Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by dlf » Sat 2 Jan 2016 21:40

Abstract only, unfortunately..........This could eventually prove to be an important avenue of research.

http://www.ncbi.nlm.nih.gov/pubmed/26718339

J Immunol. 2015 Dec 30. pii: 1501861. [Epub ahead of print]
Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.
Jacek E1, Tang KS1, Komorowski L2, Ajamian M1, Probst C2, Stevenson B3, Wormser GP4, Marques AR5, Alaedini A6.

Abstract
Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms.

duncan
Posts: 1370
Joined: Wed 5 Sep 2012 18:48

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by duncan » Sat 2 Jan 2016 21:55

Wormser, Marques and Alaedini...

dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by dlf » Sat 2 Jan 2016 22:50

Yes, duncan.......It still remains to be seen how badly they might have (mis)handled this research.......I am trying very hard to maintain an open mind until we see the full text version. ;)

duncan
Posts: 1370
Joined: Wed 5 Sep 2012 18:48

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by duncan » Sat 2 Jan 2016 23:10

I know. :)

Here is my concern: This is like their efforts with acute Lyme, i.e., some of it can be good - up to the point where diagnostics and treatment efficacy come into play. That they seem to embrace late stage Lyme here does appear encouraging.

A problem might be that their historic position seems to be that late stage Lyme is a rarity these days, and that when it occurs, it is almost invariably resolved with IDSA-recommended therapy.

So, what on the surface may be a meaningful effort, and suggest these researchers are dutifully mining the mysteries of the disease, the reality may be something not as positive.

You are correct, though, in with-holding judgement until we see the study in its entirety.

Henry
Posts: 1108
Joined: Thu 10 Nov 2011 18:49

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by Henry » Sun 3 Jan 2016 17:31

dlf, and Duncan: Your idiotic comments are unwarranted. If you click on the link provided
http://www.ncbi.nlm.nih.gov/pubmed/26718339, and then in the upper right hand corner of the abstract -- where it refers to complete article-- you will find the COMPLETE text of the article in question. If you bother to read it, you will find that the work represents a serious attempt to identify a biomarker that can be used to distinguish early, intermediate, and late stages of Lyme disease. I should think that with all of the whining the two of you have done in the past, you might find this work to be a good first step in that direction. Unfortunately, your extreme bias will not permit you to think constructively. :bonk: Shame on both of you. But, I have the feeling this will not be the last time you will react in such a way to reports that you don't happen to agree with. Both of you are really quite sick -- and I'm not just talking about Lyme disease. .......

duncan
Posts: 1370
Joined: Wed 5 Sep 2012 18:48

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by duncan » Sun 3 Jan 2016 18:44

Henry, you may wish to refrain from lecturing any part of the Lyme patient community about bias - many of us have been on the wrong end of it far too many times. Who do you imagine we have to thank for that?

Thank you for pointing out where to find the study in its entirety. I look forward to reading it.

dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by dlf » Sun 3 Jan 2016 20:45

Henry, I must have checked too many links to other studies for full text versions that led only to the pay per view option just before looking at this one, so I missed it. Thanks for pointing out that this one is accessible.

As to your other comments, I guess you must have gotten up on the wrong side of the bed this morning, or forgotten your manners. Please, bear in mind that I have never assailed you (or anyone else who posts here) personally. I can generally count on anticipating mean-spirited attacks from hv808ct, (even when they don't appear), but I normally find you to be somewhat more controlled in your invective, at least toward me.

At any rate, your assumptions are completely unfounded. Although it will take me quite some time to digest the full import of this study, from what I did read, I think it does provide a useful and important foundation for future research.

It confirms that IgG1 and IgG3 are primarily responsible for immune reactivity in patients who are not immunocompromised. When more becomes understood about those of us who develop immune dysfunction or do become immunocompromised after being infected this information might provide some help in answering why.

This avenue of research could also ultimately provide some answers with regard to immune evasion by Borrelia and pathogen persistence.

One additional thing I would have liked to have seen would have been for the researchers to have characterized the OspC types and ribosomal spacer types for those patients whose erythema migrans lesions were cultured, and studied any differences between them. I also would have liked to see the researchers include the patient samples from the following (prior) two studies and especially those patient samples where OspC types and RSTs previously did not test positive with strain B31 two-tier serology. Something to look forward to in the future, hopefully.

Wormser GP, Liveris D, et al. Effect of Borrelia burgdorferi Genotype on the Sensitivity of C6 and 2-Tier Testing in North American Patients with Culture-Confirmed Lyme Disease. Clin Infect Dis. 2008; 47 (7): 910–914.
Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773679/

Ivanova L, Christova I, Neves V, et al. Comprehensive Seroprofiling of Sixteen B. burgdorferi OspC: Implications for Lyme Disease Diagnostics Design. Clinical immunology. 2009;132(3):393-400.
Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752154/

lou
Posts: 215
Joined: Fri 2 Nov 2007 0:41

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by lou » Tue 5 Jan 2016 20:07

I see nothing unreasonable about people assuming that apples will be found on apple trees, instead of orange trees. Snapping at those people is not useful and should not be allowed on the forum.

Having these researchers produce anything that helped us or in fact was truthful about chronic lyme would be like finding oranges on apple trees.

