A well-written blog article on Tunev et al's previous research on B cells and plasma cells and their associated (lack of) T cell response in reaction to Bb infection can be found here:
Spirochetes Unwound Blog - Does Borrelia burgdorferi cause an inadequate antibody response by altering B cell activation in the lymph node?
I recommend reading that link first before proceeding to the following abstract.
Christine J. Hastey, Rebecca A. Elsner, Stephen W. Barthold and Nicole Baumgarth. Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection. The Journal of Immunology. April 30, 2012
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.
This work was supported in part by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant AI073911 (to N.B. and S.W.B.) and T32 Training Grant AI060555 (to C.J.H. and R.A.E.).
Full text is available behind pay wall here: http://www.jimmunol.org/content/early/2012/04/30/jimmunol.1103735.full.pdf+html
This is an interesting development in the ongoing process of trying to understand how Borrelia burgdorferi evades the immune system. What we know is what starts out looking like the host mounting a strong immune response to infection ends up looking like a poorly differentiated immune response where plasma cells are inadequate and not engaging in the right immune class switching to fight infection - and where T cells are not fully participating in B cell activation.
This study indicated that not only is the immune response inadequate and ill-directed in its early phase in lymph nodes (which Tunev et al studied) but that in later stages antibody response is inadequate as well.
These studies indicate that the host immune response fails to clear Borrelia burgdorferi and somehow the bacteria is able to evade it. More details on specifically how is likely available in the pay-for-view full text of the paper (until the six month NIH/NIAID publication embargo is over).
Questions remain as to how this research applies to human hosts. Does the same immune response occur in humans that occurs in mice? How does the introduction of antibiotics affect this response? Knowing how both the host immune system and antibiotics work together in combatting this infection would be useful.
One thing I would like to see Tunev, Hastey, Barthold, and others doing this work is to somehow detect which outer surface proteins are upregulated during the time they are invading the lymph nodes and generating a lot of inflammation. In particular, I am wondering if OspA is being expressed in the lymph nodes as much as it has been proposed as being expressed in the CNS in neuroborreliosis.
I leave those reading to consider this paper which was published in Nature, and the following excerpt from it:
OspA-CD40 dyad: ligand-receptor interaction in the translocation of neuroinvasive Borrelia across the blood-brain barrier
"Some authors have suggested downregulation of OspA in early phase of the infection 21, 22, while others have reported expression of OspA in the unique environment of the brain and CSF, but not in the serum 23, 24. Therefore, it was essential to determine whether OspA is expressed in borreliae that are present in the brain vasculature in vivo in infected laboratory animals. PCR analysis of the brain and brain microvasculature of Wistar rats infected with SKT-7.1, revealed not only the presence but also the augmented expression of OspA (Fig. 3). This finding is crucial to support a role of OspA as an adhesive molecule in the transient tethering of Borrelia."After reading a passage like this - plus these studies on B cell activation during Bb infection - I have to ask if OspA plays a role in in vivo infection not only inside the CNS in neuroborreliosis - but also in dissemination to other parts of the body. Would this account for the widespread pain patients experience from inflammation, since OspA is highly immunogenic? What is OspA's degradability?
"OspA is undoubtedly a multifunctional protein that is absolutely necessary in the various stages of borrelial lifecycle and pathogenesis. OspA is abundantly expressed in tick gut as an important adhesive molecule 29. To avoid an inflammatory response, expression of OspA is downregulated in the early stages of Lyme disease. However, OspA expression in vivo can be significantly induced if the spirochetes are kept in an inflammatory environment 46. OspA plays an important role in binding to neuronal cells. These data indicate that OspA must be upregulated during the CNS invasion and acts as an important adhesion factor, which is essential in the pathogenesis of Lyme neuroborreliosis 23. It is also well known that Borrelia can bind plasminogen via OspA on their surface 47. OspA also upregulates membrane urokinase-type plasminogen activator receptor (uPAR) 48. Plasminogen can be activated to plasmin 47, 48 leading to degradation of the extracellular matrix. The mammalian plasminogen-plasmin proteolytic system plays a crucial role in extracellular matrix degradation (intercellular junctions) and cell migration 49. Binding of host-derived proteinases (like plasminogen and MMPs) via OspA supports the theory that Borrelia exploits these proteinases to degrade the intercellular tight junctions. Owing to the hypervariability of OspA among several Borrelia strains, it is important to note that only expression of OspA is not sufficient, but its ability to interact with host's receptors is crucial in the invasion processes."
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