Maintaining IgM Antibodies for Years, Poor Prognosis in LD

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
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Spanky
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Spanky » Mon 30 Apr 2012 17:08

"Claudia":
28. Craft JE, Fischer DK, Shimamoto GT, Steere AC. Antigens of Borrelia burgdorferi recognized during Lyme disease: appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest 1986; 78: 934-939.
You're citing Steere's work from 1986?

Gee, do you think that any perceptions may have changed since then?

Like, for instance, attitudes toward the following:
"...specific IgM to B. burgdorferi is sometimes the only antibody detected in persistent disease".
So, you have managed to find a Japanese abstract from 1997 and some out-dated material from Steere in 1986 in support of your theory...

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Tue 4 Sep 2012 22:05

Henry, you wrote something here http://www.lymeneteurope.org/forum/view ... 3&start=50 that I am very interested in, as it pertains to my son's health.
Henry wrote:
Look at the date-- 1991. Things have improved since then, especially with regard to Western blots. Current data from the CDC indicates that the 45 kDa, 58 kDa, 66 kDa and 93 kDa are characteristic of late Lyme disease. So, some or all of these bands should be present if [one] truly has a long-standing active infection. Although Tosho did not mention these bands specifically, it doesn't make sense that they are not present.
Earlier upstream on this thread I wrote:

Claudia wrote:Thanks, Camp Other. I have wanted to get my hands on that very expensive textbook since Rita/rlstanley posted about it a while back. Here's what struck me about the passage you quoted:
Found on page 504 of the 2010 book, Borrelia: Molecular Biology, Host Interaction and Pathogenesis:

"The general picture to have emerged over the years is that IgG and IgM antibodies to the spirochaete develop slowly and are directed against an increasingly diverse array of proteins as infection progresses (Craft et al, 1986; Dressler et al, 1993; Nowalk et al 2006).
My son was seronegative until beginning antibiotic treatment in late 2005. In early 2007, IgM band 34 (OspB) and IgM band 39 (major protein of Bb flagellin; specific for Bb) first appeared on his Western blots. Then in 2008 more new IgM bands appeared. Doesn't this suggest, that despite antibiotic treatment (exceeding the IDSA guidelines), that his infection was persistent, active and progressing during this time period as these antibodies slowly developed and were directed against "an increasingly diverse array" of Bb proteins?:
Found on page 504 of the 2010 book, Borrelia: Molecular Biology, Host Interaction and Pathogenesis:

This temporal pattern is consistent with the notion that the bacterium draws upon an expanding repertoire of differentially expressed proteins once within its vertebrate host, including phased expression of paralogous surface-exposed lipoproteins.
I can understand that maintaining IgM antibodies for years may not have clinical significance, but developing NEW IgM bands over the course of years -- while still having disease symptoms?
and
Claudia wrote:
Other than definitely being exposed to Bb, it seems that there should be some basic pattern or logic to how, when, and why these are expressed.
and that these are my son's bands/WB history while on antibiotics during most of this time
Claudia wrote:

2009: IgM 41, 34, 39, 66, 93
IgG 41

2008: IgM 41, 34, 39, 66, 93
IgG 41

2007: IgM 41, 34, 39, 58, 93
IgG Negative

2006: IgM 41
IgG Negative

2005: IgM 41 Equivocal
IgG Negative
As has been stated here on LNE, and in the medical literature, antibiotics are known to abort an IgG response. So from the recent CDC information that you have posted on WB bands that should be present in a "long-standing ACTIVE infection", it looks like my son meets that criteria, with the development of 3 of those 4 bands, despite/during antibiotic treatment(s), and that his infection was indeed persistent, active and progressing during this time.

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Thu 20 Sep 2012 15:00

Camp Other wrote:
Claudia,

I've been working on more research on this topic and came across the same resources you have. I'm trying to tie in any research I can find in general about antibody response - including an undulatory immune response - to make sense of the variations if there is sense to be made.
CO: I came across this interesting comment about fluctuating and increasing IgM response to Bb proteins in later stages of infection in mice, not sure if it's on your radar or how it may or may not be pertinent to our discussion here, but the authors of this study found it noteworthy:
Infect Immun. 2003 December; 71(12): 6943–6952.
doi: 10.1128/IAI.71.12.6943-6952.2003
PMCID: PMC308935

Temporal Analysis of Borrelia burgdorferi Erp Protein Expression throughout the Mammal-Tick Infectious Cycle
Jennifer C. Miller,* Kate von Lackum, Kelly Babb, Jason D. McAlister, and Brian Stevenson

