CXCL13 as a putative marker of LNB?

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

Post by panda » Sat 11 Aug 2012 15:19

As you all know CXCL13 is a chemokine that is responsible for the trafficking of special immune cells: it is called “B cell-attracting chemokine”. In earlier times CXCL13 was named also BLC or BCA-1. The receptor of CXCL13 is CXCR5 = CD185 = BLR1.

J Exp Med. 1998 Feb 16;187(4):655-60.
B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5.
Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B.
http://www.ncbi.nlm.nih.gov/pubmed/9463416 [abstract]
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed [full text]


Increased levels of CXCL13 – measuring in serum, CSF, and tissue – are found in various diseases, as borreliosis (neuroborreliosis, lymphocytoma), neurosyphilis, relapsing fever, multiple sclerosis, chronic lymphocytic leukemia (CLL), angioimmunoblastic T-cell lymphoma (AITL), prostate cancer, renal inflammation, Sjögren’s syndrome (salivary gland) and others.
Pubmed shows today 547 results searching for CXCL13.


The first scientists examining CXCL13 in connection with lyme disease were Pachner et al. 2002 measuring the chemokine in muscle tissue of Rhesus monkeys:
Increased expression of B-lymphocyte chemoattractant, but not pro-inflammatory cytokines, in muscle tissue in rhesus chronic Lyme borreliosis.
Pachner AR, Dail D, Narayan K, Dutta K, Cadavid D.
Cytokine. 2002 Sep 21;19(6):297-307.
PMID: 12421572
http://www.ncbi.nlm.nih.gov/pubmed/12421572 [abstract]


Since 2005 also neurologists have become aware of the chemokine as a diagnostic marker:

The nervous system as ectopic germinal center: CXCL13 and IgG in lyme neuroborreliosis.
Narayan K, Dail D, Li L, Cadavid D, Amrute S, Fitzgerald-Bocarsly P, Pachner AR.
Ann Neurol. 2005 Jun;57(6):813-23.
PMID: 15929033
http://www.ncbi.nlm.nih.gov/pubmed/15929033 [abstract]
“Lyme neuroborreliosis (LNB) is a chronic infection in which B-cell activation, plasma cell infiltration, and enhanced Ig production in infected tissue are prominent feature. However, little is known about how B cells and plasma cells invade and persist in target organs. To assess this issue, we developed real-time PCR measurements of IgG and CXCL13 production. We used these RNA assays and specific enzyme-linked immunosorbent assays for protein and demonstrated that human peripheral blood mononuclear cells (PBMCs), stimulated by Borrelia burgdorferi sonicate, produced CXCL13 and IgG. Magnetic separation of PBMC populations and flow cytometry showed that CXCL13 is produced by dendritic cells. We then measure the expression of CXCL13 and IgG in tissues and correlated the expression of these host genes with spirochetal load. We also measured expression of dbpA and BBK32, two spirochetal genes important in chronic infection. There was a strong correlation between host immune response gene expression (CXCL13 and IgG) and spirochetal load. Immunohistochemistry of infected nonhuman primates tissue confirmed that CXCL13 is expressed in the nervous system. We conclude that persistent production of CXCL13 and IgG within infected tissue, two characteristics of ectopic germinal centers, are definitive features of LNB.”

Sublime diagnosis of Lyme neuroborreliosis.
Segal BM, Logigian EL.
Neurology. 2005 Aug 9;65(3):351-2. No abstract available.
PMID: 16087895
http://www.neurology.org/content/65/3/351.long

The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis.
Rupprecht TA, Pfister HW, Angele B, Kastenbauer S, Wilske B, Koedel U.
Neurology. 2005 Aug 9;65(3):448-50.
PMID: 16087912
http://www.ncbi.nlm.nih.gov/pubmed/16087912 [abstract]
http://www.neurology.org/content/65/3/448.long
“Using protein expression profiling, the authors identified an upregulation of the chemokine B lymphocyte chemoattractant (BLC) in the CSF of patients with neuroborreliosis but not in patients with noninflammatory and various other inflammatory neurologic diseases. This upregulation was confirmed by ELISA, showing increased BLC levels in every neuroborreliosis patient while being undetectable in patients with noninflammatory neurologic diseases. These results point to BLC as a putative additional diagnostic marker for neuroborreliosis.”

T.A. Rupprecht, part of a German [Munich] lyme experts group, again and again published contributions on CXCL13 as diagnostic marker, supported by his academic teacher H.-W. Pfister. And a prospective recommendation is already included in the guidelines of the German Neurological Society (LNB) => http://www.awmf.org/uploads/tx_szleitli ... eliose.pdf [German].

http://www.ncbi.nlm.nih.gov/pubmed?term ... ]%20CXCL13
http://www.aerztezeitung.de/medizin/kra ... sid=534234 [German, Pfister]

Example:
A prospective study on the role of CXCL13 in Lyme neuroborreliosis.
Schmidt C, Plate A, Angele B, Pfister HW, Wick M, Koedel U, Rupprecht TA.
Neurology. 2011 Mar 22;76(12):1051-8.
PMID: 21422457
http://www.ncbi.nlm.nih.gov/pubmed/21422457 [abstract]
http://www.neurology.org/content/76/12/1051.long

„CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean = 15,149 pg/mL) compared with that in the patients without LNB (mean = 247 pg/mL). At a cutoff of 1,229 pg/mL, the sensitivity of CXCL13 was 94.1%, which is higher than the AI (85.7%). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cutoff, resulting in a specificity equal to the AI of 96.1%. “
CXCL13_Rupprecht2011.jpg
CXCL13_Rupprecht2011.jpg (97.99 KiB) Viewed 5342 times

Compare a study on children and adults with neuroborreliosis:
N. Wutte, CXCL13 Chemokine as a diagnostic marker for Lyme Neuroborreliosis, Master Thesis 2009:
http://forschung.meduni-graz.at/fodok/s ... d_in=97080 [abstract, German]
https://online.medunigraz.at/mug_online ... 2&pOrgNR=1 [full text, pdf]

