CXCL13 as a putative marker of LNB?

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
RitaA
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Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Tue 26 Mar 2013 9:43

Lorima wrote:On the other hand, it could be dismissed as an "autoimmune" response, as in MS. In that case it would be seen as a justification for trial of "immune modulators", which would be inadvisable if an infection is present.
I just wanted to second Lorima's concern about patients receiving immune modulating therapy if there is even a remote chance that an active infection is present (and possibly masquerading as something else).

http://www.ncbi.nlm.nih.gov/pubmed/21448162
Nat Rev Rheumatol. 2011 Mar 29;7(7):429-34. doi: 10.1038/nrrheum.2011.35.

Autoimmune-like syndromes during TNF blockade: does infection have a role?

Prinz JC.

Source

Department of Dermatology and Allergology, Ludwig-Maximilians University of Munich, Frauenlobstraße 9-11, D-80337 Munich, Germany.

Tumor necrosis factor (TNF) antagonists are effective treatments for immune-mediated inflammatory disorders. The most dreaded adverse events associated with these agents are severe infections. Occasionally, patients develop autoimmune-like syndromes (AILS), which include episodes of lupus-like syndrome, multiple-sclerosis-like demyelination and inflammatory neuropathies. The underlying pathologic mechanisms of these syndromes remain, however, matters of debate. Evidence indicates that the onset of systemic lupus erythematosus, inflammatory nervous system demyelination or peripheral neuropathies in the general population may have infectious etiologies. This article discusses whether infectious agents might also have a role in the development of AILS during anti-TNF therapy. TNF antagonists might facilitate the dissemination of dormant or newly acquired viral or bacterial infections, which either directly promote symptoms that mimic autoimmune diseases or break immunological tolerance and induce autoimmunity in predisposed individuals. The occurrence of AILS during TNF blockade should, therefore, lead to reliable infection screening strategies to identify infection-induced autoimmunity and autoimmune mimics.

PMID:
21448162
[PubMed - indexed for MEDLINE]
I think infection screening PRIOR to TNF antagonist or any other immune modulating therapy should be mandatory.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004926/
PubMed Clinical Q&A.

Comparing Targeted Immune Modulators

Laura Dean, MD.

Created: November 21, 2012.

Targeted immune modulators (also referred to as biologics) form a relatively new class of drugs for diseases with chronic inflammation and an inappropriate immune response. Such diseases include rheumatoid arthritis, psoriasis, and inflammatory bowel diseases.

These drugs work by selectively blocking steps in the inflammatory and immune cascades. For example, abatacept and alefacept dampen the immune response by interfering with the activation of T cells, while adalimumab, etanercept, and infliximab target the inflammatory mediator TNF-α.

The "Drug Class Review on Targeted Immune Modulators" compares the safety and effectiveness of twelve drugs. A summary of the findings is below.

[snip]

Drugs included in this review

Generic Name / Trade Names
Abatacept / Orencia
Adalimumab / Humira
Alefacept / Amevive
Anakinra / Kineret
Certolizumab pegol / Cimzia
Etanercept / Enbrel
Golimumab / Simponi
Infliximab / Remicade
Natalizumab / Tysabri
Rituximab / Rituxan
Tocilizumab / Actemra
Ustekinumab / Stelara

RitaA
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Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Tue 26 Mar 2013 22:55

http://infectious-diseases.jwatch.org/c ... 2011/406/3
Diagnosing Lyme Neuroborreliosis

High cerebrospinal fluid levels of the chemokine CXCL13 were found in patients with acute untreated CNS Lyme disease.

Diagnosing central nervous system (CNS) Lyme disease — Lyme neuroborreliosis — is difficult. Currently, the most definitive test involves comparing the concentrations of Borrelia burgdorferi–specific antibodies in concurrent cerebrospinal fluid (CSF) and serum samples. European investigators recently observed that CSF concentrations of a B-cell attractant chemokine, CXCL13, appeared to be elevated in patients with Lyme neuroborreliosis. Now, researchers have prospectively assessed the usefulness of CSF CXCL13 levels in diagnosing this condition. (One of the researchers has a patent pending on a related rapid test.)

The study involved 192 patients at a Munich, Germany, hospital who had CSF and serum samples submitted for B. burgdorferi–specific antibody testing between March 2008 and August 2009; all had CSF pleocytosis. Of the 14 patients who showed definitive evidence of acute neuroborreliosis, 4 were still untreated. CSF and serum samples (collected between August 2000 and November 2005) were also available for 13 additional patients with definite and untreated Lyme neuroborreliosis.

