CXC ligand 13 orchestrates an immunoactive microenvironment and enhances immunotherapy response in head and neck squamous cell carcinoma.

Objectives: This study aims to systematically explore the role of chemokine CXC ligand 13 (CXCL13) in head and neck squamous cell carcinoma (HNSCC). Methods: The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases provided the RNA-seq data for cancer and normal tissues, respectively. Gene set enrichment analysis was applied to search the cancer hallmarks associated with CXCL13 expression. TIMER2.0 was the main platform used to investigate the immune cell infiltration related to CXCL13. Immunohistochemistry was applied to explore the relationship between CXCL13 and patients' prognosis and the relationship between CXCL13 and tertiary lymphoid structures (TLSs). Results: The expression of CXCL13 was upregulated in most tumors, including HNSCC. The higher expression of CXCL13 was closely related to the positive prognosis of HNSCC. CXCL13 was mainly expressed in B cells and CD8 + T cells, revealing the relationship between its expression and immune activation in the tumor microenvironment. Furthermore, immunohistochemistry and multiple fluorescence staining analysis of HNSCC samples showed a powerful correlation between CXCL13 expression, TLSs formation, and positive prognosis. Finally, CXCL13 significantly increased the response to cancer immunotherapy. Conclusions: CXCL13 may function as a potential biomarker for predicting prognosis and immunotherapy response and associate with TLSs in HNSCC.

Use of cerebrospinal fluid CXCL13 concentration for diagnosis and monitoring of neurosyphilis: a three-case report

Introduction: Previous retrospective studies have demonstrated that the concentration of chemokine ligand CXCL13 in cerebrospinal fluid (CSF-CXCL13) is a promising biomarker in the diagnosis of neurosyphilis and, additionally, in the monitoring of therapeutic efficacy. Objective: To describe three cases of patients with neurosyphilis (NS) treated at Hospital Universitário Gaffrée e Guinle, in Rio de Janeiro, Brazil, with suspected active syphilis with neurological symptoms. Case report: Three patients from Rio de Janeiro, Brazil, were investigated for symptomatic NS. The concentration of CSF-CXCL13 was prospectively performed by enzyme-linked immunosorbent assay (ELISA) in all participants at baseline and in follow-up visits at 3 months after therapy. CSF-CXCL13 concentrations were significantly higher in all three patients with established NS. The CSF-CXCL13 concentrations decreased after 3 months of therapy compared to baseline in all cases reported. The added high concentration of CSF-CXCL13 plus CSF-TPHA reactivity above 1:40 titer agreed with the diagnosis of NS in 100% of the cases. Conclusion: In this case series, we present three cases of NS diagnosed using CXCL13 in CSF as a complementary test. These case series suggest that the clinical use of CSF-CXCL13 is useful as a supplementary biomarker for NS and for monitoring the effectiveness of NS therapy, especially in patients with nonreactive CSF-VDRL, excluding other neurologic diseases

Comparison of the Euroimmun Borrelia 'antibody index' with Virotech immunoblot-based detection of intrathecal Borrelia antibody production for the diagnosis of Lyme neuroborreliosis.

For diagnosis of neuroborreliosis, calculation of the antibody index, based on Euroimmun Anti-Borrelia plus VlsE ELISA was compared to Virotech Borrelia Europe plus TpN17 immunoblot-based detection of Borrelia-specific intrathecal antibody production. CXCL13 results in cerebrospinal fluid were used to evaluate discordant results. A total of 64 serum/CSF pairs were analysed. Patients were classified according to European Federation of Neurological Societies criteria incorporating Virotech results. For the Euroimmun assay, a sensitivity of 100% and specificity of 94% was found. Agreement between the both tests was almost perfect (κ 0.81). Both methods are appropriate for the detection of Borrelia-specific intrathecal antibody production.

Serum, but Not Saliva, CXCL13 Levels Associate With Infiltrating CXCL13+ Cells in the Minor Salivary Gland Lesions and Other Histologic Parameters in Patients With Sjögren's Syndrome.

