Issue #20: Antibody dreaming and the Y in immunology

Setting it Straight - Issue #20

Written by Nobel Laureate Professor Peter Doherty

A Sci-Fi dream sequence: you’re floating in the air, legs straight, feet together and arms outstretched at a 60 degree angle. If you were standing, you would be a perfect Y. Strapped to the outer side of each forearm there’s a light metal tube (a propulsion system? anti-gravity device?). It feels bionic, has a couple of finger-like projections at its top, and has somehow arranged your fingers and thumb in a way that’s identical for both hands. Looking around, you’re vaguely aware of other Ys floating in the general vicinity.

A spaceship approaches fast, out of nowhere, then hovers right above you. Oval to circular with no windows, it seems to be checking out the land mass that’s only a few hundred feet below. You’re dragged towards this alien invader by some kind of ‘attractor’ and, as you hit the surface, each hand sticks to a particular ‘jewel’ in two of the many identical, projecting crowns embedded in the spaceship ‘skin’. You realise that the same thing has happened to a few of the other floating Ys. They’re much closer now. You see their faces. Major shock! Some of them are you! You’re a Y1 clone-soldier who has been ‘recruited’ to grab the same crown jewel. And you can also see that there are, at least, Y2-Y7 other clones that have attached to different ‘jewels in the crown’.

Ignoring the attached Ys, the spaceship is heading down to the earth’s surface. It’s aiming for a park populated by identical, regally-attired store mannequins. Suddenly, the earth takes control (gravity at work?). You realise that, along with the other Y1-Y7 clone-soldiers, your feet are stuck to the ground while your hands, still firmly attached to the spaceship crowns, are preventing them from docking with the royal display dummies. That feels OK for a moment then – and this is where you wake up screaming in horror – the ground yawns open like a sinkhole and the whole complex of spaceship, crowns and Y defenders is dragged down into a pool of acid where everything is dissolved. Your last dream thought: ‘I’m a space cadet who has made the ultimate sacrifice’. End of dream, but it comes back every night for a week.

You talk to your psychotherapist, who refers you on to a clinical immunologist. She explains your dream. You and, indeed, all the Y1-Y7  clone soldiers are IgG (immunoglobulin G) antibody molecules that are the secreted products of seven different B cell/plasma cell lineages. That’s what we call a polyclonal antibody response, with each of the seven clones having a unique Ig receptor. These Ig receptors reflect seven distinct configurations for the fingers and hands, each of which grabs a different ‘antigenic epitope’ (jewel in the crown). Your arms are part of the IgG heavy chains, while the tubes are the light chains, with ‘chain’ being another word for protein. The ‘air’ is one or other body fluid (blood, mucus, lymph), while the ‘earth’ is a large white blood cell (WBC), a monocyte/macrophage, in a ‘galaxy’ that is an individual human being. The galaxy has, like you, recently been given a defence system, in our case a vaccine that generates a polyclonal IgG response to the SARS-CoV-2 spike protein.

The alien spaceship is a SARS-CoV-2 virus particle, while the embedded crowns are the spike proteins with their RBD (receptor binding domain) that attaches to the ACE2 molecule (the royal dummies) on the surface of our cells, enabling virus invasion. Your feet are what’s called the Fc region (‘fragment crystallisation’, it’s just a technical term!) of the Ig protein which is ‘grabbed’ by a different  member of the same family (for all seven IgG clones) of specific Fc receptor on the surface (the earth) of a ‘big eater’ WBC (see the Red and the White essay) called the macrophage. The ‘pool of acid’ at the bottom of the ‘sinkhole’ is a mix of acid hydrolases (enzymes) in a cytoplasmic organelle called the lysosome that destroys the Ig/SARS-CoV-2 complex and breaks it down into little ‘bits’ (peptides, nucleic acids) that can be reused in different ways. You’ve been wasted, but your bits haven’t!

The IgG molecules that bind to different antigens on the SARS-CoV-2 spike protein are the neutralising antibodies that block the attachment of the spike RBD to ACE2 and thus prevent infection. Those Ig/spike complexes also ‘label’ the virus for destruction by several different mechanisms, including the acid/enzyme digestion discussed above. Assaying neutralising Igs by demonstrating their capacity to protect susceptible tissue culture cells from SARS-CoV-2 infection is the benchmark serological test for the protective immunity established by vaccination, or in COVID-19 survivors.

If you’ve been reading into the SARS-CoV-2 story, you may have encountered some safety concerns about the possibility that a candidate vaccine might provoke a phenomenon called  ‘immune enhancement’. This is a  form of antibody-mediated immunopathology (tissue damage) that has long been discussed for the very severe, mosquito-transmitted tropical disease haemorrhagic dengue. What is thought to happen is that, while suboptimal binding of a ‘low affinity’ IgG still facilitates virus entry into a macrophage, or its precursor WBC, the more mobile monocyte, the weak antigen/antibody (crown jewel/Y for SARS-CoV-2) bond breaks before the virus is dissolved and, instead, the would-be destroyer cell becomes infected.

That can in turn lead to the virus being disseminated by these motile WBCs, along with the overproduction of potentially toxic chemicals (chemokines and cytokines, see I language essay). We haven’t seen hints to date that this is happening with candidate SARS-CoV-2 vaccines, but it’s one of the ‘safety’ signals that will be closely monitored as vaccines are tested by exposing people in communities with high rates of infection. Next time, we’ll go on with a broader overview of the protective Ig response.