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1.  The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. 
Genitourinary Medicine  1993;69(2):102-107.
OBJECTIVE--To study the localisation of treponemes and to analyse the inflammatory infiltrate in biopsy specimens from patients with primary or secondary syphilis, or early infectious yaws. MATERIALS AND METHODS--Skin biopsies originating from human lesions of primary (29x) or secondary (15x) syphilis (Rotterdam), or early yaws (18x) (West Sumatra) were studied. Different histochemical and immunohistochemical detection methods were used in this study. RESULTS AND CONCLUSION--The histochemical silver staining method according to Steiner revealed the presence of T. pallidum in all cases of primary syphilis studied. In 10 out of 14 cases of secondary syphilis, treponemes were demonstrated. With an immunofluorescence staining technique (IF) using anti-T. pallidum antiserum raised in rabbits (a-Tp), T. pallidum was demonstrated in 28 out of 29 cases of primary syphilis, and in 14 out of 14 studied cases of secondary syphilis. The silver staining method and IF showed identical localisations of T. pallidum (mainly in the dermal-epidermal junction zone or throughout the dermis). Using a-Tp antiserum in the indirect immunofluorescence technique, T. pertenue could be demonstrated in the dermis more often than with Steiner silver staining. However, epidermotropism of T. pertenue in yaws specimens was remarkable, compared with more mesodermotropism of T. pallidum; numbers of T. pertenue in the dermis were limited in all specimens. The dermal inflammatory infiltrate in primary and secondary syphilis was composed mainly of lymphocytes and plasma cells. In most cases more T (CD3 positive) cells than B (CD22 positive) cells were present. Regarding T cell subpopulations, in primary syphilis, T helper/inducer (CD4 positive) cells predominated in 86% of cases. In secondary syphilitic lesions, numbers of T helper/inducer cells were less frequent than or equal to T-suppressor/cytotoxic (CD8 positive) cells in 60% of cases. Remarkably, in yaws specimens the inflammatory infiltrate consisted mainly of IgG, but also IgA and IgM producing plasma cells. T or B lymphocytes were scarce, which is in sharp contrast with findings in syphilitic lesions.
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PMCID: PMC1195039  PMID: 8509088
2.  EXPERIMENTAL SYPHILIS IN THE RABBIT  
From a study of the phenomena of the primary infection on the one hand, and the phenomena of local spread, or dissemination, on the other, it is seen that a multiplicity of lesions develops in the testicle and scrotum of the rabbit which have much the same characteristics irrespective of their origin. Some of these lesions are clearly recognizable as primary lesions or parts of a primary reaction to infection, while others are just as clearly the results of dissemination of the virus from a primary focus of infection or correspond with lesions which are commonly spoken of as secondary lesions. The effort to draw a sharp line of distinction between these two groups of lesions or between a primary and a secondary stage of infection in the rabbit, however, would be largely an arbitrary procedure. The fact is that the tissues of the scrotum and testicle of the rabbit constitute favorable surroundings for the localization and development of pallidum infections. Under ordinary circumstances, a large part of the reaction to infection which expresses itself in the formation of lesions recognizable by ordinary methods of examination takes place in these tissues. These lesions present certain broad and general characteristics without regard to whether they are primary or secondary in origin; the reaction is merely a reaction to a syphilitic infection which in either case may assume the most diverse character. Further, it would appear that in rabbits infected with such strains of Treponema pallidum as we have used, the virus is never confined to the area occupied by the so called primary lesion, or chancre, but always spreads and always gives rise to a regional adenopathy. There may be no lesions to indicate the progress of this dissemination, but an examination of the inguinal nodes shows that dissemination occurs very soon after inoculation, and a pallidum reaction may be detected in these glands even before infection can be recognized in the scrotum. Subsequently lesions develop in all parts of the scrotum and testicle, sometimes involving the entire testicle or scrotum, and at others, forming focalized lesions with an especial predilection for certain locations such as the epididymis, the mediastinum testis, the tunics, and the dorsal folds of the scrotum. In some instances, more or less continuous lesions form along the course of the perivascular lymphatics, suggesting that this is one path taken in the dissemination of the organism. It is probable, however, that lesions of a gross character develop more as a result of accumulation of spirochetes than of mere invasion of the lymphatics since they are not a constant accompaniment of the local infection, while invasion of the lymphatics and extension of the infection to the regional lymph nodes occur in all cases.
PMCID: PMC2128250  PMID: 19868424
3.  Repeat Syphilis Among Men Who Have Sex With Men in California, 2002–2006: Implications for Syphilis Elimination Efforts 
Objectives
We examined rates of and risk factors for repeat syphilis infection among men who have sex with men (MSM) in California.
Methods
We analyzed 2002 to 2006 California syphilis surveillance system data.
