Immune Dysfunction in Schizophrenia Spectrum Disorders.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Diagnostic role of CXCL13 and CSF serology in patients with neurosyphilis.

BACKGROUND: Considering the unknown prevalence of neurosyphilis in West China, and the confusing diagnosis of neurosyphilis, the role of CSF_CXCL13 and syphilis serology was studied to provide a more accurate reference for the clinical detection and diagnosis of neurosyphilis. METHODS: A retrospective data set I was used to investigate the prevalence of neurosyphilis, as well as the laboratory characteristics of 244 patients. Besides, to explore the diagnostic value of CSF_CXCL13 and syphilis serology for neurosyphilis, another 116 CSF_serum paired samples (data set II) were collected from 44 neurosyphilis and 72 non-neurosyphilis/syphilis patients. RESULTS: About 6.25% (156 out of 2494) syphilis was neurosyphilis. When Treponema pallidum infection occurs, syphilis serology (sero_TRUST ≥1:16 and sero_TPPA titre ≥1:10240) can be good predictors of neurosyphilis, as well as syphilis CSF serology (CSF_TPPA ≥1:320, CSF_TRUST and venereal disease research laboratory). The sensitivity of serology in neurosyphilis can be complemented by CSF_CXCL13, which could be the therapy monitor of neurosyphilis. CONCLUSION: Due to the lack of ideal biomarkers for neurosyphilis, the importance of syphilis serology cannot be ignored, and their combination with CSF_CXCL13 or other biomarkers should be further investigated.

[Immunological markers of defeat of nervous tissue as an element of predictive model of damage of nervous system at syphilis.]

To develop predictive model of damage of nervous system on the basis of definition of concentration of interleukins-23, 12p40 and also a glial fibrillar acid protein (GFAP) in liquor of patients with various forms of syphilis. Comprehensive laboratory examination of patients with neurosyphilis and syphilis without specific damage of nervous system who were observed in venereologic office of BOUZAS of OO «Clinical Dermatovenerologic Clinic¼ of Omsk is conducted. To all patients were carried out: a serological blood analysis, serological and clinical trial of liquor, and also immunological research of liquor (interleukins - 23, 12p40, and also GFAP). On the basis of the research IL-23, SILT-12p40, GFAP, the level of protein and a pleocytosis in liquor the predictive model of development of neurosyphilis in patients with syphilis without specific damage of nervous system is offered. The analysis of immunological changes in liquor of patients showed that the research of a number of cytokines and markers of damage of nervous tissue to liquor as the most specific and reliable, especially in the absence of clinical symptomatology from central nervous system can be an integral part of diagnostics of neurosyphilis also.

Cytokine and immune cell profiling in the cerebrospinal fluid of patients with neuro-inflammatory diseases.

BACKGROUND: Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters. METHODS: Using multiplex assays, we simultaneously measured 36 cytokines (CCL1-3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22-27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11-13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1ß) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry. RESULTS: We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and QAlbumin. Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB. CONCLUSIONS: Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.

Concurrent aquaporin-4-positive NMOSD and neurosyphilis: A case report.

Neuromyelitis optica spectrum disorder (NMOSD) is a common neuroinflammatory demyelinating disease associated with aquaporin-4 (AQP4) antibody in the central nervous system. Neurosyphilis is a neurological disease caused by Treponema pallidum infection. NMOSD commonly occurs concurrently with autoimmune diseases. However, they have rarely been associated with infectious diseases. In this report we describe a rare case of concurrent AQP4-positive NMOSD and neurosyphilis. A 60-year-old man was admitted to our hospital with a complaint of progressive weakness in his legs for one month. T2-weighted magnetic resonance images of the spinal cord showed longitudinal extensive lesions at C7-T7. The rapid plasma reagin test and T. pallidum particle agglutination assay performed using patient serum and cerebrospinal fluid (CSF) were positive. Additionally, the AQP4-immunoglobulin (Ig) G was detected in the serum and CSF. The patient's symptom gradually improved after penicillin and methylprednisolone treatment. This case report highlights the possibility of the presence of an infectious disease in patients with NMOSD.

A comparison of nontreponemal tests in cerebrospinal fluid for neurosyphilis diagnosis: equivalent detection of specific antibodies.

