09 Feb 2012 

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Pharma/CDC on Brain damage from vaccines, Fauci, Phages, Bioweapons manufacture

HHS.gov is Incompetent; BMJ calls fraud "crime.")

Official: CFIDS and MS-Lyme are the same disease; Epstein-Barr 


CDC Greed (won't answer the FOIA)

ELISA = arbitrary cutoff.

Disclaimer

Overview
 

TUSKEGEE - By Jerry Leonard

1998, CIA Oilmen & Israelis plan to overthrow Saddam for the oil.

Bush/Gore  Oil/War-(Oct,2000)  

Bush's own explainer (Oct 2000): Iraq Oil

Iraq was an oil-theft war.

 

INDICES OF PATHOLOGY    working....   MS, Lyme, ALS, CFIDS,

This page is intended to show you that there are known markers of real illness in these bogus illnesses such as Chronic Fatigue Syndrome and Fibromyalgia.   If you get this book: http://www.columbia-lyme.org/flatp/resources.html

Title: Lyme Disease - Molecular and Immunologic Approaches
Editor: Steven E. Schutzer, MD
Publisher: Cold Spring Harbor Laboratory Press
Date: 1992

You will find it to be invaluable.  Lenny Sigal tells about real markers of illness, rather than his usual BS about Lyme being Fibromyalgia being "catastrophizing" in women.

Here are the real markers of disease, which everyone should know about, because it is the "bad guys" themselves describing the real signs of illness (and not hypochondria): BIOMARKERS 

PsychMisdiagnoses... A Sample:  Rapid Cycling Bipolar  See also Bransfield, Fallon, and Sherr, Neuropsychiatry.

- - - - - - - - - - -

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11179309

"Thus, the immunosuppressive effect is dependent on glycosylated and acylated 19-kDa lipoprotein present in the phagosome containing the mycobacterium. These results suggest that the diminished protection against challenge with M. tuberculosis seen in mice vaccinated with M. smegmatis expressing the 19-kDa lipoprotein is the result of reduced TNF-alpha and IL-12 production, possibly leading to reduced induction of T-cell activation."
 

It is important to know that the results of rOspA were spun by the RICO/Enterprise of Imugen/Glaxo-SmithKline/Yale/Connaught/Corixa/ALDF.com/CDC.gov/CastleConnolly.com/EUCALB and  Corixa intends to work in more tuberculosis vaccines, while rOspA was never shown to be a vaccine.  The trial of rOspA in the Rhesus Monkey by Mario Philipp did not demonstrate efficacy, and they had the same problem reading the Western Blots that Persing/Sigal/Molloy did.  (Select "rOspA, What's bad about it?" from the Navigation Bar to your left, or go here:  http://www.journals.uchicago.edu/CID/journal/issues/v31n1/991200/991200.html

So, we won't tolerate a repeat of the Nonsensical Lipoprotein A vaccine, from these crooks again.

 

The complexities of Pathologies in Borreliosis are not anywhere near resolved.

======

Starting points

Several people, such as Lynn Margulis and Alan Barbour suggest Borreliae should be its own Phylum.  Plasmid vectored DNA, blebbing, the presence of bacteriophages, and lateral gene transfer, suggest that Borrelia either shared these methods with Rickettisiae, or vice-versa.  The closed-pin telomeres of these plasmid remind Durland Fish and Alan Barbour of the pox- and iridiviruses found in Ornithodorous ticks, which vector Relapsing Fever and African Swine Fever Virus (ASFV), which was why Fish studied the vector competence of Ixodes and ASVF on Plum Island.

http://info.med.yale.edu/eph/vectorbio/fish/

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1475522&dopt=Abstract

Moreover, the molecular analysis of the terminal ends of one of the linear minichromosomes has revealed that this unique replicon has sequence similarities with poxviruses and particularly the viral agent of African swine fever. The presence of nucleic-acid-containing vesicles and its possible role in mediating DNA transfer between borreliae is an additional, very interesting feature of these organisms

 

Tick borne borrelia persist in the eye and brain past treatment with anything.

Borreliosis is a permanent infection of the brain, and 2/3 of all people who showed up in Dattwyler's, and other's offices and had their spinal fluid sampled, had Borrelia burgdorferi DNA in their spinal fluid.  That means for 2 out of 3 people who have an EM rash, it is too late to prevent the brain infection.  We don't know what kind of DNA, but let's assume chromosomal.

    See also:  Barbour (Vancomycin treatment of mice, OspC and the Vmps, etc, and the nature of his grants.)

 

Neoplasms, Monoclonal Gammopathy, Pseudolymphoma

Anti-Flagellin

=================

http://cdli.asm.org/cgi/content/full/9/6/1348?view=full&pmid=12414773

Humoral Immune Response Associated with Lyme Borreliosis in Nonhuman Primates: Analysis by Immunoblotting and Enzyme-Linked Immunosorbent Assay with Sonicates or Recombinant Proteins

A. R. Pachner,^1* D. Dail,¹ L. Li,¹ L. Gurey,¹ S. Feng,² E. Hodzic,² and S. Barthold²

Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103,¹ Center of Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616²

Received 7 March 2002/ Returned for modification 21 June 2002/ Accepted 10 July 2002

 

 J Neurochem. 1994 Sep;63(3):1178-80.

 
Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases.

Milstien S, Sakai N, Brew BJ, Krieger C, Vickers JH, Saito K, Heyes MP.

Laboratory of Neurochemistry, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.

Nitric oxide has been proposed to mediate cytotoxic effects in inflammatory diseases. To investigate the possibility that overproduction of nitric oxide might play a role in the neuropathology of inflammatory and noninflammatory neurological diseases, we compared levels of the markers of nitric oxide, nitrite plus nitrate, in the CSF of controls with those in patients with various neurologic diseases, including Huntington's and Alzheimer's disease, amyotrophic lateral sclerosis, and HIV infection. We found that there were no significant increases in the CSF levels of these nitric oxide metabolites, even in patients infected with HIV or in monkeys infected with poliovirus, both of which have significantly elevated levels of the neurotoxin quinolinic acid and the marker of macrophage activation, neopterin. However, CSF quinolinic acid, neopterin, and nitrite/nitrate levels were significantly increased in a small group of patients with bacterial and viral meningitis.

PMID: 8051562 [PubMed - indexed for MEDLINE]

 

Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9010-4. Epub 2002 Jun 11

 
Amyotrophic lateral sclerosis: a proposed mechanism.

Okado-Matsumoto A, Fridovich I.

Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for approximately 20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons. Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS. We previously reported that SOD1 exists in the intermembrane space of mitochondria. Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1. The binding of mutant SOD1 to Hsps in the extract of neuroblastoma cells leads to formation of sedimentable aggregates. Many antiapoptotic effects of Hsps have been reported. We now propose that this binding of Hsps to mutant forms of a protein abundant in motor neurons, such as SOD1, makes Hsps unavailable for their antiapoptotic functions and leads ultimately to motor neuron death. It also appears that the Hsp-SOD1 complex recruits other proteins present in the neuroblastoma cell and presumably in motor neurons to form sedimentable aggregates.

PMID: 12060716 [PubMed - indexed for MEDLINE]

 

 

Monoclonal Gammopathy and Epstein Barr

        See Duray, and Borrelia and Epstein-Barr

 

--ASEPTIC MENINGITIS/COINFECTIONS:  A first marker?  "...Laboratory tests may reveal pancytopenia and elevated hepatic transaminases, BUN, and creatinine."     http://www.emedicine.com/neuro/topic697.htm

=======

Paul Duray, Pathologist, Histology

Persistence Mechanisms-  See ActionLyme History, ALbany OPMC Hearing Submission, and http://www.lymeinfo.net/lymefiles.html

SPLEENS (B cells)  SERIOUS PATHOLOGY

 

NIH NEUROBORRELIOSIS "RARE DISEASES" CONFERENCE: http://rarediseases.info.nih.gov/news-reports/workshops/humanneuro20010909.html   This is essentially the same data which went into the Rhode Island Tick Borne Diseases Management Plan, submitted to the RI TBDs Commission by K.M. Dickson for ActionLyme.

Benach, Halperin, Coyle, Dattwyler, Roland Martin and the NIH MS team, Pachner, Philipp, Schutzer, ...brain imaging, CNS markers, CSF markers, mechanisms of neuropathologies, and the analytical methods to detect these, when available.

Markers of Neuroborreliosis Pathology, Overview

Neurotoxins, Shoemaker,    Donta,   Benach (porins) Borrelia and Porins

Transporters

 

            Classification of Membrane Transport Proteins (BCL molecules and porins) http://www.chem.qmul.ac.uk/iubmb/mtp/propfam1.html

 

Glial Fibrillary Acidic protein (Schoen, 2 abstracts)

Quinolinic acid (Halperin, "excitotoxin")

Autoreactive T cells (Roland Martin, MIH, MS Group)

Antiganglioside antibodies (Benach)

Antiphospholipid antibodies (Steere, Yale's "Lyme and Lupus Clinic")

Sulfatides

Steere and NO  Induction of NO synthase by bacterial agents within the brain may represent a common pathway of CNS inflammation and neurotoxicity.
 

"Autoantibodies"  (Klempner "Is it Thee or Me?" MOBP and OspA)

"Cross reacting" antibodies (Sigal, and anti- 60kD heat shock protein,, human nerve tissue target)

Matrix-metalloproteinases (Klempner and others)

Cytokines (multiple-- significant: IL-10 has never been assayed in spinal fluid)"Cytokines and the Brain: Implications for Clinical Psychiatry"

EEG and Borreliosis

Brain Imaging and Lyme (Fallon, Columbia)

Gadolinium Contrast MRI

Pachner_Philipp and the Monkeys

Immune Complex Pathology

Blood profiles

B cell pathology, gammopathy

=====================

TBDs Management Plan (The fact of the matter is, this disease is incurable, and the only thing that can be done about it is chronic antibiotic treatment and immune enhancement. Every late neurologic patients should get minimum 3-4 months IV to get rid of peripheral bugs.)

