B. burgdorferi infection and immune responses

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
dlf
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B. burgdorferi infection and immune responses

Post by dlf » Thu 16 Oct 2014 2:24

http://iai.asm.org/content/early/2014/1 ... 4.abstract
CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection
Rebecca A. Elsner1,2, Christine J. Hastey1,2 and Nicole Baumgarth1,2,3⇑
- Author Affiliations

Center for Comparative Medicine1
Microbiology Graduate Group2
University of California, Davis, and Dept. Pathology, Microbiology and Immunology3, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
ABSTRACT

CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells and memory B cells. Previous studies showed that immune response to Borrelia burgdorferi (Bb) appear to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection and non-switched IgM antibodies are continuously produced during this chronic disease. This data prompted us to evaluate the induction and functionality of Bb infection-induced CD4 TFH cells. We report that CD4 T cells were effectively primed and TFH cells induced after Bb infection. These CD4 T cells contributed to the control of Bb-burden and supported the induction of Bb-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependent Bb protein “arthritis-related protein” (Arp) were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells, or a strong induction of regulatory T cells. In vitro T-B co-cultures demonstrated that T cells isolated from Bb-infected but not Bb-immunized mice supported the rapid differentiation of B cells to antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived, instead of long-lived T-dependent antibody responses in vivo. The data further suggest that Bb-infection drives humoral response away from protective, high-affinity and long-lived antibody responses and towards rapid induction of strongly induced, short-lived antibodies, of limited efficacy.
I located this abstract after finding the following post on the relative risk blog. His post is below.

http://rel-risk.blogspot.de/2014_10_01_archive.html
The Fault in Bb Immunity
Notes from:
Elsner RA, Hastey CJ, Baumgarth N. CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection. Infect Immun. 2014 Oct 13.


Tick-borne infections with the Lyme disease agent, Borrelia burgdorferi (Bb), induce chronic non-resolving infections that result in tissue inflammation, most frequently “Lyme” arthritis and myocarditis and in some humans and non-human primates, but not mice, also inflammation of the central nervous system. The presence of IFN-γ producing CD4 T cells has been associated mostly with increased tissue pathology in humans and mice, and treatment of mice with anti-IL-12 mAb reduced arthritis-development in C3H mice. Thus, much focus on CD4 T cell responses to Bb has been on their pathological and pro-inflammatory role.

Early studies provided both evidence for and against a positive role of T cells on the course of B. burgdorferi-induced disease, leading some to conclude that CD4 T cells are largely dispensable for the control of Bb infection. Yet, while the anti-IL-12 treatment reduced tissue-pathology, it also increased Bb tissue-burden and the lack of IFN-γ was shown to increase joint swelling.

Others reported that the adoptive transfer of IFN-γ-secreting CD4+ T cells into Bb-infected T-cell-deficient mice promoted carditis resolution. Thus, together these data suggest that CD4 T cells can play an immune enhancing role against Bb by activating cellular immune response components, such as macrophages, and thereby reducing tissue-spirochete burden, albeit at the cost of causing tissue damage.

Another important function of CD4 T cells is their ability to enhance antibody-mediated immunity by driving affinity maturation and the development of long-lived plasma cells and memory B cells. Strong evidence links infection-induced, antibody-mediated immunity to the control of Bb tissue-burden and to disease resolution, however, not to the clearance of Bb-infection.

However, it appears unlikely that protective B cell response to Bb, a highly complex pathogen expressing many immunogenic surface antigens, is confined to T independent antibody responses alone.

Studies with multiple pathogens have demonstrated a specific role for CD4 T follicular helper cells (TFH) in the activation of B cells, including the induction of germinal centers, hallmarks of T-dependent B cell responses and birthplaces of long-term humoral immunity. Our recent studies suggested that germinal center responses were non-functional after primary Bb-infection, as long-lived antibody-secreting plasma cells and memory B cells (Elsner et al, submitted) were not induced for months after infection. Importantly, a co-administered influenza-vaccine antigen similarly failed to induce long-term immunity when given during Bb-infection (Elsner et al, submitted).

Thus, these studies pointed to specific deficits in the T-dependent B cell responses against Bb.

Here we sought to directly assess the impact of Bb-infection on the induction and functionality of CD4 T cells, particularly the induction of the TFH cells. The study confirms our previous findings on an inability of T-dependent Bb-specific germinal center-derived antibodies to be maintained long-term after Bb-infection. While CD4 T cell responses appeared effectively primed and TFH cells were induced following Bb infection, affecting a reduction of Bb-tissue burden, they differed in functionality from TFH cells induced following immunization with Bb. Infection-induced TFH cells showed a greater in vitro propensity to drive rapid B cell differentiation but not proliferation, mirroring the induction of rapid short-lived, instead of long-lived T-dependent antibody responses.