For the 17 patients with Lyme neuroborreliosis whose samples were obtained before antibiotic therapy, CSF CXCL13 concentrations ranged from 697 to 45,357 pg/mL (mean, 15,149 pg/mL). Concentrations were less elevated for the 10 patients with this condition who had already received appropriate antibiotic therapy: 1192 to 1552 pg/mL for the 5 patients treated for <14 days and 39 to 666 pg/mL for the 5 treated for ≥14 days. The mean concentration for the 178 patients with other diagnoses (primarily multiple sclerosis and viral meningitis) was 247 pg/mL. Only seven of these patients — five with CNS lymphoma and two with bacterial meningitis — had levels >1229 pg/mL, giving this cutoff a sensitivity of 94% and a specificity of 96%.

Comment: These results are encouraging, but the usefulness of the identified cutoff must be prospectively assessed. In addition, as the authors note, the underlying borrelial species were not determined, and many of the patients with Lyme neuroborreliosis were likely infected with Borrelia garinii. Thus, whether the present findings can be generalized to patients in North America (where only B. burgdorferi is endemic) is unknown.

— Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases April 6, 2011

Citation(s):

Schmidt C et al. A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 2011 Mar 22; 76:1051.
Edited to add: The link above no longer works unless you are a Journal Watch subscriber, but I did come across the content on a regular Google search. I haven't located the CXCL13 rapid test patent yet.

The following is an automatic translation from German to English:

http://www.rhoen-klinikum-ag.com/rka/cm ... 84722.html
Who runs the Outpatient Clinic for neuroborreliosis?

Directed the Outpatient Clinic of Professor Dr. med Tobias Rupprecht, consultant neurologist and senior physician at the hospital in Dachau. Dr. Rupprecht was previously ten years at the University Hospital Munich-Grosshadern worked there and has published many scientific papers for neuroborreliosis and treats patients with neuroborreliosis. He was also in the group of Prof. Pfister instrumental in the development of the biomarker CXCL13. For this he received the 2007 Foundation Award of the German Society of CSF (cerebrospinal fluid analysis). Dr. Rupprecht is a coauthor of the European guidelines for the diagnosis and treatment of neuroborreliosis.

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panda
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Re: CXCL13 as a putative marker of LNB?

Post by panda » Wed 27 Mar 2013 4:57

@ Rita

The patent 'vanished' meanwhile, but was registered in 2010 at "Deutsches Patent- und Markenamt", Munich.
CXCL13_Patent_Rupprecht.jpg
CXCL13_Patent_Rupprecht.jpg (162.31 KiB) Viewed 3291 times
Abstract
Method for rapid test of neuroborreliosis, comprises dripping fluid from cerebrospinal fluid to a portion of a test strip and subsequently reading an optical indicator in a different section of the test strip. An independent claim is included for an apparatus for the rapid test of neuroborreliosis, comprising a bibulous test strip that divided into several sections, where: in a first section (1), a zone is located that is designed for the dripping of cerebrospinal fluid liquid; in a second section (2), dye-labeled, non-human anti-C-X-C motif chemokine 13 (CXCL13) antibodies are located; in a third section (3), adherent anti-CXCL13 antibody is located on the test strip in low concentrations; in a fourth section (4), adherent anti-CXCL13 antibody is located on the test strip in high concentrations; and in a fifth section (5), adherent antibody against the non-human anti-CXCL13 antibody is located on the test strip.
One could assume that measuring CXCL13 with special anti-CXCL13 antibodies really is no new invention.

Panda

RitaA
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Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Wed 27 Mar 2013 7:07

Thank you, Panda!
panda wrote:One could assume that measuring CXCL13 with special anti-CXCL13 antibodies really is no new invention.
I wondered about that too at one point. The closest thing I could find was this patent where there is a reference to a 2006 article by Rupprecht et al:

http://www.patentgenius.com/patent/8182811.html
8182811 Antibodies to CXCL13

[snip]

Rupprecht, T. et al., 2006, "Zyktokin CXCL13 Ein fruher Liquormarker fur die Neuroborreliose", Nervenarzt, 77:470-473. (English language abstract found within reference at p. 472). cited by other.
(Please forgive me if the following has already been posted earlier in this thread. I'm losing track because all the article titles are starting to look the same to me.)

