Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease

J Med Microbiol. 2006 Jul;55(Pt 7):947-52.

Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease.

Ikejima H, Friedman H, Yamamoto Y.

1Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, FL 33612, USA.

Chlamydia pneumoniae is the aetiological cause of a wide variety of chronic inflammatory diseases and may be associated with neurological disease. Microbiological and immunological aspects of the interaction between C. pneumoniae and the central nervous system (CNSi) are not well understood because of the lack of a suitable infection model for neuronal studies. In the present study, an in vitro C. pneumoniae infection model was developed in the established microglial cell line EOC 20. Infection of the cells resulted in obvious induction of proinflammatory cytokines. The infection also selectively induced matrix metalloproteinase-9 (MMP-9) but not MMP-2. Moreover, beta interferon, which is known to modulate CNS disease, inhibited induction of MMP-9 following C. pneumoniae infection. These results support the view that C. pneumoniae infection may be associated with marked alteration of the ability of microglial cells to enhance cytokine production as well as induction of an MMP.

PMID: 16772424 [PubMed - in process]

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Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjögren's syndrome

YrjöT. Konttinen1, 2, Sirkka Halinen1, Roeland Hanemaaijer3, Timo Sorsa4, Jarkko Hietanen5, Arnoldas Ceponis1, 2, Jing-Wen Xu1, Rolf Manthorpe6, Joy Whittington7, Åke Larsson8, Tuula Salo9, Lars Kjeldsen10, Ulf-Håkan Stenman11 and Arthur Z. Eisen12

1 Department of Anatomy, University of Helsinki, Helsinki, Finland
2 Department of Medicine/Rheumatology, University of Helsinki, Helsinki, Finland
3 Gaubius Laboratory, Leiden, The Netherlands
4 Department of Oral Surgery, Periodontology, University of Helsinki, Helsinki, Finland
5 Department of Oral Pathology, University of Helsinki, Helsinki, Finland
6 Sjögren's Syndrome Research Center, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden
7 Medgar Evers College, Brooklyn, New York, USA
8 Department of Oral Pathology, University of Lund, Lund, Sweden
9 Department of Pathology and Oral Surgery, University of Oulu, Oulu, Finland
10 Department of Hematology, Finsen Center, University Hospital, Copenhagen, Denmark
11 Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
12 Department of Dermatology, Washington University School of Medicine at Washington University Medical Center, St. Louis, Missouri, USA

Received 2 February 1998;  accepted 23 June 1998.  Available online 11 October 2002.


Department of Anatomy, University of Helsinki, Helsinki, Finland Department of Medicine/Rheumatology, University of Helsinki, Helsinki, Finland Gaubius Laboratory, Leiden, The Netherlands Department of Oral Surgery, Periodontology, University of Helsinki, Helsinki, Finland Department of Oral Pathology, University of Helsinki, Helsinki, Finland Sjögren's Syndrome Research Center, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden Medgar Evers College, Brooklyn, New York, USA Department of Oral Pathology, University of Lund, Lund, Sweden Department of Pathology and Oral Surgery, University of Oulu, Oulu, Finland Department of Hematology, Finsen Center, University Hospital, Copenhagen, Denmark Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland Department of Dermatology, Washington University School of Medicine at Washington University Medical Center, St. Louis, Missouri, USA Received 2 February 1998;  accepted 23 June 1998.  Available online 11 October 2002. Abstract

Type IV collagenases/gelatinases (matrix metalloproteinases MMP-2 and MMP-9) in labial salivary glands (LSG) and saliva in Sjögren's syndrome (SS) and healthy controls were studied. Zymograms and Western blots disclosed that SS saliva contained 92/82 kD MMP-9/type IV collagenase duplex. Specific activity measurement disclosed 53.1 ± 9.8 U/mg protein MMP-9 in SS compared to 16.5 ± 2.6 U/mg in healthy controls (p = 0.01). MMP-2 did not differ between SS and controls. In SS salivary glands, MMP-2 and MMP-9 were also expressed, in addition to stromal fibroblasts and occasional infiltrating neutrophils, respectively, in acinar end piece cells. In addition, an effective proMMP-9 activator, human trypsin-2 (also known as tumor-associated trypsin-2 or TAT-2), was found in acinar end piece cells and in saliva. Interestingly, proteolytically processed MMP-9 was found in saliva (vide supra), and in vivo activated MMP-9 was significantly higher in SS than in controls (p = 0.002). LSGs, particularly in SS, were characterized ultrastructurally by areas containing small cytoplasmic vesicles in the basal parts of the epithelial cells associated with areas of disordered and thickened basal lamina. Based on our results, we conclude here that SS saliva contains increased concentrations of MMP-9, which is of glandular origin in part. Pro MMP-9 is to a large extent proteolytically activated. This is probably mediated by the most potent pro MMP-9 activator found in vivo thus far, namely trypsin-2. Therefore, the MMP-9/trypsin-2 cascade may be resposible for the increased remodelling and/or structural destruction of the basement membrane scaffolding in salivary glands in SS. Due to the role of basal lamina as an important molecular sieve and extracellular matrix-cell signal, these pathological changes may contribute to the pathogenesis of the syndrome.

