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In order for the immune system to be stimulated to produce antibodies, there must be a surface protein of the invading pathogen which binds to a receptor on B cell surface somewhat loosely. We need this first step for the initiation of the somatic hypermutation phase to produce specific antibodies.

But what if there is a pathogen which does not have such a surface protein? i.e. its surface proteins, if it has any, do not bind with sufficiently high affinity to surface proteins on existing B cells to trigger further aspects of the immune response.

One may argue that this is unlikely to be the case because:

a) naturally occurring pathogens evolve from existing ones, so the changes in the antigens will generally be minor. A new strain will have surface proteins that are similar enough to those of an existing strain for some loose affinity to present antibodies in the host.

b) I think, though am not at all sure, that pathogens need to invade cells to be dangerous.I'm not entirely sure what the nature of a pathogen which cannot invade cells would be. Perhaps not a pathogen at all? In any case, if the starting assertion is true, the dangerous pathogens have a surface receptor which binds with surface proteins on cells to enter them. What if many antibodies are based on the same proteins? (Though I have trouble believing this because the natural agonists of these cellular receptors are some biologically relevant and useful proteins, which we would not want an immune response to. For instance, a generally accepted mechanism of entry of SARS-CoV-2 into cells is by binding the ACE2 receptor, which has angiotensin II- a vasoconstrictor peptide- as an agonist.

So my questions are:

a) Could we synthesise a pathogen which has no surface proteins but which nevertheless does harm in some way? How could it do this harm?

b) Can we make a pathogen which has surface proteins such that it can enter cells or do damage that pathogens normally do, but goes undetected by the immune system?

In the above I have assumed that surface proteins (or perhaps also other surface molecular- maybe carbohydrates will do- are necessary for activating the immune response. If this is not the case, please let me know.

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"I think, though am not at all sure, that pathogens need to invade cells to be dangerous."

True in the case of viruses and some bacteria.

Hiding within the cells of the host is the intracellular pathogenesis. But other "tricks" are possible. Four examples:

  • biofilms
  • surface proteins that "catch" antibodies
  • fast mutation of surface epitopes, like the (in)famous HIV
  • using host molecules (the HIV again)

Source: Extracellular Immune Avoidance (LibreTexts)

Also interesting: How bacterial pathogens colonize their hosts and invade deeper tissues (Microbes and Infection Volume 17, Issue 3, March 2015, Pages 173-183).

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