[snip]

Intriguingly, IgM antibodies directed against ErpA/I/N were stronger and of longer duration than those produced in response to ErpL or ErpQ, peaking at 3.5 months of infection, declining, and periodically increasing in the later stages of infection (Fig. ​(Fig.3A).3A). IgG titers produced in response to all examined Erp proteins also varied over time, and often increased, suggestive of continued stimulation of the immune systems throughout duration of the infection (Fig. ​(Fig.3C).3C). These fluctuations are even more dramatic when ELISA results for each mouse were considered individually (Fig. 3B and D and data not shown).

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC308935/

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Spanky » Thu 20 Sep 2012 16:01

"Claudia":

Well, how do you, then, explain, reconcile, this?
Infect Immun. 2003 December; 71(12): 6943–6952.
doi: 10.1128/IAI.71.12.6943-6952.2003
PMCID: PMC308935

Temporal Analysis of Borrelia burgdorferi Erp Protein Expression throughout the Mammal-Tick Infectious Cycle
Jennifer C. Miller,* Kate von Lackum, Kelly Babb, Jason D. McAlister, and Brian Stevenson

(snip)

IgG titers produced in response to all examined Erp proteins also varied over time, and often increased, suggestive of continued stimulation of the immune systems throughout duration of the infection.
This is what I just don't get about what you are saying about your son's case. WHY no IgG?

If there is a continuing IgM response...then why no IgG?

And from the preceding post, as to IgG:
Claudia: As has been stated here on LNE, and in the medical literature, antibiotics are known to abort an IgG response.
That, as I understand it, really deals with early treatment and its effect on IgG antibody response.

And it may be something of a misnomer to describe it as "interference". The antibody response is blunted by the killing of the organism, and therefore, there is decreased antigen. As I understand it.

If there were, in fact, continuing infection, wouldn't you expect a continuing, measureable IgG response, also?

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Lorima » Fri 21 Sep 2012 20:26

Claudia,
I'm interested in this topic. I, too, have seen sequential Western blots from patients with evolving IgM responses; bands getting strong and then getting weak, new bands appearing, etc. I too think it's likely that this indicates persistent infection. Someone would really have to dislike the idea, to concoct an alternative explanation.

These patients have very weak IgG responses, so is something inhibiting class-switching? This question is quite far removed from my area of expertise, so I communicated with Nicole Baumgarth (see below) about it, and she said she didn't know why, and that was why she was interested in Bb infection. She didn't speculate, and I didn't press her. I'm impressed that she has the guts to do and publish research on such a touchy subject, considering that Steere, Inc. says that late IgM's aren't relevant to diagnosis, and have made IgM blots in late disease a no-no. (How does that make any sense? and why doesn't the medical community rise up as a whole and point out that it makes no sense? More fodder for my study of medical culture and the "hidden curriculum".)
J Immunol. 2012 Jun 1;188(11):5612-22. Epub 2012 Apr 30.
Delays and diversions mark the development of B cell responses to Borrelia burgdorferi infection.
Hastey CJ, Elsner RA, Barthold SW, Baumgarth N.
Source
Graduate Group in Microbiology, University of California, Davis, Davis, CA 95616, USA.
Abstract
B cell responses modulate disease during infection with Borrelia burgdorferi, the causative agent of Lyme disease, but are unable to clear the infection. Previous studies have demonstrated that B. burgdorferi infection induces predominantly T-independent B cell responses, potentially explaining some of these findings. However, others have shown effects of T cells on the isotype profile and the magnitude of the B. burgdorferi-specific Abs. This study aimed to further investigate the humoral response to B. burgdorferi and its degree of T cell dependence, with the ultimate goal of elucidating the mechanisms underlying the failure of effective immunity to this emerging infectious disease agent. Our study identifies distinct stages in the B cell response using a mouse model, all marked by the generation of unusually strong and persistent T-dependent and T-independent IgM Abs. The initial phase is dominated by a strong T-independent accumulation of B cells in lymph nodes and the induction of specific Abs in the absence of germinal centers. A second phase begins around week 2.5 to 3, in which relatively short-lived germinal centers develop in lymph nodes, despite a lymph node architecture that lacks clearly demarcated T and B cell zones. This response failed, however, to generate appreciable numbers of long-lived bone marrow plasma cells. Finally, there is a slow accumulation of long-lived Ab-secreting plasma cells in bone marrow, reflected by a strong but ultimately ineffective serum Ab response. Overall, the study indicates that B. burgdorferi might evade B cell immunity by interfering with its response kinetics and quality.