Lorima
Posts: 914
Joined: Mon 29 Oct 2007 20:47

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by Lorima » Fri 8 Jan 2016 1:22

I rather enjoy it when Henry decompensates. It's so much more honest.

I like your apples and oranges analogy, Lou. Sadly, that does seems to be the big problem we are facing. Real LD clinical science can't progress, while these people are dominating the field, and worse, training their successors.
"I have to understand the world, you see."
Richard Feynman

User avatar
LHCTom
Posts: 341
Joined: Mon 22 Oct 2012 4:18

Re: Evolution of Human B Cell Responses to Bb VlsE Protein from Early to Late Stages of Lyme Disease

Post by LHCTom » Wed 13 Jan 2016 20:35

This is an important study for a number of reasons. The broadest is that the core IDSA oriented researchers are beginning to move into research that is investigating aspects of persistent symptoms and important aspects are being uncovered. They also seem to realize now that the immune response is very complex and varies temporally as the infection evolves which begs the question of the CDC 2T being based on a single strain with its dominant epitopes and whether distant strains or even less common species in say California or non-Northeast might have lesser ELISA or Western Blot reactivity and the resulting false negative possibility.

The study also shows that for all 3 Vlse epitopes, IgG1 and IgG3 are the dominant IgG classes. I wonder if this is true of all Lyme Ag epitopes? For someone with low IgG1 and IgG3 subclasses, how will that effect testing? Both the ELISA and Western Blot for IgG assume there is an adequate IgG response to achieve the positive threshold and would a subclass deficiency in IgG1/3 impact the chosen ELISA and Western Blot cutoffs and to what extent? Too bad they did not do IgG subclass testing on the cohort to investigate this?

It also shows that the C6 ELISA is a good test with a flat response as the infection evolves except very early Lyme but the reported ELISA value could be affected by a IgG subclass 1/3 deficiency. That begs the question as to whether a decline in C6 is indictive of a successful spirochete erradication as the last step in the evolution. Maybe test these patients after symptoms resolve? Obviously the strain or species causing the infection must have the correct IR6 epitope, something that has not been well studied. On one hand, the IR6 region appears on other species making it less strain/species sensitive.

When I read the CDC study that was used to justify not changing to the C6 over the 2T, the argument was less than a 1% lower specificity. But the list of conditions they investigated as possibly causing a false positive DID NOT INCLUDE borreliosis by other species such as B. bissettii, B. miyamotoi etc.. that are now appearing. Just a few cases of non-Bb that were actually borreliosis true positives would have changed the specifity as being better than the 2T. Unless you don't count non-Bb species ( or even distant strains) as Lyme using sematics to define medicine and bias decisions. Why wouldn't the test be called a borreliosis test rather than a burgdorferi test given they are closely related and have similar sysmptoms and are treated identically. Always baffled me. Why would you just leave the non-burgdorferi positives swinging in the wind even if it was 2%. 2% of 300,000 is 6000 people left swinging in the proverbial wind left to later stages of Lyme.

Given some new species are now appearing in the US like B. bissettii and B. miyamotoi etc.. (albeit halfway between Bb and Relapsing Fever). It may still have the IR6 conserved. How does this apply to the other closer species. Does miyamotoi have the same IR6 epitope? And therefore the C6 would be a good interim Bm test. But some strains are known to not have the correct IR6 epitope which would cause false negatives. The study just begs to investigate this across more than the B31 strain even though its representaive, its not universal.

This also begs the question as to whether the dominant epitopes on Ags on the current B31 test are truly universal or could variations as seen here lead to 2T test problems due to the single strain assumptions its based on. Is the 2T a Northeast test but decays in validity as strains evolve in distant places like the West Coast or South?

So my impression is the mainstream researchers are beginning to test hypothesis that accept or consider the persistent infection concept. In this one study, some very important evidence emerged. Hope this drives some research into implications or obvious follow up hypothesis with regards to testing over infection evolution, possible issues with a single strain mainstay test that is missing some percentage of infections plus how a subclass deficiency might effect testing and a successful immune response.

For example: If someone has both a subclass deficiency in IgG1 and IgG3 and a TH2 dominance lowering the innate and cellular response mechanisms and increased adaptive response, could that contribute to why Lyme ( and other viral or bacterial infections) could become chronic. So as an example: Say someone has a IgG1/3 subclass deficiency and a TH2 dominated response due to significant allergies or parasitic infections driving up Il-4 and IgE, the TH1 innate and cellular response is blunted with all three fighting against the well known Immune System cleanup after antibiotic treatment. In this case, the push toward an IgE shifted B cells would also blunt the number of B and T cells available for fighting the bacterial infections. The subclass deficiency would contribute to less effective spirochete ( or bacterial and viral in general) killing off. If both the innate/cellular immune system is blunted and infectious Ab production lowered, that may be an aquired form of immune suppresion that inhibits the killing off of the last viral or bacterial cell enabling persistence. Throw in a few spirochete persisters and we are off to the races - over and over and over.... Is correcting the Th1/Th2 balance part of the problem? Plus correcting the IgG1/3 deficiency? Just a crazy thought.

Good study!

I
The greater the ignorance, the greater the dogmatism.

Attributed to William Osler, 1902

Post Reply