Results
During the study period, a mean of 5.9% (range: 4.9%–7.1% per year) of MSM had a repeat primary or secondary (PS) syphilis infection within 2 years of an initial infection. There was no significant increase in the annual proportion of MSM with a repeat syphilis infection (P=.42). In a multivariable model, factors associated with repeat syphilis infection were HIV infection (odds ratio [OR] = 1.65; 95% confidence interval [CI] = 1.14, 2.37), Black race (OR = 1.84; 95% CI = 1.12, 3.04), and 10 or more recent sex partners (OR = 1.99; 95% CI = 1.12, 3.50).
Conclusions
Approximately 6% of MSM in California have a repeat PS syphilis infection within 2 years of an initial infection. HIV infection, Black race, and having multiple sex partners are associated with increased odds of repeat infection. Syphilis elimination efforts should include messages about the risk for repeat infection and the importance of follow-up testing. Public health attention to individuals repeatedly infected with syphilis may help reduce local disease burdens.
doi:10.2105/AJPH.2011.300383
PMCID: PMC3490561  PMID: 22095364
4.  Multilevel and spatial analysis of syphilis in Shenzhen, China, to inform spatially targeted control measures 
Sexually transmitted infections  2012;88(5):325-329.
Objectives
The present study investigates the varied spatial distribution of syphilis cases in Shenzhen, China, and explores the individual-, neighbourhood- and district-level factors affecting the distribution.
Methods
This study uses spatial analysis and multi-level generalised estimating equations to explore the spatial distribution of reported syphilis cases among individuals in Shenzhen, Guangdong Province, China. The spatial distribution of primary/secondary and latent cases was investigated using the Moran’s I-statistic. Primary/secondary syphilis cases were compared with all syphilis cases using a three-level model with individual (n=6496), neighbourhood (n=55) and district (n=6) levels.
Results
A total of 6496 syphilis cases were reported in 2009 with 35.8% primary and secondary syphilis cases. Both primary/secondary syphilis cases (Moran’s I value=0.33, p<0.01) and latent syphilis cases (Moran’s I value=0.19, p<0.01) showed significant spatial clustering at the neighbourhood level. Adjusting for the number of reporting hospitals, the best model found that the following characteristics were associated with primary/secondary syphilis infection: individuals who are younger in age (p=0.003), male (p<0.001), migrant labourers (p=0.047) and those who live in districts with a higher gross domestic product (p<0.001).
Conclusions
There is substantial clustering of primary and secondary syphilis cases at the neighbourhood level in Shenzhen, suggesting the need for greater STD health service provision in these clustered neighbourhoods. Spatially targeted syphilis control measures may be useful to optimise testing, treatment and partner services.
doi:10.1136/sextrans-2011-050397
PMCID: PMC3642620  PMID: 22378936
5.  Syphilis in adults 
Sexually Transmitted Infections  2005;81(6):448-452.
Syphilis is a sexually transmitted disease with protean manifestations resulting from infection by Treponema pallidum. It is systemic early from the outset, the primary pathology being vasculitis. Acquired syphilis can be divided into primary, secondary, latent, and tertiary stages. The infection can also be transmitted vertically resulting in congenital syphilis, and occasionally by blood transfusion and non-sexual contact. Diagnosis is mainly by dark field microscopy in early syphilis and by serological tests. The management in the tropics depends on the diagnostic facilities available: in resource poor countries, primary syphilis is managed syndromically as for anogenital ulcer. The introduction of rapid "desktop" serological tests may simplify and promote widespread screening for syphilis. The mainstay of treatment is with long acting penicillin. Syphilis promotes the transmission of HIV and both infections can simulate and interact with each other. Treponemes may persist despite effective treatment and may have a role in reactivation in immunosuppressed patients. Partner notification, health education, and screening in high risk populations and pregnant women to prevent congenital syphilis are essential aspects in controlling the infection.
doi:10.1136/sti.2005.015875
PMCID: PMC1745064  PMID: 16326843
6.  Alterations in T lymphocytes and T-lymphocyte subpopulations in patients with syphilis. 
The distribution of T-lymphocyte subpopulations was studied in 34 patients with primary or secondary syphilis before and after treatment. An absolute and relative T lymphopenia was found in all patients. In primary syphilis the concentration of helper cells--T cells with Fc receptors for IgM (T mu)--was low whereas in secondary syphilis the suppressor cell concentration--T cells with Fc receptors for IgG (T gamma)--was reduced. Using lymphocytes from healthy subjects this could be imitated in vitro by the addition of serum from patients with secondary syphilis. In many autoimmune diseases a low concentration of T gamma may be a primary factor in the production of autoantibodies. The occurrence of similar changes in patients with secondary syphilis, however, indicates that such fluctuations in the T-cell subpopulations may take place during a strong immune response.
PMCID: PMC1045993  PMID: 6459815
7.  New Syphilis Cases and Concurrent STI Screening in a Southeastern U.S. HIV Clinic: A Call to Action 
AIDS Patient Care and STDs  2010;24(1):23-29.
