Barts-MS rose-tinted-odometer: ★
The Twittersphere is abuzz with the preliminary seroconversion rates in Israelis patients with MS on various DMTs in response to the Pfizer-BionTech COVID-19 vaccine (see below). As expected the antibody seroconversion rates in response to anti-CD20 therapies and S1P modulators are blunted and in most cases inhibited. The backstory or biology around anti-CD20 therapy is well-rehearsed; anti-CD20 therapy depletes B-cells and annihilates germinal centres in lymph nodes and the spleen.
The question I have just been asked is why does fingolimod block antibody responses? To answer this we need to go back to the basics of immunology.
Fingolimod and other S1P modulators work by internalising the S1P receptor making lymphocytes unresponsive to the S1P signalling or chemotaxis gradient in secondary lymph organs such as lymph nodes. In lay language, this causes lymphocytes to park-up in a long-term car park with a wheel lock-on. Even if you wanted to drive your car out of the car park by starting it up you wouldn’t be able to move it without removing the wheel-lock (fingolimod). By blocking lymphocyte mobility helper T-cells can’t migrate to the so-called germinal centres in the lymph nodes and spleen to help B-cells switch from IgM to IgG antibody production and to then help the B-cells to affinity mature their antibodies, i.e. to make good quality antibodies. Normally these affinity matured B-cells would leave the germinal centre to become memory B-cells or plasmablasts. The plasmablasts then mature to become plasma cells and produce high-quality antibodies, which in the case of anti-spike protein protect you from getting COVID-19 in particular severe COVID-19. Fingolimod and other S1P modulators prevent this normal immunology from happening hence the low or absent anti-COVID-19 antibody response after COVID-19 vaccination.
I like to think of the germinal centres as being the immune system’s university; this is where the immune system sends its primed T-cells to help educate B-cells. After a brutal natural selection process in the germinal centres, a few B-cells survive and graduate with a PhD, i.e. a highly specialised degree or class-switched high-affinity IgG antibodies. This then allows the B-cells to become memory B cells and go into semi-retirement or to set-up their own production company as plasma cells and to produce high-quality antibodies. Anti-CD20 therapies work by blowing up the B-cell university and S1P modulators stop the teachers (T-cells) from educating their students (B-cells). Having no university or no teacher-student interactions have the same effect and result in no educated B-cells and hence no IgG antibody responses.
Please note the above information does not change my personal advice regarding vaccination, whether you are on an anti-CD20 therapy, fingolimod or another S1P modulator (siponimod, ozanimod, ponesimod) #GetVaccinated ASAP; some immunity is better than no immunity. Please note having no anti-SARS-CoV-2 antibodies doesn’t necessarily mean you have no immunity. These antibody studies don’t tell us anything about T-cell responses, which are likely to be as important as antibodies in providing protecttive immunity against SARS-CoV-2.
Han et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood. 2004 Dec 15;104(13):4129-33. doi: 10.1182/blood-2004-06-2075. Epub 2004 Aug 19.
FTY720 is a novel immunosuppressant that is highly effective in inhibiting rejection of allografts and autoimmunity in various animal models. It has been shown that the sphingosine 1 phosphate (S1P) receptors are the direct molecular targets of FTY720. However, the mechanisms responsible for inhibiting specific immune responses by FTY720 are not well resolved. In particular, there is no available information on whether or how this compound affects humoral immunity. We have investigated the effect of FTY720 treatment on B-cell response during the immune response to a well-defined T-dependent antigen. Our data demonstrated that germinal center reaction was significantly reduced in peripheral lymphoid tissues of mice treated with FTY720. In addition, FTY720 treatment inhibited the production of high-affinity, class-switched antibodies, but not the production of low-affinity, immunoglobulin M (IgM) antibody. Consistently, FTY720 did not have a significant effect on antibody response to a T-independent antigen. Our results may have important implications in application of FTY720 in immune regulation.
Also see the post by MD from a few days ago. Fingolimod also stops B cells moving within the follciles and and stops them contacting areas where they the B cells are likely to be stimulated.