WORKING →     Immune complex data (Coyle and Schutzer, Steere, Reik), and more (B cell problems, Duray and Dorward), and some from none other than Allen Steere, who says Chronic Lyme patients have "some psychiatric illness"- from "StAlKiNg StErE"- by David Grann, in the New York Times Magazine.  (Silliness, and a  good look at who is actually crazy in the Lyme world)

These are the markers of Central and Peripheral Nervous System pathology, primarily

(Part I of the plan was regarding serology, both Western Blot and non-protein antigen assay)

                from the RI TBDs Management Plan- Submitted to the RI Tick-Borne Diseases Commission

        sanctioned by the Rhode Island  Governor  and his Asst, Joe Larissa, April 21, 2002,  by K. M. Dickson

PATIENT MANAGEMENT IN ADDITION TO IMPROVED DETECTION OF LYME EXPOSURE

           

METHODS AND MARKERS OF PATHOPHYSIOLOGY

             QUALIFICATION OF PATIENT PRESENTATION

 

MARKERS OF PATHOPHYSIOLOGY

The following are some, but not all markers of pathophysiology.  They are noteworthy because they appear to be related to cognitive changes in borreliosis patients.  If Lyme disease was just an arthritis, there would be very little disability.

 It is not known whether antiphospholipid or antiglycolipid antibodies seen in borreliosis patients are of bacterial origin or the result of neurological damage and are therefore autoantibodies.  The 5 kD glycolipid is specifically a marker of borreliosis and is associated with more severe neurological disease, as are the antiphospholipid cases and is suspected in borreliosis patients with anti-brain antiganglioside antibodies.  Additionally, it has been suggested that possibly autoreactive T cells, matrix-metalloproteinases (MMPs), quinolinic acid (QUIN), neopterin, and glial fibrillary acid protein (GFAp) in the CSF are signs of ongoing neurological injury.  These process-markers are addressed in other illnesses, e.g., clinical trials of MMP inhibitors in MS and, cyclophosphamide for monoclonal gammopathies and for GFAp in Alzheimer’s, glatiramer acetate and neuroborreliosis (which failed).  There are other objectively detectable signs of pathology in borreliosis patients, such as increased CSF protein, pleocytosis, dysregulated cytokines, gadolinium-enhanced MRI imaging which used for meningitis detection, and EEG changes.

That these process-markers overlap markers of pathophysiology in other illnesses, especially in other illnesses where there is a significant association to Bb exposure, such as in ALS and MS, is the objective evidence that borreliosis is the multi-symptom disease that subjective reporting first showed.  It is not to say that Lyme causes MS or ALS.  It is to say, symptoms reported by borreliosis patients have a basis in reality.  A differential diagnosis is made based on other disease-specific criteria.

At this point in time, there are no single set of lab tests that are 100% accurate for diagnosing ALS or MS or Lupus or Guillain-Barre.  These are also clinical diagnoses, as is Lyme.  It is important to note that just as the Chronic Lyme symptom complex overlaps CFIDS or Fibromyalgia, they also overlap these other diseases with known pathophysiology.  When these pathophysiologies are looked for in chronic borreliosis patients, they are more frequently found, than not when using the best methods.  To not look for them in a patient, and instead assign a re-diagnosis of a chronic borreliosis patient with an illness that has overlapping subjective symptoms, such as Fibromyalgia, CFIDS, or “some psychiatric disorder” (Steere, in NewYork Times Magazine, Stalking Steere), but without these overlapping objective signs, is a medical negligence liability.

Yale University at one time had a Lyme and Lupus Clinic, run by Rheumatologists, who looked for things like anticardiolipin antibodies in both diseases (and found them).  This clinic was spun- off as a biotech firm, and is now known as L2 Diagnostics.  It was never called the Lupus and Fibromyalgia Clinic, nor is its name now LF Diagnostics.

The spectrum of illness, and the pathophysiological markers of disease process in borreliosis frequently coinfected, say that this not simply an antibody-antibiotic dynamic.  Currently, chronic borreliosis patients appear to have two options, long term antibiotic treatment, or be told their illness has become a non-disease, in the absence of proper pathophysiological analyses.  Limiting treatment to X days of antimicrobials for a simple infection, does not appear to suffice.  Spirochetes, alone, are not, and never have been, simple infections.  Paul Erhlich used the arsenic-containing drug Salvarsan to treat syphilis.  The fulcrum shift might be to, politically, legally, frame spirochetal and other tick borne diseases as chronic illnesses.  That’s what the following data says to do.  

QUINOLINIC ACID

The noted pathologies associated with chronic neuroborreliosis include quinolinic acid (QUIN) in the cerebrospinal fluid.  Lumbar puncture is a safe and common procedure according to Mark Klempner of Tufts (Diseases of Summer Conference, 2001, South County Hospital).  QUIN is a marker of immune activation or infection.  National Institutes of Mental Health has determined that quinolinic acid, an excitotoxin/neurotoxin, comes from macrophages.   The precise source of QUIN in neuroborreliosis patients is unknown.

 QUIN’s excitotoxic properties are related to N-methyl –D-aspartate (NMDA) NMDA agonism.  QUIN, an intermediate in the tryptophan to dopamine pathway, has oxidative/foreign antigen lytic properties.  QUIN has been implicated as a dopamine antagonist and associated with pathology to GABA bearing neurons and thus seizures (25, 26).  The known manifestations that possibly correlate with QUIN/NMDA/GABA pathology in borreliosis are myoclonus, complex partial seizures (Neurocognitive abnormalities in children after classic manifestations of Lyme disease Steere, et al, Pediatr Infect Dis J. 1998 Mar;17(3):189-96.), sleep disorders, explosive rage reaction (“Lyme-Rage”), “a schizophrenia-like disorder”, other manifestations of psychosis and dementia.  Hypnogogic and other types of hallucinations observed in Lyme neuroborreliosis are of the type more commonly associated with delirium.

 

In acute neuroborreliosis, QUIN levels are in the range of, 325 +/-96 nM, while in chronic borreliosis encephalopathy, 

he levels are in the range of, 31 +/4 nM, or about 50% above normal.  The assay was performed with GC and negative 

ionization mass spectrometry.

Neuroactive kynurenines in Lyme borreliosis., Neurology  1992 Jan;42(1):43-50 , 

Halperin JJ, Heyes MP., Department of Neurology, SUNY, Stony Brook.

“Although neurologic dysfunction occurs frequently in patients with Lyme borreliosis, it is rarely possible to demonstrate 

the causative organism within the neuraxis. This discordance could arise if neurologic symptoms were actually due to 

soluble neuromodulators produced in response to infection. Since immune stimulation is associated with the production 

of quinolinic acid (QUIN), an excitotoxin and N-methyl-D-aspartate (NMDA) agonist, we measured levels of CSF and 

serum QUIN, and lymphokines. Samples were obtained from 16 patients with CNS Borrelia burgdorferi infection, eight 

patients with Lyme encephalopathy (confusion without intra-CNS inflammation), and 45 controls. CSF QUIN was 

substantially elevated in patients with CNS Lyme and correlated strongly with CSF leukocytosis. In patients with 

encephalopathy, serum QUIN was elevated with corresponding increments in CSF QUIN. Lymphokine concentrations 

were not consistently elevated. We conclude that CSF QUIN is significantly elevated in B burgdorferi infection--

dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA 

synaptic function—a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic 

and cognitive deficits seen in many Lyme disease patients.”  PMID: 1531156

The question remains, do the remaining elevated levels mean an ongoing contribution to ongoing encephalopathy?

The state of the art in neuroprotection against QUIN and other reactive oxygen species damage is development of synthetic kynurenines and free radical scavengers.

NEOPTERIN

There was only one citation found on PubMed for neopterin production in borreliosis.  The full text has not been obtained because this is a foreign journal and is not readily available:

 

It was detected in the cerebrospinal fluid, here:

Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis

versus late Lyme encephalopathy.,   Eur J Clin Chem Clin Biochem  1994 Sep;32(9):685-9 

Gasse T, Murr C, Meyersbach P, Schmutzhard E, Wachter H, Fuchs D.

Klinik fur Neurologie, Universitat Innsbruck, Austria.

“Fourteen patients with Borrelia burgdorferi infection were investigated for possible abnormalities of tryptophan and 

neopterin metabolism. Four patients (2 were investigated before therapy, 2 when therapy had been already started) 

had acute Lyme neuroborreliosis, and 10 patients were investigated months to years after an acute infection. Increased 

concentrations of neopterin and of the tryptophan-degradation product, L-kynurenine, were detected in the cerebrospinal 

fluid of patients with acute Lyme neuroborreliosis; one patient presented with subnormal tryptophan. Similar but less 

marked changes were seen in the treated patients and in some of the patients with Lyme encephalopathy. No such 

abnormalities were seen in the serum of the patients. The data indicate a role of the immune system and particularly of 

endogenously formed cytokines, like interferon-gamma and tumour necrosis factor-alpha, effecting tryptophan and 

neopterin metabolism in patients with acute Lyme neuroborreliosis.” PMID: 7865624 

Neopterin and other pterins may be assayed with HPLC.

There is little data available regarding disturbances to brain function associated with this marker.