PMID: 22547698 [PubMed - indexed for MEDLINE] PMCID: PMC3358496 [Available on 2013/6/1]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102705/
PLoS Pathog. 2011 May;7(5):e1002066. Epub 2011 May 26.
Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation.
Tunev SS, Hastey CJ, Hodzic E, Feng S, Barthold SW, Baumgarth N.
Source
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Abstract
Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochetes accumulate in the cortical areas of lymph nodes following infection of mice with either host-adapted, or tick-borne B. burgdorferi and that they, but not inactivated spirochetes, drive the lymphadenopathy. The ensuing lymph node response is characterized by strong, rapid extrafollicular B cell proliferation and differentiation to plasma cells, as assessed by immunohistochemistry, flow cytometry and ELISPOT analysis, while germinal center reactions were not consistently observed. The extrafollicular nature of this B cell response and its strongly IgM-skewed isotype profile bear the hallmarks of a T-independent response. The induced B cell response does appear, however, to be largely antigen-specific. Use of a cocktail of recombinant, in vivo-expressed B. burgdorferi-antigens revealed the robust induction of borrelia-specific antibody-secreting cells by ELISPOT. Furthermore, nearly a quarter of hybridomas generated from regional lymph nodes during acute infection showed reactivity against a small number of recombinant Borrelia-antigens. Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88. Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.

PMID: 21637808 [PubMed - indexed for MEDLINE] PMCID: PMC3102705 Free PMC Article
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Spanky
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Spanky » Fri 21 Sep 2012 21:40

"Lorima":
I'm interested in this topic. I, too, have seen sequential Western blots from patients with evolving IgM responses; bands getting strong and then getting weak, new bands appearing, etc. I too think it's likely that this indicates persistent infection. Someone would really have to dislike the idea, to concoct an alternative explanation.
Not if I understand (part of) this... (Henry's reply when this issue was discussed here previously):

by Henry » Sat 2 Jun 2012 18:35

CO: IgM antibody is much more reactive -- about 1,000 times more reactive-- than IgG antibody. This is because the former is pentavalent whereas the latter is divalent. Since, according to the mathematical equation used to calculate binding constants, the relationship between binding strength and valency is exponential, a 3-fold difference in valency results in approximately a 1,000-fold difference in binding strength.

During the course of infection and with the development of an antibody response, antibodies are produced against very minor -- as well as major-- antigenic determinants. Antibodies made against some of the minor components may cross react with irrelevant antigens that are shared by extraneous microoorganisms in the natural environment. Since IgM antibodies against some of these minor determinants will bind to some of these irrelevant cross reactive determinants, the likelihood of getting a false positive test is increased if one is using a diagnostic test based on the detection of IgM antibody late during an immune response. This is true for antibody response to any microorganism and is not unique to antibody responses against Borrelia burgdorferi. The issue of cross reactive antibodies is not a problem -- or not so much of a problem -- using a diagnostic test based on the detection of IgG antibody. At or after 30 days post infection, most of the antibody being produced is of the IgG class anyway. CDC criteria require the detection of 5 or 10 possible bands for a positive IgG Western blot to minimize false positive tests. Hope this helps to clarify.
And:
Henry: Most of what I said about differences between IgM and IgG antibodies with respect to valency and binding characteristic cam be found in any text book on immuochemistry. Since humans are not inbred, there are difference in their immune potential. However, in all cases, the IgM response precedes the IgG response mainly because the receptors or antigen on antibody producing cells are cell-bound IgM and IgG antibodies with the same reactivity and characteristics.
http://www.lymeneteurope.org/forum/view ... f=5&t=3865

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Sat 22 Sep 2012 0:02

Lorima wrote:Claudia,
I'm interested in this topic. I, too, have seen sequential Western blots from patients with evolving IgM responses; bands getting strong and then getting weak, new bands appearing, etc. I too think it's likely that this indicates persistent infection. Someone would really have to dislike the idea, to concoct an alternative explanation.