Author Keywords: gelatinase associated lipocalin; matrix metalloproteinase; Sjogren syndrome; tissue inhibitor of metalloproteinases-1(TIMP-1); tumor associated trypsin-2 (TAT-2)

Abbreviations: ECM, extracellular matrix; LSG, labial salivary glands; MMP, matrix metalloproteinase; NGAL, gelatinase associated lipocalin; PMN, polymorphonuclear neutrophil; SS, Sjögren's syndrome



200mg doxyi daily, 500 zithromax mwf,flagyli 1000 m-fri.rifampin 2x daily,chloestryramine 2x daily

Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjögren's syndrome

YrjöT. Konttinen1, 2, Sirkka Halinen1, Roeland Hanemaaijer3, Timo Sorsa4, Jarkko Hietanen5, Arnoldas Ceponis1, 2, Jing-Wen Xu1, Rolf Manthorpe6, Joy Whittington7, Åke Larsson8, Tuula Salo9, Lars Kjeldsen10, Ulf-Håkan Stenman11 and Arthur Z. Eisen12

1 Department of Anatomy, University of Helsinki, Helsinki, Finland
2 Department of Medicine/Rheumatology, University of Helsinki, Helsinki, Finland
3 Gaubius Laboratory, Leiden, The Netherlands
4 Department of Oral Surgery, Periodontology, University of Helsinki, Helsinki, Finland
5 Department of Oral Pathology, University of Helsinki, Helsinki, Finland
6 Sjögren's Syndrome Research Center, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden
7 Medgar Evers College, Brooklyn, New York, USA
8 Department of Oral Pathology, University of Lund, Lund, Sweden
9 Department of Pathology and Oral Surgery, University of Oulu, Oulu, Finland
10 Department of Hematology, Finsen Center, University Hospital, Copenhagen, Denmark
11 Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
12 Department of Dermatology, Washington University School of Medicine at Washington University Medical Center, St. Louis, Missouri, USA

Received 2 February 1998;  accepted 23 June 1998.  Available online 11 October 2002.


Department of Anatomy, University of Helsinki, Helsinki, Finland Department of Medicine/Rheumatology, University of Helsinki, Helsinki, Finland Gaubius Laboratory, Leiden, The Netherlands Department of Oral Surgery, Periodontology, University of Helsinki, Helsinki, Finland Department of Oral Pathology, University of Helsinki, Helsinki, Finland Sjögren's Syndrome Research Center, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden Medgar Evers College, Brooklyn, New York, USA Department of Oral Pathology, University of Lund, Lund, Sweden Department of Pathology and Oral Surgery, University of Oulu, Oulu, Finland Department of Hematology, Finsen Center, University Hospital, Copenhagen, Denmark Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland Department of Dermatology, Washington University School of Medicine at Washington University Medical Center, St. Louis, Missouri, USA Received 2 February 1998;  accepted 23 June 1998.  Available online 11 October 2002. Abstract