“We studied the chemokine CXCL13, which is expressed physiologically in secondary lymphatic tissue. During inflammatory processes, like in Lyme Borreliosis, CXCL13 is also expressed ectopically in CSF, serum and inflamed tissues. Our aim was to further investigate the diagnostic significance of CXCL13 as a specific, early marker for neuroborreliosis in serum and CSF and to confirm an expected reduction in CXCL13 levels after therapy. According to current literature CXCL13 levels have not been measured in serum. We analysed 75 CSF/serum samples of children and adult patients with suspected Lyme neuroborreliosis. Patients who did not have neuroborreliosis in later follow-up were used as controls. All patients with definite neuroborreliosis showed significantly elevated CXCL13 levels above 100 pg/ml. In 28,6% of cases, CSF CXCL13 levels were elevated before the production of intrathecal antibodies. Neurological control patients with aseptic meningitis and/or facial palsy as differential diagnosis of neuroborreliosis showed normal CXCL13 levels. This study is the first to analyse CXCL13 levels in children. No significant difference in CXCL13 levels was found compared to adult patients. Serum CXCL13 levels are very variable and do not significantly indicate active borrelial infection of the CNS as does CSF CXCL13. We also determined CXCL13 serum levels with ELISA in 95 patients with chronic Lyme Borreliosis (positive Lyme serology, acrodermatitis chronica atrophicans) and compared them to 13 patients with clinically confirmed acute Lyme Borreliosis and 300 healthy control patients, as well as 87 patients with other dermatoses. Our goal was to determine whether patients with chronic Lyme disease (positive Lyme serology) show elevated CXCL13 serum levels. The cut-off for CXCL13 in serum was found to be best set at 105-115 pg/ml. Because of the great variance of CXCL13 serum levels within the patient groups, CXCL13 serum levels cannot be used as an indicator for active Lyme Borreliosis in patients with positive IgG-antibodies, even though CXCL13 concentration decreases after therapy. Patients with erythema migrans showed normal CXCL13 levels, patients with borrelia lymphocytoma had highly elevated CXCL13 levels. In dermatologic patients with skin cancer, erysipelas, psoriasis vulgaris and autoimmunological dermatoses highly elevated CXCL13 serum levels were found as well.”


Now we have cutoff levels between >100 pg/mL and 1229 pg/mL for CXCL13 in CSF (LNB). Converted into ng/mL that means 0.1–1.229 ng/mL.
MS patients without disrupted blood–brain barrier show CXCL13 values in CSF between 0 and 0.65 ng/mL (s. below Krumbholz et al. 2006, fig. 3B). OIND (other inflammatory neurological diseases; other than multiple sclerosis, including neuroborreliosis, viral inflammatory CNS disease [meningitis, encephalitis, zoster oticus and FSME], intracerebral abscess and mycoplasma meningitis) with disruption of the blood–brain barrier have CXCL13 levels from 0 to 8 ng/mL.
In my opinion that is no specific test for neuroborreliosis, but a marker for local inflammation with invading B cells which regularly produce some kinds of antibodies (immunoglobulins).


But also neurologists investigating multiple sclerosis (MS) claim CXCL13 as a marker for MS.

Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis.
Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A, Gambini C, Mancardi GL, Uccelli A, Pistoia V.
Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11064-9. Epub 2004 Jul 19.
PMID: 15263096
http://www.ncbi.nlm.nih.gov/pubmed/15263096 [abstract]
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed [full text]
“Lymphotoxin-α, CXC ligand (CXCL) 12, and CXCL13, key mediators of lymphoid neogenesis, were present in the CSF from patients with MS and other inflammatory neurological disorders and were expressed in MS brain tissue, with selective localization in the outer layer of the capillary vessel wall. In conclusion, this study suggests that a compartmentalized B cell response occurs within the CNS during an ongoing inflammatory reaction, through a recapitulation of all stages of B cell differentiation observed in secondary lymphoid organs. The presence of lymphotoxin-α, CXCL12, and CXCL13 in the CNS may provide favorable microenvironmental conditions for these events.”


Example:
Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.
Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, Ransohoff RM, Hofbauer M, Farina C, Derfuss T, Hartle C, Newcombe J, Hohlfeld R, Meinl E.
Brain. 2006 Jan;129(Pt 1):200-11. Epub 2005 Nov 9.
PMID: 16280350
http://www.ncbi.nlm.nih.gov/pubmed/16280350 [abstract]
http://brain.oxfordjournals.org/content/129/1/200.long [full text]

“Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing–remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5.”
CXCL13_Krumbholz2006.jpg
CXCL13_Krumbholz2006.jpg (49.09 KiB) Viewed 5342 times
“Among the OIND [= other inflammatory neurological diseases] patients there were great variations in the levels of CXCL13. Both OIND patients without a disrupted BBB and high CXCL13 levels had neuroborreliosis. Not only neuroborreliosis, but also other inflammatory diseases of the CNS were associated with high levels of CXCL13 in the CSF. Eight OIND patients had a CXCL13 level in the CSF >1000 pg/ml. Five of them had acute neuroborreliosis, one a viral encephalitis, one a cerebral abscess and one was diagnosed with a cranial neuritis distinct from neuroborreliosis, since he was repeatedly negative by PCR and antibody testing. Patients with a BBB disturbance had higher CXCL13 levels in the CSF than those without (Fig. 3B). We assume that the higher level of CXCL13 in the CSF of the subgroup of OIND patients with a disturbed BBB due to the higher intensity of CNS inflammation, a more pronounced meningeal involvement, and possibly transfer from blood.”
“Our PCR analysis of a total of 14 multiple sclerosis lesions and the CSF examinations indicated that intracerebral CXCL13 production is a feature of acute inflammation in the CNS.”
“The intracerebral CXCL13 production strongly correlated with intrathecal Ig production, as well as the number of B cells, plasma blasts and T cells in CSF. Thus, CXCL13 is identified as a chemokine that is involved in recruitment of B cells and T cells to the inflamed CNS.”