Biochemical changes in cerebrospinal fluid associated with the neurotoxicaction of HIV-1, [Article in Spanish] 

Actas Luso Esp Neurol Psiquiatr Cienc Afines  1996 Jul-Aug;24(4):209-18,  Gomez Alcalde MS, Reyes Martin A., 

Departamento de Ciencias Sanitarias y Medico Sociales de la Facultad de Medicina de Alcala de Henares.

“The aim of this study is to evaluate the usefulness of different markers to diagnose neurologic and psychiatric diseases 

due to HIV-1 infection Increased concentration of quinolenic acid has been implicated in the neurologic deficits and brain 

atrophy that may accompany infection with the HIV-1 virus. CFS concentrations of quinolenic acid have been implicated 

in the pathogenesis of the AIDS dementia complex. Cytokines liberation are very altered and this factor may be correlated 

with direct toxicity about central nervous system cells. Also are increased the values of neopterin. In the different stages 

of AIDS, the highest values are obtained in dementia complex. Neopterin, tryptofan and kinorenina, in blood and CFS are 

directly correlated with neurologic and psychiatry sintomatology. The highest values of soluble intercellular adhesion molecule 

1 are found in HIV encephalopathy As well as are important the values, in CSF and blood of beta-2-M, Ag HIV, Ac41,

 tumor necrosis factor-alpha in the neurologic disease in HIV-1 infection.”

PMID: 8984853 

There may be other pterins associated with a disease process.

 

MMPs

 

The matrix-metalloproteinases obviously degrade matrix/connective tissue.  The concern of Mark Klempner (27) was, “Since MMPs can digest myelin, basic protein, B. burgdorferi could promote CNS injury indirectly by inducing the expresion of MMPs in neural cells.  MMPs also digest at least two proteins of the adult CNS extracellular matrix: the aggregating proteoglycan versican and tenascin.” -- Perides G, Steere AC, Klempner MS, et al, Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis.  J Infect Dis. 1998 Feb;177(2):401-8.

There are other reports of identification of MMPs in the CNS of neuroborreliosis, and these are not in complete agreement 

with Mark Klempner’s findings.  The method above was SDS-PAGE zymography.

The relationship of MMPs to the other markers of CNS degradation in the CSF of neuroborreliosis patients is unknown, nor is it known the full extent of behavioral and cognitive effects of this active marker alone.

  

GFAp

 

Glial fibrillary acidic protein in the CSF of borreliosis patients:

 

Astroglial and neuronal proteins in cerebrospinal fluid as markers of CNS involvement in Lyme neuroborreliosis.,  

Eur J Neurol  1999 Mar;6(2):169-78 , Dotevall L, Hagberg L, Karlsson JE, Rosengren LE., Department of Infectious 

Diseases, Goteborg University, Goteborg, Sweden.

“Is Lyme neuroborreliosis, even in its early phase, a parenchymatous disorder in the central nervous system (CNS), and 

not merely a meningitic process? We quantified cerebrospinal fluid (CSF) levels of four nerve and glial cell marker proteins 

in Lyme neuroborreliosis patients with pretreatment durations of 7-240 days. All 23 patients had meningoradiculitis, and six 

had objective signs of encephalopathy. Glial fibrillary acidic protein (GFAp) pretreatment levels in CSF, and the light 

subunit of neurofilament protein (NFL) levels were related to clinical outcome and declined significantly after treatment 

(P < 0.001 and P < 0.01, respectively). NFL was detectable in 11 out of 22 patients, and pre- and post-treatment NFL 

levels were associated with the duration of neurological symptoms within 100 days prior to treatment. Neuron-specific 

enolase (NSE) concentrations also decreased after therapy (P < 0.001), while CSF levels of glial S-100 protein remained 

unchanged. The pretreatment duration of disease was related to postinfectious sequelae. GFAp, NSE and NFL levels in 

CSF are unspecific indicators of astroglial and neuronal involvement in CNS disease. The findings in the present study are 

in agreement with the hypothesis that early and late stages of Lyme neuroborreliosis damage the CNS parenchyma. 

Copyright 1999 Lippincott Williams & Wilkins.” PMID: 10053229 

Increased cerebrospinal fluid levels of glial fibrillary acidic protein (GFAp) in Lyme neuroborreliosis.,  

Infection  1996 Mar-Apr;24(2):125-9, Dotevall L, Rosengren LE, Hagberg L.

Dept. of Infectious Diseases, Ostra University Hospital, Goteborg University, Sweden.

“Glial fibrillary acidic protein (GFAp), the main protein constituent of the intermediate filaments of astrocytes, was analysed 

in the cerebrospinal fluid (CSF) of 20 patients with Lyme neuroborreliosis as a marker of the astroglial reaction. The mean 

GFAp level before antibiotic treatment in the study group was significantly elevated (592 pg/ml +/- 596 [SD]) compared to 

that in 24 healthy controls (121 +/- 87 [SD]) (p < 0.01). The highest CSF-GFAp levels were seen in the patients with the 

most severe disease, but the levels were also increased in patients with peripheral paresis, such as facial palsy with no or 

only minor encephalitic symptoms. This implies that the infection was not limited to radix dorsalis or the meningeal tissues, 

but affected the central nervous system as well. Furthermore, the astroglial reaction seemed to occur early in Lyme 

neuroborreliosis since CSF-GFAp levels were elevated also in patients with recent (< 3 weeks) onset of disease. After antibiotic

 treatment, the GFAp levels decreased. It is suggested the CSF-GFAp concentrations might be useful for monitoring CNS 

involvement in Lyme neuroborreliosis.” PMID: 8740104 

 

GFAp in the CSF is also seen in ALS and Alzheimer’s.  Exposure to Bb in ALS patients met statistical significance:

 “There appears to be a statistically significant association between ALS and immunoreactivity to B burgdorferi, at least among men living in hyperendemic areas.”— Halperin JJ, Dattwyler, RJ, et al, Immunologic reactivity against Borrelia burgdorferi in patients with motor neuron disease. Arch Neurol. 1990 May;47(5):586-94. PMID: 2334308

 

Robert T. Schoen, Yale Rheumatology, Annals of Internel Medicine, Vol 132, No 8:  

"Other peripheral neuropathies and Lyme meningitis are also seen at this stage.  In late-stage disease, the central nervous system may be involved.  A new diagnostic test measuring glial fibrillary acidic protein in cerebrospinal fluid may prove to be a useful tool for measuring such involvement (20)."

 

Robert T. Schoen, Yale Rheumatology, Prevention Magazine:

“While it's especially important at this time of year to be aware of the warning signs of the disease – a skin rash around the site of a tick bite, headache, fever, fatigue and muscle or joint pain – Lyme paranoia, as I call it, is not warranted.”-- The previous text was excerpted from Prevention magazine, published by Rodale Press. Lyme fear prevails more than disease. , The Washington Times, 04-18-1999

  

GFAp has been assayed by ELISA, Western Blot.  This needs further analytical development.

 GFAp has been implicated in disturbance to brain function:

Effects of gliosis on dopamine metabolism in rat striatum., Brain Res  1994 Nov 14;663(2):199-205, Wang J, 

Lieberman D, Tabubo H, Finberg JP, Oldfield EH, Bankiewicz KS., CNS Implantation and Regeneration Unit, NINDS, 

NIH, Bethesda, MD 20892.

“Neuroimplantation is inevitably accompanied by gliosis. Although graft-induced trophic effects on host neurons may 

be mediated by glial cells, the effects of gliosis on dopamine (DA) metabolism remains unclear. To examine these effects, 

basic fibroblast growth factor (bFGF) was directly infused into the striatum of 12 male rats (250-280 g). One week later, 

substantial gliosis was demonstrated in the infused striatum by immunochemical staining for glial fibrillary acidic

protein (GFAP) and quantified by GFAP Western blot analysis. One week after bFGF infusion, extracellular DA and its m

etabolites were measured by in vivo microdialysis using HPLC. Infusion of L-dopa through the dialysis probe resulted in 

a 60% reduction in the L-dopa-induced DA peak in the gliotic striatum compared with the normal side. After L-dopa infusion, 

dihydroxyphenylacetic acid (DOPAC) levels were similar between the gliotic and normal striatum. In contrast, homovanillic 

acid (HVA) levels were 26% higher in the gliotic striatum. Enzyme assays demonstrated that aromatic L-amino acid 

decarboxylase activity was unchanged in the gliotic striatum, but both MAO-A and MAO-B activities increased by 23% 

and 21%, respectively. These results suggest that the reduced striatal DA peak in the gliotic striatum after L-dopa 

administration was due to accelerated DA catabolism through enhanced MAO activity. The bFGF-induced striatal gliosis 

may serve as a model to study neurotransmitter metabolism in the gliotic brain caused by disease processes, aging, or tissue 

grafting.” PMID: 7874502 

ANTIPHOSPHOLIPID ANTIBODIES

 

Antiphospholipid antibody production in neuroborreliosis patients, as has been identified by Allen Steere, is positively correlated with neurologic symptoms.  

