IMS researchers have discovered a two-step process that 7is essential for generating a broad antibody response against influenza viruses.The rapid rollout of COVID-19 vaccines has been a saving grace in the ongoing pandemic. However, frequent coverage of the efficacy of the wide variety of available shots has offered a reminder that not all vaccines are cre-ated equal.This reality also holds true for influenza. Although in-fluenza shots come in two main types: live attenuated and inactivated, the latter is preferred in many countries in-cluding Japan because it causes fewer side effects. However, inactivated vaccines only stimulate the immune system to produce protective antibodies against the strains used for inoculation. Live attenuated vaccines, on the other hand, like natural infection, lead to a broader immune response against multiple related strains.Exactly how this broad immunity arises, however, is unclear. “Infection gives rise to a totally different type of antibody response compared to inactivated vaccines,” said Masato Kubo, Team Leader of the Laboratory of Cytokine Regulation at IMS. “We wanted to know why.”To unravel this mystery, Kubo and his colleagues stud-ied the phenomenon in mice. In their study published in Nature Communications, the team first checked that the animals in fact exhibit the narrow versus broad antibody response by either inoculating them with an inactivated vaccine or infecting them through the nose with one strain of the influenza virus, before exposing them to the same or Figure: IL-4 acts as an essential fuel to expand minor B cell populations in the germinal center (GC) factoryVirus infection induces the production of broadly reactive antibodies through two steps: (1) The virus enters the respiratory system and promotes viral replication deep in the lungs. This process induces structural changes in the virus hemagglutinin (HA) protein, causing it to expose rare antigenic epitopes; (2) In the germinal center (GC), follicular helper T cell (TFH)-derived IL-4 plays a crucial role in the expansion of minor B cell populations that recog-nize common HA epitopes.Original paper:Miyauchi K, Adachi Y, Tonouchi K, Yajima T, Harada Y, Fukuyama H, Deno S, Iwakura Y, Yoshimura A, Hasegawa H, Yugi K, Fujii S, Ohara O, Takahashi Y, and Kubo M. Influenza virus infection expands the IL-4a different virus two weeks later. As expected, vaccination only protected against exposure to the same virus, whereas natural infection led to the additional production of anti-bodies against another strain of the same subtype.Through a series of assays and cell and tissue analyses, the team discovered that two processes were essential for generating this broad antibody response. The first starts with viral replication in the lungs. This causes structural changes in a mushroom-shaped protein called hemaggluti-nin (HA) located on the surface of influenza, causing it to expose normally-hidden antigenic epitopes that are shared across different virus strains.Intriguingly, the team found that the mice already har-boured existing B cells that recognise these newly exposed epitopes. However, these cells are normally rare and need to be amplified to have an effect.In the second step, a subset of immune cells known as follicular helper T cells located in specialised lymph node structures called germinal centers multiply and secrete the cytokine IL-4. “IL-4 is key to expanding these rare B cell populations,” Kubo said.These findings could lead to new strategies for inocula-tion that not only offer broader protection but also cause fewer side effects. However, Kubo emphasizes that more details of the mechanism need to be resolved first.In addition to ironing out these specifics, the team is now applying a similar strategy to study coronaviruses, with the hope of finding an effective way to protect against upcoming variants.B cell expansionbreadth of antibody responses through IL-4 signal in B cells. Nat Commun 12, 3789 (2021)GC factoryTFHNasal administrationactivationVirus-unique epitopeBroadly reactive B cellsB cell selectionVirus replicationBroadly reactiveantibodiesBlock virus infection!Airway epithermal cells Masato KuboTwo steps to broader immunity
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