__________________________________
Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course.
Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg F, Hillert J, Piehl F, Olsson T.
Mult Scler. 2011 Mar;17(3):335-43. Epub 2010 Dec 6.
PMID: 21135023
http://www.ncbi.nlm.nih.gov/pubmed/21135023 [abstract]
http://msj.sagepub.com/content/17/3/335.long
http://www.jensenstiftelsen.se/publikat ... (2010).pdf [pdf]

„CXCL13 was recently demonstrated to be up-regulated in pooled CSFs from patients with Lyme neuroborreliosis, but not in patients with non-Lyme meningitis or other inflammatory neurological disorders. It was therefore suggested as a possible early diagnostic marker in acute Lyme neuroborreliosis. [fn. 20, 21] However, elevated levels of CXCL13 are also evident in CSF during MS relapses, [fn. 17] neurosyphilis, [fn. 22] herpes encephalitis and Epstein–Barr virus encephalitis (present study) indicating that CSF CXCL13 is thus not a disease-specific diagnostic marker. Elevated serum levels of CXCL13 have also been reported in several human diseases, as reviewed by Festa and colleagues. [fn. 23] “

_____________________________________
CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.
Kowarik MC, Cepok S, Sellner J, Grummel V, Weber MS, Korn T, Berthele A, Hemmer B.
J Neuroinflammation. 2012 May 16;9(1):93. [Epub ahead of print]
PMID: 22591862
http://www.ncbi.nlm.nih.gov/pubmed/22591862 [abstract]
http://www.jneuroinflammation.com/conte ... 4-9-93.pdf [full text]

“BACKGROUND:
The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS)compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.
METHODS:
Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry.
RESULTS:
CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with B cells, plasmablasts and intrathecal Ig synthesis.
CONCLUSIONS:
CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.
CXCL13_Kowarik2012.jpg
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Best wishes,
Panda

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Mon 3 Sep 2012 7:49

Panda,

Thanks very much for this great collection of articles. Here are a few additional articles that you may be interested in:

http://www.ncbi.nlm.nih.gov/pubmed/20042073
J Neuroinflammation. 2009 Dec 30;6:42.

The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis.

Rupprecht TA, Plate A, Adam M, Wick M, Kastenbauer S, Schmidt C, Klein M, Pfister HW, Koedel U.

Source

Department of Neurology, Ludwig-Maximilians University, Marchioninistr 15, 81377 Munich, Germany.

Abstract

BACKGROUND:
The chemokine CXCL13 is known to dictate homing and motility of B cells in lymphoid tissue and has been implicated in the formation of ectopic lymphoid tissue in chronic inflammation. Whether it influences B cell trafficking during acute infection, is largely unclear. In previous studies, we showed that (I) CXCL13 levels are markedly increased in the B cell-rich cerebrospinal fluid (CSF) of patients with acute Lyme neuroborreliosis (LNB), and (II) CXCL13 is released by monocytes upon recognition of borrelial outer surface proteins by Toll-like receptor 2. Here, we assessed the role of CXCL13--in comparison to other chemokines--in the recruitment of B cells to the CSF of patients with acute LNB.

METHODS:
Measurement of chemokines was done by ELISA. B cells were isolated from whole blood using magnetic cell separation (MACS). For migration experiments, a modified Boyden chamber assay was used and the migrated B cells were further analysed by FACS. The migration was inhibited either by preincubation of the CSF samples with neutralizing antibodies, heating to 60 degrees C, removal of proteins >3 kDa, or by pre-treatment of the B cells with pertussis toxin. The principal statistical tests used were one-way analysis of variance and Bonferroni test (chemokine measurements) as well as paired Student's t-test (migration experiments).

RESULTS:
Measurements of chemokine levels revealed an increase in three of the four known major B cell chemoattractants CXCL13, CCL19 and CXCL12 in LNB CSF. The CXCL13 CSF:serum ratio, as a measure of the chemotactic gradient, was substantially higher than that of CCL19 and CXCL12. Moreover, the chemotactic activity of LNB CSF was reduced up to 56% after preincubation with a neutralizing CXCL13 antibody, while combined preincubation with antibodies against CXCL13, CCL19, and CXCL12 did not lead to further reduction. Since treatment with pertussis toxin, heating to 60 degrees C, and removal of proteins >3 kDa abrogated the chemotactic activity, further not yet identified chemokines seem to be involved in B cell recruitment to LNB CSF.

CONCLUSION:
Combined, our study suggests a key role of CXCL13 in B cell migration to sites of infection as shown here for the CSF of LNB patients.

PMID:
20042073
[PubMed - indexed for MEDLINE]
PMCID:
PMC2811704
Free PMC Article
The full article is available here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811704/
[snip]

Discussion

The mechanisms underlying the B cell rich CSF pleocytosis in LNB are still undefined. Here we demonstrate that CSF of LNB patients is chemotactic to peripheral blood human B cells, and that CXCL13 is a major regulator of B cell recruitment in acute LNB.

[snip]

All of the LNB patients had not been treated with antibiotics before the lumbar puncture. One of the NS patients received an antibiotic therapy for two weeks before CSF sampling and showed the lowest CXCL13 CSF value of all NS patients. This observation fits perfectly to recent studies demonstrating that (I) viable spirochetes are needed for the production of CXCL13 in monocytic cells [16] and (II) CSF CXCL13 concentrations rapidly decreases under antibiotic therapy in LNB patients [10].

[snip]

As the inhibition of CXCL13, CCL19 and CXCL12 does not completely abrogate the chemotactic activity of LNB CSF samples, additional factors have to be involved.

[snip]

Conclusions

In summary, CXCL13 plays a key role for the immigration of B cells into the CSF in LNB. Therefore - apart from its unquestioned role in dictating homing and motility of lymphocytes in lymphoid tissues [37] - this potent B cell attracting chemokine appears to be also important for attracting B cells to sites of acute bacterial infection.
http://www.ncbi.nlm.nih.gov/pubmed/19965843/
J Neurol Neurosurg Psychiatry. 2010 Aug;81(8):929-33. Epub 2009 Dec 3.

The chemokine CXCL13 in acute neuroborreliosis.

Senel M, Rupprecht TA, Tumani H, Pfister HW, Ludolph AC, Brettschneider J.