“Sera from 28 patients with Lyme disease were tested for the presence of anticardiolipin antibodies (ACLA). Seven serum samples had elevated levels of IgM ACLA, and 4 had elevated levels of IgG ACLA. Higher IgM ACLA positivity tended to be associated with neurologic disease, and IgM ACLA levels correlated with the specific IgM response to the infecting spirochete (P less than 0.01).  Absorption experiments  indicated that ACLA and antispirochete antibodies are largely separate populations. Thus, ACLA may occur in patients with Lyme disease,  particularly in those with neurologic abnormalities, and the production of these antibodies seems to be linked to the specific IgM response.”— Anticardiolipin antibodies in Lyme disease Mackworth-Young CG, Steere AC, et al, Arthritis Rheum  1988 Aug;31(8):1052-6, PMID: 3408508

  

The analytical methods used there should also be employed as part of patient workup, until further investigations reveal a more sensitive and specific method.  Antiphospholipid-negative assay results do not exclude the diagnosis of Lupus.  Although the Lupus/MS haplotypes HLA-DQB1*0602 and *1501 have been identified as possible correlates in chronic CNS Lyme disease, it is possible to make a differential diagnosis at least of Lupus.  The phospholipids found in borrelia are phosphatidylcholine and phosphatidylglycerol (28).   Adequate assays for antibodies to these are recommended.  The VRDL used in Lupus was not adequate to detect anticardiolipin antibodies in borreliosis and Steere presented a more sensitive method: radioimmunoassay (RIA).   The differential diagnosis of the Antiphospholipid Syndrome, Lupus, and antiphospholipid antibodies from the borrelioses may be a considerable challenge. 

We haven’t run across any recent developments from L2 Diagnostics.

 Antiphospholipid antibodies are implicated in the neuropsychiatric symptoms.

 

ANTIGLYCOLIPIDS

Antibodies to glycolipids can also be determined.  Jorge Benach of SUNY Stony Brook has found that IgM to borrelial gangliosides may result in autoimmune response similar to Guillain Barre, or possible antibody competition for receptors, and clearly, the nodes of Ranvier, which are suspected to result in compromise to nerve conduction.  Although these mechanisms of nerve conduction may be reversible and temporary, animal models of Lyme borreliosis, such as in Rhesus macaques, have shown irreversible nerve damage via immune cell response.  Likeliest, these neurological lesions are the result of spirochetal blebbing, or the shedding of antigen and macrophage activity.

Alan Barbour (UC Irvine) and Stephen Bartold (Yale):  “Many researchers believe that the secret to B. burgdorferi's infectivity and inflammatory capacity lies in the interaction of its surface proteins with the host's immunological system. Yale researcher Stephen Barthold, a veterinarian and professor of comparative medicine who developed the first mouse model of Lyme disease, studies the expression of B. burgdorferi surface proteins throughout various stages of the spirochete's life cycle. He finds that during the early stages of infection, B. burgdorferi avoids immune detection by decreasing its expression of surface proteins or cloaking its expressed surface proteins under a layer of slime. "It's using some sort of stealth-bomber-type mechanism," he says. Or, using another diversionary tactic called blebbing, the spirochete can pinch off bits of its membrane in order to release its surface proteins. Explains Barbour: "It's like a bacterial Star Wars defense program,"  in which released surface proteins might intercept incoming host antibodies, keeping the spirochete safe from immunological attack. “— The Scientist, Vol:10, #14, pg.13, July 8, 1996. http://www.the-scientist.com/asp/Registration/login.asp?redir=http://www.the-scientist.com/yr1996/july/research_960708.html

Even when spirochetes are not detected in a borreliosis nerve lesion, it is suspected some spirochetal material (blebs) remains:  "Nerve changes.  A detailed survey of the central nervous system lesions was carried out, which included 50 sampling sites.  The lesions observed are listed in Table 4.  Sensory ganglia of the dorsal root and trigeminal ganglia of animals J 831 and K 216 had individual neurons that immunostained positive with anti-Bb 7.5kD lipoprotein mAb (fig 16).  These neurons were swollen and were undergoing chromatolysis.  The dorsal root ganglia of the thoracic and cervical regions were especially affected.  Nerve sheath fibrosis within the spinal cord was limited to the thoracic segment in animal J 831.  Positive staining with anti-Bb mAb, accompanied by vacuolization of peripheral nerves, was observed in three of four animals. This change occurred as a radiculoneuropathy of the thoracic segment and peripheral nerves (Fig 17).  Animal L 131 had five peripheral nerves affected.  When the same nerves were stained for fat, focal vacuolization was observed (Figs 18 and 19). Focal demyelination  of the cervical cord was limited to J 831.  Lymphocyte infiltration of the affected nerves was mild in extent and confined to perivascular spaces.  In animals L 131 and K 383,Bb could be demonstrated by immunostaining (Fig 20).

“ The pathogenesis of Lyme disease neuropathies is poorly understood...Sensory ganglia involvement has previously been 

described in human borreliosis (27-28).  In our study, many of the ganglia positive for Bb by immunstaining were undergoing 

necrosis.  This staining was seen in two out of five animals and was not accompanied by a cellular infiltrate.

" Nerve tissues with perivascular lymphocyte infiltrate were present in three out of five animals.  This was the only lesions 

where extracellular Bb could be demonstrated. Peripheral cutaneous nerves were prominantly affected in the early phase 

of borreliosis of rhesus macaques(20, 28-29). Changes of the nercous system include the full range of changes observed in 

neuroborreliosis, which suggests a variety of disease mechanisms, including sensitization or mimicry as suggested by the 

vacuolization of peripheral nerves and cytokine-mediated destruction of nerves as a result of the infiltrating lymphocytes..." 

--- Chronic lyme disease in the rhesus monkey , Lab Invest 1995 Feb;72(2):146-60, Roberts, ED, et al.

Experimental immunization with Borrelia burgdorferi induces development of antibodies to gangliosides., Infect 

Immun  1995 Oct;63(10):4130-7, Garcia-Monco JC, Seidman RJ, Benach JL., Department of Neurology, Hospital de 

Galdacano, Vizcaya, Spain.

“Patients with neuroborreliosis produce antibodies, mostly of the immunoglobulin M (IgM) class, to gangliosides, particularly 

to those with Gal(beta 1-3)GalNac terminal sequences. Lewis rats were immunized with a nonpathogenic strain of Borrelia 

burgdorferi and with a chloroform-methanol extract (nonprotein) of this organism (CM) to determine whether antibodies to 

B. burgdorferi also recognized gangliosides. Rats were also immunized with asialo-GM1 to determine whether the elicited 

antibodies recognized antigens in B. burgdorferi. Rats immunized with B. burgdorferi produced low levels of IgM antibodies 

that cross-reacted with asialo-GM1 and GM1. Rats immunized with CM had marked IgM reactivity to asialo-GM1 and GM1. 

Immunization with asialo-GM1 resulted in antibodies that cross-reacted with B. burgdorferi antigens. Although antibodies to 

B. burgdorferi were of both the IgM and IgG classes, those to CM and to asialo-GM1 and GM1 were predominantly in the 

IgM fraction. Reactivity of the IgM antibodies decreased after adsorption with the heterologous and the homologous antigens,

indicating bidirectional cross-reactivity between CM, asialo-GM1, and GM1 and that immunization with one produces antibodies 

o the other. There was no in vivo deposition of Ig in peripheral nerves, nor was there nerve pathology as a result of 

immunizations, but IgM antibodies to asialo-GM1 and CM recognized homologous antigens in the nodes of Ranvier of peripheral

nerves from nonimmunized rats. This immunization model suggests that antibodies to gangliosides in Lyme disease have a 

microbial origin and are potentially relevant in pathogenesis.” PMID: 7558329 

Reactivity of neuroborreliosis patients (Lyme disease) to cardiolipin and gangliosides.

J Neurol Sci  1993 Jul;117(1-2):206-14, Garcia Monco JC, Wheeler CM, Benach JL, Furie RA, Lukehart SA, Stanek G, 

Steere AC., Department of Pathology, SUNY, Stony Brook 11794.

“A subset of patients (50%) with neuroborreliosis (Lyme disease) showed IgG reactivity to cardiolipin in solid phase ELISA. 

In addition, a subset of patients with neuroborreliosis (29%) and syphilis (59%) had IgM reactivity to gangliosides with a 

Gal(beta 1-3) GalNac terminal sequence (GM1, GD1b, and asialo GM1). Anti-ganglioside IgM antibodies were significantly 

more frequent in these two groups of patients compared to patients with cutaneous and articular Lyme disease, primary 

antiphospholipid syndrome, systemic lupus erythematosus and normal controls. Correlative evidence and adsorption experiments

indicated that antibodies to cardiolipin had separate specificities from those directed against the gangliosides. IgM antibodies 

to Gal(beta 1-3) GalNac gangliosides appeared to have similar specificities since these were positively correlated and inhibitable 

by cross adsorption assays. Given the clinical associations of patients with neuroborreliosis and syphilis with IgM reactivity to 

gangliosides sharing the Gal(beta 1-3) GalNac terminus, we suggest that these antibodies could represent a response to injury 

in neurological disease or a cross reactive event caused by spirochetes.” PMID: 8410057 

In, Role of the cerebrosides and a galactodiglyceride in the antigenic cross-reaction between nerve tissue and treponema., J Immunol. 1972 Jul;109(1):146-53., Dupouey P. writes: “This cross reaction between the GDG [galactodiglyceride] contained in certain species of treponema and cerebrosides of the cerebral tissue poses a problem of pathogenesis, Similar problems have been discussed in a recent review of the role of microorganisms in autoimmune response (13).  With regard to this subject it should, however, be noted: 1) That the central nervous system is infected in syphilis and yet T. pallidum does not seem to contain any GDG (8).  2) That the anti-erebroside and anti-GDG studied here are circulating antibodies.  Antibodies of this type are considered to be proof of, not the agents of, autoimmune response.  3)  That certain infectious or traumatic diseases liable to liberate cerebral constituents within the organism should be able to give rise to anti-cerebroside antibodies which are therefore GDG.  4)  That these anti-GDG antibodies are sometimes encountered at high titers in human subjects who are in apparent perfect health.”

