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I am thinking of why some patients do not have natural immunity after exposure to the A-B toxin of diphthria. I think the A-B exotoxin is the key factor causing this disease and should trigger memory cells to form.

DT has both local and systemic effects. Locally, its action on epithelial cells leads to necrosis and inflammation, forming a pseudomembrane composed of a coagulum of fibrin, leukocytes and cellular debris. Absorption and circulation of DT allow binding throughout the body. Local effects produce pseudomembrane.

The major impact of transduction in pathogens is the introduction and stable inheritance of virulence genes such as those coding for toxins. C diphtheriae is lysogenic with a phage containing the diphtheria toxin gene. Diphtheria toxin is produced by C diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria

The toxicity for intact cells depends on toxin binding and uptake. In other words, the net effect of the toxin depends on the function of the target protein and the function of the cell. B subunit binds to receptors that regulate cell growth and differentiation, thus exploiting a normal cell function. A subunit inhibits protein synthesis. B subunit binding determines cell susceptibility. Absorption and circulation of DT allow binding throughout the body. I think this uptake does not occur sufficiently with patients without natural immunity stimulation.

I think the reason for no natural immunity for some patients after toxin exposure is that the host does not stimulate enough adaptive immunity and no memory cells are built. Again, this is because the bacteria has little invasive capacity. Diphtheria is due to the local and systemic effects of DT with potent cytotoxic features. The uptake of the toxin varies also among some patients. So other patients have probably more local effects. This would explain partially why the adaptive immunity is not triggered.

Diphtheria toxin is antigenic itself. So it can stimulate the production of protective antitoxin antibodies during natural infection. In those patients without development of natural immunity, A subunit fails to bind EF-2, probably.

One reason is that the toxin does not get into bloodstream in 6-8% cases, and so natural immunity is developed. So there is too low effective dose of diphtheria for some patients to invade the epithelium and trigger the adaptive immune response and create memory cells.

Sources: Murray Microbiology, Sherris Microbiology and Jawetz Microbiology.

Why do 6-8% of diphtheria patients not develop natural immunity after being infected?

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Couple of quick thoughts. Extoxins by definition are secreted, and making antibodies to them can be great to limit their toxic effects, but does little to diphtheria, which is what you would want to remove if it's being pathogenic. I'm going to have to look more into the lit to see if it seems host or path specific. –  Atl LED Mar 9 at 0:56
    
@Masi Do you have a source for the 6-8%? –  Chris Mar 22 at 22:18

3 Answers 3

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+100

There are two other, but rather exotic possibilites which explain why people do not develop immunity after an diphtheria infection. These are unlikely to get to 6-8% of the cases which @Masi writes, but I am missing the reference here.

The first possibility are people with chronic renal failure. They have problems with their immune responses since their antigenpresenting cells do not get the necessary co-stimulatory signal by the T-cells. See this paper. People with other problems in their T-cells or the co-stimulatory signal would have this problem, too. See this article.

The other possibility would be the distribution of the antibodies. The diphteria toxin is made out of two subunits, A and B. B is important for making the way of A into the cell, A gets cleaved in this process and fully active. When the antibodies made in the process are mostly against A (and then against parts, which change their conformation after the cleavage), this antibodies are mostly useless to fight the toxin. See this paper.

One (but is complete speculative) possibility is on the toxin itself. It could be possible, that some people are more sensitive to the diphtheria toxin, so that the amounts necessary for the negative effects are too small to trigger an adequate immune response. This is known for the tetanus toxin, where even a survived infection doesn't provide immunity (except when people are vaccinated afterwards) as the toxin is so toxic, that it doesn't trigger the immune system. The caveat is, that the diphteria toxin is about 3 orders of magnitude less toxic than the tetanus toxin.

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In this article they look at the development of natural immunity to diptheria in those who were vaccinated. I could not find any studies on people who had acquired it naturally. http://www.sciencedirect.com/science/article/pii/S0264410X97001485

They found that the development of immunity to diptheria vaccine depended on several factors:

  1. Time lapsed since last vaccination
  2. Females had lower immunity rates
  3. Number of previous vaccinations
  4. Last vaccination within the first 3 years of life
  5. Age

What this may mean for individuals who are affected is that similar factors could play a role preventing them from acquiring immmunity to diptheria. Indeed, some of the factors like last immunization and number of vaccinations are logical since diptheria may evolve or there may be different strains so the body needs to have the lastest antibodies for immunity.

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All the points above are interesting, but they are only important for answering the question why people get diphtheria and not why they are not developing immunity after having the disease. Evolution of strains is not a problem, since the vaccine is directed against the toxin and not against some fast changing component. Otherwise we would need a new vaccination every year (or at least every few years) which is not the case. –  Chris Mar 23 at 8:13
    
The question asks why do some people not develop immunity. My answer consists of reasons why this may be the case-- at the macro level (for vaccinations). I did not go into molecular mechanisms of why diptheria does not result in immunity in the 6-8% because I could not find any references in the literature. If you imagine the evidence that would need to be gathered to establish this, you would realize this is a tall order. Evolution of strains is documented in the literature -- see this article for insight jid.oxfordjournals.org/content/181/Supplement_1/S168.full . –  V_ix Mar 23 at 14:26
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Thats why I asked Masi for the reference on this quote. There are some possible mechanisms why people are not developing a immune response, I will write about this later. The evolution of the strains is obviously not causing problems, the vaccination seems to work. –  Chris Mar 23 at 16:39

Just wanted to add that this is a common problem with vaccines.

...consider an actual measles outbreak in Colorado in December 1994.5 Out of 625 children exposed to the disease, 17 got measles. Of those 609 who had previously been vaccinated, only 10 (or 1.6%) developed measles. Of the 16 children who were not immunized, 7 (or 44%) developed measles. Thus, the risk for immunized children was less than 2% while the risk for unimmunized children was 44%.

Most vaccine development struggles to reach high immune efficacy; You usually can't just inject some dead bacteria or virus and expect to get an immune response.

In particular I think there has been adaptations in the immune system to DT such that it tends to stimulate an immune response. This is pretty much a reaction to the peptide sequence itself. We know this because since the 1980s there has been concern that the live toxins in DPT vaccines might be causing health problems with young children. (They don't). As such, acellular vaccines were developed where just a few proteins were included - the cell was not used, and DT was produced where only a fragment was added or the toxin was rendered inactive by mutagenesis. DT is such a reliable component that by itself it can illicit an 88% immunity rate.

These DT fragments are formulated with other bacterial components to create new vaccines.

The failure of the vaccine on occasion is most likely the result of individual variations in immune loci. The immune system is highly complex and also highly variable from individual to individual even amongst close relatives. their immune activation or their defenses (complement and immunoglobin pathways) may make some individuals more susceptible to diphtheria than others.

The science of vaccine formulation is highly empirical; I don't think it is understood why some molecules evoke a broadly distributed reaction and others do not. Even so the diphtheria toxin is one of the more universal immune stimulants known. I don't think that a completely universal adjuvant (something added to a vaccine to stimulate an immune response) is known.

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This is a common problem with vaccinations, they have no 100% succes rate. For the diphtheria number Masi mentioned it would be interesting to know if these are immunized and so on... –  Chris Mar 24 at 7:33
    
expanded answer –  shigeta Mar 24 at 11:56

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