Recent studies suggest that elevated CXCL13 serum levels in patients with primary Sjögren's syndrome (pSS) associate with minor salivary gland (MSG) histologic features, disease severity, as well as high-risk status for non-Hodgkin lymphoma (NHL) development and NHL itself. In contrast, limited discriminative value of CXCL13 saliva levels has been reported. Prompt by these reports, we sought to validate the clinical utility of CXCL13 by investigating potential correlations of serum and saliva levels with MSG histopathologic [including CXCL13+-cell number, severity of infiltrates and germinal center (GC) formation], serologic and clinical parameters, as well as NHL. CXCL13 levels were evaluated in paired serum and saliva specimens of 45 pSS patients (15 with NHL; pSS-associated NHL: SSL), 11 sicca-controls (sicca-complaining individuals with negative MSG biopsy and negative autoantibody profile), 10 healthy individuals (healthy-controls) and 6 non-SS-NHLs. CXCL13+-cells were measured in paired MSG-tissues of 22 of pSS patients studied (including 7 SSLs) and all sicca-controls. CXCL13 serum levels were significantly increased in pSS and SSL patients compared to sicca- and healthy-controls and were positively correlated with the CXCL13+-cell number and biopsy focus-score. Serum CXCL13 was significantly higher in pSS patients with GCs, rheumatoid factor, hypocomplementemia, high disease activity, NHL and in high-risk patients for NHL development. CXCL13 saliva levels were significantly increased in SSL patients (compared to non-SS-NHLs), patients with GCs and in high-risk for NHL patients. Univariate analysis revealed that CXCL13 serum, but not saliva, levels were associated with lymphoma, an association that did not survive multivariate analysis. Conclusively, our findings confirm that serum, but not saliva, levels of CXCL13 are associated with histologic, serologic and clinical features indicative of more severe pSS.

Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma.

BACKGROUND: Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFH have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8+T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13+CD8+T cells in clear cell renal cell carcinoma (ccRCC). METHODS: We analyzed prognostic value and immune contexture that associated with CXCL13+CD8+T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13+CD8+T cells and total CD8+T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC. RESULTS: Intratumoral CXCL13+CD8+T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13+CD8+T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8+T cells in high-level CXCL13+CD8+T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13+CD8+T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3+ regulatory T cells, TLS and decreased natural killer cells, GZMB+ cells. CONCLUSIONS: Intratumoral CXCL13+CD8+T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13+CD8+T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13+CD8+T cells abundance impaired total CD8+T cells' immune function. Intratumoral CXCL13+CD8+T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13+CD8+T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.

The Role of CXCL13 and CXCL9 in Early Breast Cancer.

BACKGROUND: Chemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis. RESULTS: CXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016). CONCLUSIONS: Both biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively.

Diagnostic performance of cerebrospinal fluid free light chains in Lyme neuroborreliosis - a pilot study.

Background The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) free light chains (FLCs) in the diagnosis of Lyme neuroborreliosis (LNB). Methods Serum and CSF levels of κ- and λ-FLC, albumin and total concentration of immunoglobulin M (IgM) were determined together with CSF chemokine CXCL13 in 23 patients with definite LNB, 35 inflammatory neurological disease control (INDC) and 18 non-inflammatory control (NIC) patients. Indices and intrathecal fractions (IFs) of FLC and IgM were calculated. Results Significant differences in FLC indices and IFs were found between the LNB group and both control groups, p ≤ 0.007. Sensitivity of intrathecal κ- and λ-FLC synthesis reached 78%-87% in LNB patients with a specificity of 94%-100% in NIC patients, whereas specificity in INDC patients was 69%. The corresponding frequencies of positive results for IF and index of IgM and CSF CXCL13 in these three diagnostic groups were 74%-96% in LNB patients, 0% in NIC patients and 3%-6% in INDC patients at the chosen cut-off levels. Conclusions The findings of this study show a moderate to high sensitivity of CSF κ- and λ-FLC in LNB patients with a high specificity in NIC patients. However, overlap in CSF κ- and λ-FLC levels between LNB and INDC patients calls for caution in the interpretation and limits the diagnostic usefulness in the LNB diagnosis. CSF CXCL13 appears to be the most valuable additional biomarker of LNB aside from routine parameters such as CSF pleocytosis and anti-Borrelia antibody index.