Source

Department of Neurology, University of Ulm, Ulm, Germany.

Erratum in
J Neurol Neurosurg Psychiatry. 2010 Oct;81(10):1177.

Abstract

OBJECTIVE:
Recent studies have suggested an important role of the B cell chemoattractant CXCL13 in acute neuroborreliosis (NB). Our aim was to confirm the diagnostic role of CXCL13 and to evaluate its relevance as a therapy response and disease activity marker in NB.

METHODS:
CXCL13 was measured in cerebrospinal fluid (CSF) and serum of patients with NB (n=28), systemic borreliosis (SB, n=9), Guillain-Barré syndrome (GBS, n=11), Bell's palsy (BP, n=19), other cranial nerve palsies (CNP, n=5), cephalgia (C, n=20), bacterial CNS infections (B-CNS-I, n=16) and viral CNS infections (V-CNS-I, n=18). For follow-up studies, serial sample pairs were evaluated from 25 patients with NB (n=56), 11 with B-CNS-I (n=25) and 14 with V-CNS-I (n=36).

RESULTS:
CSF-CXCL13 was significantly elevated in NB compared with other neurological diseases (p<0.001). Using receiver operating characteristic analysis, 337 ng/g was determined as a cut-off with a sensitivity of 96.4% and a specificity of 96.9%. Of all the parameters investigated, CSF CXCL13 showed the fastest response to antibiotic therapy, decreasing significantly (p=0.008) within 1 week. In untreated patients, CSF CXCL13 was elevated in patients with a short duration of disease. Borrelia burgdorferi antibody index showed no significant (p=0.356) change over follow-up.

CONCLUSIONS:
The study confirms the relevance of CXCL13 as a diagnostic biomarker of NB and suggests that CSF CXCL13 in NB is linked to duration of disease and could be a marker of disease activity and response to antibiotic therapy.

PMID:
19965843
[PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20605642
J Neuroimmunol. 2010 Jul 27;224(1-2):56-61. Epub 2010 Jun 1.

Lymphoid chemokines in the CNS.

Lalor SJ, Segal BM.

Source
Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, 4013 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.

Abstract
Lymphoid chemokines, including CCL19, CCL21 and CXCL13, are critical in the development and organization of secondary lymphoid tissues and in the generation of adaptive immune responses. These molecules have also been implicated in the development of ectopic lymphoid structures in the setting of chronic inflammation. Here we review current knowledge on the production of lymphoid chemokines in the central nervous system during both homeostatic conditions and in disease states. Accumulating evidence suggests that constitutive expression of CCL19 plays a critical immunosurveillance role in healthy individuals. In contrast, aberrant induction of CCL19, CCL21 and CXCL13 may support the establishment of chronic autoimmunity and hematopoietic tumors within the CNS.

(c) 2010 Elsevier B.V. All rights reserved.

PMID:
20605642
[PubMed - indexed for MEDLINE]
PMCID:
PMC2910210
Free PMC Article
The full text is available here:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910210/

Here's the part that's relevant to neuroborreliosis:

4. Lymphoid chemokines in infections of the CNS

Lyme neuroborreliosis (NB) is a CNS infection caused by the spirochete Borrelia burgdoferi (B. burgdoferi). It can manifest as a basilar meningitis with cranial neuropathies, radiculitis, transverse myelitis, or encephalitis causing focal white matter lesions (Ruppercht et al., 2008). Myeloid cells are a major source of CNS CXCL13 in animal models of NB. CXCL13 has been localized to microglia and infiltrating macrophages/ DC in brain and spinal cord sections of rhesus macaques with acute NB (Ramesh et al., 2009; Narayan et al., 2005). Interestingly, sonicates of B. burgdoferi stimulate human myeloid and plasmacytoid DC to produce CXCL13 in vitro (Narayan et al., 2005).

Multiple laboratories have found that CXCL13 is significantly elevated in the CSF of patients with NB compared to other neurological diseases, including Guillane Barre syndrome and Bell's palsy (Ruppercht et al., 2009; Senel et al., 2009). There is no correlation between CSF CXCL13 and serum CXCL13 or measures of BBB disruption, indicating that the chemokine is produced intrathecally. In a recent study, CSF CXCL13 revealed a higher combined sensitivity and specificity for the diagnosis of NB than any other parameter investigated (Senel et al., 2009). Its level fell in response to antibiotic treatment faster than the other parameters. In a separate study, B cell chemotaxis towards CSF from patients with acute NB was reduced over 50% when the samples were preincubated with an anti-CXCL13 neutralizing antibody (Ruppercht et al., 2009). This suggests that CXCL13 may be involved in the recruitment of B cells to the subarachnoid space of B. burgdoferi infected patients.
http://www.ncbi.nlm.nih.gov/pubmed/21367992/
J Clin Microbiol. 2011 May;49(5):2027-30. Epub 2011 Mar 2.

Discriminating Lyme neuroborreliosis from other neuroinflammatory diseases by levels of CXCL13 in cerebrospinal fluid.

van Burgel ND, Bakels F, Kroes AC, van Dam AP.
Source

Department of Medical Microbiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, Netherlands.

Abstract

CXCL13 in cerebrospinal fluid (CSF) could be an important component for diagnosing Lyme neuroborreliosis (LNB). Levels of intrathecal CXCL13 were determined for 58 LNB patients and 210 controls; sensitivity was 88% and specificity was 89% (cutoff, 250 pg of CXCL13/ml of CSF). Elevated levels of CXCL13 can aid in the diagnosis of LNB, but levels should be interpreted with care.

PMID:
21367992
[PubMed - indexed for MEDLINE]
PMCID:
PMC3122636
Free PMC Article
The full article is available here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122636/

[snip]

TEXT

Diagnosing Lyme neuroborreliosis (LNB) is difficult because one of the most specific markers, the antibody index (AI), is negative in 21 to 45% of patients (1). Intrathecal levels of CXCL13 have been suggested to be a potential biomarker for LNB. CXCL13 is produced by antigen-presenting cells and is a selective chemoattractant for B cells and B-helper T cells. It has been shown that CXCL13 is expressed at high levels in cerebrospinal fluid (CSF) from LNB patients, while levels were barely detectable in CSF from subjects with noninflammatory neurological disease. Overall sensitivity for LNB ranged from 96 to 100%, and specificity ranged from 63 to 98% (3, 6, 11, 12). Case reports describing early diagnosis of LNB using CXCL13 levels in CSF have already been published (5, 9).