Abstract from the same publication:

“Various authors have demonstrated an antigenic identity between various nervous tissue and treponema.  This report shows 

that this antigenic diversity is due to the presence in the treponema extracts of a galactodiglyceride hapten: i.e., 

2, 3-di-O-acyl-1-O-(b -D-galactopyranosyl)-D-glycerol.  This hapten shows a cross reaction with the cerebrosides; 

moreover, the the nervous tissue contains a lipid which, on deacylation, liberates a O-(b-D-galactosyl_-1-1’-glycerol (11).  

The part palyed by each of the constituents as well as the possible consequences of this antigenic community are discussed.”

It was recognized long ago that anti-nerve antibodies might possibly be coming from cross reaction, or they may be coming 

from degradation of host tissue, which, upon injury of some sort, becomes autoantigenic.  Thirty years ago, scientists looked 

at these questions in spirochetal illnesses.  In 1988 and later, Steere looked at anti-nerve antibodies in borreliosis patients 

and found them.  Yet these markers of illness are not only not addressed in management of patients --not only are they are

not routinely looked for-- but the lay media are instead told patients have “some psychiatric illness”, there are no adverse 

outcomes in Lyme disease, Lyme is curable, and there is no such thing as Chronic Lyme. The Post-Lyme syndrome is

 “ill-defined”, according to the Infectious Diseases Society of America: “Clinical Infectious Diseases    2000;31:1-14, 

GUIDELINES FROM THE INFECTIOUS DISEASES SOCIETY OF AMERICA, Practice Guidelines for the 

Treatment of Lyme Disease, Gary P. Wormser, Robert B. Nadelman, Raymond J. Dattwyler, David T. Dennis, 

Eugene D. Shapiro, Allen C. Steere, Thomas J. Rush, Daniel W. Rahn, Patricia K. Coyle, David H. Persing, Durland Fish, 

and Benjamin J. Luft.”

Many of the above authors are the very people who were involved in the development and discovery of methods and 

markers of chronic illness in Chronic Lyme disease.

It is not known if IgM antibodies to nerve cell components would be present in the absence of spirochetes.  That 

condition, 100% spirochete clearance, has never been proven in any animal model.

A recent public relations Lyme prevention announcement:

“Once a dog is infected, it is infected for life.” –American Lyme Disease Foundation, Somers, New York, PR Newswire, United 

Business Media, April, 2002

AUTOREACTIVE T CELLS, NEUROLOGICAL

 

Very little concrete data to support autoreactive T cells in Lyme borreliosis exists.  However, there remain the genetic correlates in Klempner’s and Martin’s MHC Class II antigen-presenting molecules to be explained.  Whether Class II should be considered alone, and outside the dynamic of Class I and B cell contribution to the association of Class II to an autoimmune disease with a known etiology such as a permanent spirochetal infection, will probably be played out in the NIH and CDC funding competition arena.

 The data are:

 

AUDIO TRANSCRIPT:  Mark Klempner, Tufts Unibversity.  South County Hospital Diseases of Summer Conference, July 2001, regarding his treatment study of borreliosis, reported July 12, 2001, NEJM.

 

“Um, There, these patients obviously, are very, very much interested in that question, as we are, and I just want to highlight a preliminary piece of data of where we think we’re going from here, unpublished*, and not for large, uh, dissemination, but here is the preliminary data. And, that is, that when you look for the possibility of an autoimmune disease, the best way to look is to see if there is any genetic clustering in HLA haplotypes. The reason for that is the way antigens get presented in the context of who you are, that is, your HLA haplotype.  And we can talk in some detail about that.  Those diseases that I think everybody would agree are so called Autoimmune :lupus, rheumatoid arthritis, type 1 diabetes, and perhaps MS, have some clear genetic clustering that leads us to believe that these are indeed autoimmune diseases, although we do not satisfy so-called Koch’s Postulates of autoimmune disease that we’ve written[?-KMD] about.  And the odds ratio for your having that particular HLA type, in the case of R.A, a DR4,  or a DQB0602 to protect you from type 1 diabetes, are on the order of 3 to 6.  One of the ones that is probably  highest, of course, is B27, in patients with alkyloiding spondolytis and the like.  It turns out that if you look at the first 51 patients with post-treatment chronic Lyme disease, the patient population that participated in our study, there was a very high incidence of DQB0602 with an odds ratio of 770%.  So it may well be that exposure to THAT organism with THAT background of HLA haplotype may lead you to develop chronic symptoms.  That is a hypothesis that needs to be tested.  It would obviously lead to an entirely new form and approach to therapy.”

 

Borrelia burgdorferi--specific and autoreactive T-cell lines from cerebrospinal fluid in Lyme radiculomyelitis. Ann Neurol

1988 Oct;24(4):509-16
Martin R, Ortlauf J, Sticht-Groh V, Bogdahn U, Goldmann SF, Mertens HG.
Department of Neurology, University of Wurzburg, FRG.

In 3 patients with Lyme radiculomyelitis, cellular immune reactions of cerebrospinal fluid (CSF) lymphocytes were analyzed. Phenotypic analysis of CSF cells demonstrated that the majority were T cells (CD3+) of the helper/inducer subset (CD4+). These T cells were directly expanded from the CSF by limiting dilution. A total of 505 T-cell lines were tested for Borrelia burgdorferi (Bb)-specific proliferation and also partly tested for reactivity to a panel of central and peripheral nervous system antigens. Proliferative assays revealed 33 of them to be Bb specific, 16 to be specific for myelin basic protein, 16 to be specific for peripheral myelin, 1 to be specific for cardiolipin, and 2 to be specific for galactocerebrosides. The antigen-specific proliferation was restricted by autologous human leukocyte antigen (HLA) class II molecules. The majority of CSF-derived T-cell lines stained positively for CD3, CD4, and HLA class II antigens and negatively for CD8 (cytotoxic/suppressor subset). One T-cell line provided help for the production of specific IgG by autologous B cells and secreted gamma-interferon upon stimulation with Bb antigen in the presence of autologous antigen-presenting cells. These data show that in patients with severe neurological manifestations of late Lyme disease, not only Bb-specific T-cell lines but also T cells reactive to central or peripheral nervous system autoantigens can be found.PMID: 3266455 [PubMed - indexed for MEDLINE]

Identification of candidate T-cell epitopes and molecular mimics in chronic Lymedisease., Nat Med  1999 Dec;5(12):

1375-82, Hemmer B, Gran B, Zhao Y, Marques A, Pascal J, Tzou A, Kondo T, Cortese I, Bielekova B, Straus SE, McFarland 

HF, Houghten R, Simon R, Pinilla C, Martin R., Neuroimmunology Branch, National Institute of Neurological Disorders and 

Stroke, National Institutes of Health, Building 10, Room 5B-16, 10 Center DR MSC 1400, Bethesda, Maryland 20892-1400, 

USA.

“Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and 

designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial 

proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may 

add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method 

to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional 

scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic 

neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both 

Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet 

the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in 

T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in 

infectious diseases, tumors and autoimmune diseases. “PMID: 10581079 

The above patient had HLA-DRB1*1501.

A trial of glatiramer actetate for putative T cell autoimmunity in Lyme disease failed:

Mechanisms of immunomodulation by glatiramer acetate., Neurology  2000 Dec 12;55(11):1704-14, Gran B, Tranquill 

LR, Chen M, Bielekova B, Zhou W, Dhib-Jalbut S, Martin R. Cellular Immunology Section, Neuroimmunology Branch, 

NINDS, NIH, Bethesda, MD 20892, USA.

OBJECTIVE: To define the mechanism of action of glatiramer acetate (GA; formerly known as copolymer-1) as an 

immunomodulatory treatment for MS. BACKGROUND: The proposed mechanisms of action of GA include 1) functional 

inhibition of myelin-reactive T cells by human leukocyte antigen (HLA) blocking, 2) T-cell receptor (TCR) antagonism, 

and 3) induction of T helper 2 (Th2) immunomodulatory cells. In this report, the authors examined the effects of GA on 

the functional activation of human T-cell clones (TCC) specific for myelin basic protein (MBP) and for foreign antigens. 

Several questions were addressed: Is the inhibitory effect of GA specific for autoantigens? Is it mediated by blocking 

the interaction between peptide and HLA molecule? Is GA a partial agonist or TCR antagonist, or does it induce anergy? 

Does it induce Th2 modulatory T cells? METHODS: The effects of GA on antigen-induced activation of human TCC 

specific for MBP, influenza virus hemagglutinin, and Borrelia burgdorferi were studied by proliferation and cytokine 

measurements, TCR downmodulation, and anergy assays. GA-specific TCC were generated in vitro from the peripheral 

blood of patients and healthy controls by limiting dilution. RESULTS: GA more strongly inhibited the proliferation of MBP, 

as compared with foreign antigen-specific TCC; in some MBP-specific TCC, the production of Th1-type cytokines was 

preferentially inhibited. In addition to HLA competition, the induction of anergy, but not direct TCR antagonism, was 

observed. Numerous GA-specific TCC were generated from the peripheral blood of both MS patients and normal 

controls, and a fraction of these showed a Th2 phenotype. CONCLUSIONS: This study confirms a preferential inhibitory 

effect of GA on autoreactive TCC. With respect to cellular mechanisms, although HLA competition appears to play the

most important role in functional inhibition in vitro, a direct effect on the TCR may be involved at least in some autoreactive 

T cells as shown by anergy induction.  Although not confirmed at the clonal level, it is demonstrated further that GA induces 

T cells that crossreact with myelin proteins. GA-specific, Th2-modulatory cells may play an important role in mediating the 

effect of the drug in vivo.  PMID: 11113226 

DETECTING MENINGITIS

 Gadolinium Contrast MRI was used to look for spirochetal meningitis the nonhuman primate model:

Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme 

neuroborreliosis faithful to the human disease., Neurology  1995 Jan;45(1):165-72, Pachner AR, Delaney E, 

O'Neill T, Major E., Department of Neurology, Georgetown University Medical Center, Washington, DC.