BACKGROUND: Syphilis is a re-emerging sexually-transmitted infection, caused by the spirochete Treponema pallidum, that may penetrate early into the central nervous system. The venereal disease research laboratory test (VDRL) on the cerebrospinal fluid (CSF) is the most widely used for neurosyphilis diagnosis. We evaluated the performance of two other nontreponemal tests (rapid plasma reagin [RPR] and unheated serum reagin [USR] tests) in comparison with the VDRL in CSF. METHODS: We analyzed CSF samples from 120 individuals based on VDRL reactivity in the CSF and the clinical picture of neurosyphilis. RESULTS: High inter-rater reliability was found among all three tests, with equivalent sensitivity and specificity. Intraclass correlation coefficient for absolute agreement was 1 for VDRL versus USR, 0.99 for VDRL versus RPR, and 0.99 for RPR versus USR. CONCLUSIONS: Rapid plasma reagin and unheated serum reagin tests were identified as excellent alternatives for neurosyphilis diagnosis.

A comparison of nontreponemal tests in cerebrospinal fluid for neurosyphilis diagnosis: equivalent detection of specific antibodies / Uma comparação de testes não treponêmicos no líquido cefalorraquidiano para diagnóstico de neurossífilis: detecção equivalente de anticorpos específicos

ABSTRACT Syphilis is a re-emerging sexually-transmitted infection, caused by the spirochete Treponema pallidum, that may penetrate early into the central nervous system. The venereal disease research laboratory test (VDRL) on the cerebrospinal fluid (CSF) is the most widely used for neurosyphilis diagnosis. We evaluated the performance of two other nontreponemal tests (rapid plasma reagin [RPR] and unheated serum reagin [USR] tests) in comparison with the VDRL in CSF. Methods: We analyzed CSF samples from 120 individuals based on VDRL reactivity in the CSF and the clinical picture of neurosyphilis. Results: High inter-rater reliability was found among all three tests, with equivalent sensitivity and specificity. Intraclass correlation coefficient for absolute agreement was 1 for VDRL versus USR, 0.99 for VDRL versus RPR, and 0.99 for RPR versus USR. Conclusions: Rapid plasma reagin and unheated serum reagin tests were identified as excellent alternatives for neurosyphilis diagnosis.

RESUMO A sífilis é uma infecção reemergente sexualmente transmissível pelo espiroqueta Treponema pallidum, que pode penetrar precocemente no sistema nervoso central. O teste venereal disease research laboratory test (VDRL) no líquido cefalorraquidiano (LCR) é o mais amplamente utilizado para diagnóstico de neurossífilis. Avalia-se o desempenho de dois outros testes não treponêmicos (rapid plasma reagin - RPR and unheated serum reagin - USR tests) em comparação ao VDRL no LCR. Métodos: Foram analisadas amostras de LCR de 120 indivíduos com base no quadro clínico compatível com neurossifilis e reatividade no VDRL no LCR. Resultados: Os testes apresentaram elevada concordância. O coeficiente de correlação intraclasse para concordância absoluta foi de 1 para VDRL versus USR, 0,99 para VDRL versus RPR e 0,99 para RPR versus USR. Conclusões: Os testes rapid plasma reagin e unheated serum reagin foram identificados como excelentes alternativas para o diagnóstico de neurossífilis.

Risk of neurosyphilis in HIV-infected persons with syphilis lacking signs or symptoms of central nervous system infection.

OBJECTIVES: People living with HIV (PLWH) are at increased risk of asymptomatic neurosyphilis; thus, it has been common practice to perform a lumbar puncture (LP) in all PLWH presenting with syphilis regardless of stage, signs or symptoms. However, this practice varies widely among clinicians. Our objective was to elucidate the number of LPs required to diagnose a single case of asymptomatic neurosyphilis. METHODS: We performed an electronic health record (EHR) review of PLWH who were diagnosed with syphilis of any stage over a 10-year period. EHRs were reviewed to determine the number of subjects who had an LP performed, what proportion had neurological signs or symptoms, and whether a diagnosis of neurosyphilis was made at presentation or follow-up. RESULTS: In 261 separate episodes of syphilis in 230 subjects, we found the major risk factors for asymptomatic neurosyphilis to be low CD4 T-cell count (P = 0.0007), high rapid plasma reagin (RPR) titre (P = 0.019) and lack of HIV virological suppression (P = 0.003). The majority of our subjects (78%) with neurosyphilis presented with central nervous system (CNS) symptoms. We estimate, if standard practice is to perform LP in all patients, that the number needed to test (NNTT) = 38. CONCLUSIONS: This large number of potentially unnecessary LPs, along with heterogeneity of presentation, and the never-nil risk of asymptomatic neurosyphilis should be incorporated into clinical decision-making. The majority of PLWH presenting with a serological diagnosis of syphilis, but no neurological signs or symptoms, do not necessarily require an LP for an evaluation of asymptomatic neurosyphilis.