Our aim was to determine the diagnostic potential of levels of intrathecal CXCL13 to distinguish acute and late LNB from other central nervous system diseases in the pediatric and adult population.

[snip]

As controls, we included 36 patients with Lyme borreliosis that did not meet the criteria for LNB, 93 patients with an infectious cause of meningitis/encephalitis, 62 patients with neurological inflammatory diseases, and 12 patients with noninflammatory neurological complaints. Furthermore, seven HIV patients with no neurological complaints or evidence of an intrathecal infection were tested. For patient characteristics, see Table S1 in the supplemental material.

[snip]

Results of the levels of CXCL13 in CSF are shown in Fig. 1. Median levels of CXCL13 were significantly elevated in LNB patients compared to those in the Lyme nonneuroborreliosis controls (medians, 1,183 and 3 pg of CXCL13/ml of CSF, respectively; P < 0.001).

[snip]

Patients with autoimmune diseases and elevated expression of CXCL13 intrathecally have also been described previously; patients with multiple sclerosis (MS) have shown elevated CXCL13 levels (6, 10). We confirm this finding and additionally find that patients with acute disseminated encephalomyelitis (ADEM) and patients developing Henoch-Schönlein purpura (HSP) after an enteroviral infection can have high levels of CXCL13. HSP and systemic lupus erythematosus (SLE) share common clinical features, and for SLE, elevated blood CXCL13 levels have already been described (7, 8). We conclude that CXCL13 levels in CSF can also be elevated in patients with autoimmune diseases.

Treatment of LNB leads to a vast reduction in CXCL13 CSF levels, which makes CXCL13 a potential marker for studying disease activity and effective clearance after treatment (3, 11). In our study, follow-up CXCL13 levels in the CSF of four LNB patients were determined 30 to 350 days after adequate treatment. In all four patients, levels of CXCL13 declined after treatment to a value below 40% of the initial value (data not shown).

In conclusion, high levels of intrathecal CXCL13 expression are found in most, but not all, adult and pediatric patients with LNB. Some immunocompromised patients and patients with an autoimmune disorder which can have a presentation clinically similar to that for LNB have high levels of CXCL13 in their CSF. Determining levels of CXCL13 as a marker for LNB can aid in the diagnosis but should be interpreted with care.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Tue 8 Jan 2013 5:46

http://www.biomedcentral.com/1471-2377/13/2/abstract
Research article

Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection

Daniel Bremell, Niklas Mattsson, Mikael Edsbagge, Kaj Blennow, Ulf Andreasson, Carsten Wikkelsö, Henrik Zetterberg and Lars Hagberg

BMC Neurology 2013, 13:2 doi:10.1186/1471-2377-13-2
Published: 7 January 2013

Abstract (provisional)

Background

It has been suggested that cerebrospinal fluid (CSF) CXCL13 is a diagnostic marker of Lyme neuroborreliosis (LNB), as its levels have been shown to be significantly higher in LNB than in several other CNS infections. Levels have also been shown to decline after treatment with intravenous ceftriaxone, but levels after treatment with oral doxycycline have previously not been studied. Like Borrelia burgdorferi, HIV also has neurotropic properties. Elevated serum CXCL13 concentrations have been reported in HIV patients, but data on CSF levels are limited.

Methods

We longitudinally analysed CSF CXCL13 concentrations in 25 LNB patients before and after oral doxycycline treatment. Furthermore, we analysed CSF CXCL13 concentrations in 16 untreated LNB patients, 27 asymptomatic untreated HIV-1 infected patients and 39 controls with no signs of infectious or inflammatory disease.

Results

In the longitudinal LNB study, initially high CSF CXCL13 levels declined significantly after doxycycline treatment, which correlated to a decreased CSF mononuclear cell count. In the cross-sectional study, all the LNB patients had CSF CXCL13 levels elevated above the lowest standard point of the assay (7.8 pg/mL), with a median concentration of 500 pg/mL (range 34--11,678). Of the HIV patients, 52% had elevated CSF CXCL13 levels (median 10 pg/mL, range 0--498). There was a clear overlap in CSF CXCL13 concentrations between LNB patients and asymptomatic HIV patients. All but one of the 39 controls had CSF CXCL13 levels below 7.8 pg/mL.

Conclusions

We confirm previous reports of highly elevated CSF CXCL13 levels in LNB patients and that these levels decline after oral doxycycline treatment. The same pattern is seen for CSF mononuclear cells. CSF CXCL13 levels are elevated in neurologically asymptomatic HIV patients and the levels overlap those of LNB patients. The diagnostic value of CSF CXCL13 in LNB remains to be established.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.


The complete provisional article is here:

http://www.biomedcentral.com/content/pd ... 7-13-2.pdf

Here's a snippet:
It is difficult to compare CSF CXCL13 results from various studies. CSF CXCL13 has
previously been related to CSF protein (and presented as CSF CXCL13/CSF protein, ng/g) to
correlate with impaired blood brain barrier function and possible leakage into the CSF of
CXCL13 [6]. The fact that CXCL13 levels in LNB patients are higher in CSF than in serum
[23,24] indicates that CSF CXCL13 is produced intrathecally and absolute CSF CXCL13
values are therefore presented in our study and other recent studies [10,23,25]. We studied
two separate groups of LNB patients. The median CSF CXCL13 values differed between the
longitudinal study (3,727 pg/mL) and the cross-sectional study (500 pg/mL), although the
difference did not reach statistical significance (P = 0.065). This cause of this difference is
not clear. It could be a random effect, or it could related to the difference between the two
groups in the CSF levels of mononuclear cells (median 118 cells/μL compared with median
58 cells/μL), as we show a significant correlation between CSF levels of mononuclear cells
and CXCL13 in Figure 4B. The median value of 500 pg/mL in the cross-sectional study is
lower than in other reports, which could be considered a weakness of this present study.
However, two recent studies produced such widely differing mean and median values for
CSF CXCL13 in LNB as 15,149 pg/mL (mean) and 1,183 pg/mL (median). The latter study
used the same analytic kit as the one used in this study [10,23]. The differences between
studies might reflect inter-centre variability or variability depending on the analytic kits used
for measurements. Both are known problems for research-grade biomarker kits and kits for
analyses for which certified reference methods and materials for kit calibration are lacking

[26,27].

duncan
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Re: CXCL13 as a putative marker of LNB?