The article (in German) is here:

http://link.springer.com/article/10.100 ... rue#page-1

I found a French/English entry, along with the translated article title (from German to English) and an English abstract here:

http://cat.inist.fr/?aModele=afficheN&cpsidt=17673470
Titre du document / Document title

Zyktokin CXCL13 : Ein früher Liquormarker für die Neuroborreliose? = Cytokine CXCL13 - : a possible early CSF marker for neuroborreliosis

Auteur(s) / Author(s)
RUPPRECHT T. ; KOEDEL U. ; ANGELE B. ; FINGERLE V. ; PFISTER H.-W. ;
Résumé / Abstract

The definitive diagnosis of acute neuroborreliosis (NB) is based upon the presence of lymphomonocytic CSF pleocytosis and intrathecal Borrelia burgdorferi (B.b.)-specific antibody production (expressed by an antibody index of >2). However, the latter might be absent in early stages of the disease. Now a recently discovered additional CSF marker-the cytokine CXCL13-was found to be positive in every initial CSF sample from patients with NB and therefore could be a valuable tool for early diagnosis and initiation of antibiotic therapy. We report an unusual case of NB in a patient with a history of metastatic carcinoma of the prostate and unilateral polyradiculitis. While no intrathecal B.b.-specific antibody production could be demonstrated initially, the CSF CXCL13 level was high (>500 ng/g vs <1.7 ng/g in healthy controls). During the course of the disease, the antibody index turned positive (4.8) and the patient responded to antibiotic therapy, thus confirming the diagnosis. In this case, measuring CXCL13 in the CSF would have led to earlier diagnosis and treatment of NB.

Revue / Journal Title
Nervenarzt ISSN 0028-2804 CODEN NERVAF
Source / Source
2006, vol. 77, no4, [Note(s): 470-473 [3 p.]]
Langue / Language
Allemand [German]
Here's the PubMed entry:

http://www.ncbi.nlm.nih.gov/pubmed/16308679

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panda
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Re: CXCL13 as a putative marker of LNB?

Post by panda » Wed 27 Mar 2013 8:37

And one more:

Scand J Infect Dis. 2013 Mar 22. [Epub ahead of print]
Cerebrospinal fluid chemokine CXCL13 in the diagnosis of neuroborreliosis in children.
Sillanpää H, Skogman BH, Sarvas H, Seppälä IJ, Lahdenne P.
From the Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki , Helsinki , Finland.
Abstract
Background: The diagnosis of Lyme neuroborreliosis (LNB) requires laboratory confirmation because neurological symptoms indicative of LNB are not specific. Recent studies have suggested that a chemokine, CXCL13, could have an important role in the diagnosis of LNB. The aim of this study was to assess CXCL13 levels in the cerebrospinal fluid (CSF) of children with LNB. Methods: CSF samples were available for 57 children with symptoms indicative of LNB. Based on the presence of anti-flagella antibodies and pleocytosis in CSF, patients were divided into 3 different groups: confirmed LNB (n = 24), possible LNB (n = 16), and non-LNB (n = 17). CXCL13 levels were determined with a commercial kit (Quantikine). Results: All 24 patients with confirmed LNB had elevated CXCL13 levels in CSF. Elevated CXCL13 was also observed in the majority of patients without anti-flagella antibodies in the CSF (possible LNB). Of the 17 non-LNB and 50 control samples, 1 was positive. Conclusions: In LNB, the production of CXCL13 in CSF seems to precede antibody production. Assessment of CSF CXCL13 may improve the diagnostics for children with possible LNB.
http://www.ncbi.nlm.nih.gov/pubmed/23521134

RitaA
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Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Fri 12 Apr 2013 5:38

More links to non-borrelia causes of raised CXCL13 levels are included here:

http://www.ncbi.nlm.nih.gov/gene/10563
CXCL13 chemokine (C-X-C motif) ligand 13 [ Homo sapiens (human) ]

Gene ID: 10563, updated on 7-Apr-2013

RitaA
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Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Wed 9 Mar 2016 0:09

http://www.ncbi.nlm.nih.gov/pubmed/26855687
Adv Neuroimmune Biol. 2015;6(1):1-8. Epub 2015 Nov 13.

Targeting CXCL13 During Neuroinflammation.

Huber AK1, Irani DN1.

Author information

1 Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.

Abstract

The chemokine, C-X-C motif ligand 13 (CXCL13), is constitutively expressed in lymphoid organs and controls the recruitment and compartmentalization of lymphocytes and antigen presenting cells within these specialized structures. Recent data, however, also find induction of this molecule during central nervous system (CNS) inflammation under a variety of circumstances. While its role(s) in the pathogenesis of neoplastic, infectious and autoimmune disorders of the CNS remain incompletely understood, several lines of evidence suggest that CXCL13 could become a relevant therapeutic target in at least some of these diseases. This review focuses on how CXCL13 contributes to the pathogenesis of selected CNS disorders involving both experimental animals and humans, paying particular attention to the issue of whether (and if so, how) blockade of this ligand or its receptor might benefit the host. Current blocking strategies largely involve the use of monoclonal antibodies, but an improved understanding of downstream signaling pathways makes small molecule inhibition a future possibility.