Lyme neuroborreliosis.

PURPOSE OF REVIEW: To review the recent evidence clarifying the symptomatology and diagnosis of nervous system Lyme disease. RECENT FINDINGS: Two-tier testing combining pairs of ELISAs, using C6 or VlsE assays to replace second tier Western blots, may eliminate confusion about test interpretation. Cerebrospinal fluid (CSF) can be informative in diagnosing central nervous system (CNS) Lyme disease, not peripheral nervous system (PNS) disorders. CSF CXCL13 may provide useful adjunctive information in CNS infection; its specificity remains to be defined. Lyme encephalopathy is not indicative of CNS infection. Post treatment Lyme disease symptoms do not occur in patients who have had definite CNS Lyme infection. Whether post treatment Lyme disease symptom (PTLDS) is an actual entity, or reflects anchoring bias when commonly occurring symptoms arise in patients previously treated for Lyme disease, remains to be determined. Regardless, these symptoms do not reflect CNS infection and do not respond to additional antimicrobial therapy. SUMMARY: Serologic testing is robust in individuals with a priori likelihood of infection of greater than 2-6 weeks duration. Western blots provide useful confirmation of screening ELISAs, but may be replaced by second ELISAs. CSF testing, including CXCL13, may be informative in CNS Lyme, not PNS, and is generally normal in Lyme encephalopathy. PTLDS does not occur following CNS infection, and may not be a distinct entity.

MicroRNA-155 Suppresses Mesangial Cell Proliferation and TGF-ß1 Production via Inhibiting CXCR5-ERK Signaling Pathway in Lupus Nephritis.

Increasing evidence shows miR-155 plays an important role in regulating inflammatory processes in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). Because the chemokine CXCL13 is implicated in the pathogenesis of LN, here we examined whether miR-155 can modulate the activity of CXCL13 or its receptor CXCR5. We determined the expression of CXCL13 in normal and MRL/lpr mice and found elevated levels of CXCL13 in the kidneys of MRL/lpr mice compared with normal kidneys. Besides, CXCL13 expression was mainly detected in the glomerulus, specifically to mesangial areas. We then transfected a miR-155 mimic in human renal mesangial cells (HRMCs) to overexpress miR-155 and detected decreased protein levels of CXCR5 by western blot analysis. Transfection of the miR-155 mimic into CXCL13-treated HRMCs resulted in a significantly reduced proliferation rate of HRMCs as measured by the cell-counting assay and flow cytometry. Moreover, increased intracellular miR-155 also led to decreased phosphorylation of ERK and TGF-ß1 production. Together, these results revealed that miR-155 may play a role in the pathogenesis of LN.

B Cell-Attracting Chemokine-1 and Progranulin in Bronchoalveolar Lavage Fluid of Patients with Advanced Non-small Cell Lung Cancer: New Prognostic Factors.

Progranulin is a growth and survival factor implicated in tumorigenesis and drug resistance. Several studies showed that progranulin is expressed in breast cancer tissue and inversely correlates with survival. B lymphocyte chemoattractant, also known as B cell-attracting chemokine 1 (BCA-1), is a member of the CXC subtype of the chemokine superfamily. BCA-1 is critical for secondary lymphoid tissue development and navigation of lymphocytes within the microcompartments of the tissue. There are no data on the content of progranulin and BCA-1 in bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients. To study this issue, we measured BALF content of progranulin and BCA-1 in 46 NSCLC patients before chemotherapy and 15 healthy subjects. Both markers were elevated in cancer patients compared to healthy subjects (progranulin: 61.4 (1.6-384.0) vs. 6.5 (0.6-12.9) ng/ml, p = 0.001 and BCA-1: 30.8 (24.3-70.8) vs. 15.4 (13.3-19.5) pg/ml, p = 0.0001). The cut-off BALF level concerning NSCLC vs. controls, investigated using the receiver-operating characteristic (ROC) curve, yielded 6.5 ng/ml for progranulin and 15.4 pg/ml for BCA-1. We failed to find any association between the BALF content of progranulin or BCA-1 and the stage of tumor or prospectively assessed treatment response. However, BALF progranulin associated with time to tumor progression (r = 0.61; p = 0.04). In addition, a higher BALF content of BCA-1 in NSCLC patients associated with shorter overall survival. We conclude that progranulin and BCA-1 in BALF of NSCLC patients before chemotherapy may be prognostic factors of cancer progression.