Post by duncan » Tue 8 Jan 2013 11:11

RitaA and Panda, thank you for these excellent studies postings. I'm not sure if anyone can help, but I have a couple quick questions:

Although I note a brief reference to late stage LNB, the studies seem to focus on acute, or recent LNB. So the findings here may not be applicable to late stage NB? For instance, the inflammatory process which I infer invokes the CXCL13 response may not be as prevalent or applicable in late stage LNB? Are those reasonable assumptions?

Also, wouldn't the anti-inflammatory properties of antibiotics explain the report in the decline in the levels of CXCL13?

Again, thanks for posting!

User avatar
panda
Posts: 279
Joined: Fri 20 Jul 2012 21:59

Re: CXCL13 as a putative marker of LNB?

Post by panda » Sun 24 Mar 2013 4:18

@ duncan,

Yes, you're right; CXCL13 is primarily a marker of inflammation and not only found in CSF of LNB-patients, but also of multiple sclerosis patients and others.

In Germany, where the above mentioned T. Rupprecht is working, who had also registered a patent for CSF-CXCL13 test kits, encephalopathy is not acknowledged as a clinical picture of LD or LNB by some guideline authors. That is, because to diagnose LNB a CSF test is obligate; to test positive the patient must show a positive antibody index (means higher ab concentration in CSF than in blood samples), pleocytosis (higher cell count, mostly lymphocytes, in CSF), and higher protein in CSF (means brain barrier disruption).
Pleocytosis is also a sign of inflammation. The three criteria do not fit with encephalopathy patients, therefore they cannot be ill with LNB. That is the official version.


CSF examinations:
Rafael Jurado and H. Kenneth Walker,
Chapter 74: Cerebrospinal Fluid, in:
Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.
Walker HK, Hall WD, Hurst JW, editors.
Boston: Butterworths; 1990.
http://www.ncbi.nlm.nih.gov/books/NBK398/

Best,
Panda

User avatar
panda
Posts: 279
Joined: Fri 20 Jul 2012 21:59

Re: CXCL13 as a putative marker of LNB?

Post by panda » Sun 24 Mar 2013 4:40

Mult Scler. 2013 Jan 15. [Epub ahead of print]
CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions.
Alvarez E, Piccio L, Mikesell RJ, Klawiter EC, Parks BJ, Naismith RT, Cross AH.
Department of Neurology, Washington University in Saint Louis, USA.
Abstract
CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.
[...]
Discussion
CXCL13 may play a role in MS and NMO pathogenesis by recruiting inflammatory cells into the CNS. Although the
sample numbers were low, we found sufficient overlap in CSF CXCL13 levels between groups to believe that
CXCL13 will not distinguish the disease groups studied
. Some NMO CSF samples contained CXCL13 concentrations in the very high range reported in CNS lymphoma and viral meningitis. Additionally, some MS and NMO samples had low levels in the range of noninflammatory controls. CSF CXCL13 correlated with inflammation (WBC count, total protein, IgG index, and oligoclonal bands (OCB) number) for all samples taken together, but in specific disease subgroups CSF CXCL13 correlated with only some markers. As in prior reports,1,2 CSF CXCL13 in MS samples correlated with IgG index. We did not find an association with WBC. In samples from NMO subjects, who often have elevated WBC but not IgG index, CSF CXCL13 correlated with CSF WBC but not IgG index. In the present study CSF CXCL13 levels in MS and NMO correlated with disability, which will need to be explored further.
NMO-IgG is often present at higher titers in serum than CSF,10 suggesting that the autoimmune process in NMO is
not CNS restricted. Our finding that NMO patients have elevated serum CXCL13 levels, not described previously,
also supports a systemic pathophysiology. Serum and CSF levels of CXCL13 were not correlated (Supplementary
Figure 1(a) online), suggesting separate sources or differential degradation in the CNS and periphery.
http://www.ncbi.nlm.nih.gov/pubmed/23322500 [abstract]

Best wishes,
Panda

Lorima
Posts: 914
Joined: Mon 29 Oct 2007 20:47

Re: CXCL13 as a putative marker of LNB?

Post by Lorima » Sun 24 Mar 2013 14:54

Thanks, Panda. I hadn't read this thread in detail, because it seemed so implausible to me, that CXCL13 could be a specific marker for LNB. it would be peculiar, biologically, for one particular infection to cause elevation of one particular cytokine in the CSF. I hadn't gone over all the papers in detail; I see you've done just that, above.

I suppose it could be useful, for people who are being told their illness is psychosomatic; at least it shows that there is some kind of immune response going on in the CNS. It could be used as justification for a trial of antibiotics. 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.

Also, as Duncan pointed out, most of this has to do with acute LNB. I doubt there is that level of immune system activity in late LNB, when the patient has become partially tolerized to the spirochete, and/or most of the spirochetes are now in locations somewhat protected against immune surveillance. This is speculation, of course. It's just how I'm currently thinking about it, which will get refined as I continue to learn, and as more research comes out.
"I have to understand the world, you see."
Richard Feynman

User avatar
panda
Posts: 279
Joined: Fri 20 Jul 2012 21:59

Re: CXCL13 as a putative marker of LNB?

Post by panda » Tue 26 Mar 2013 3:36

@ Lorima

I posted this because CXCL13 is recommended by various neurologists, guideline authors, and other scientists with influence (Key Opinion Leaders).