The failure to induce fully functional germinal center responses after Bb infection explain the clinical observations that humans and animals, particularly those living in endemic areas, can be frequently re-infected. They also explain the challenge in using serological evaluation of patient sera to test for prior exposure to Bb. IgG responses to Bb are known to severely decline following antibiotic treatment and this in fact is sometimes used as a sign of effective treatment. Thus, Bb serodiagnostic may greatly underestimate the number of prior exposures, not necessarily because the available tests are of low quality, but because of the pathophysiology of the Bb infection-induced B cell responses.

CD4 T cells and T-dependent antibody responses are targets for attack or evasion by many highly successful viral, bacterial, and parasitic pathogens. Thus, reducing the effectiveness of CD4 T cells during Bb-infection to support long-term humoral immunity and potentially also other mechanisms of immune protection would not be without precedent. This study may suggest that the functionality of the helper T cells induced during Bb-infection could be responsible in part for the preponderance of strong, low-affinity over long-lived high-affinity antibody responses to Bb infection. Such a shift in the quality of the humoral response would benefit the pathogen.

Ultimately, the question is whether the CD4 T cell function during Bb infection can be manipulated therapeutically to improve resistance from Bb-infection.

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ChronicLyme19
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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Thu 16 Oct 2014 3:58

Dang, so if I understand this correctly, it screws up the T cells triggering the B cell response, thereby screwing up the antibody production, driving it to short term antibody response instead of long term protection? Also it prohibited a flu vaccine from giving long term anti-body protection? That's rather scary if it not only prevent your body from remembering it, but from remembering other diseases as well.

So could this potential be a cause immunoglobulin deficiencies?
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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Re: B. burgdorferi infection and immune responses

Post by X-member » Mon 20 Oct 2014 1:25

I think that Dr Burrascano mention something about hypogammaglobulinemia on one of the links in the thread below:

http://www.lymeneteurope.org/forum/view ... 263#p39865

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ChronicLyme19
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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Mon 20 Oct 2014 3:16

Ah thanks I'll check that out.

I'm a little unclear from this article if it reduces the amount of IgGs to borrelia or reduces their functionality/lifespan. Or both.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Mon 20 Oct 2014 3:47

He mentioned in one of the videos he works with an immunologist. I gotta figure out who he works with and get my immunologist on board.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

dlf
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Re: B. burgdorferi infection and immune responses

Post by dlf » Tue 21 Oct 2014 17:02

ChronicLyme19 wrote:
So could this potential be a cause immunoglobulin deficiencies?
Like you, that is the inference I wondered about in reading the abstract. But, I don't have enough knowledge to be able to figure this out one way or the other. Maybe if you could show your immunologist the abstract and provide the link, he/she could get the full text without having to pay for it and would have enough knowledge to determine whether there is enough research contained in the study to draw any conclusions. It could be that other factors including genetics would also impact on this because not all patients develop overt immunoglobulin deficiencies and some develop what appears to be some aspects, but not as severe as others like you.

One definition of immunoglobulin that I read was:
A protein molecule formed by mature B cells in response to foreign proteins in the body. There are five types of immunoglobulins, but the major one is gamma globulin or immunoglobulin G.
From the original abstract:
However, while affinity maturation of antibodies against a prototypic T-dependent Bb protein “arthritis-related protein” (Arp) were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells, or a strong induction of regulatory T cells. In vitro T-B co-cultures demonstrated that T cells isolated from Bb-infected but not Bb-immunized mice supported the rapid differentiation of B cells to antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived, instead of long-lived T-dependent antibody responses in vivo.


From Relative Risk's excerpts:
Studies with multiple pathogens have demonstrated a specific role for CD4 T follicular helper cells (TFH) in the activation of B cells, including the induction of germinal centers, hallmarks of T-dependent B cell responses and birthplaces of long-term humoral immunity. Our recent studies suggested that germinal center responses were non-functional after primary Bb-infection, as long-lived antibody-secreting plasma cells and memory B cells (Elsner et al, submitted) were not induced for months after infection. Importantly, a co-administered influenza-vaccine antigen similarly failed to induce long-term immunity when given during Bb-infection (Elsner et al, submitted).
To me, this implies that the B cells are not maturing fully enough to produce immunoglobulins, but I don't have sufficient knowledge to say this with any certainty because I don't understand the mechanism that drives that production.