Relevance in biology and mechanisms of immune and treatment evasion of Treponema pallidum.

INTRODUCTION: During syphilis a compelling fight is engaged between the host's humoral and cellular immune responses that work to eliminate the infection and Treponema pallidum (T. pallidum) that manages to evade eradication and cause chronic infection. Different mechanisms are utilized by treponemes to overcome immunological response. Although penicillin (BPG) proved to be effective in quelling the early manifestations of the disease and consequently its contagiousness, questions remain about its ability to prevent the late complications and to provide a microbiological eradication in vivo. In fact, both serological and microbiological failures have been reported following conventional treatment. EVIDENCE ACQUISITION: We reviewed some biologic properties of T. pallidum in order to establish a relationship with the persistence of the infection and the alleged treatment resistance. EVIDENCE SYNTHESIS: The host humoral response, sometimes, may not protect completely against T. pallidum and accounts for the persistent infection and tertiary damages. In fact, the cell mediated response during infection may be downregulate in response to pathogen-derived molecules, or indirectly by generating Treg cells. It is also possible that there are strain types of T. pallidum with higher ability of evasion determining neurosyphilis. In addition, apart the impressive results that BPG has made on the syphilis cutaneous lesions, concerns still remain on its efficacy in preventing late complications. CONCLUSIONS: Understanding the biology of the T. pallidum may help researchers in this field to develop future target therapies in order to prevent persistent infection and progression of the disease.

Reported Cases of Neurosyphilis Among Early Syphilis Cases-United States, 2009 to 2015.

The surveillance of neurosyphilis, an uncommon but severe consequence of syphilis, is complex; surveillance classification of neurosyphilis requires a lumbar puncture and cerebrospinal fluid analysis. We examined the prevalence of reported neurosyphilis among primary, secondary, and early latent syphilis cases reported in the United States from 2009 to 2015. Overall, the prevalence of reported neurosyphilis from 2009 to 2015 was low (0.84%); however, this is likely an underestimate of the true burden in the United States.

A negative nontreponemal and/or specific antitreponemal IgM test does not exclude active infectious syphilis: evidence from a rabbit infectivity test: A case report.

BACKGROUND: The diagnostic criteria for active infectious syphilis in the clinic are important matter of controversy and debate. So far, clinicians habitually do use the negative results of the nontreponemal and/or the specific antitreponemal IgM as the evidences of disease-free or active infection-free status. METHOD: We present a case study involving a patient who was admitted to Zhongshan Hospital because of cerebral infarct. Clinical examination indicated he had a history of latent syphilis with negative nontreponemal and specific antitreponemal IgM tests. The cerebrospinal fluid sample from the patient was inoculated into seronegative New Zealand rabbit. RESULTS: Motile Treponema pallidum was detected by a rabbit infectivity test in the patient's cerebrospinal fluid. This syphilis strain was confirmed by DNA subtyping form of "centers for disease control subtype/tp0548 sequence type", and the strain type was 14d/f. Treatment with benzathine penicillin provided no apparent benefit, but treatment with aqueous crystalline penicillin G, especially recommended for neurosyphilis, led to disease regression. No evidence of cerebral infarct was observed during a 2-year follow-up period. CONCLUSION: The definitive differential diagnosis of active infectious syphilis should be reconsidered. Moreover, selecting the appropriate penicillin preparation is important because T pallidum can reside in sequestered sites. It is necessary to treat a patient with known invasion of the central nervous system with aqueous crystalline penicillin G, if previous treatment for syphilis failed and patients had some clinical neurological presentation that is otherwise unexplained, but that could represent neurosyphilis. Additional studies are needed to confirm the results in other syphilis patients.

Prevalence Estimates of Complicated Syphilis.

We reviewed 68 cases of possible neurosyphilis among 573 syphilis cases in King County, WA, from 3rd January 2012 to 30th September 2013; 7.9% (95% confidence interval, 5.8%-10.5%) had vision or hearing changes, and 3.5% (95% confidence interval, 2.2%-5.4%) had both symptoms and objective confirmation of complicated syphilis with either abnormal cerebrospinal fluid or an abnormal ophthalmologic examination.

