Lyme Disease: How The Lymphatic System, Humoral Immunity, Collagen, and Decorin Binding are Interconnected.

I started researching Tick-Borne Diseases in 2012 after my daughter came down with a mysterious illness and went a year before we received a diagnosis Ehrlichia Chaffeensis, Lyme and Co-infections  (her story here). I read on average 1-5 peer reviewed studies and/or Journal articles per week. Why? Because my daughter did not get better after 4 weeks on Doxycyline; the Medical Field is largely ignoring the 10-20% of patients with lingering symptoms following standard treatment for Lyme; and because I, like so many others, have fallen into the Search Engine Rabbit Hole while looking for a cure.



There is a plethora of new information out there so I will say this, if anyone you know is quoting Lyme studies prior to 2000 they are completely missing the boat. It would be analogous to using diagnostic criteria and treatment protocols for HIV and AIDS from the 90's.

A few weeks ago I read a UC Davis study about how Borrelia burgdorferi causes suppression of long-term humoral immunity (anti-body mediated immunity) towards Lyme. [1] In humoral immunity the body relies on the blood to detect and produce antibodies, then form memory cells to help clear the infection and later prevent reinfection. As depicted below:

In Lyme disease, the precise mechanisms underlying a lack of long-term protective immunity remains unknown. Part of this is likely attributed to Borrelia's ability to change form: from Spirochete, to Cyst, to L-form; and the fact that it undergoes near complete replacement of vIsE alleles every 14-28 days.[2]  Borrelia burgdorferi's cell envelope is exceptional and it differs significantly from the typical Gram-negative bacteria (see image below). There is even evidence of Biofilm aggregates which complicates things even more. [3] In it's usual spirochete form, Borrelia is able to drill through and invade almost any tissue in the body. When the bacteria is threatened by antibiotics or the immune system the spirochetes roll up into a ball and form a protective cyst. When threatened again it will use another diversionary tactic called blebbing, where the spirochete pinches off bits of its cell membrane in order to release it's surface proteins allowing it to go dormant, and hide from the immune system. Lyme researcher and former CDC officer Dr. Alan Barbour, MD called this "some sort of stealth-bomber-type mechanism" where the surface proteins can intercept the incoming host antibodies "like a bacterial Star Wars defense program," keeping the spirochete safe from immunological attack. [4]

The UC Davis study goes into great depth on the T-cell dependent and T-cell independent  Borrelia burgdorferi (Bb) antigens, as well as the lack of memory B-cells. And it wasn't just a lack of immunity towards Borreila they also found that influenza vaccine antigens, when applied during Borrelia infection, failed to induce a strong antibody response or immune protection against the flu. Not only has B.burgdorferi developed multiple immune evasion mechanisms that appear to render the antibody responses ineffective, but that "the ongoing B.b. infection continuously shapes and reshapes the host immune system" supporting ongoing infection and reinfection.  The report concludes: 

"Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat."

What really stood out to me was the fact that Bb infected the lymphatic system within 24 hours after infection. They noted that the Germinal Centers, which are responsible for long-lived plasma cells and protective antibody secretion, responded within the first two weeks but then involuted over the next two weeks. What they posed as a question in the end is possibly the key to humoral immunity:

"By identifying the GC response as a target of Bb infection-induced immunosuppression, we have opened the field to a new set of questions, including what are the molecular targets of this suppression and what are the Bb-antigens that are driving these effects? Answering these important questions might reveal new therapeutic targets to overcome infection with Bb by strengthening and supporting the host’s own immune system."

So this got me to thinking about several studies I'd read:

1. Borrelia burgdorferi loves collagen-rich sites particularly: the dermis, connective tissue, tendons, ligaments, perineurium, and the periaortic connective tissue at the base of the heart. [5]
2. Borrelia burgdorferi attacks the lymphatic system which is where Lymphocytes, the warriors of the immune system, are made. [6]
3. Borrelia burgdorferi drives Type 1 interferon in the lymph nodes altering the cellular composition of the nodes, with potential detrimental effects for the immune response.[7]
4. Borrelia burgdorferi evades B Cell immunity and reduces the number of long-lived bone marrow plasma cells. [8]
5. We know from animal studies that Bb can hide and resurge even 12 months following antibiotic treatment. [9]

All this got me to wondering.  Is Decorin the molecular target of the Bb proteins? If so can we use that knowledge to help the immune system identify and fight off Bb? Is this the key to a clearing Bb from the body?

*As an aside, I wanted to mention there are new insights into Lyme disease, suggesting Lyme borreliosis may lead to a state of mitochondria dysfunction. [10 ]

Because the average patient with Lyme is going 2+ years before a diagnosis I think healing from a this destructive bacteria will require more than just antibiotics, but that's another topic…

References:
1. Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection | PLOS Pathogens
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004976

2. Detailed Analysis of Sequence Changes Occuring during vIsE Antigenic Variation in the Mouse Model of Borrelia burdgorferi Infection | PLOS Pathogens
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632889/

3. Morphologial and biochemical features of Borrelia burgdorferi pleomorphic forms | Microbiology
http://www.ncbi.nlm.nih.gov/pubmed/25564498

4. Alan Barbour | Profession of Medicine and Microbiology & Molecular Genetics | UC Irvine
http://spiro.mmg.uci.edu

5. Molecular analysis of decorin-binding protein A (DbpA) reveals five major groups among European Borrelia burgdorferi sense alto strains with impact for the development of serological assays and indicates lateral gene transfer of the dbpA gene | International Journal of Microbiology | Science Direct
http://www.ncbi.nlm.nih.gov/pubmed/23797360

6. Lymphoadenopathy during Lyme Borreliosis is Caused by Spirohete Migration-Induced Specific B Cell Activation. | PLOS pathogens
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102705/

7. MyD88- and TRIF-Independent Induction of Type 1 Interferon Drives Naive B Cell Accumulaiton but Not Loss of Lymph Node Architecture in Lyme Disease. | Infection and Immunity | American Society for Microbiology
http://iai.asm.org/content/82/4/1548.full?hits=10&fulltext=adapted&FIRSTINDEX=200&sortspec=date

8. Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection | The Journal of Immunology
http://www.jimmunol.org/content/188/11/5612.abstract

[9] Resurgence of Persisting Non-cultivable Borrelia burgdorferi Following Antibiotic Tratment in Mice | PLOSone
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086907

[10] New Insights into Lyme Disease | Redox Biology | Science Direct
http://www.sciencedirect.com/science/article/pii/S2213231715000282

*Edited Title and 1st Paragraph for content (Sept. 20, 2015)