These patients have very weak IgG responses, so is something inhibiting class-switching? This question is quite far removed from my area of expertise, so I communicated with Nicole Baumgarth (see below) about it, and she said she didn't know why, and that was why she was interested in Bb infection. She didn't speculate, and I didn't press her. I'm impressed that she has the guts to do and publish research on such a touchy subject, considering that Steere, Inc. says that late IgM's aren't relevant to diagnosis, and have made IgM blots in late disease a no-no. (How does that make any sense? and why doesn't the medical community rise up as a whole and point out that it makes no sense? More fodder for my study of medical culture and the "hidden curriculum".)
Thanks, Lorima, very interesting. And I don't disagree with your comments.

Last year Henry posted a few comments about IgM/IgG which prompted me to call Stony Brook to ask a few direct questions of the experts myself. Like Nicole Baumgarth, the woman I spoke with at the lab didn't know why exactly there were humoral responses such as these that don't convert to IgG or are weak except for the known relation to antibiotic use, but said that "like everything else with Lyme disease it [Western blot results/interpretation] is controversial" when beginning her response. In case you are interested here are the posts and more of what was said/written:
http://www.lymeneteurope.org/forum/view ... 7&start=50
Claudia wrote:
Henry wrote:

It's like this. If one has Lyme disease and has had it for a long period of time -- as is the case for many people who claim that they have chronic Lyme disease-- there will be IgG antibody in the serum that is detectable by both ELISA and IgG Western blot by CDC criteria-- unless ones immune defense system is completely suppressed. To believe otherwise would be like suspending the law of gravitation. There is no such thing as seronegative Lyme disease.
Henry, you posted a similar statement a while back. Back when you first posted it, it was of interest to me. I called Stony Brook University Medical Center Lyme Disease Laboratory to ask about this and read them your post/comment. In fact, the lab sees confirmed cases of Lyme disease that are IgM only and that never convert to IgG, as is my son's case. The person that I spoke with from the lab said that she couldn't give me exact statistics on the percentage, but that it happens, that everyone's humoral response is different, and that antibiotics are known to abort an IgG response.
Henry wrote:Claudia: I see no conflict. The first type of antibody that is produced is IgM antibody, as is the case for practically every bacterial infection. About 3-4 weeks after the start of infection, IgG antibody begins to be produced and increases with time. If antibiotic treatment is started early, the infection -- which acts as a stimulus to antibody formation-- is arrested so that little --if any-- IgG antibody is produced.

It should be noted that IgG antibody --once produced-- can be detected for a long period of time after the infection has been cured. It's presence should not be interpreted as active infection, but as prior exposure. It is not known exactly why this occurs. It may be due to the presence of dead bacterial cells that "stick around" long enough to stimulate antibody production.
Note what Henry said specifically about IgG: "once produced -- can be detected for a long period of time after the infection has been cured. It's presence should not be interpreted as active infection, but as prior exposure," and what is written in this medical textbook on Infectious Disease (the series editor is from the National Institute of Allergy and Infectious Disease) quoted on page 1 of this thread; also what is not said, and what is said, about IgM by both Henry and the book:
Chapter on Borrelia burgdorferi, diagnosis section, page 281:
IgM antibody levels rise approximately 2 to 4 weeks after the onset of EM, peak at approximately 6 to 8 weeks, and become nondetectable 4 to 6 months after EM. Persistence of IgM may be an indicator of persistent infection or re-infection. IgG antibody levels rise 6 to 8 weeks after EM, peak at 4 to 6 months after EM, and remain elevated for life [4, 28].
Among many things related to the topics in this thread, another thing that I wonder about and wish I was able to ask the woman in Steere's original studies that I met while hiking, is about her yearly follow-up evaluations and lab work done by the Yale researchers:

Claudia wrote: Fri 29 Aug 2008
(from http://www.lymeneteurope.org/forum/view ... 8&start=10)


Last year I was hiking on some local trails here in Connecticut with my dog and met a woman also out hiking along with her two dogs. As we hiked and began talking, I mentioned that my son and dog both had chronic Lyme infections. She listened to me and later into the conversation she told me she was one of the original Old Lyme patients that the Steere/Yale team studied back in the 1970's and she was coming up on the thirtieth anniversary of it all.

Here's what she told me:

She was six years old at the time that she became infected -- her family spent summer vacations camping at the beach camping grounds in Old Lyme. That summer she had a massive circular rash and became unable to move from terrible back, hip and knee pain. At its worse, her father had to carry her, she couldn't move. She had to start first grade on crutches. She was placed in the antibiotic placebo group in the study. She went on to fully recover within several weeks and has been followed up with yearly by Yale, tested each year with blood work. She still tests "highly positive." She has continually refused the antibiotics she has been offered each time based on each year's positive test. Mainly because she feels no need for them because overall she feels fine.

