B. burgdorferi infection and immune responses

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Fri 24 Oct 2014 2:54

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
This is in mice:
We demonstrate that infection with B. burgdorferi results in the loss of the lymph node's normal tissue architecture within the first week after infection, which is then followed a few days later by the IFNR signaling-dependent accumulation of unusually large numbers of naive B cells at that site.
...
This may explain the rapid loss of germinal; centers in lymph nodes of B. burgdorferi-infected mice (7) and/or the lack of adequate long-term immune protection observed following infection (9, 33).
The large number of naive B cells was not from B cell proliferation changes and they normally responded to CXCL13 signaling and there wasn't an overproduction of CXCL13. The buildup of B cells mediated by type 1 IFN signaling and is independent of MyD88 & TRIF.
Blocking type 1 IFN reduced Lyme arthritis in mouse studies.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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

Re: B. burgdorferi infection and immune responses

Post by duncan » Fri 24 Oct 2014 3:17

I once asked Marques about CXCL13, and she seemed to shrug off its significance. If I recall correctly, I think in that conversation she mentioned the opinion held by some that it is really only useful in acute cases, but I sensed she was not very keen on even that constrained utility.

There IS an immune response for Bb. It hasn't been pieced together. Not enough eyes studying the right things for long enough time.

So much of that work remains to be done. For instance, acute immune markers vs those in later stage.

And then you've got to toss into the stew epigenetics and environment. Then that's complicated by species characteristics.

Buried underneath that Bb grit are commonalities across species and strains. This is where they need to be concentrating at least some of their resources. If there are any immune markers that are reliable and cross elastic, that's what we need to be looking for.

The NIH is supposed to be mining that kind of data, only I'm not too sure they are.

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Thu 30 Oct 2014 2:09

Ok, so I went through and tried to summarize the one article by some of the same authors. Dlf, you were right, it said B.b highly favors IgM production and the IgGs never really get produced well. This adds to the reasons why the test miss half the cases. If you miss the small window where you do get some IgG response, you won't test positive. :bonk:

Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection
Christine J. Hastey, Rebecca A. Elsner, Stephen W. Barthold and Nicole Baumgarth
http://www.jimmunol.org/content/188/11/5612.long
Published online before printApril 30, 2012, doi: 10.4049/​jimmunol.1103735
The Journal of Immunology June 1, 2012 vol. 188 no. 11 5612-5622

Conclusions
-“Alters normal B cell response development in the lymph nodes in multiple ways”, suggesting “that B. burgdorferi-infected mice might be unable to develop strong T-dependent germinal centers and thereby might lack long-lived plasma cells and memory responses.”
-Dominated by “Unusually strong and persistent T-dependent and T-independent IgM Abs”, “both induced early in the lymph nodes and also found later in the bone marrow”, a good fraction of which is T-dependant. Most likely a result of a non-class-switched B-2 cell response and not likely T-independent B-1 cells (blood) or B-2 cells (bone marrow).
-“Because of its large size, IgM might not be able to reach B. burgdorferi in the tissues in the absence of inflammation and the resulting increase in vascular leakage” and therefore is harder to clear the infection from tissues.
-“The data thereby suggest that B. burgdorferi might interfere with the processes underlying efficient class-switch recombination of B cells.”
-“They failed to mount strong T-dependent B cell responses and formed only transient germinal centers.“
-“The destruction of the lymph node architecture”
-“B cells rapidly and strongly accumulate in regional lymph nodes in response to the presence of live B. burgdorferi, but independent of either MyD88 signaling (5) or T cell help”.
-“Given the fact that passive transfer of serum Abs from mice infected for 2 mo can protect from challenge with B. burgdorferi (15), the same serum is unable to clear an infected host” and serum from long-term infected mice loses this capacity“. “Even relatively minor delays in induction of protective Ab responses might play a role in allowing B. burgdorferi to evade immunity by rapidly and widely disseminating in an infected host (35).”
-“Ongoing dynamic interaction between the host adaptive immune system and the spirochetes in long-term B. burgdorferi-infected hosts that ultimately benefits the spirochete, enabling establishment of persistent infections.”

Immune Response Stages

1) “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.”
3) “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. “
3) “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.”

B. burgdorferi & B cells
-“B cell responses modulate” & “control of disease progression and resolution”... “but are unable to clear the infection.”
-“In wild-type mice, as B cell deficiency resulted in more severe disease”
-“Support for a role of B. burgdorferi-specific Abs in B cell-mediated disease resolution comes from studies showing that passive transfer of serum from infected, but not naive, immune-competent mice results in arthritis and carditis resolution in SCID mice “
-“Given the fact that passive transfer of serum Abs from mice infected for 2 mo can protect from challenge with B. burgdorferi (15), the same serum is unable to clear an infected host” and serum from long-term infected mice loses this capacity“.
-“predominantly T-independent B cell responses”
-“increased lymph node cellularity shortly postinfection was attributable in large part to the accumulation of CD19+ B cells”
-“the ratio of CD19+ B cells to CD4+ T cells increased in the lymph nodes, with increasing numbers of B cells per CD4 T cell at early time points, peaking at day 10. That ratio stayed elevated through day 60.”
-Total B cell counts were normal, increase in frequency was localized and T cell independent.