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ChronicLyme19
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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Tue 21 Oct 2014 18:57

dlf wrote:But, I don't have enough knowledge to be able to figure this out one way or the other. Maybe if you could show your immunologist the abstract and provide the link, he/she could get the full text without having to pay for it and would have enough knowledge to determine whether there is enough research contained in the study to draw any conclusions. It could be that other factors including genetics would also impact on this because not all patients develop overt immunoglobulin deficiencies and some develop what appears to be some aspects, but not as severe as others like you.
Oh don't worry I was on this like white on rice. Article printed out and ready to take in to the immunologist. I've only a little cursory knowledge of the immune system as well so I may be barking up the wrong tree, but it certainly seems to me if this can mess up your B cells, then it could potentially cause the Ig deficiencies, as they come from them I think.

I know my Lyme doctor has said it suppresses the immune system, but he didn't have a detailed explanation of how, just that he saw many patients with problems. Dr. Burrascano mentions a few things along those lines in one of the NorVect conference videos and mentions he's worked with an immunologist. I'm trying to track down which immunologist he meant and see if I can get that one to talk to my immunologist.

I developed my immune problem during the year I got really sick, so it could fit that the borrelia caused it, but then again correlation doesn't equal causation. Hence why this type of study gets me excited because it could explain that missing link. It would be nice not to have to inject myself every week with someone elses immune system.
This study may suggest that the functionality of the helper T cells induced during Bb-infection could be responsible in part for the preponderance of strong, low-affinity over long-lived high-affinity antibody responses to Bb infection. Such a shift in the quality of the humoral response would benefit the pathogen.
The other thing I wondered about from this article is that maybe this is why people get such bad inflammatory responses if it's throwing a monkey wrench into your immune system and reving up the wrong part. What does it mean when it's "strong, low affinity" vs "long-lived high affinity"?
Half of what you are taught is incorrect, but which half? What if there's another half missing?

dlf
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Re: B. burgdorferi infection and immune responses

Post by dlf » Wed 22 Oct 2014 0:13

I just found this, which appears to be work that this team did prior to the study for the abstract at the top of the thread. It may provide some more clues, but obviously not the answer, as the team is continuing to study the whole issue of immune reactions. It is good because it lays more ground work and it is a full text article with lots of references that might also provide more clues. It may also be helpful for your immunologist to have to see what the team did before.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993384/
MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease
Christine J. Hastey, Jennine Ochoa, [...], and Nicole Baumgarth

Additional article information

ABSTRACT
Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.


ChronicLyme19 wrote:
The other thing I wondered about from this article is that maybe this is why people get such bad inflammatory responses if it's throwing a monkey wrench into your immune system and reving up the wrong part. What does it mean when it's "strong, low affinity" vs "long-lived high affinity"?
I think the first part is one of the things they tried to look at in this older study, but it didn't look like they were able to determine the mechanism which causes this. They know it happens, the trick is to figure out why and establish how generalized it is. At least they seem to be asking the right questions.

My guess for strong, low affinity is IgM reactivity. They seem to appear in droves (strong) but are less able to bind to the pathogen and therefore unable to actually resolve the infection and kill off the bacteria (low affinity). My guess is that long-lived high affinity would refer to IgG immunoglobulins. But that is only a guess.

Once you talk with your immunologist, maybe you could also try writing the study authors and ask them whether they are planning additional research and whether it's possible that the immune system dysfunction they have established could also extend to patients possibly developing hypogammaglobulinemia as a result.

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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Wed 22 Oct 2014 4:10

Yeh, I go to the Mt. Sinai practice in NYC, which is supposed to have one of the best docs for hypogammaglobulinemia there. I'll take a close read of this tomorrow and print this one out as well to take in. Good thinking looking back through their previous work.

It's one thing to have to take replacement IgGs your whole life if you know the cause and there's nothing you can do about it. But until I know exactly what's causing mine and that it's not from Lyme, I'm not giving up searching for a clue as to why it's broken and the solution to fixing it.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Fri 24 Oct 2014 0:44

Found two more older works by Christine J Hastey, at UC Davis on ResearchGate

Delays and diversions mark the development of B cell responses to Borrelia burgdorferi infection
http://www.jimmunol.org/content/188/11/5612.long

"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."

AND

Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation.
http://www.plospathogens.org/article/in ... at.1002066

"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."
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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