Significance of molecular biomarkers in idiopathic pulmonary fibrosis: A mini review.

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible condition with poor prognosis that is characterized by a variable clinical course in each patient, which renders it a complex disease with unknown causes. Despite the proven efficacy of novel antifibrotic therapies, including pirfenidone and nintedanib, the diagnosis and follow-up of IPF remain challenging. Hence, the identification of molecular biomarkers for early detection of IPF and to predict biologically determined individual clinical courses, has recently piqued the interest of researchers. Previous studies have demonstrated the diagnostic and prognostic efficacy of blood proteins such as KL-6, Surfactant protein (SP)-A, and SP-D, in patients with IPF. Due to their use in clinical practice in Japan, for approximately twenty years, a significant amount of data about these biomarkers has been accumulated. This paper reviews the recent literature on molecular biomarkers for IPF that have been developed in Japan as well as other potential molecular biomarkers.

Analysis of possible structures of inducible skin-associated lymphoid tissue in lupus erythematosus profundus.

Lupus erythematosus profundus (LEP) is a variant of lupus erythematosus, involving the deep dermis and subcutaneous fat. LEP is characterized by the presence of lymphoid follicles (LF) and germinal centers (GC). However, it remains unknown whether these lymphoid structures correspond to the lymphoid tissues such as cutaneous tertiary lymphoid organs (TLO). Previously, we identified dynamically orchestrated cellular elements in murine contact dermatitis that resembled lymphoid structures, which we termed inducible skin-associated lymphoid tissues (iSALT). We subsequently reported structures analogous to iSALT in human secondary syphilis, suggesting that iSALT can also exist in humans. Here, we studied ectopic lymphoid tissues in the lesions of LEP by immunohistochemistry and compared their characteristics with those of TLO. We demonstrated that LF of LEP were composed of B-cell follicles intermingled with CXCL13-expressing cells, distinct aggregations of T cells, and some blood vessels expressing peripheral node addressin. These findings indicate that LF of LEP can be considered as a type of iSALT.

Diagnostic markers for CNS lymphoma in blood and cerebrospinal fluid: a systematic review.

Diagnosing central nervous system (CNS) lymphoma remains a challenge. Most patients have to undergo brain biopsy to obtain tissue for diagnosis, with associated risks of serious complications. Diagnostic markers in blood or cerebrospinal fluid (CSF) could facilitate early diagnosis with low complication rates. We performed a systematic literature search for studies on markers in blood or cerebrospinal fluid for the diagnosis CNS lymphoma and assessed the methodological quality of studies with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). We evaluated diagnostic value of the markers at a given threshold, as well as differences between mean or median levels in patients versus control groups. Twenty-five studies were included, reporting diagnostic value for 18 markers in CSF (microRNAs -21, -19b, and -92a, RNU2-1f, CXCL13, interleukins -6, -8, and -10, soluble interleukin-2-receptor, soluble CD19, soluble CD27, tumour necrosis factor-alfa, beta-2-microglobulin, antithrombin III, soluble transmembrane activator and calcium modulator and cyclophilin ligand interactor, soluble B cell maturation antigen, neopterin and osteopontin) and three markers in blood (microRNA-21 soluble CD27, and beta-2-microglobulin). All studies were at considerable risk of bias and there were concerns regarding the applicability of 15 studies. CXCL-13, beta-2-microglobulin and neopterin have the highest potential in diagnosing CNS lymphoma, but further study is still needed before they can be used in clinical practice.

