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bobze
bobze is offline
#11
Jan28-12, 02:00 PM
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Quote Quote by gravenewworld View Post
Is there a list of all known antigens for pathogens and the amino acid sequence for the proteins? If so, why doesn't someone just take that list, create the peptide in an automatic synthesizer, put the peptide into the syringe and activate the immune system by injecting it? Would it work? If you knew how many proteins you were synthesizing, you can then precisely control the dose given of the antigen.


How many peptides on average does an antigen need to be before it will be recognized? Of course our current technology won't allow for efficient synthetic synthesis of long peptides, but it did in the future, could we easily create pseudo vaccines from synthetic antigens?
There are, as I alluded to earlier some problems with this. First a very brief run through of antigen processing and presentation (cause I don't know how much immuno you've had).

Extracellular proteins get taken up by antigen presenting cells (APCs) and endocytized via endosomes. In these endosomes the protein is processed (broken down) into 13-18 long amino acid peptides. They are fused with vesicles containing major histocompatability complex (MHC) proteins--In this case, MHC II proteins (MHC I proteins mediate "internal surveillance, more on that later). The MHCII-antigen (16-18 aa's) then get presented to CD4 T cells (helper Ts or Th henceforth). There are "2 routes" your Th response can go from here. First they can take the Th1 approach, which is important for mediating cell-mediated immunity (for internal pathogens, like viruses for instance, CMI for short) or the Th2 response for humoral immunity (B cells, which make antibodies, HI for short). Which "path" gets chosen is a complex interaction of cytokines that modulate the response.

That now said we come to the first problem--Control. If we just "synthesized one long protein"--you'd have no control over how the pieces are "chopped up"--So certainly you'd generate some relevant antigen recognition, but you'd also generate a response to lots of "nonsense" antigen--Or antigens that don't necessarily exist as pathogenic antigens.

This rolls into the second and very big problem--Autoimmunity. While our bodies do a very good job at culling T cell lines that don't show self tolerance (searchable term), it isn't perfect. And from time to time and in individual to individual T cells sensitized to antigens against ourselves do unfortunately sneak through the selection process. This can happen for a variety of reasons, but the one most relevant to the discussion here is molecular mimicry. A common and well known example of this is with the highly immunogenic M proteins on the surface of streptococcus pyogenes (causative agent of strep throat). Post-streptococcal infection people can get rheumatic fever. The gist of which is--your body makes antibodies (Ab henceforth) against some of those M proteins, that also happen to have the right shape to bind to cardiac myocytes (we call this Ab cross-reaction). The problem then that occurs is the antibodies can be cytotoxic to the myocytes OR can cause Ab dependent cell cytotoxicity (ADCC)--mediated by other immune cells (like NK cells).

The reason then, no one is all that interested in making a M-protein vaccine (for which there are 100+ M proteins, last I had checked) against strep throat is because no one really wants to take the risk or bare the burden (lawsuits anyone???) of developing a vaccine with the black box warning of "MAY CAUSE SUBACUTE RHEUMATIC FEVER"--Though cardiologists might not mind the increase in business (okay, okay I kid, I kid--bad joke). And especially considering that S. pyogenes is highly susceptible to penicillins (dirt cheap), the risk isn't even close to the reward.

So in the case of your agglomerate peptide, who's processing we cannot control, you run a serious, serious risk of generating immunogenic peptides which will be cross-reactive with self-antigens and sensitizing your immune system to them. That last part being extremely bad for business.


Last quick problem with the idea involves those Th1 and Th2 responses I mentioned above. Some types of infections require a Th1 (CMI) response to clear them, while others require a Th2 (HI) response. I short-changed you above with the conventional "viruses=intracellular=Th1" above. Its actually more complicated than that. For instance TB (mycobacterium tuberculosis) is a bacteria and you might reason that the Th2 response is very important in mediating immunity. Makes perfectly logical sense, however nature doesn't like hard and fast rules. TB actually thrives intracellularly and requires a Th1 (CMI) response to clear. In deed, people who produce Th2 responses to mycobacterial infections don't tend to do so well--prognostically speaking.

Similarly, rotovirus--A leading cause diarrheal illness and morbidity/mortality the world over, is caused by a virus (a reovirus to be exact). You possibly would reason then that CMI and the Th1 response is important to preventing rotoviral infections--Again, nature and her disdain for our rules. Immunity to rotoviral infections is gained through sIgA (secretory immunoglobulin A), a humoral response--Th2 (for a variety of complex reasons outside the depth of this post). A vaccine which induced a CMI response would do little to help in providing roto-immunity.

The problem coming to shape here is that while a large, single protein sequence of "all antigens" could potentially sensitize people to said antigen, there isn't a guarantee that the adaptive immune response developed would produce the adequate response to establish immunity and memory.


-Bob