She said that Dr. Steere told her that "you never totally get rid of the infection," even with antibiotics.

What she told me is that she occasionally feels "Lymie" over the years, "you can just tell" she said "when it's the Lyme," this happens when she is really stressed, not sleeping well, and her immune system is further compromised from being sick from a bad flu or virus. She told me that the worse relapse she had was while away at college when she was over-tired from not getting enough sleep, stressed with class work during finals, and caught a bad stomach illness/flu that was making a lot of people ill in her dorm, including her roommate. She left her college campus in Colorado, returned home to Connecticut and saw Dr. Steere, who had left New Haven/Yale and was in Boston. He wanted to put her on IV antibiotics, but she refused it because she wanted to get back to college and didn't want to be hooked up to an IV line at college. She eventually returned to feeling well again.

When I had this interesting chance meeting with her she was 36 years old, had a successful professional career, commuting into NYC for her job, and had even bought her own home as a single woman. She had recently become engaged to be married. Her only fear was passing the infection on to any children they may have, based on the fact that she continues to test positive for an active infection.

She was orginally acutely ill with Lyme disease, never took any antibiotics, and in her case it resolved on it's own with only one major relapse in 30 years and several minor relapses.

Did the children in these two examples of untreated, long-term remission have just Bb and no other complicating TBI's? Is there something different about their immune systems? Their genetics? Will they eventually become chronically ill down the road?
What I'd like to ask her is what test or tests are they using to determine that she is still "highly positive" for an "ACTIVE infection?" She is offered antibiotics each year based on this result, despite being in very good health and symptom free for the vast majority of the time over the decades. According the the above information from Henry, the medical text book, and papers posted on the thread, IgG wouldn't be useful in telling them the infection was active, so what are they using? IgM? Some specific banding on the Western blot? Some other test for research purposes not available to the general public? I'd love to know the details and facts about this.

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by duncan » Sat 22 Sep 2012 14:25

Claudia, I share these very same questions. How do clinicians decide, based on IgG values, if an infection is active or not?

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Spanky » Sat 22 Sep 2012 15:58

"duncan":
Claudia, I share these very same questions. How do clinicians decide, based on IgG values, if an infection is active or not?
They don't, as I understand it.

What was being said, was that in a longstanding infection, there should be a robust IgG response.

I think that this really goes to the issue of "false positives" rather than whether there is active infection or not.

What is curious about what Claudia has said about her son's case, then, is the lack of IgG. If there were, indeed, persistent or relapsing infection, then you would expect to see what the material she, herself, quoted, above, indicates:
IgG titers produced in response to all examined Erp proteins also varied over time, and often increased, suggestive of continued stimulation of the immune systems throughout duration of the infection.
And there are problems with the diagnostic usefulness of late-stage IgM reactions as Henry explained, previously:
Since IgM antibodies against some of these minor determinants will bind to some of these irrelevant cross reactive determinants, the likelihood of getting a false positive test is increased if one is using a diagnostic test based on the detection of IgM antibody late during an immune response.
My understanding, also, is that IgG repsonses are negatively affected by antibiotic administration in EARLY stage ONLY...before the IgG response has had time to adequately form.

So, it wouldn't appear to be a factor, if there were an ongoing, longstanding infection.

As I understand it.

(Anyone else on this)?

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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by duncan » Sat 22 Sep 2012 17:21

I think the reality is clinicians DO make judgements based in the CDC's two-tiered approach, which embrace high IgG values as a diagnostic tool. Sorry, not trying to bench Claudia's concerns with her son, but if the support for IgG values as a metric are confusing, then that may also be pertinent to the virtually wholesale exclusion of IgM numbers as useful criteria after, say, three months.

If I get Lyme, I might ALWAYS have IgG positive results according to the IDSA, I believe, or at least high results for many years. But if I have untreated or undertreated lyme that has devolved into late-stage disseminated, a way to reinforce that evaluation is through high IgG values. How does a clinician distinguish one case from another? On an anecdotal level, I have been told by two doctors that my IgG values demonstrate I have Lyme, but my symptoms most likely have nothing to do with that - even though my symptoms were/are classic Lyme symptoms.

This is an important debate because I think the two-tier diagnostic criteria, endorsed by the IDSA, are for many the defacto go-to benchmarks regardless of whether they were meant to be or not.

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