Last week, I posted an excerpt from my upcoming book, Lyme Brain. We talked about the first cause of Lyme Brain, which is actual pathogens in the neurological system. Today you get the next installment What Causes Lyme Brain (Part 2) – the inflammatory response as a cause of Lyme Brain. Stay tuned next week for the third cause – neurotoxins.
The Inflammatory Response
As mentioned previously, direct impact of the pathogens on the nerve cells, which either causes demyelination or nerve cell death, is one way that Borrelia and its co-infections cause brain problems.
The second major mechanism is the inflammatory response. In fact, inflammation in the brain is perhaps the most significant cause of Lyme Brain.
Let’s review some basic physiology. Inflammation can occur for a number of reasons, but notably in response to a pathogen in the body that the immune system is trying to fight. Even though it can seem like a bad thing, it’s actually part of the body’s protective response. Inflammation can involve not only white blood cells, but also blood vessels in the area and cells in the damaged tissue, too. It is only a bad thing when the immune system becomes too active or the inflammatory response is prolonged.
When there is a pathogen such as Borrelia, the immune system activates to counter the threat and kill the pathogen. In doing so, the white blood cells of the immune system go to the affected area.
A whole cascade of events follows, the details of which are beyond the scope of this book. Suffice it to say that there are a few key features that are part of the inflammatory process.
One of these features is the production of cytokines. Cytokines are small proteins that are released by various cells of the immune system and function to facilitate communication and signaling between various cells. They orchestrate the trafficking of immune cells, direct them to the sites of injury and influence immune cell function. They are released by a range of immune cells including B cells, T cells, macrophages and mast cells. In very simple terms, they are messengers and facilitators. Types of cytokines include chemokines, interleukins, interferons, lymphokines and tumor necrosis factors. Cytokines can also influence Th-1 and Th-2 balance within the immune system, which is significant in chronic infections such as Lyme disease.
Chronic Lyme patients are found to have high levels of cytokines such as interferon-gamma, IL-10, TNF-alpha, interleukin-6, interleukin-1b, interleukin-8, interleukin-12 and C-reactive protein. Some cytokines are anti-inflammatory (IL-10 for example); however, the majority of cytokines found in Lyme patients are pro-inflammatory.[i],[ii],[iii]
Chemokines are chemicals that induce the movement of cells towards an area of damage or inflammation. Many chemokines have been found in Lyme patients: chemokine ligands CXCL12, CXCL13, CCL2, CCL3, CCL4 and CCL5.[iv],[v]
Nitric oxide (NO) is another inflammatory mediator. Nitric oxide is a reactive molecule that can cause oxidative stress and cell damage, giving rise to further inflammatory processes. Higher levels of nitric oxide have been found in Lyme patients as opposed to healthy subjects. Nitric oxide also controls blood vessel dilation and constriction, so nitric oxide levels may play a role in the blood flow and oxygenation of cerebral vascular tissue in Lyme patients.[vi],[vii]
In an article in the Townsend Letter (Feb/ Mar 2006)[x], Professor Robert W. Bradford and Henry W. Allen postulate that there might be a role for therapeutic agents that inhibit PDE-5, an enzyme that regulates c-GMP, which in turn influences nitric oxide. Medications that inhibit PDE-5 include sildenafil (Viagra), Cialis and Levitra. From a naturopathic standpoint, the amino acid arginine may have similar effects. Further research would be needed to determine whether this, indeed, is therapeutically significant and potentially beneficial for Lyme patients.
Another byproduct of immune activation is changes in the vascular system and blood clotting mechanisms. Inflammation creates increased dilation of the blood vessels and increased permeability in the vessel walls. This allows more fluid to move into the tissue space, giving rise to stasis of the blood cells in the vessels. This serves a worthwhile purpose: it allows white blood cells to move along the vessel walls to the site of injury (think of all the traffic on a freeway as it pulls over and stops on the side of the road to allow an ambulance through. If the traffic were flowing as it usually does, the ambulance would have a hard time making its way to the problem location). However, it can also lead to negative effects such as reduced oxygenation of the tissues.