Type IV collagenases/gelatinases (matrix metalloproteinases MMP-2 and MMP-9) in labial salivary glands (LSG) and saliva in Sjögren's syndrome (SS) and healthy controls were studied. Zymograms and Western blots disclosed that SS saliva contained 92/82 kD MMP-9/type IV collagenase duplex. Specific activity measurement disclosed 53.1 ± 9.8 U/mg protein MMP-9 in SS compared to 16.5 ± 2.6 U/mg in healthy controls (p = 0.01). MMP-2 did not differ between SS and controls. In SS salivary glands, MMP-2 and MMP-9 were also expressed, in addition to stromal fibroblasts and occasional infiltrating neutrophils, respectively, in acinar end piece cells. In addition, an effective proMMP-9 activator, human trypsin-2 (also known as tumor-associated trypsin-2 or TAT-2), was found in acinar end piece cells and in saliva. Interestingly, proteolytically processed MMP-9 was found in saliva (vide supra), and in vivo activated MMP-9 was significantly higher in SS than in controls (p = 0.002). LSGs, particularly in SS, were characterized ultrastructurally by areas containing small cytoplasmic vesicles in the basal parts of the epithelial cells associated with areas of disordered and thickened basal lamina. Based on our results, we conclude here that SS saliva contains increased concentrations of MMP-9, which is of glandular origin in part. Pro MMP-9 is to a large extent proteolytically activated. This is probably mediated by the most potent pro MMP-9 activator found in vivo thus far, namely trypsin-2. Therefore, the MMP-9/trypsin-2 cascade may be resposible for the increased remodelling and/or structural destruction of the basement membrane scaffolding in salivary glands in SS. Due to the role of basal lamina as an important molecular sieve and extracellular matrix-cell signal, these pathological changes may contribute to the pathogenesis of the syndrome.

Author Keywords: gelatinase associated lipocalin; matrix metalloproteinase; Sjogren syndrome; tissue inhibitor of metalloproteinases-1(TIMP-1); tumor associated trypsin-2 (TAT-2)

Abbreviations: ECM, extracellular matrix; LSG, labial salivary glands; MMP, matrix metalloproteinase; NGAL, gelatinase associated lipocalin; PMN, polymorphonuclear neutrophil; SS, Sjögren's syndrome



200mg doxyi daily, 500 zithromax mwf,flagyli 1000 m-fri.rifampin 2x daily,chloestryramine 2x daily

I like the Cpni carry-over inferred by linking these two pieces, but would someone who speaks both Medical-ese and English please translate or paraphrase the meanings and linkage implications in these abstracts for us non-med types?  Thanks, Cypriane

Joyce~caregiver-advocate in Dallas for Steve J (SPMSi).  CAPi since August 06, Cpni, Mpn, B. burgdorferi, systemic candidiasis, EBVi, CMV & other herpes family viral infectionsi, elevated heavy metals, gluten+casein sensitivity. 

This articles links infection with brain tumors.

http://www.livescience.com/humanbiology/061212_sibling_tumors.html

Combined Antibiotic Protocol for chlamydia pneumoniae in fibromyalgiai, interstitial cystitisi, sinus: minocycline, Zithromycin, Tinidazole or Flagyli

minocycline, azithromycine, metronidazole 2007-2009, chelation for lead poisoning, muscle pain, insomnia, interstitial cystitisi (almost well), sinus, dry eyes, stiff neck, veins, hypothyroid, TMJ, hip joints (no longer hurt)

Article 1: MMP-9 is selectively upregulated by Cpni. Article 2: MMP-9 upregulation is implicated in Sjogrens Syndrome. This activation may be via trypsin-2 and may cause the remodeling/destruction of the basement membrane seen in SS salivary glands.

Thats it in a nutshell-hope that makes sense! As a biochemist I would comment that this type of speculative association holds no weight at all, and I would like to see some evidence of Cpn presence in SS before even implying that the two were linked! [As a scientist I would really like to see the whole paper and look at the quality of their research too, but abstracts are often all you can get for free...]

Dan

MBioChem, currently studying medicine, research project on Cpni and atherosclerosis

Dan, I did a quick google for "Sjogren chlamydia" and didn't find anything perfectly fitted, but I did find 

Amplification of autoimmune disease by infection, David N Posnett and Dmitry Yarilin; Arthritis Research & Therapy 2005, 7:74-84 (Full-text, yet!)

There's a handy chart of henchmen organisms, and the citations have a good number of Sjogren  henchmen articles, but nothing specifically relating Sjogren's to chlamydia pneumoniae.

The article itself discusses the association of various persistent microorganisms with autoimmune disease, and I believe begs the question of whether the autoimmune disease or organism came first. Still, they do recommend considering antimicrobials for autoimmune diseasesi, which is some gain.

Ron 

On CAPi for CFSi starting 01/06 (NE Ohio, USA)

Currently: doxyi & zithi -- continous; metronidazole -- 4days on, 7 days off.

