Memory B cells with a flavour for flaviviruses
Memory B cells with a flavour for flaviviruses
Contributed by Jeremy F Brooks PhD
A hallmark of an immune response to viral infection is the generation of memory cells that ‘remember’ the virus. If the body re-encounters the virus, those memory cells mount a “stronger, faster” response than during the initial infection.
Memory B cells rapidly differentiate into antibody-secreting plasma cells upon re-encountering the pathogen. These antibodies are critical for protection against the infection. I previously wrote about a counterintuitive trade-off that occurs when the pool of memory B cells in the body attempts to diversify itself against malaria. While the response to a dominant single region (called an epitope) of the pathogen is seemingly dampened over time, the immune system is actually giving itself a chance to develop antibodies against various other malaria epitopes. The hope is that these ‘diverse’ antibodies can ‘cross-react’ with mutants or closely related species of a pathogen and gives us a better chance at neutralizing subsequent infections.
Such biology is not limited to malaria infection. In fact, we believe this element of the immune response - to diversify itself - might be built in. This would make a lot of sense evolutionarily because 1) pathogens frequently mutate under selective pressure and 2) closely related pathogens often co-exist in the same geographical areas. Hence the immune response must prepare its memory B cell pool to anticipate changes in the virus upon second exposure.
However, as with many aspects of biology, there is a darker side to this that pathogens have learned to exploit. In the case of flaviviruses, the immune system also develops antibodies that can cross-react with different strains – for example, West Nile Virus (WNV) antibodies can react with closely related Japanese Encephalitis Virus (JEV). However, these antibodies bind to the virus and actually promote its infection because these antibody-virus complexes are internalized by cells that express receptors for antibodies. How this happens is not well understood.
In a recent study published in the journal Immunity, research led by Dr Deepta Bhattacharya at the University of Arizona investigates this unique problem in detail.
The researchers first establish that memory B cells generated by immunization with WNV can cross-react with JEV. They then combine a series of elegant genetic perturbations and immunization regimes to isolate how these cross-reactive memory B cells behave. In experiments where mice are immunized and then boosted – to assess how these memory cells contribute to a second infection – it appears that their binding affinity for the pathogen is not further improved. Essentially, they are restricted to whatever affinity they had initially achieved during the first infection. This was true if other more distantly related flaviviruses like dengue virus or zika virus were used in experiments.
The researchers work backwards to identify where these memory B cells come from. The researchers test when and from which earlier B cell population are these memory B cells generated during the initial immunization. While they are continuously generated over the course of the immune response, it would appear that they are generated from a distinct population of B cells compared to those that go on to become plasma cells that secrete high affinity antibody. In fact the cross-reactive memory cells appear to be predisposed to become memory B cells.
Of most interest, authors note that these cross-reactive memory B cells are low affinity. When the immune system encounters JEV after encountering WNV, it will use the memory B cells that can cross-recognise JEV, but those memory B cells cannot further enhance their capacity to bind the JEV pathogen. The implication here is that these low-affinity B cells will make antibodies that only weakly neutralize the JEV pathogen, if at all. It may also explain, as described above, how the virus can hijack low-affinity antibodies to enhance its access to a cell for infection.
The authors of the study caution that vaccines – which are in development for flaviviruses – must avoid triggering this population of cross-reactive B cells. For example, it may mean that someone previously infected with WNV will have more severe infection with related flaviviruses because of cross-reactive antibodies generated by the vaccine. Future work will need to design vaccine immunogens that specifically avoid the cross-reactive epitopes between these flaviviruses to overcome this challenge.
Dr Jeremy Brooks is a postdoctoral fellow in the Zikherman laboratory at UCSF. Jeremy’s work focuses on antibodies and the immune cells that produce them. Correspondence can be addressed to jeremy.brooks@ucsf.edu