Expression of TFH Markers and Detection of RHOA p.G17V and IDH2 p.R172K/S Mutations in Cutaneous Localizations of Angioimmunoblastic T-Cell Lymphomas.

Skin biopsies of 41 angioimmunoblastic T-cell lymphoma patients were retrospectively analyzed for the expression of follicular helper T-cell (TFH) markers, Epstein-Barr virus (EBV), and the presence of RHOA (p.G17V) and IDH2 (p.R172K/S) mutations using allele-specific polymerase chain reaction. We categorized cases into 4 distinctive patterns: (1) low-density lymphocytic perivascular infiltrates (n=11), (2) dense perivascular infiltrates with atypical cells and occasional inflammatory cells (n=13), (3) diffuse infiltrates reminiscent of angioimmunoblastic T-cell lymphoma (n=4), or (4) other aspects (n=13). Two EBV and 2 plasmacytoid lymphoproliferative disorders were seen. We observed variable expression of TFH markers (CD10 [50%], BCLB6 [84%], PD1 [94%], CXCL13 [84%], and ICOS [97.5%]), and EBV B-blasts (26%). A TFH phenotype was identified in 82% and 73%, respectively, of cases with the most challenging patterns 1 and 2. TFH markers and EBV can thus help for diagnosis and are detected in samples with low-density infiltrates. We found RHOA G17V and IDH2 R172K/S mutations in the skin in 14/18 (78%) and 3/16 (19%) cases, respectively. The RHOA G17V mutation was identified in a proportion of biopsies with patterns 1 and 2, which represent a diagnostic challenge. The RHOA G17V mutation was detected both in the skin and lymph node (LN) biopsies in 7/9 (64%) cases, and in only the skin or the LN of 1 sample each. The frequency of RHOA G17V mutation was similar to that reported in LNs. It may represent a sensitive diagnostic marker in the skin, helpful in cases with low-density infiltrates.

B Lymphocyte Chemoattractant (CXCL13) Is an Indicator of Acute Gastrointestinal GVHD in Murine Model.

Gastrointestinal acute graft-vs.-host disease (GI aGVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation and is a major cause of morbidity and mortality. In addition, GI aGVHD is often clinically indistinguishable from other causes of GI dysfunction such as conditioning regimen toxicity, infections, or medications, which complicates the diagnosis. Thus, specific biomarkers are needed to help improve diagnosis and obtain a deeper understanding of the cytokine changes in GI aGVHD. An MHC-mismatched model of aGVHD was established by transplanting 1 × 107 bone marrow nuclear cells and 3 × 107 spleen cells from C57/Bl6 mice or from BALB/c mice into lethally irradiated BALB/c recipients. The mice in the allogeneic transplantation group were intraperitoneally treated with 20 mg kg-1 day-1 cyclosporin A after aGVHD developed. Five micrograms of lipopolysaccharide were administered intraperitoneally daily to syngeneic recipients at day 11 to imitate infection; the same volume of phosphate-buffered saline was administered to control mice. The mice were killed at the indicated time points. Forty molecules derived from the GI tract were screened cytokine array. The data demonstrated that the expression of B lymphocyte chemoattractant (CXCL13) was increased by ~10-, 12-, and 16-fold upon the occurrence of aGVHD compared with infection, aGVHD after treatment, and the syngeneic control group, respectively. Thus, the elevation of BLC (CXCL13) is an indicator of acute GI GVHD.

CXCL13 and TH1/Th2 cytokines in the serum and cerebrospinal fluid of neurosyphilis patients.