Ron

On CAPi for CFSi starting 01/06 (NE Ohio, USA)

Began rifampin trial 1/14/09

Currently: on intermittent

Dan,

I have classic reactions to treatment. That tells me I am on the right road. Not much research on sjogren's all together. Before vanderbilt linked cpni to msi there was not a link to that. Like sarah has said these articles are just another piece of the puzzle that fit. I had pnuemonia at 25 and could not tolerate antibioticsi after that. My husband had RA and dog has lupus. I have no family history of autoimmune so in my head it is something infectious. I tested positive for cpn. My reactions are almost identical to sarah first pulse not much  second floored me 5 pulse left me with reflex dystrophy. I hope you are not on here to refute and analyze every article. This is a support group. I assume you are not sick. When you walk a day in our shoes you would realize that hope is everything. I could go on but I won't. I think you get my point. My advice go find an article on sjogren;s and cross correlate it with  the way cpn behaves and you will get a hit everytime. If the pharm company's would get that butts our of research you might find some real answers.

Here is your article

Korean J Intern Med. 2006 Jun;21(2):116-9. Related Articles, Links

Concurrence of Sjogren's syndrome in a patient with Chlamydia-induced reactive arthritis; an unusual finding.

Chang HK, Bang KT, Lee BH, Kim JH, Bae KW, Kim MJ, Kim SK.

this one was found by Lee:

Department of Internal Medicine, College of Medicine, Dankook University, Cheonan, Korea.

A 40-year-old Korean man presented with painful swelling and tenderness of both ankle joints as well as the plantar surfaces of both feet, along with inflammatory back pain, and a purulent discharge from the urethral orifice. The patient also complained of sicca-like symptoms including dry eyes and dry mouth. An immunological analysis revealed a high titer of rheumatoid factor, positive results for antinuclear antibody and anti-Ro antibody, and a positive result for HLA-B27. An antibody titer for Chlamydia was also significantly increased. Positive results of the Schirmer's test and for keratoconjunctivitis sicca were confirmed by an ophthalmologist. These clinical manifestations were compatible with Chlamydia-induced reactive arthritis (ReA) accompanied by Sjogren's syndrome (SS). This is the first report of the combination of these two distinct disease entities in the Korean population.

Publication Types:
Case Reports

 

 

 

sjogren's diagnosed 2/03, 200mg minocin daily, mwf zithromax, flagyli every 3 weeks.

200mg doxyi daily, 500 zithromax mwf,flagyli 1000 m-fri.rifampin 2x daily,chloestryramine 2x daily

Ron- This article is a great find! Very informative about some possible links between persistent inflammationi and persistent organisms.

Dan & Lee- As this is both a site for support in CAPi treatment and a place where scientific discussions are had, we have to be mindful of our overall context. Most of us don't have the scientific background to critique the level of detail to each particular study that Dan is alluding to, or folks like Eric Johnson or David Wheldoni. But, while that level of detail is crucial in terms of rigorous scientific proof, it is less so in a discussion which is trying gather the possible links between Cpni and a disease when the rock-solid data is  simply not there. 

In other words, a collection of suggestive, even obliquely,  studies which support the linkage between a hitherto unconnected disease and Cpn that have enough collective weight to warrant an empirical trial of the CAP has primacy here, as our over-riding purpose is scientifically informed treatment, not science per se.

The acknowledged reality is, of course, that we are operating ahead of the science in many things here. Although the CAP is based on sound scientific research and on empirical clinical findings, we all have made the personal choice to take a leap (an informed one at least) beyond the current scientific verities, as those verities have proven clinically useless for treatment of what ails us.

Dan- we welcome your knowledgeable comments here. Every Cpnhelp member is a priceless resource, whether a storehouse of practical treatment experience or a storehouse of scientific training. But please keep in mind the purpose of the particular discussion here. Some are free-brawling scientific arguments. Many are attempts from those who are at the bleeding edge of knowledge, using the CAP successfully in a disease that has little direct evidence of Cpn involvement, and are gathering useful "clouds" of data, or recasting research which has not been looked at in the light of what we are learning about Cpn before. While speculative from a strictly scientific standard, it meets the criteria of utility more than adequately.

CAP for Chlamydia pneumonia since 11/04. 25yrs CFSi & FMSi- Currently: 150mg INHi, 300mg Rifampin, 200 Doxycycline, 500mg mwf Azithromycin, plus 500mg Tinidazole 2x/day pulses every two weeks. Whew! That's a lot! about 60% recovery. Ohio,

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

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