“We injected rhesus macaques with a highly infective strain of Borrelia burgdorferi to assess whether experimentally 

inoculated nonhuman primates (NHPs) could serve as models of human Lyme neuroborreliosis (LNB). The animals 

developed biopsy-confirmed erythema migrans in the area of the inoculations. ELISA testing of sera revealed strong 

antibody reactivity to B burgdorferi antigens, and Western blotting showed that 16-, 22-, 31-, 34-, and 41-kd proteins 

of the spirochete were major antigens recognized by antibody. Culture and polymerase chain reaction (PCR) testing 

of serial CSF specimens revealed that chronic infection of the CNS occurred in all NHPs injected. CSF pleocytosis 

occurred concurrently with CNS infection. Brain MRI revealed intense meningeal inflammation in one NHP as manifested 

by gadolinium uptake by the dura at the base of the temporal lobes. All animals had measurable antibody in the CSF after 

invasion. These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human 

disease, with spirochetal invasion of the subarachnoid space. This also is the first report of CSF samples positive by culture 

in experimental LNB.  Inflammation in the CNS as manifested by CSF pleocytosis and MRI findings was also correlated 

with the presence of spirochetal DNA detected by PCR. These data support the hypothesis that the pathogenesis of LNB 

is associated with direct spirochetal invasion, and provide evidence that CNS involvement is more common than heretofore 

thought.” PMID: 7824109 

Note that the monkeys only had one of CDC’s specific bands, and if these were all IgG, none would have been a 

reportable case.  This is evidence of faithfulness to human disease.  These monkeys would have been classified as 

“Unconfirmed Lyme” in the SKB LymeRIX trial.  “Unconfirmed Lyme” data was not included in analysis of safety 

and efficacy of the vaccine. Less than 5 bands-Lyme data was simply discarded.  (OspA and B were excluded in 

CDC’s IgG.)

Gad-MRI has been used in humans to detect spirochetal meningitis.  

Contrast enhancement of the cerebrospinal fluid on MRI in two cases of spirochaetal meningitis., Good CD, 

Jager HR., Lysholm Radiological Department, National Hospital for Neurology and Neurosurgery, London, UK., 

“We report two patients with meningitis due to spirochaetal infection, both of whom showed diffusely enhancing 

meninges around the brain and spinal cord. In addition, there was enhancement of the cerebrospinal fluid after 

intravenous administration of Gd-DTPA.”

PMID: 10929307

It is not known why this is method not used more commonly.  It seems that this might be more economical and specific 

than a neuropsychiatric evaluation.

             EEG

 

Changes in electroencephalography, consistent with delirium, were identified in Lyme patients: QEEG and evoked potentials

in central nervous system Lyme disease., Chabot RJ, Sigal LH., Clin Electroencephalogr. 1995 Jul;26(3):137-45.

 “Quantitative EEG, 
flash visual evoked potentials, auditory evoked potentials to common and rare 
tones, and median nerve 

somatosensory evoked 
potentials were obtained from 12 patients with active CNS Lyme disease and from 
11 patients previously t

reated for active CNS Lyme disease. Abnormal QEEG and/or EPs were found in 75% of the active Lyme disease patients and in 

54% of the post CNS Lyme disease patients. Three different types of neurophysiological abnormality were observed in these patients including QEEG slowing, possible signs of cortical hyperexcitability, and focal patterns indicating disturbed interhemispheric

relationships. In patients tested before and after treatment QEEG and EP normalization was associated with clinical improvement.”

PMID: 7554300

 

Compare to:

The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome. Arthritis Rheum  2000 

Nov;43(11):2493-500, Hassett AL, Cone JD, Patella SJ, Sigal LH.,  Department of Medicine, University of Medicine and 

Dentistry of New Jersey-Robert Wood Johnson Medical School, New 

Brunswick 08903, USA.

“OBJECTIVE: Although 2 recent studies have found associations between catastrophizing and poor medical outcomes in 

patients with fibromyalgia syndrome (FMS), neither assessed these findings in comparison with a similar group of patients 

with chronic pain. Our study examined the complex relationships between depression, catastrophizing, and the multidimensional 

aspects of pain in women with FMS and compared these relationships with those in women with rheumatoid arthritis (RA).

 METHODS: Sixty-four FMS patients and 30 RA patients completed the Coping Strategies Questionnaire (CSQ), the Beck 

Depression Inventory II (BDI-II), and the McGill Pain Questionnaire. RESULTS: Compared with subjects with RA, FMS subjects 

scored significantly higher on the catastrophizing subscale of the CSQ. FMS patients also earned higher scores on 

overall depression and on the cognitive subscale of the BDI-II.  Furthermore, the relationship between catastrophizing 

and depression was significant in the FMS group only. Regression analyses revealed that in FMS, catastrophizing as a

measure of coping predicted patients' perception of pain better than demographic variables such as age, duration of illness, 

and education. CONCLUSION: Cognitive factors, such as catastrophizing and depressive self-statements, have a more 

pronounced role in the self-reported pain of patients with FMS than in patients with RA.  Clinically, this indicates that 

treating pain and depression in FMS by adding cognitive therapy and coping skills components to a comprehensive 

treatment program may improve the outcomes obtained with pharmacologic interventions.” PMID: 11083273

The above two examples show the inconsistent and non-systematic use of objective measures, in addition to non-validated-

by-physiology subjective measures, deployed in service of Managed Care financial goals.  

Leonard Sigal: Chapter 8, page 145, Rahn and Evans’ book, “Lyme Disease, ACP Key Diseases Series”, 1998

 “Lyme Anxiety

 Lyme anxiety is common in and near areas endemic for Lyme disease.  There is widespread concern that Lyme disease is incurable

and that this infection can only be brought into temporary remission and will continue to flare. With widespread anxiety about

Lyme disease has come Munchausen syndrome and Munchausen by Proxy in those concerned about Lyme disease.  The

psychologic and financial costs of the misdiagnosis of “chronic” Lyme disease are staggering but have not been considered in

most discussions of the public burden of the mismanagement of Lyme disease.” 

 

MUNCHAUSENS... Sigal in Rahn and Evans....(to be added) 

 

DYSREGULATION OF CSF MONOAMINES AND CYTOKINES

 

Cytokines

 

IL-6 in the CSF is associated with physical and emotional depression.  The downstream effect of increased IL-6 in the 

CNS on neurotransmission needs further study.

 

Interleukin-6 is expressed at high levels in the CNS in Lyme neuroborreliosis., Neurology  1997 Jul;49(1):147-52, 

Pachner AR, Amemiya K, Delaney E, O'Neill T, Hughes CA, Zhang WF., Department of Neurology, Georgetown 

University School of Medicine, Washington,

DC 20007, USA.

In patients with Lyme neuroborreliosis, inflammation and symptoms of fatigue and malaise occur out of proportion to the

 relatively low number of spirochetes present. Previous studies have identified interleukin-6 (IL-6) as a candidate molecule 

for amplification of CNS inflammation in this disease. We pursued this possibility by measuring cytokine gene expression 

by reverse-transcriptase polymerase chain reaction (RT-PCR) in the brain of rhesus macaques actively infected with 

Borrelia burgdorferi. Samples of brain tissue were screened for IL-6 and interferon gamma using RT-PCR-ELISA, a 

technique that uses RT-PCR, subsequent hybridization of the PCR product with a biotinylated probe, and capture and 

ELISA readout of hybridization product. The number of copies in positive samples was then quantitated using qRT-PCR-

ELISA, in which wild-type cytokine cDNA competes with recombinant competitor DNA in the PCR. Elevated

levels of IL-6 cDNA and, to a lesser extent, interferon gamma were detected in three of three nonhuman primates with 

persistent infection with B burgdorferi, whereas the brains of three uninfected animals and undetectable levels of gene 

expression of these cytokines. These data support the hypothesis that cytokines such as IL-6 are important amplification 

molecules for CNS inflammation in Lyme neuroborreliosis.PMID: 9222183 

IL-10-- ('Has never been assayed for cerebrospinal fluid, yet we know this antiinflammatory cytokine

is produced by lymphocytes when exposed to Borrelia burgdorferi.)

The following excerpt was taken from the results section of a report of an experiment ex vivo.  No data was been 

published as per a search of MEDLINE for the query parameters: “borrelia and CSF and IL-10”. It is not known the

 influence of IL-10 on cognitive changes.  It is suspected that IL-10 plays a role in the persistence of the spirochete.  

OspA appears to exert an effect on IL-10 expression and might play a role in vaccine adverse events (Haupl T, Landgraf 

S, et al, FEMS Immunol Med Microbiol 1997 Sep;19(1):15-23: “ High induction of IL-10 by L-OspA further suggested a 

negative feedback on monocyte activation by the lipidated form.” Activation of monocytes by three OspA vaccine

candidates: lipoprotein OspA is a potent stimulator of monokines.).

Modulation of cytokine release in ex vivo-stimulated blood from borreliosis patients. Infect Immun 2001 

Feb;69(2):687-94, Diterich I, Harter L, Hassler D, Wendel A, Hartung T., Biochemical Pharmacology, Department of 

Biology, University of Konstanz, D-78457 Konstanz, Germany.