Neurosyphilis is a chronic infectious disease with involvement of central nervous system infection by Treponema pallidum. This study was to investigate the contents of B lymphocyte chemokine 1 (BLC-1/chemokine [C-X-C motif] ligand 13), Th1 cytokines (Interleukin [IL]-2, IL-12, and Interferon [IFN]-γ), and Th2 cytokines (IL-6 and IL-10) in serum and cerebrospinal fluid (CSF) of HIV-negative patients with neurosyphilis before and after treatment, aiming to elucidate roles of CXCL13 and Th1/Th2 cytokines in immune response to and pathogenesis of neurosyphilis.Enzyme-linked immunosorbent assay was employed to detect the contents of CXCL13, IL-2, IL-12, IFN-γ, IL-6, and IL-10 in serum and CSF of 47 HIV-negative patients with neurosyphilis, 36 syphilis patients without neurological involvement and 23 controls (noninfectious intracranial disease) before, 3 and 12 months after treatment with high dose penicillin.Results showed that there was no significant difference in blood CXCL13 content among 3 groups (P > .05); CSF CXCL13 content in neurosyphilis patients was significantly higher than in other 2 groups (P < .001), and positively related to leucocyte count, protein concentration, and IgG index. IL-6 and IL-10 contents of the serum and CSF in neurosyphilis patients were markedly higher than in other 2 groups (P < .05 or .01), but IL-2, IL-12, and IFN-γ of the serum and CSF were significantly lower than in other 2 groups (P < .05 or .01). The IL-6, IL-10, IL-2, IL-12, and IFN-γ contents of the serum and CSF were comparable between control group and syphilis group (P > .05). CSF CXCL13 content was positively related with IL-6 and IL-10 content, while negatively related to IL-12 content in neurosyphilis patients. CSF IL-6 content was negatively related with IL-12 content. In neurosyphilis patients, the CSF CXCL13 content reduced significantly at 3 and 12 months (P < .001), the CSF IL-2 and IL-12 contents increased significantly at 12 months, and CSF IL-6 contents reduced significantly at 12 months after treatment (P < .05 or .01).It is concluded that neurosyphilis patients did not have normal immune function. CXCL13 and Th1/Th2 cytokines are involved in the immune response of neurosyphilis patients. CSF CXCL13 and Th1/Th2 cytokines contents may be used for the diagnosis and evaluation of therapeutic efficacy of neurosyphilis.

Predictive significance of CCL21 and CXCL13 levels in the minor salivary glands of patients with Sjögren's syndrome.

OBJECTIVES: To investigate whether CCL21 and CXCL13 expression levels in the minor salivary gland are associated with the laboratory and clinical manifestations of Sjögren's syndrome (SS). METHODS: Sociodemographic data on 106 SS patients were obtained and the glandular and extraglandular manifestations of the disease were documented. In addition, minor salivary gland biopsies were performed and the patients' laboratory findings were analysed. European League Against Rheumatism SS disease activity index (ESSDAI) values of SS disease activity at the time of biopsy and the SS disease damage index (SSDDI) values were also recorded. An immunohistochemical approach was used to semiquantitatively measure the CCL21 and CXCL13 expression in the minor salivary glands. RESULTS: The minor salivary glands of SS patients stained positively for CCL21 and CXCL13 in 46.2% (49/106) and 70.7% (75/106) of all cases, respectively. Higher-level expression of CCL21 and CXCL13 was associated with increases in ESR, IgG and rheumatoid factor levels, as well as anti-SS-A and -SS-B titers. A higher focus score and ESSDAI value at the time of biopsy were also associated with these chemokines. In patients with extraglandular manifestations of SS, the prevalence of lymphadenopathy increased with increasing CCL21 levels. CONCLUSIONS: The expression levels of CCL21 and CXCL13 within the lymphocytic infiltrates of SS patients were associated with several laboratory features of the disease as well as lymphadenopathy and the extent of clinical disease activity. CCL21 and CXCL13 levels can therefore serve as useful markers to predict the disease activity and prognosis of patients with SS.

Comparative virulence of in vitro-cultured primate- and pig-associated Helicobacter suis strains in a BALB/c mouse and a Mongolian gerbil model.