KEYWORDS:

CXCL13; CXCR5; lymphoid chemokines; multiple sclerosis; neuroborreliosis; post-stroke dementia; primary central nervous system lymphoma

PMID: 26855687 [PubMed] PMCID: PMC4743661 Free PMC Article
The full, free article is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743661/

Snippet from the section "CXCL13 EXPRESSION DURING LYME NEUROBORRELIOSIS (LNB)"
CXCL13 levels in the CSF typically fall with antimicrobial treatment [56, 61]; persistent elevations suggest that the pathogen has evaded clearance and remains infective. Again, while local humoral immunity supports pathogen clearance from the CNS [47–50, 62], self-reactive antibodies can also emerge with notable frequency in the setting of chronic infection [63–65]. Some of these antibodies are directed at epitopes such as gangliosides that may be shared between the pathogen and neural tissues [66], but others are directed at myelin or neuronal proteins whose emergence cannot be readily explained by molecular mimicry [64, 65]. If B cells making these anti-myelin antibodies clonally expand within the CNS as one study suggests [65], then how and where they are generated, how they are recruited, and how they persist within the brain requires further study. Chronic LNB remains poorly understood and may in fact represent multiple disorders that in some cases reflect pathogen persistence in the CNS and in others a more bona fide autoimmune process [66].

RitaA
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Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Mon 8 Aug 2016 6:29

http://www.jns-journal.com/article/S002 ... 6/abstract
Prospective study on the chemokine CXCL13 in neuroborreliosis and other aseptic neuroinfections

D. PíchaPress enter key for correspondence informationPress enter key to Email the author, L. Moravcová, D. Smíšková

Department of Infectious Diseases, 2nd Faculty of Medicine, Charles University and Na Bulovce Hospital, Prague, Czech Republic

Publication History

Published Online:May 31, 2016
Accepted:May 30, 2016
Received in revised form:May 20, 2016
Received:October 21, 2015

Highlights

• CSF CXCL13 levels were higher in neuroborreliosis than in viral neuroinfections.
• CXCL13 CSF levels correlated more closely with pleocytosis than with antibody index.
Part of neuroborreliosis patients had positive antibody index and low CXCL13 levels.
• CXCL13 testing could help in early neuroborreliosis with negative antibody index.


Abstract

The study evaluates the clinical significance of CXCL13 (leukocyte chemoattractant synthesized in CSF ) in Lyme neuroborreliosis (LNB) and other aseptic CNS infections.

244 patients with symptoms of neuroinfection and/or LNB were divided into groups: A - patients with LNB-positive antibodies in serum and CSF (96) or CSF only (14); B - patients with aseptic non-borrelial neuroinfections (82); C - negative controls (52). Group A was divided into A1–A4 according to pleocytosis in CSF and AIIgG positivity.

The highest CSF CXCL13 concentrations (max. 81,287.60 pg/ml; median 1766.90 pg/ml) were in A1 (positive AI, pleocytosis) and A3 (negative AIIgG, pleocytosis; max. 7201,60 pg/ml, median 56.22 pg/ml). A2 (positive AI without pleocytosis) and A4 (negative AI without pleocytosis) had low CXCL13 levels - A2 max. 650.50 pg/ml (median < 7.80 pg/ml); A4 max. 118.56 pg/ml (median < 7.8 pg/ml). In B the median was 28.10 pg/ml (max. 595.87 pg/ml). In C the CXCL13 concentrations were the lowest (max. 83.83 pg/ml; median < 7.80 pg/ml). The lowest cut-off was 29 pg/ml (sensitivity 90.0%, specificity 72.2%), the highest one 400 pg/ml (sensitivity 59.6%, specificity 94.0%). The group differences of serum CXCL13 were insignificant.

The highest concentrations were at the beginning of the disease. In LNB CXCL13 correlates better with the CSF pleocytosis than AI positivity.

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ChronicLyme19
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Re: CXCL13 as a putative marker of LNB?

Post by ChronicLyme19 » Wed 17 Aug 2016 1:33

TNF antagonists might facilitate the dissemination of dormant or newly acquired viral or bacterial infections, which either directly promote symptoms that mimic autoimmune diseases or break immunological tolerance and induce autoimmunity in predisposed individuals.
Wasn't that suggested in the post-study letter by the authors of the study that tried to culture an entire damn mouse after giving it antibiotics to prove it was cured? They then gave it TNF-alpha modulators and suddenly they could culture borrelia again. I've always wondered if this could be a good method of getting rid of the persistent borrelia infections. Load the patient up with Humira and high levels of antibiotics and maybe you could get rid of it? I wonder if dapsone or artemisinin modulates TNF-alpha at all...

As a side note for my own case, this thread might help explain why my spinal tap was neg, since I had been on antibiotics for awhile before hand.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

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