Some examples:

German LNB guideline (2008–2013):
Dem Nachweis des Chemokins CXCL13 im Liquor kommt möglicherweise eine wichtige Bedeutung in der Diagnostik der Neuroborreliose zu (Rupprecht et al. 2005, 2006, 2007). Da jedoch prospektive Studien fehlen, kann die Bestimmung von CXCL13 im Liquor noch nicht für die Routinediagnostik empfohlen werden.
Translation: The detection of the chemokine CXCL 13 in the cerebrospinal fluid may become an important significance in the diagnosis of neuroborreliosis (Rupprecht et al. 2005, 2006, 2007). However, prospective studies are missing, yet the determination of CXCL 13 in the cerebrospinal fluid is recommended for routine diagnosis.

http://www.awmf.org/uploads/tx_szleitli ... eliose.pdf [German, pdf]



Pfister (co-author of the German LNB guideline):
CXCL13 shows high sensitivity and specificity for acute, untreated LNB.
Neurology. 2011 Mar 22;76(12):1051-8. doi: 10.1212/WNL.0b013e318211c39a.
A prospective study on the role of CXCL13 in Lyme neuroborreliosis.
Schmidt C, Plate A, Angele B, Pfister HW, Wick M, Koedel U, Rupprecht TA.
http://www.ncbi.nlm.nih.gov/pubmed/21422457


Fingerle (head of the German National Reference Centre for Borrelia, co-author of the EFNS guidelines, co-author of the German guideline ‘Cutaneous manifestations of Lyme borreliosis’):
CXCL13 is a novel biomarker with high sensitivity and specificity for acute LNB.
BMC Infect Dis. 2012 Dec 10;12:344. doi: 10.1186/1471-2334-12-344.
CXCL13 may improve diagnosis in early neuroborreliosis with atypical laboratory findings.
Borde JP, Meier S, Fingerle V, Klier C, Hübner J, Kern WV.
http://www.biomedcentral.com/1471-2334/12/344


Rupprecht (co-author of the EFNS guidelines; head of the Outpatient Clinic for neuroborreliosis in Dachau)
is also advertising the test on his internet page of the LNB-Clinic:
Der Biomarker CXCL 13 ist im Nervenwasser nur bei der aktiven Neuroborreliose nachweisbar. Das Protein zeigt präzise die Anwesenheit von Borrelien im Nervensystem an und liefert damit den eindeutigen Beweis der Behandlungsbedürftigkeit mit Antibiotika. Auch als Frühmarker bei (noch) Antikörper-negativer Neuroborreliose ist CXCL13 geeignet.
Automatic translation: “The biomarker CXCL 13 is only detectable in the cerebrospinal fluid in active neuroborreliosis. The protein accurately indicates the presence of Borrelia burgdorferi in the nervous system and thus provides clear proof of the need for treatment with antibiotics. Even as an early marker at (still) antibody - negative neuroborreliosis CXCL13 is suitable.”
http://www.rhoen-klinikum-ag.com/rka/cm ... 84722.html [German]

In 2011 Rupprecht and his collaborators of the test manufacturer announced:
Several recent studies proposed the chemokine CXCL13 in CSF as an additional biomarker for acute LNB with a sensitivity between 94 and 96% and a specificity between 96 and 97%. CXCL13 declines during antibiotic therapy and therefore serves as an activity marker, indicating only active infections. As a consequence, the presence of CXCL13 might actually even replace the counting of leukocytes in the CSF in the diagnostic workup of suspected LNB.
http://www.tbd-symposium.com/media/publ ... erm-ib.pdf


Kaiser (co-author of the German LNB guideline):
dagegen konnte das Chemokin CXCL13 wiederholt als Marker einer akuten Neuroborreliose identifiziert werden (Rupprecht et al 2006).
Translation: “in contrast, the chemokine CXCL13 was repeatedly identified as a marker of acute neuroborreliosis (Rupprecht et al 2006).”
Aktuelle Aspekte der Zeckenassoziierten neurologischen Infektionen
Reinhard Kaiser
Intensivmed.up2date 2008; 4(2): 89-90
DOI: 10.1055/s-2007-995521
http://www.thieme-connect.com/ejournals ... 007-995521 [German]


Ivar Tjernberg, Anna J Henningsson, Ingvar Eliasson, Pia Forsberg and Jan Ernerudh,
Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis., 2011, Journal of Infection, (62), 2, 149-158.
p. 20:
In conclusion, this large study confirms CXCL13 in CSF as a reliable marker of LNB. The CSF-Serum CXCL13 ratio differentiates LNB well from other conditions
http://www.diva-portal.org/smash/get/di ... FULLTEXT01 [pdf]
http://liu.diva-portal.org/smash/get/di ... FULLTEXT01 [pdf]

___________________________________________________
Case Rep Neurol. 2012 Jan;4(1):47-53. doi: 10.1159/000337223. Epub 2012 Mar 14.
A case of relapsing-remitting neuroborreliosis? Challenges in the differential diagnosis of recurrent myelitis.
Albrecht P, Henke N, Lehmann HC, Macht S, Hefter H, Goebels N, Mackenzie C, Rupprecht TA, Fingerle V, Hartung HP, Methner A.
Department of Neurology, Heinrich Heine University, Düsseldorf, Oberschleissheim, Germany.
Abstract
We report the case of a 31-year-old woman with 4 episodes of myelitis with pleocytosis, a positive Borrelia burgdorferi serology with positive antibody indices, and full recovery each time after antibiotic and steroid treatment, suggesting neuroborreliosis. We nevertheless believe that recurrent neuroborreliosis is improbable based on the levels of the chemokine CXCL13 in cerebrospinal fluid and favor the diagnosis of post-infectious autoimmune-mediated transverse myelitis possibly triggered by an initial neuroborreliosis as the cause of the relapses observed in our patient. We demonstrate the diagnostic steps and procedures which were important in the differential diagnosis of this unusual and challenging case.
http://www.ncbi.nlm.nih.gov/pubmed/22649342 [abstract]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362302/ [full text]