So, we see that inflammation causes blood coagulation, but coagulation itself also has the capacity to regulate immune response, again, largely through the activation of various signaling molecules.[xi]
Coagulation is balanced by the fibrinolytic system, which acts as an anticoagulant, preventing ongoing blood clotting. Anticoagulants also function to reduce cytokine production and protect the endothelial cells from the damage caused by inflammation.[xii]
So you can see that while inflammation is a necessary part of immune response, it is not without its negative effects on the body.
Think of it like a military invasion. If an intruder comes on to home soil, the military (immune system) are going to counter that threat. They will first go to the location of the invasion, spreading out to the extent that the bad guys have spread out. They will come in with guns firing and missiles blazing. The goal is to kill as many of the baddies as possible with the least impact on the home turf. But, in the process of the invasion, some collateral damage may occur. Yes, the military might kill at least some (hopefully all) of the bad guys, but they may also take out a few local civilians, buildings might get blown up, and infrastructures may be destroyed. Some of this may be necessary to contain the original threat, but it’s certainly not the goal of the military’s defense strategy. Hopefully, once the invaders are neutralized, rebuilding of home base can occur to repair any collateral damage.
And so it is with inflammation in Lyme disease. When the immune system tries to protect the body from an invasion by pathogens, baddies will be eradicated, but inflammation will occur as a byproduct, which can damage tissues and create symptoms of its own. This is one of the necessary secondary effects but is also the mechanism for much of the collateral damage that we see.
In chronic Lyme disease, collateral damage is often more extensive, due to the fact that the battle is ongoing over months and years, compared with shorter battles that occur in acute infections.
[i] Pohl-Koppe, A, K E Balashov, A C Steere, E L Logigan, and D A Hafler. “Identification of a T cell subset capable of both IFN-gamma and IL-10 secretion in patients with chronic Borrelia burgdorferi infection.” J Immunol 160, no. 4 (February 1998): 1804-10.
[ii] Soloski, M J, L A Crowder, L J Lahey, C A Wagner, W H Robinson, and J N Aucott. “Serum inflammatory mediators as markers of human Lyme disease activity.” PLos One 9, no. 4 (April 2014): e93243.
[iii] Bransfield, R C. “The psychoimmunology of lyme/tick-borne diseases and its association with neuropsychiatric symptoms.” Open Neurol J, 2012: 88-93.
[iv] Bransfield. “The psychoimmunology.”
[v] Myers, T A, D Kaushal, and M T Phillip. “Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells.” PLos Pathog 5, no. 11 (November 2009): e1000659.
[vi] Ratajczak-Wrona, W, et al. “Nitric oxide in Lyme borreliosis. Evaluation of serum levels of nitric oxide and its biomarkers in patients with Lyme borreliosis.” Prog Health Sci 3 (2013): 2.
[vii] Garcia-Monco, J C, and J L Benach. “Mechanisms of injury in Lyme neuroborreliosis.” Semin Neurol 17, no. 1 (March 1997): 57-62.
[viii] Bourret, T J, J A Boylan, K A Lawrence, and F C Gherardini. “Nitrosative damage to free and zinc-bound cysteine thiols underlies nitric oxide toxicity in wild-type Borrelia burgdorferi.” Mol Microbiol 81, no. 1 (July 2011): 249-73.
[ix] Seiler, K P, Z Vavrin, E Eichwald, Jr., J B Hibbs, and J J Weis. “Nitric oxide production during murine Lyme disease: lack of involvement in host resistance or pathology.” Infect Immun 63, no. 10 (October 1995): 3886-3895.
[x] Bradford, Robert W, and Henry W Allen. “Biochemistry of Lyme Disease: Borrelia Burgdorferi Spirochete/Cyst.” Townsend Letter, the Examiner of Alternative Medicine. February/March 2006.
[xi] Petägä, J. “Inflammation and coagulation. An overview.” Thromb Res 127 , no. Suppl 2 (January 2011): S34-7.
[xii] Esmon, C T. “The interactions between inflammation and coagulation.” Br J Haematol 131, no. 4 (November 2005): 417-30.