BACKGROUND: Helicobacter suis (H. suis) is the most prevalent gastric non-H. pylori Helicobacter species in humans. This bacterium mainly colonizes the stomach of pigs, but it has also been detected in the stomach of nonhuman primates. The aim of this study was to obtain better insights into potential differences between pig- and primate-associated H. suis strains in virulence and pathogenesis. MATERIALS AND METHODS: In vitro-isolated H. suis strains obtained from pigs, cynomolgus monkeys (Macaca fascicularis), and rhesus monkeys (Macaca mulatta) were used for intragastric inoculation of BALB/c mice and Mongolian gerbils. Nine weeks and six months later, samples of the stomach of inoculated and control animals were taken for PCR analysis and histopathological examination. RESULTS: The cynomolgus monkey-associated H. suis strain only colonized the stomach of mice, but not of Mongolian gerbils. All other H. suis strains colonized the stomach in both rodent models. In all colonized animals, severe gastric inflammation was induced. Gastric lymphoid follicles and destruction of the antral epithelium were observed in infected gerbils, but not in mice. Infection with both pig- and primate-associated H. suis strains evoked a similar marked Th17 response in mice and gerbils, accompanied by increased CXCL-13 expression levels. CONCLUSIONS: Apart from the cynomolgus monkey-associated strain which was unable of colonizing the stomach of Mongolian gerbils, no substantial differences in virulence were found in rodent models between in vitro-cultured pig-associated, cynomolgus monkey-associated and rhesus monkey-associated H. suis strains. The experimental host determines the outcome of the immune response against H. suis infection, rather than the original host.

Evaluation of two assays for CXCL13 analysis in cerebrospinal fluid for laboratory diagnosis of Lyme neuroborreliosis.

We evaluated the diagnostic performance of two assays, one bead-based assay and one enzyme-linked immunosorbent assay (ELISA), for the determination of CXCL13 levels in cerebrospinal fluid (CSF) from patients with suspected Lyme neuroborreliosis (LNB). Patients investigated for LNB were retrospectively included (n = 132): 35 with definite LNB, 8 with possible LNB with CSF pleocytosis but normal antibody index (AI), 6 with possible LNB with elevated AI but no CSF pleocytosis and 83 non-LNB patients. CSF samples had been drawn before antibiotic treatment and were analysed for CXCL13 by Quantikine ELISA (R&D Systems) and recomBead (Mikrogen). Receiver operating characteristic analyses based on the definite LNB and non-LNB groups revealed a best performance cut-off of 56 pg/mL for Quantikine and 158 pg/mL for recomBead (sensitivity and specificity 100% for both assays). When applying these cut-off levels on the study groups, the two assays performed equally well regarding sensitivity and specificity. In the group of patients with pleocytosis but negative AI, the majority of whom were children with short symptom duration, the CXCL13 analysis supported the LNB diagnosis in half of the cases. We consider CSF-CXCL13 analysis a useful diagnostic tool, in addition to Borrelia-specific AI, in laboratory diagnostics of LNB.

A Challenging Cutaneous T-Cell Lymphoma.

Cutaneous peripheral T-cell lymphomas not otherwise specified (CPTL-NOS) are rare neoplasms accounting for just 2% of cutaneous peripheral T-cell lymphomas (CPTL). Only very few case series have been reported. They represent a phenotypically and prognostically heterogenous group of CPTL that do not fit into any of CPTL well-defined subtypes. The authors report a case of a 64-year-old man with simultaneous plaque-like lesions and disseminated nodules growing rapidly on the face, trunk, and extremities over a 6-month period. There was no a history of preceding patches, erythematous plaques, rash, or pruritic lesions. These lesions were extending over 80% of the skin surface. Histopathologic analysis revealed dense diffuse infiltrates composed of mostly medium-sized to large lymphoid cells throughout the entire dermis without epidermotropism. Neoplastic cells were atypical with markedly pleomorphic nuclei. Immunohistochemistry showed that the tumor cells were positive for CD3, CD4, and CD5 with a loss of CD7. They were negative for CD20, CD8, CD56, CXCL13, PD1, TIA-1, granzyme-B, perforin, CD25, and CD30. The proliferative fraction was low, with MIB-1 labeling less than 10% of cells. The authors diagnosed the patient with primary CPTL-NOS. Despite the rarity of these tumors, clinicians as well as dermatopathologists and pathologists should be familiar with these rare CPTL especially because most of these lymphomas have an aggressive behavior and exhibit an unfavorable prognosis.