Treponemal antibody in CSF and cellular immunity in peripheral blood of syphilitic patients with persisting positive rapid plasma regain.

The ratio of patients with RPR constant positive more than 2 years despite receiving standard syphilis treatment has been reported to be 11.54%~31.3%. The current interpretations on this phenomenon are cellular immune function restrained and the existence of neurosyphilis or asymptomatic neurosyphilis. We conducted this study to detect the treponemal antibody in cerebrospinal fluid (CSF) and lymphocyte subsets in peripheral blood of syphilis patients with persisting RPR positive more than 2 years without neurologic signs, and then explore their relationship. In this study, Treponemal antibody in CSF of 46 syphilitic with HIV negative were measured by syphilis serum test and compared with that of 5 neurosyphilis. Lymphocyte subsets were measured by flow cytometry (FCM) and compared with that of 30 healthy controls. We observed that treponemal antibody in CSF was detected not only in 12 cases (25.21%) of 46 treated patients, but also in 5 neurosyphilis. The ratio of lymphocyte subsets revealed that CD3+, CD4+ T cells and natural killer (NK) cells showed no significant differences between the patient and healthy controls (P>0.05), while CD8+ T cells in patients were significant higher than that in healthy controls (P<0.001). Lymphocyte subsets showed no significant differences between the patients with treponemal antibody positive and negative in CSF (P>0.05). In conclusion, the treponemal antibody in CSF of treated patients suggests that part of them were asymptomatic neurosyphilis and with cellular immunodifeciency. And there is no significant relationship between asymptomatic neurosyphilis and cellular immunodeficiency in peripheral blood.

Neurosyphilis and ophthalmic syphilis in persons with negative rapid plasma reagin and positive treponemal antibody test results.

The detection of serodiscordant syphilis test results raises several important clinical and public health questions. Based on our retrospective review, the probability of neurosyphilis in persons with serodiscordant serologies is low. The probability of ophthalmic syphilis may be higher, but we lack objective measures for that diagnosis.

Increased interleukin-17 in peripheral blood and cerebrospinal fluid of neurosyphilis patients.

BACKGROUND: Treponema pallidum infection evokes vigorous immune responses, resulting in tissue damage. Several studies have demonstrated that IL-17 may be involved in the pathogenesis of syphilis. However, the role of Th17 response in neurosyphilis remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, Th17 in peripheral blood from 103 neurosyphilis patients, 69 syphilis patients without neurological involvement, and 70 healthy donors were analyzed by flow cytometry. The level of IL-17 in cerebrospinal fluid (CSF) was quantified by ELISA. One-year follow up for 44 neurosyphilis patients was further monitored to investigate the role of Th17/IL-17 in neurosyphilis. We found that the frequency of Th17 cells was significantly increased in peripheral blood of patients with neurosyphilis, in comparison to healthy donors. IL-17 in CSF were detected from 55.3% neurosyphilis patients (in average of 2.29 (0-59.83) pg/ml), especially in those with symptomatic neurosyphilis (61.9%). CSF IL-17 was predominantly derived from Th17 cells in neurosyphilis patients. Levels of IL-17 in CSF of neurosyphilis patients were positively associated with total CSF protein levels and CSF VDRL (Venereal Disease Research Laboratory) titers. Notably, neurosyphilis patients with undetectable CSF IL-17 were more likely to confer to CSF VDRL negative after treatment. CONCLUSIONS: These findings indicate that Th17 response may be involved in central nervous system damage and associated with clinical symptoms in neurosyphilis patients. Th17/IL-17 may be used as an alternative surrogate marker for assessing the efficacy of clinical treatment of neurosyphilis patients.

Solitary spinal dural syphilis granuloma mimicking a spinal meningioma.