(From the Results Section):

“To compare the patterns of cytokine release induced by LPS and Borrelia lysate, the concentrations of endotoxin

from four different LPS preparations were adjusted to induce the same levels of TNF- release as seen with 10 µg 

of protein per ml of Borrelia lysate. The release of the cytokines TNF-, IFN-, G-CSF, and IL-10 induced by endotoxins

from S. enterica serovar Abortusequi (200 pg/ml), E. coli (10 ng/ml), K. pneumoniae (100 pg/ml), and S. enterica serovar 

Enteritidis (50 pg/ml) was uniform in blood from healthy volunteers (Fig. 3), suggesting that different endotoxins share a 

leukocyte activation principle. However, a pronounced difference was seen between the four LPS preparations and the 

Borrelia lysate: at concentrations which induced the same TNF- release as 10 µg of protein per ml of Borrelia lysate, 

endotoxins induced much more IFN- than Borrelia lysate did. Instead, Borrelia lysate induced a 5- to 10-fold-higher

 release of the anti-inflammatory cytokines IL-10 and G-CSF than the LPS preparations did. The lysates from other Borrelia 

species, i.e., B. afzelii and B. garinii, induced the same cytokine pattern as did those from B. burgdorferi (data not shown). 

These findings show that LPS induces the release predominantly of the proinflammatory cytokine IFN- while Borrelia lysate 

is a stronger inducer of the anti-inflammatory cytokines IL-10 and G-CSF. Such an inverse cytokine induction pattern 

demonstrates that the immunostimulatory components of B. burgdorferi differ from those of endotoxins.”

IL-10 has not been reported found in the CSF of borreliosis patients in MEDLINE.  This may be a failure of search strategy. 

There is other cytokine dysregulation in borreliosis.  These were only a sampling.  It needs to be looked at systematically and

probably put into a database.  Different combinations of TBDs may have different effects.  Note that the above two examples were

controlled studies of infecting monkeys with Bb alone.

  

Monoamines

 

Neurotransmitters and their metabolites in the CSF of post-meningitis patients have not been extensively studied.  Evidence of

immune activation such as quinolinic acid in HIV and neuroborreliosis and behavioral effects suggest that there may be evidence

of dysregulation, which can be correlated.  MMPs are related to neurologic sequelae in childhood meningitis with degree of damage

a function of concentration dependence.  Monoamine dysregulation in the CSF of autistic children has been studied.  MMR

vaccination in childhood has been implicated in the development of autism, particularly since many of these children experience

normal development until approximately 18 months of age, the recommended age to administer MMR.  This is not to say that

MMR vaccination results in autism, this is to say, does a strong immune response from an immunogen result in permanent or

temporary changes to receptor profiles, neurotransmitters and their degradants concentration that can be detected in CSF, or

evidence of abnormal differentiation of brain cells that can be detected via monoamine assay?  

 

Vaccination effects other than autism, due to MHC capacities, are now being studied, but from the reverse standpoint.  Scientists

are now looking at targeting vaccines towards people predisposed to autoimmune disease by HLA identification.

 

 

ANTIBODIES TO HEAT SHOCK PROTEINS

 

Antibodies to heat shock proteins (sometimes considered part of “common antigens”) are considered possible cross-reacting

antibodies, since microbial and mammalian heat shock proteins are similar.  There are times when mammalian heat shock proteins

are surface-expressed.  Bb contains at least 12 heat shock proteins.  This is not surprising, since it has multiple hosts, including

 the tick, which often survives near zero C temperatures.  Bb itself survives freezing, as the spirochete has been recovered from

frozen banked blood.  Lyme patients are prohibited from donating blood to the Red Cross.

 

Heat shock proteins (HSPs) of Bb expressed in humans have apparent molecular weights of 60, 62, 72, 74 kilodaltons.  P66, one of

at least three pore-forming antigens of Bb (others: P28, P45) has qualities of heat shock proteins and may bind heat shock protein

antibodies.  HSPs are not always detectable via antibody.  They are not as immunogenic in some people as they are in others. 

When they show up in neurologically impaired patients, one might expect an MS-like syndrome.  HSPs obviously have less

specificity than Bb-specific lipoproteins, but do not exclude illness symptoms.

 

Characterization of the heat shock response and identification of heat shock protein antigens of Borrelia 

burgdorferi., Infect Immun  1990 Jul;58(7):2186-91, Carreiro MM, Laux DC, Nelson DR., Department of Microbiology, 

University of Rhode Island, Kingston 02881.

“The heat shock response of Borrelia burgdorferi B31 cells was characterized with regard to the heat shock proteins

(Hsps) produced. Five to seven Hsps were detected by sodium dodecyl sulfate-gel electrophoresis and fluorography of 

proteins from cells labeled with [35S]methionine after shifts from 33 degrees C to 37 or 40 degrees C or from 20 degrees

C to 33, 37, or 40 degrees C. Analysis of [35S]methionine-labeled Hsps by two-dimensional electrophoresis and

autoradiography revealed 12 Hsps. Western immunoblot analysis with antisera to highly conserved Escherichia coli and 

Mycobacterium tuberculosis Hsps revealed a single 72-kilodalton (kDa) protein band that reacted with antibodies to E. 

coli DnaK and with antibodies to the M. tuberculosis 71-kDa Hsp homolog of E. coli DnaK. Two proteins with apparent 

molecular masses of 66 and 60 kDa reacted with antibodies against the M. tuberculosis 65-kDa Hsp homolog of E. coli 

GroEL. Human immune sera collected from patients with Lyme disease reacted with both the 66-kDa Hsp and the 

60-kDa Hsp but failed to react with the 72-kDa Hsp. These data are discussed with regard to the possibility that host

 recognition of highly conserved epitopes of GroEL homologs of B. burgdorferi may result in autoimmune reactions 

causing arthritis and other pathologies.” PMID: 2194963

Anti-alpha B-crystallin immunoreactivity in inflammatory nervous system

diseases., J Neurol  2000 Dec;247(12):935-9, Celet B, Akman-Demir G, Serdaroglu P, Yentur SP, Tasci B, van 

Noort JM, Eraksoy M, Saruhan-Direskeneli G., Department of Physiology, Istanbul Medical Faculty, Istanbul University, 

Istanbul, Turkey.

alpha B-Crystallin, a small heat shock protein, is an immunodominant antigen with increased tissue expression in 

demyelination. To investigate the humoral response against alpha B-crystallin, the sera and CSF samples of patients 

with multiple sclerosis (MS), Guillain-Barre syndrome (GBS), neuro-Behcet's disease (NBD) and other non-inflammatory 

neurological diseases (NIND) were screened by enzyme-linked immunosorbent assay for anti-alpha B-crystallin IgG 

and IgM antibodies. Serum and CSF IgG antibody responses to alpha B-crystallin were significantly elevated only in 

NBD patients (serum IgG, NBD 1.29 +/- 0.49 vs. NIND 0.95 +/- 0.39, P = 0.01; CSF IgG, NBD 1.22 +/- 0.64 vs. 

NIND 0.81 +/- 0.35, P = 0.01). Similarly, high serum IgM antibody titres were also detected in NBD (1.83 +/- 0.72 vs. 

1.16 +/- 0.49, P = 0.0005) and in MS (1.57 +/- 1.07, P = 0.046), whereas elevated CSF IgM responses were observed 

only in GBS (2.09 +/- 1.09 vs. 1.41 +/- 0.7, P = 0.007). Humoral responses against alpha B-crystallin are increased in 

NBD and GBS, which may implicate this central nervous system antigen in the causation and pathogenesis of these 

inflammatory nervous system disorders.  PMID: 11200685 

Molecular mimicry in Lyme disease: monoclonal antibody H9724 to B. burgdorferi flagellin specifically 

detects chaperonin-HSP60., Biochim Biophys Acta  1993 Mar 24;1181(1):97-100 

Dai Z, Lackland H, Stein S, Li Q, Radziewicz R, Williams S, Sigal LH.  Center for Advanced Biotechnology and

Medicine, Piscataway, NJ.

“A monoclonal antibody (H9724), specific for the 41-kDa flagellar protein of the Lyme disease pathogen Borrelia b

urgdorferi, cross-reacts with human axons and detects one major protein in human neuroblastoma cell extracts. The 

homologous cross-reacting protein has now been isolated from calf adrenal and identified as chaperonin-HSP60 by 

N-terminal sequencing.” PMID: 8096152

This citation demonstrates the need for a formal physician education program in Rhode Island.  In 2000, South 

County Hospital invited Dr. Sigal to come and speak about Fibromyalgia at their Annual “Diseases of Summer” 

Conference.  Fibromyalgia is not a disease of summer, nor is it associated with antibodies to heat shock proteins,

 particularly.

The 60-62 kD Bb heat shock protein is not a CDC antigen.  That an antibody to a heat shock protein from 

Bb sonicate shows up in a patient with suspected TBDs implies simply that:  The patient has a heat shock protein

antibody that they are reacting to, not necessarily from Bb, possibly cross-reactive.  The patient may have neurologic 

symptoms, as a consequence.

Some people exposed to bacterial HSPs develop autoimmune disorders.  As a result, research in vaccines is heading in this

direction.  It is thought that exposure to bacterial HSPs before involution of the thymus may protect against autoimmune

disease.  HSPs as vaccines is a direction of research in development of vaccines against MS (a search of the patent database w

ill best reveal the research).  Children tend to have better outcomes from Bb exposure.  Some children with congenital Lyme

exposure and persisting antibodies have no illness symptoms.  They may have thus become immune tolerant.  Others clearly

do not fair as well, as is seen also in congenital syphilis. 

