researchers are able to understand the
importance of having a functional IL-12 receptor site. If this
receptor site is mutated and a patient is given the vaccine for
tuberculosis, then the patient is infected with a tuberculosis-like
disease. Through learning more about these receptors, researchers
can modify the vaccine so that less people will become infected and
die from a vaccine that is meant to save them.