The other day a patient a seemingly simple question: "Doctor, why is my case of Lyme disease so mild." Perhaps the answer to this question can lead us down the path of understanding Lyme disease.
The standard(LLMD)paradigms would suggest that the Lyme disease syndrome is the product of a multi-pathogen state. The co-infections, including Bartonella and Babesia are additional tick borne pathogens which contribute to the character and severity of the illness. But is this right? Perhaps not. What I have seen in very ill patients, consistently, is the presence of other, to date unrecognized "germs," swimming in the blood of such patients, undeterred- in the face of large and prolonged courses of antibiotics. Some of these organisms for example look like Toxoplasmosis. The existence of "Toxo like organisms" has been touched on in medical literature. Others are small gram negative bacteria which resemble Bartonella but are not Bartonella. In fact such "mystery bacteria" resembles hundreds of other bacteria which might stain in the same way. There exists a plethora of bacteria which share a similar morphology; for now, these are unknowns. Are these blood organisms seen in Lyme patients really tick borne pathogens?. Perhaps not. I propose that these anomalous bugs are pre-existing endogenous organisms, normally contained by the host immune system- prior to the onset of the illness- until the genie is let out of the bag.
Before chronic Lyme, or post-Lyme as some like to call it there was chronic fatigue syndrome. CFS became CFIDS: chronic fatigue and immunodeficiency syndrome. It has been pointed out by numerous observers that the two syndromes have much in common. The CDC has defined criteria for the syndrome. It usually starts after a "flu like illness." It has a new onset: it is not lifelong. It is associated with fatigue not relieved with rest. It is associated with: impaired memory or concentration, unrefreshing sleep, muscle pain, joint pain, headaches, sore throat and tender lymph nodes. Many other symptoms may occur as well. It is characterized by impaired immune responses. It is understood to be a "multi-system" disease. Its cause is not understood and it has a poor prognosis. Does this sound familiar?
Let us shift gears to chronic Toxoplasmosis. The seroprevalence of Toxoplasmosis is incredibly high. Most of the world's population is colonized by this parasite and they are ostensibly asymptomatic. It is thought that the "normal" immune system keeps it in check. Numerous symptoms may be associated with chronic Toxo. These include: fever, malaise, swollen lymph glands, eye symptoms and more. In immunocompromised patients, including the population with AIDS, symptoms include: fever, chills, skin rash, brain symptoms, heart and lung symptoms, confusion, headache, tremor, muscle weakness and more.
The existence of immunosuppression is one hall mark of Lyme disease or what is now called tick borne disease. I have repeatedly spoken of the "opportunistic" nature of co-infections. Evidence of immune compromise is regularly seen seen in patient lab studies. Many patients have low white blood cell counts with low neutrophils and increased lymphocytes. Patients may have low levels of natural killer T cells per the CD57 test. Patients have alterations in vitamin D suggesting a shift in helper cell Th1 and Th2 responses. These patients have a compromised immune system. This compromise is specific and limited. It does not lead to the full blown immunological defects seen in certain inherited disorders or acquired disorders like AIDS. It appears this subtlety has made it difficult for skeptics to appreciates its very existence.
Whereas some point to the Lyme spirochete as the culprit which initiates the cascade leading to immune dysfunction, other advocates point to CPN, Mycoplasma, yeast and other agents as the inciting cause. The disease may go by many names including CFIDS and fibromyalgia.
There are common threads. These chronically ill patients suffer with varying degrees of immunosuppression. The syndromes and their attendant symptoms overlap. Previously innocuous germs perhaps become interwoven into the fabric of a systemic, multi-system disease process. These germs may include: CPN, Mycoplasmas, Toxo like organisms, gram negative bacteria- or Bartonella like organisms if you like, yet unspecified "others" and perhaps a host of viruses including EBV, CMV and HHV6. In many cases the Lyme germ, Borrelia burdorferi may also be an innocent bystander, until something tips the immunological balance in favor of the disease process.
There may be an interplay behind the germs and other environmental factors. Certainly non-infectious proteins such as gluten can trigger abnormal immunological responses. Host factors such as exposure to toxins and stress may very well play an important role in some cases.
But this cannot be the whole story. Per the title of this piece, we are dealing with not only immune suppression, but immune dysregulation. Patients with this disease syndrome suffer with immune consequences impacting both sides of the immunological continuum. We have immunosuppression. On the flip side there is immune system over-activation, leading to the myriad of complex autoimmune responses which complicate the course of the illness more often than not.
Lyme and related organisms have clearly been implicated in a wide host of autoimmune syndromes ranging from inflammatory arthritis to MS and CIDP.
The spirochete dysregulates the immune system at both ends of the spectrum simultaneously- a nasty trick. It creates an environment ideal for opportunistic pathogens while at the same time it contributes to the destruction of erstwhile healthy tissues via an autoimmune process.
Perhaps chronic Lyme disease, fibromyalgia, CFIDS and other related disorders could potentially be combined into a new rubric, forming the foundation of an entirely new class of medical disease.