 

QUALIFYING PATIENT PRESENTATION

 

The current state of the art in analysis of the psychological condition of TBDs patients is that many of the neuropsychiatric

testing instruments typically employed have not been validated against the presence of the biophysical markers of disease

state.  Neuroborreliosis patients present with psychiatric symptoms ranging from mild depression to psychosis, but essentially

fall within the scope of a mild Delirium, as described by the Comprehensive Textbook of Psychiatry, 2002.   The following is

an older, but adequate description:

 

DELIRIUM-Diagnostic Criteria

• Reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli.

  Thus at least 1 of:

  • Questions had to be repeated because attention wandered
  • Perseverated answers to previous questions
• Disorganized thinking
• Confusion developed over a short period of time
• Fluctuating level of confusion
• At least 2 out of 6 of:
  • Reduced level of consciousness
  • Perceptual disturbances
  • Disturbance of sleep-wake cycle
  • Increased or decreased psychomotor activity
  • Disorientation to time, place, or person
  • Memory impairment
• Either of the following:
  • Evidence that an organic factor initiated and maintained this confusion
  • Confusion cannot be accounted for by any nonorganic mental disorder

 

Associated Features

• Learning Problem
• Dysarthria/Involuntary Movement
• Hypoactivity
• Psychotic
• Euphoric Mood
• Depressed Mood
• Somatic/Sexual Dysfunction
• Hyperactivity
• Addiction
• Sexually Deviant Behavior

 

Differential Diagnosis

Schizophrenia; Schizophreniform Disorder; and other psychotic disorders; Dementia; Factitious Disorder with Psychological

Symptoms.

Internet Mental Health (www.mentalhealth.com) copyright © 1995-2000 by Phillip W. Long, M.D.

Since *0602 is associated with Lupus, MS, and narcolepsy as well, it must be noted that there are recognized psychiatric

manifestations.  There may be infectious etiologies of mental illnesses.  Yale University recently undertook study of the

treatment of children with a susceptibility to Staphylococcus infection and the noted resultant development of Obsessive

Compulsive Disorder (Pediatric Autoimmune Neuropsychiatric Diseases Disorder Associated With Group A Streptococcal

Infection (PANDAS) and performed a clinical trial of treating these patients with prophylactic antibiotics. 

 

Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects., Am J 

sychiatry  2002 Feb;159(2):297-301, Hajek T, Paskova B, Janovska D, Bahbouh R, Hajek P, Libiger J, Hoschl C., 

Prague Psychiatric Center, Department of Epidemiology, Charles University, Third Faculty of Medicine, Czech Republic

“OBJECTIVE: Borrelia burgdorferi infection can affect the CNS and mimic psychiatric disorders. It is not known 

whether Borrelia burgdorferi contributes to overall psychiatric morbidity. The authors compared the prevalence of 

antibodies to Borrelia burgdorferi in groups of psychiatric patients and healthy subjects to find out whether there is 

an association between this infection and psychiatric morbidity. METHOD: Between 1995 and 1999 the authors 

screened for antibodies to Borrelia burgdorferi in 926 psychiatric patients consecutively admitted to Prague Psychiatric 

Center. They compared the results of this screening with findings from 884 consecutive healthy subjects who took

 part in an epidemiological survey of antibodies to Borrelia burgdorferi in the general population of the Czech Republic. 

Sera were tested by means of enzyme-linked immunosorbent assay. Circulating immune complexes were isolated

by polyethylene glycol precipitation. To control for potential confounders, the two groups of patients and healthy 

subjects were matched according to gender and age. Results were obtained in a sample of 499 matched pairs. 

RESULTS: Among the matched pairs, 166 (33%) of the psychiatric patients and 94 (19%) of the healthy comparison 

subjects were seropositive in at least one of the four assays.  CONCLUSIONS: These findings support the hypothesis 

that there is an association between Borrelia burgdorferi infection and psychiatric morbidity. In countries where this 

infection is endemic, a proportion of psychiatric inpatients may be suffering from neuropathogenic effects of Borrelia 

burgdorferi.” PMID: 11823274

HLA-DR4 and Lyme Arthritis:

Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of 

Borrelia burgdorferi., Infect Immun  1993 Jul;61(7):2774-9, Kalish RA, Leong JM, Steere AC, Division of Rheumatology

/Immunology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111.

“Chronic Lyme arthritis that is unresponsive to antibiotic therapy is associated with an increased frequency of the HLA-DR4 

specificity. To determine whether the immune response to a particular polypeptide of Borrelia burgdorferi may be associated 

with treatment-resistant chronic Lyme arthritis, we correlated the clinical courses and HLA-DR specificities of 128 patients 

with Lyme disease with their antibody responses to spirochetal polypeptides. Antibody reactivity was determined by Western 

blotting (immunoblotting) with sonicated whole B. burgdorferi and recombinant forms of its outer surface proteins, OspA and 

OspB, as the antigen preparations. Of 15 patients monitored for 4 to 12 years, 11 (73%) developed strong immunoglobulin G 

responses to both OspA and OspB near the beginning of prolonged episodes of arthritis, from 5 months to 7 years after 

disease onset. When single serum samples from 80 patients with Lyme arthritis, were tested, 57 (71%) showed antibody 

reactivity to recombinant Osp proteins; in contrast, none of 43 patients who had erythema migrans or Lyme meningitis 

(P < 0.00001) and 1 of 5 patients who had chronic neuroborreliosis but who never had arthritis (P = 0.03) showed antibody 

reactivity to these proteins. Among the 60 antibiotic-treated patients with Lyme arthritis, those with the HLA-DR4 specificity 

and Osp reactivity had arthritis for a significantly longer time after treatment than those who lacked Osp reactivity (median

 duration, 9.5 versus 4 months; P = 0.009); a similar trend was found for the HLA-DR2 specificity. For other HLA-DR 

specificities, arthritis resolved within a median duration of 2 months in both Osp-reactive and nonreactive patients. We 

conclude that the combination of the HLA-DR4 specificity and OspA or OspB reactivity is associated with chronic arthritis 

and the lack of a response to antibiotic therapy.PMID: 7685738

Rheumatoid Arthritis and HLA-DR4

Rheumatoid arthritis (RA)-associated HLA-DR alleles form less stable complexes with class II-associated

invariant chain peptide than non-RA-associated HLA-DR alleles., J Immunol  2001 Dec 15;167(12):7157-68, Patil NS, 

Pashine A, Belmares MP, Liu W, Kaneshiro B, Rabinowitz J, McConnell H, Mellins ED., Department of Pediatrics, 

Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. npatil@genencor.com

“Certain HLA-DR alleles confer strong susceptibility to the autoimmune disease rheumatoid arthritis (RA). We compared 

RA-associated alleles, HLA-DR*0401, HLA-DR*0404, and HLA-DR*0405, with closely related, non-RA-associated alleles, 

HLA-DR*0402 and HLA-DR*0403, to determine whether they differ in their interactions with the class II chaperone, 

invariant chain (Ii). Ii binds to class II molecules in the endoplasmic reticulum, inhibits binding of other ligands, and directs 

class II-Ii complexes to endosomes, where Ii is degraded to class II-associated Ii peptide (CLIP). To evaluate the 

interaction of Ii and CLIP with these DR4 alleles, we introduced HLA-DR*0401, *0402, and *0404 alleles into a human 

B cell line that lacked endogenous HLA-DR or HLA-DM molecules. In a similar experiment, we introduced HLA-DR*0403 

and *0405 into an HLA-DM-expressing B cell line, 8.1.6, and its DM-negative derivative, 9.5.3.  Surface abundance of 

DR4-CLIP peptide complexes and their susceptibility to SDS-induced denaturation suggested that the different DR4-CLIP 

omplexes had different stabilities. Pulse-chase experiments showed CLIP dissociated more rapidly from RA-associated 

DR molecules in B cell lines. In vitro assays using soluble rDR4 molecules showed that DR-CLIP complexes of DR*0401 

and DR*0404 were less stable than complexes of DR*0402. Using CLIP peptide variants, we mapped the reduced CLIP 

interaction of RA-associated alleles to the shared epitope region. The reduced interaction of RA-associated HLA-DR4 

molecules with CLIP may contribute to the pathophysiology of autoimmunity in RA.”  PMID: 11739539

If autoimmune phenomena are generally thought to occur post-infection, then Dr. Klempner has surely found a neuroautoimmune

haplotype in great frequency in the seronegative borreliosis patients, which, if it had been reported, would have lent credibility

to patient complaints of chronic illness.  Instead, the public relations’ focus announced, far and wide, that patients should not

be given “long term” antibiotic treatment.  The degree of political ferocity behind these machinations, is evidenced by Klempner’s

suggestion to NEJM editors, that his “results” be “Early Released” in June instead of July, 2001, at the beginning of tick-infection

season.  Very important data regarding the neuroautoimmune association with markers of pathophysiology found in Chronic Lyme

patients (MMPs and *0602) was not reported in the NEJM, but Dr. Klempner mentioned these findings at the South County

Hospital “Diseases of Summer Conference”, 2001. 

 

SUMMARY OF RI TBDs MANAGEMENT OBJECTIVES

 A  statewide physician education program is clearly necessary to patient management.

 Improved surveillance for known and new TBDs, i.e., The development of a sentinel TBDs identification database and DNA

ident/sequencing.

 Immediate testing improvement measures via the discontinuation of the use of  labs that fail to report correctly or use even

the current US recommended stains.

 The development of a patient/pathology database to identify cohorts of patients who would be eligible for neuroprotective

regimens such as MMP inhibition, therapeutic kynurenines, or whatever is on the horizon in new antibiotic trials, blood brain

barrier, physical, and cognitive rehabilitation after resolution of infections, when or if that becomes possible. 

===

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