B. burgdorferi & T cells
-Others have shown T cells & CD40L modulate the isotype profile and “amplify and regulate the quality of the B. burgdorferi-specific Ab response.”
-“CD4 T cells engage with B cells in a CD40L- and SAP-dependent but ICOS-independent manner to enhance early B. burgdorferi-specific Ab responses in lymph nodes”
-“T cell deficiency had little impact on arthritis resolution and the development of other inflammatory disease manifestations.”
-Adding T cells made inflammation worse.
-“Overall T cell numbers do not significantly increase in lymph nodes”
-“The unusually high B/T ratio might suggest that CD4 T cells were not activated upon infection”, however “transient and short-lived CD4 T cell activation and differentiation to TFH nonetheless occurred.”
-“The kinetics of germinal center B cells closely followed that of the TFH cell population (Fig. 2A), appearing somewhat slow in induction and very rapid in decline”, “between days 21 and 28.”
-“Depletion of CD4 T cells caused a significant reduction in germinal center B cells, as did the absence of CD40L−/− and SAP−/− mice”
Last edited by ChronicLyme19 on Thu 30 Oct 2014 12:44, edited 1 time in total.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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

Re: B. burgdorferi infection and immune responses

Post by dlf » Thu 30 Oct 2014 6:12

BY JOVE, I THINK YOU GOT IT! :D

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

Re: B. burgdorferi infection and immune responses

Post by duncan » Thu 30 Oct 2014 11:53

One difficulty that plagues progress in both Lyme and ME/CFS quarters, is the tendency for seemingly meaningful independent studies to sprout from the research landscape, only to languish from a lack of interest from vested agencies.

In short, the NIH (or similar govt agencies in other countries) needs to replicate and publish on the same phenomenon, with mice, and draw the same inferences.

Alternatively, I suppose a collective of universities with lineage and brand and clout could perform the same exercise of replication to offer counterpoint to the usual clique of academics whose either shrill cry of disapproval, or complete silence, usually doom the study to virtual irrelevance. This group would have to have cohesion, and it would have to boast the same sort of lineage. It would also have to have the willingness and ability to court and win over the press.

And THEN, these agencies or fleet of universities would have to try to reproduce and observe and document, to as great a degree as possible, the same results with human subjects.

All that takes money and the willingness - and requisite influence - to make it happen.

If individuals like Barthold held sway over the real powers in Lyme research, or could cause a strong and sustained reaction from the press and captivate that institution, we would be onto something. But if history has taught us anything, it's we don't enjoy kind of relation. That means our studies typically are relegated to the dusty shelves of hypotheses and other sad versions of what-might-be-meaningful.

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Thu 30 Oct 2014 12:55

The first three really make me want to get my hands on the latest article that dlf posted first. You can find the first three studies online for free, latest one not I haven't found a free copy yet. They seem to keep building on the same thread of how lyme modulates/evades the immune system.

I do agree with you Duncan, the next steps are for another lab to pick up on this thread of logic and verify some of their claims, and then do the same in people. But this is so promising. :woohoo:

They are simultaneously proving how lyme wacks out your immune system AND showing how it could evade the immune system and persist. Both very needed things.

The IDSA keeps claiming that post treatment lyme symptoms are permanent damage that lyme caused to make your immune system go haywire. I think they are right about the inflammation and it being an immune problem, but I disagree that it's necessarily only from a resolved infection.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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

Re: B. burgdorferi infection and immune responses

Post by lou » Mon 3 Nov 2014 23:42

Yes, this looks like really important work. Amazing/disgusting that it has taken so long to get these insights into publication and that the NIH is not jumping all over this. Hope the lyme patient grant funding groups have this high on their lists to pursue.

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Thu 6 Nov 2014 20:13

Oh, thought of one more implication of this work... This could explain why lyme patients return to being seropositive when the treatment is successful. I know my doctors uses the seropositivity as a sign of disease clearance. If Lyme prevents the class switching and formation of IgGs, then when the IgG bands reappear after treatment going well it would make perfect sense. I know the other IDSA doc I had gone to before the LLMD, kept testing regularly in hopes the test would turn positive again and she would then be able to get insurance to cover more aggressive treatment. This explains why it would happen.

Recapping, this could explain:
1) Why really sick or chronic patients are IgG seronegative, and why the tests have such bad sensitivity
2) How Lyme could cause IgG deficiencies by preventing class switching
3) Why with successful treatment, patients turn seropositive
4) How lyme modulates the immune system to drive a strong short lived IgM response and extreme inflammation that we all know and love
Half of what you are taught is incorrect, but which half? What if there's another half missing?

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Thu 6 Nov 2014 20:30

Now my next question is this common to all borrelia species or just B.b?
Half of what you are taught is incorrect, but which half? What if there's another half missing?

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: B. burgdorferi infection and immune responses

Post by ChronicLyme19 » Tue 11 Nov 2014 0:37

So I did get to talk to the LLMD about theses UC Davis papers today. He said he's seen Baumgarth speak in person at a talk and that her work as well as she was brilliant and matches what they see in clinical practice. IgM levels are strong, but IgGs are really weak for the majority of Lyme patients. However he did mention there's a random few that have the exact opposite, that IgGs are "like a Christmas tree" and poor IgMs. He said these second set with strong IgG responses usually kick the infection really easily once put on antibiotics, the rest with poor IgG levels tend to have a rough time kicking it. He said they think the IgG deficiencies are one part genetic susceptibility or existing condition and one part the suppression that comes from the Lyme and coinfections. I'm still hoping that the immune deficiencies are 100% caused by the Lyme and coinfections because then at least there'd be the possibility for reversal. That might be overly optimistic tho.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

Post Reply