Shapely interactions and love at first sight in the enduring Ig landscape

Setting it Straight - Issue #19

Written by Nobel Laureate Professor Peter Doherty

The perception of shape and form, the anatomical characteristics of fellow human beings are central to much of the way we interact, especially on initial contact. In the dryness of science-speak, ‘love at first sight’ could be thought of as a manifestation of visually-determined affinity for a particular mix of ‘conformational determinants’: smile, face, figure and, of course, style – from dress to the tilt of the head and the way that very particular person stands and walks. Just as in immunity, we could talk about innate (inborn) versus acquired, or learned (adaptive) responses. Some of that ‘love at first sight’ reaction will depend on our chemically-adjusted (hormones) biology, some will likely be informed by good or bad memories of others we’ve known.

The difference in shape discrimination for the brain and the immune system is that the central nervous system operates at the level of consciousness, informed initially by the receptor pathways of the eyes, the optical neurons and the visual cortex. Antigen recognition in immunity is, as we discussed last week, a property of unique receptors on the surface of B and T lymphocytes. Any specific ‘immune acknowledgment’ reflects direct contact at the level of molecular microanatomy, the intimacy of binding affinity between two complementary surfaces, or shapes.

We’ll focus here on antibodies, the Ig molecules that are the direct descendants of the BCRs (B cell receptors). A novel ‘foreign’ antigen (see Immune-scape essay) first encounters its ‘cognate’ (complementary) BCR in a precursor form on the surface of an immunologically naïve B lymphocyte. The ensuing, antigen-triggered B cell response then gives rise to both persisting B cell memory and the plasma cells that are the Ig production factories. And, in considering immunity to an invasive virus like SARS-CoV-2, we’re discussing a whole lot of different antigens expressed on each of the four main structural proteins (the building blocks) of the virus. Most of these antigenic sites, or conformational determinants, are defined by the way the protein folds from the polypeptide chain specified by the SARS-CoV-2 RNA genome: more about the virus and protein chemistry in later essays!

When it comes to vaccination and COVID-19, our main focus is on generating an Ig response to the spike protein that’s on the surface of SARS-CoV-2, particularly to the spike receptor binding domain (the RBD) that first attaches the virus to the ACE2 molecule on the surface of susceptible cells in our nose and pharynx regions. If we can block that by attaching a specific Ig to the RBD in the right place, we stop the infectious process in its tracks.

The RBD is, though, only one of many possible antigenic sites on the SARS-CoV-2 spike protein. That raises a very important point. The only ‘linker’ within any individual antibody repertoire is the selecting antigen, the microanatomy of a particular conformational determinant. As a consequence, the overall antibody response profile in any virus infection is always a mix of different, individual responses that operate in ‘ignorance of each other’. A major difference between the brain and immunity ‘in love at first sight’, is that our cerebral cortex integrates the mix of visual signals that we receive from seeing different ‘conformational determinants’ so that we register a whole person not just a collection of ’bits’, or bytes if you want to be binary. The immune system has no comparable integrative mechanism.

The overall message is thus: that the selected antibody repertoire to say, the SARS CoV-2 spike is, in fact a mix of different repertoires specific for distinct antigens, or conformational determinants. And, once the pathogen is eliminated, these ‘repertoires’ are in no way linked in the immune memory B cell pool. Challenge a COVID-19 survivor with, say, a vaccine expressing the SARS CoV-2 spike and these separate elements come back together to make a diverse, ‘boosted’ recall response, but only to the spike and not to the other virus proteins that will also have elicited antibody immunity.

In trying to communicate what an individual antibody/antigen interaction actually looks like, a common analogy is to use the example of a ‘lock and key’. That’s kind of useful to give a sense of extraordinary specificity, but the ‘love at first sight’ idea may be better in the sense that we’re talking more about interacting, to some extent deformable surfaces and shape recognition rather than the unforgiving inflexibility of metal to metal. Alternatively, visualise an electronic door lock that operates via facial recognition where there can be some variation of expression.

You may have read somewhere about the ‘protein clamp’ candidate COVID-19 vaccine made by Paul Young’s group at the University of Queensland (UQ). What this refers to is isolated (made synthetically in a flask or vat) SARS-CoV-2 spike protein that’s held to the folded shape it would have on the surface of the virus by a ‘molecular clamp’. When someone is given that vaccine, the antibody response will thus be ‘faithful to’ the same conformational determinants that are expressed on the virus. Focused, ‘enduring fidelity’ is an established pathway to happy outcomes in both life and vaccinology!