Dural granuloma is extremely rare. To our knowledge, there has no case reported solitary spinal dural syphilis granuloma worldwide so far. Here we report our findings in a 49-year-old woman, who presented with 10-year progressive left lower-limb numbness and two weeks of right lower-limb numbness. Magnetic resonance imaging (MRI) suggested a homogeneous enhanced spindle-shaped lesion, 2.9 × 1.5 cm in size, occupying the spinal intradural extramedullary space, at the level of Thoracic (T)-2/3, which mimicked the appearance of spinal meningioma. The Treponema pallidum particle agglutination (TPPA) test titer of 1:8, and the venereal diseases research laboratory of cerebral spinal fluid (VDRL-CSF) was reactive, so confirmed neurosyphilis was considered. After formal anti-syphilis treatment, posterior laminectomy surgery was performed, and the lesion was completely separated and extirpated. Final histopathologic diagnosis of the lesion was confirmed as chronic granulomatous inflammation, combined with the neurosyphilis history, spinal dural syphilis granuloma was finally diagnosed. Postoperatively, the patient recovered without any further treatment.

Criteria for the diagnosis of neurosyphilis in cerebrospinal fluid: relationships with intrathecal immunoglobulin synthesis and blood-cerebrospinal fluid barrier dysfunction.

BACKGROUND: The origin of cerebrospinal fluid (CSF) syphilis antibodies (intrathecal or blood-derived) is in doubt. Little is known about CSF test behavior under the condition of physiological or disturbed functioning of blood-CSF barrier (BCB) and intrathecal immunoglobulin (Ig) production. METHODS: We collected 126 serum/CSF pairs from patients with serological evidence of syphilis. We explored the relationships between the established facts of intrathecal Ig synthesis and/or BCB dysfunction and the results of CSF diagnostic tests: the Treponema pallidum hemagglutination (TPHA) test, the fluorescent treponemal antibody absorption (FTA-Abs) test, the Venereal Disease Research Laboratory (VDRL) test, and white blood cell counts. We checked the criteria used either to support or refute the diagnosis of neurosyphilis. RESULTS: Reactive CSF-VDRL tests, elevated CSF-white blood cell counts, and elevated CSF-TPHA titers/indices were associated with the signs of intrathecal Ig synthesis, whereas nonreactive CSF-fluorescent treponemal antibody absorption, nonreactive CSF-TPHA tests, and CSF-TPHA titers from 1:4 to 1:160 were associated with cases where the intrathecal synthesis was not detected. There were some peculiarities of the tests toward BCB dysfunction.Most of reactive CSF-VDRL test samples and CSF samples with pleocytosis were also meeting at least 1 of the CSF-TPHA titer/indices-based criteria. T. pallidum hemagglutination indices were in no better conformity with the facts of intrathecal immune response than CSF-TPHA titers. CONCLUSIONS: Our findings have shown that all the examined criteria for the diagnosis of neurosyphilis in CSF are different assessment tools of intrathecal humoral immune activity and support the hypothesis that high CSF treponemal-specific antibody titers are a consequence of inflammatory pathology of the central nervous system.

Regulatory T cells in peripheral blood and cerebrospinal fluid of syphilis patients with and without neurological involvement.

BACKGROUND: Syphilis, a sexually transmitted disease caused by spirochetal bacterium Treponema pallidum, can progress to affect the central nervous system, causing neurosyphilis. Accumulating evidence suggest that regulatory T cells (Tregs) may play an important role in the pathogenesis of syphilis. However, little is known about Treg response in neurosyphilis. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed Treg frequencies and Transforming Growth Factor-ß (TGF-ß) levels in the blood and CSF of 431 syphilis patients without neurological involvement, 100 neurosyphilis patients and 100 healthy donors. Suppressive function of Tregs in peripheral blood was also assessed. Among syphilis patients without neurological involvement, we found that secondary and serofast patients had increased Treg percentages, suppressive function and TGF-ß levels in peripheral blood compared to healthy donors. Serum Rapid Plasma Reagin (RPR) titers were positively correlated with Treg numbers in these patients. Compared to these syphilis patients without neurological involvement, neurosyphilis patients had higher Treg frequency in peripheral blood. In the central nervous system, neurosyphilis patients had higher numbers of leukocytes in CSF compared to syphilis patients without neurological involvement. CD4(+) T cells were the predominant cell type in the inflammatory infiltrates in CSF of neurosyphilis patients. Interestingly, among these neurosyphilis patients, a significant decrease in CSF CD4(+) CD25(high) Treg percentage and number was observed in symptomatic neurosyphilis patients compared to those of asymptomatic neurosyphilis patients, which may be associated with low CSF TGF-ß levels. CONCLUSIONS: Our findings suggest that Tregs might play an important role in both bacterial persistence and neurologic compromise in the pathogenesis of syphilis.