To get back to the patient's question: why are some people ill while others are not? The answer comes down to an understanding how a complex array of variables interact. As always these include genetic and environmental factors. The end result is seen in each patient's unique clinical syndrome.
Parasites have developed some incredible strategies for proliferation. There is a good layman's article on toxoplasma in the NY Times from a couple of years ago - just search for "toxoplasma" at nytimes.com and you can read it. Very, very scary stuff. Hijacking of dendrites to penetrate the brain, etc.
So, are we sicker because we have more germs, or do we have more germs because we are sicker?
The puzzle is what came from the tick, what is latent reactivated, and what showed up later and took advantage of the situation? Combination of all of these?
Someone was paying attention. This is the nugget of gold contained in this blog. My hypothesis is that it is the immune supression which accompanies the Lyme sydrome which allows previously contained microorganisms to florish. My current theory holds that the finding of these unusual organisms in the blood may turn out to be a marker of disease severity. They do not go away with antibiotics because the immune system is not doing its job properly. If I am correct then the mystery bugs should not be specifically treated. An overall therapy which addresses the major immune system deactivation, perhaps Bb should be pursued instead. Chasing the incidental bugs may just take one's eye off the important ball. When balance in the immune system is restored, hopefully the mystery bugs will disappear of their own accord- go back into the lairs where they properly belong. This was my epiphany. Of course it is just a theory and may turn out to be compeletly wrong. I reserve the right to reverse this position at a later date.
Yunzhi used in traditional Chinese medicine has been shown in the literature to re balance th1-- th2 imbalance. Vita Green Pharma sells this as an extract.
Also, theoretically, a tetanus shot might have same effect.
Any one else have any suggestions??
This discussion brings to mind two things. I recently read "Fatal Sequence" (bad title) by Kevin Tracey, a cytokine researcher. He explores how the nervous system can directly and dramatically communicate with the immune system, independent of the traditional humoral model. Because Bb has profound effects on the nervous system, it is possible nervous system disfunction impairs proper immune response. As with most things biological, it is hard to says what causes what.
The other thing I was reminded of was Jordan Fisher Smith's statement in the film Under Our Skin, regarding Lyme disease, where he asks did we really think we could completely disrupt our environment and not have it affect our heath?
The microbial ecosystem of the human body has been subject to severe disruption, particularly for the last fifty years. Who really knows the affects of vaccines, antibiotics, and the tons of manufactured chemicals we are exposed to? How does this affect a balanced system of internal microbes? What we call Lyme disease seems much more complex than an infection with a single bacteria species. Our conceptual model needs to recognize the many, complex, interrelated factors.
Here are two interesting articles:
Ann Agric Environ Med. 2008 Dec;15(2):333-8.
Preliminary study on the occurrence of Toxoplasma gondii in Ixodes ricinus ticks from north-western Poland with the use of PCR.
Sroka J, Wójcik-Fatla A, Zwoliński J, Zajac V, Sawczuk M, Dutkiewicz J.
Department of Occupational Biohazards, Institute of Agricultural Medicine, Jaczewskiego 2, Lublin, Poland. firstname.lastname@example.org
A batch of 259 Ixodes ricinus ticks collected by flagging in woodlands of north-western Poland (Szczecin area) was examined for the presence of Toxoplasma gondii DNA with nested polymerase chain reaction (PCR). Positive isolates were genotyped with the restriction fragment length polymorphism (RFLP) analysis of B1 gene marker. Another batch of 340 I. ricinus ticks from Szczecin area was homogenized and inoculated into mice. Subsequently, the biological material obtained from inoculated mice was also examined with nested PCR for the presence of Toxoplasma gondii DNA and positive isolates were genotyped with RFLP as above. The study revealed that 12.7 % of I. ricinus ticks were infected with T. gondii. Prevalence of T. gondii infection was highest in females (27.9 %), being significantly greater (p<0.05) than in males (12.3 % ) and nymphs (5.6 % ). Most of the positive isolates (78.8 % ) belonged to type I of T. gondii. Samples from brains and other organs of 60 inoculated mice showed 44 positive results for T. gondii DNA with the dominance of atypical genotype and frequent mixed infections.
PMID: 19061272 [PubMed - indexed for MEDLINE]
Comment: Maybe immune dysfunction and the presence of multiple pathogens is as important as genes in predicting the course of the disease. And maybe one can acquire toxoplasma from multiple sources, ticks being just one of them?
J Neuroinflammation. 2008 Oct 23;5:48.Click here to read Click here to read Links
Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection.
Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K, Mayr T, Kirisits MJ, Wollmann R, Ferguson DJ, Roberts CW, Hwang JH, Trendler T, Kennan RP, Suzuki Y, Reardon C, Hickey WF, Chen L, McLeod R.
Department of Ophthalmology, University of Chicago, Chicago, IL, USA. email@example.com
BACKGROUND: Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.
METHODS: To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum.
Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or alphaPD1 ligand were studied.
RESULTS: Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation.
Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation.
CONCLUSION: In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.
PMID: 18947414 [PubMed - indexed for MEDLINE]
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