http://www.lymeneteurope.org/forum/view ... 430#p30430



Here, CXCL13 was used to rule out LNB after an acute LNB episode and antibiotic treatment – in spite of relapsing symptoms, pleocytosis, and positive results of Bb antibodies in CSF (i.e. fulfilling the case definition) – and the “relapsing events of myelitis” were interpreted as autoimmune course. But for this assumption there was no proof.
The fact that a positive B. burgdorferi CSF/serum AI was found in 3 out of 4 episodes and that CSF pleocytosis and clinical symptoms ameliorated in response to antibiotic treatment seems to suggest recurrent episodes of neuroborreliosis. However, recurrent episodes of borreliosis and even more so neuroborreliosis after sufficient antibiotic treatment such as in this case, are very uncommon.
[…]
The level of CXCL13 in CSF is a very sensitive parameter for neuroborreliosis and can be of great help, especially in complex cases like ours [12, 13]. In several studies using the same ready-made ELISA from R&D Systems as in our patient, untreated neuroborreliosis could be differentiated from other neurological disorders with a high sensitivity of above 90% using cutoff values of CXCL13 concentrations in CSF of 250 pg/ml [14], 100 pg/ml [15] or 142 pg/ml [16].
[…]
Instead, it seems most probable that our patient had suffered from neuroborreliosis in the past, e.g. when she had her first episodes of neurological symptoms in 1996 and/or 1999, which was effectively treated and cured back then. We interpret the subsequent episodes in 2008 and 2011 as post-infectious autoimmune-mediated transverse myelitis triggered by the preceding neuroborreliosis.


There is a German saying: Es kann nicht sein, was nicht sein darf.
Hardly to translate: Something can not exist, what is not allowed to.

According to Ch. Morgenstern, Die unmögliche Tatsache [Palmström]:
Und er kommt zu dem Ergebnis:
Nur ein Traum war das Erlebnis.
Weil, so schließt er messerscharf,
nicht sein kann, was nicht sein darf.
http://www.christian-morgenstern.de/dcm ... e_Tatsache [German]

http://www.christian-morgenstern.de/dcm ... sible_Fact [English]

http://jerome.lettvin.com/Jerome/TheFatAbbot.pdf [pdf, other verses of Morgenstern translated]


Best wishes,
Panda

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Tue 26 Mar 2013 4:32

This is a bit troubling. While it's great to have any type of biomarker that can provide objective supporting evidence of LNB, CXCL13 levels are not always elevated in these patients. An elevated CXCL13 may be one component of a neuroborreliosis diagnosis, but relying exclusively on any single test value seems unwise to me.

Are the following cautionary words (also posted above) simply being ignored, and more importantly -- why?
J Clin Microbiol. 2011 May;49(5):2027-30. Epub 2011 Mar 2.

Discriminating Lyme neuroborreliosis from other neuroinflammatory diseases by levels of CXCL13 in cerebrospinal fluid.

van Burgel ND, Bakels F, Kroes AC, van Dam AP.

Source

Department of Medical Microbiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, Netherlands.

Abstract

CXCL13 in cerebrospinal fluid (CSF) could be an important component for diagnosing Lyme neuroborreliosis (LNB). Levels of intrathecal CXCL13 were determined for 58 LNB patients and 210 controls; sensitivity was 88% and specificity was 89% (cutoff, 250 pg of CXCL13/ml of CSF). Elevated levels of CXCL13 can aid in the diagnosis of LNB, but levels should be interpreted with care.
And as Panda pointed out previously:
Increased levels of CXCL13 – measuring in serum, CSF, and tissue – are found in various diseases, as borreliosis (neuroborreliosis, lymphocytoma), neurosyphilis, relapsing fever, multiple sclerosis, chronic lymphocytic leukemia (CLL), angioimmunoblastic T-cell lymphoma (AITL), prostate cancer, renal inflammation, Sjögren’s syndrome (salivary gland) and others.

Pubmed shows today 547 results searching for CXCL13.
After taking another look at the abstracts, I just don't buy that CXCL13 is a specific enough marker for LNB to rule out the possibility of other disorders.

This is especially troubling given that the signs and symptoms of LNB and MS and SLE can be virtually indistinguishable at times. A course of antibiotics for someone with MS or SLE may not harm that person, but it could delay them getting more effective treatment. A patient with neurological signs and symptoms caused by any type of cancer should be getting treatment for that disease -- not a course of IV antibiotics (unless that happens to be medically necessary).

More importantly (at least for Lyme disease patients), denying antibiotic treatment on the grounds that a person's CXCL13 level is not adequately elevated would not be good medicine.

I'm not suggesting that doctors ignore an elevated CXCL13 level, but it needs to be put into proper context. Neuroborreliosis isn't always an easy diagnosis to make, but neither is MS or SLE or many other conditions.

Edited to add:

And to further complicate things, any number of people can be suffering from both an infection AND an autoimmune disorder. I still haven't seen much in the way of advice/recommendations for doctors in the IDSA guidelines -- or anywhere else for that matter.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: CXCL13 as a putative marker of LNB?

Post by RitaA » Tue 26 Mar 2013 6:00

Just more confirmation -- as if we needed any:

http://www.plosone.org/article/info:doi ... ne.0011986
Citation: Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, et al. (2010) The Chemokine CXCL13 Is a Prognostic Marker in Clinically Isolated Syndrome (CIS). PLoS ONE 5(8): e11986. doi:10.1371/journal.pone.0011986

[snip]

Discussion

[snip]

CXCL13 is no disease-specific marker of MS or CIS: Particularly high concentrations of CSF CXCL13 can be found in patients with neuroborreliosis, which is the neuroinflammatory disease with the highest proportion of B cells in the CSF [24], [35]. Furthermore, CSF CXCL13 was found to be elevated in other inflammatory CNS diseases including viral meningitis and encephalitis[12], confirming its role as a suitable marker of B cell recruitment. Recent evidence also indicates that, apart from inflammatory CNS diseases, CSF CXCL13 may be of diagnostic and prognostic relevance in B cell lymphoma of the CNS [36].
Edited to remove duplicate citation.
Last edited by RitaA on Tue 26 Mar 2013 19:46, edited 1 time in total.

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