To build better vaccines, scientists want to know more about how our bodies produce sufficient numbers of effective, resistant antibodies against the influenza virus.
They look at a key pathway in the way immune cells, called B cells, perceive the virus, and then become plasma cells that make the antibodies that can destroy, or at least keep us from becoming infected.
This ufmylation pathway is known to alter proteins and thus cell function, and immunologist Dr. Nagendra Singh that it is essential for the essential production of our antibodies.
A $ 2.25 million grant (1RO1AI155774-01) from the National Institute of Infectious and Infectious Diseases is helping Singh, an associate professor in the Department of Biochemistry and Molecular Biology at the Georgia College of Medicine at Augusta University, further, study make these molecular mechanisms behind defense. plasma cells and the longevity of the specific antibodies they produce.
Its long-term goals include designing small molecules, drugs, and / or using gene editing technology such as CRISPR-Cas9, to address problems that lead to a non-immune response. so good.
Upward selective alteration of ufmylation in stem cells may mean more effective vaccines while they may be turned down to help allergy sufferers and individuals with autoimmune disease such as as a result of an overly aggressive immune response, he notes.
Our normal antibody production looks something like this: B cells develop from cells in bone marrow, then migrate to the spleen and so on.
lymphoid tissue, such as the lymph nodes, and circulating in the blood, look out for pathogens such as the influenza virus or a novel coronavirus.
When the Singh influenza virus is tested for access, usually through the nose after an infected person sneezes or coughs, part of the virus reaches our lymphoid organs . There, through a process called VDJ reactivation, B cells have the ability to quickly identify and develop receptors that allow them to respond to more than 10 billion different antigens.
When the invader binds to the produced specific B receptor cells, it transforms the B cell into a plasma cell that produces an antibody that targets that virus. It is normal for several different B cells to produce different plasma cells that each give a specific antibody in response to a single virus, Singh says.
As soon as plasma cells appear, they go back to bone marrow and target with their antibodies, which Singh looks like long bullets. One plasma cell can make about 10,000 of these missiles every second which are also in the blood, which carries them throughout the body. If all goes well, we may never know we have been attacked.
Vaccines for seasonal flu as well as new coronavirus vaccines, work in different ways to trick B cells into thinking they have seen a specific pathogen, which initiates the same process.
In this complex production, ubiquitin-fold modulator, or Ufm1, is a polypeptide that targets proteins during the ufmylation process and alters their action. Ufm1 binds to the protein Ufbp1, which Singh’s lab has shown has a new role in allowing B cells to become plasma cells and in plasma cells to produce antibody production.
Within plasma cells, Ufbp1 binds to allow the endoplasmic reticulum to expand, a membranous network within cells that, in the case of plasma cells, act as a manufacturing device for antibodies.
Singh’s lab has shown that larger is better in this case because smaller plants produce fewer antibodies. It has also been shown that the endoplasmic reticulum becomes smaller when even one of the ufmylation pathway components is missing.
Now Singh and his team are removing the parts of ufmylation from B cells in mice and also expressing a mutant form of Ufbp1 in the laboratory animals. Mice are then infected with the influenza virus and screened for plasma cell development and the neutral antibodies that target the virus.
We want to see how it affects the number of flu-specific plasma cells that develop in those mice that do not have Ufbp1 or Ufm1 or the other parts of the ufmylation pathway in B cells. “
Dr. Nagendra Singh, Immunologist and Associate Professor, Department of Biochemistry and Molecular Biology, Georgia College of Medicine, Augusta University
They expect, with little evidence, to see far fewer plasma cells against the flu without some or all of these key components, but they want to make sure they are right about the main role of ufmylation.
They also infect mice with the influenza virus and, once plasma cells develop in response and the antibodies they produce, eliminate the ufmylation components from the plasma cells, then look at how long the specific plasma cells and antibodies last.
They also look again at what happens to the size of the endoplasmic reticulum where the antibodies are made, and how many antibodies are made. Again, they have some evidence but need more, when even one part of the ufmylation pathway is missing, the antibody production site will be smaller and so will antibody production.
“Plasma cells in the body have only one function: To make antibodies,” Singh says. If they can learn more about how long these cells last, they can design these tiny molecules, drugs, or other methods to increase their longevity and antibody production.
It notes a large individual variation in how long antibodies to a virus or bacterium last and how many we have. Exposure to the novel coronavirus, for example, has produced antibodies in some individuals lasting a few weeks and in others lasting several months.
Established vaccines also carry out a wide range of timescales for efficacy, from the measles vaccine, for example, which is considered to provide lifelong protection while pertussis protection is expected to last, or whooping cough, and seizures five to 10 years. Flu vaccine is recommended
each year, both because the common rays of the virus change from year to year and because the plasma cells stimulated by the virus also live for about one year, Singh says. The half-life of these antibodies is a few weeks, so antibody levels fall shortly after plasma cells reach maturity. The hope is that all vaccines will have long-term effectiveness, he says.
Singh does not yet know whether individual changes in the ufmylation pathway also help explain the wide range of responses – from asymptomatic to death – that different people experience infection with the virus influenza in addition to what is seen with the coronavirus, but it must be a factor, he says.
“We don’t yet know if there is a difference in your ufmylation pathway that determines how much antibody you are making against it, say the coronavirus, or how long the antibodies last. that stays in your body, “Singh adds. Looking at ufmylation components in B cells and plasma cells should help provide ultimate vision, he said.
Singh published in 2019 in the magazine Nature Communication that Ufbp1 suppresses the enzyme PERK to help B cells to differentiate into plasma cells. PERK helps correct problems with improperly packed proteins (proteins need to be packaged properly to function properly) but PERK also stops the production of new proteins in the process, and thus Ufbp1 inhibits it to produce adequate protein folding and plasma cell production.
Source:
Georgia Medical College at Augusta University