Abstract
Syphilis outbreaks in the United States have been reported since 2000 with highest rates in the South and many cases among HIV-infected individuals. We evaluated incident syphilis cases and concurrent gonorrhea and chlamydia screening at a southern HIV clinic. A retrospective cohort study included HIV-infected patients with at least one reactive plasma reagin (test for serum reagin antibodies to cardiolipin-cholesterol-lecithin antigen) and primary care visit from July 2004 to June 2007. Primary, secondary, and early latent syphilis cases were identified as incident syphilis and evaluation for gonorrhea and chlamydia within 1 month were described. Logistic regression was performed to determine factors associated with incident syphilis. Among 1544 patients, 40 incident syphilis cases were identified (5 primary, 29 secondary, and 6 early latent). The majority of patients were not virologically suppressed and only 25% had gonorrhea and chlamydia testing. In adjusted analyses, younger age (0.57 per 10 years, 95% confidence interval [CI] 0.41–0.80) and minority race (2.26, 95% CI 1.12–4.59) were associated with incident syphilis. Among 40 incident syphilis cases, only 1 in 4 were further tested for gonorrhea and chlamydia. These low rates are concerning as concurrent sexually transmitted infections (STIs) increase risk for HIV transmission. HIV care provider education with emphasis on STI testing in the setting of incident syphilis is key in prevention.
doi:10.1089/apc.2009.0255
PMCID: PMC2859761  PMID: 20095902
8.  Lymphocyte Transformation in Syphilis: an In Vitro Correlate of Immune Suppression In Vivo? 
Infection and Immunity  1975;11(6):1261-1264.
Suppression of cellular immunity during primary and secondary infection may explain, in part, the unusual clinical evolution of syphilis. We have previously shown that lymphocytes from normal subjects undergo blastic transformation when exposed in vitro to Treponema refringens. This response was suppressed in patients with syphilis. the suppression being unrelated to serum factors. In the present paper we studied lymphocyte response in vitro to T. refringens, T. reiter, and T. pallidum as well as to monilia and trychophytins. The response to these antigens was suppressed in patients with syphilis although the response to phytohemagglutinin. pokeweed mitogen, and streptolysin was normal. These data support the hypothesis that human infection with T. pallidum is followed by a complex interaction between cellular and humoral immunity, the former being suppressed in primary and secondary stages.
PMCID: PMC415208  PMID: 1095482
9.  Fluctuations in natural killer cell activity in early syphilis. 
The natural killer cell activity was studied in 25 patients with primary, secondary, or latent syphilis before and after treatment. In primary syphilis natural killer cell activity was increased, especially in patients lacking circulating lipoidal antibodies. In patients who had become seroreactive in the lipoidal tests it was depressed in those with secondary and latent syphilis. The natural killer cell activity thus becomes activated by the syphilitic infection but is significantly reduced during progression of the disease. The importance of the natural killer cell activity in controlling syphilitic infection is questionable.
PMCID: PMC1046125  PMID: 6824905
10.  Are serological tests of value in diagnosing and monitoring response to treatment of syphilis in patients infected with human immunodeficiency virus? 
Genitourinary Medicine  1988;64(4):219-222.
To assess the value of serological tests in diagnosing and monitoring the response to treatment of syphilis in patients infected with the human immunodeficiency virus (HIV), case notes of eight homosexual men with a history of treated syphilis, positive reactions to serological tests for syphilis, and documented subsequent conversion to HIV seropositivity were studied. No change was noted in serological markers of syphilis after HIV infection. The case notes of one man with primary syphilis, four men with secondary syphilis, and three men with latent syphilis, of whom all were HIV seropositive, were also studied. In seven of these patients the serological responses to infection and after treatment were consistent with the experience of syphilis in HIV seronegative patients. In one man treated for secondary syphilis, and confirmed as HIV seropositive eight months after treatment, the rapid plasma reagin (RPR) test result continued to be positive at a high titre for up to 20 months after treatment.
PMCID: PMC1194219  PMID: 3169751
11.  Changes of serum IgG antibody reactivity to protein antigens of Treponema pallidum in syphilis patients after treatment. 
The changes of serum IgG antibody reactivity to protein antigens of Treponema pallidum after treatment of syphilis were observed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. Until 9 to 12 months after treatment, it was seen that there was a loss of several antibodies and some diminution in their reactivity in primary, secondary and early latent syphilis, but no changes occurred in late latent and reinfected syphilis. In primary syphilis, there was a significant loss of two IgG antibodies to the treponemal antigens of molecular weights 68,500 and 47,000 at 11 months after treatment. According to our previous study, the treponemal antigen of molecular weight 68,500 was T. pallidum specific and appeared only in primary syphilis, and that of molecular weight 47,000 was one of the major antigens of T. pallidum. The reaction between serum IgG antibodies of 14 patients who had been treated for secondary, early latent and late latent syphilis 2 to 14 years ago and major antigens of T. pallidum was observed and any loss or decrease in reactivity was not discovered. From the results obtained, it was concluded that the observation of serum IgG antibody reactivity to protein antigens of T. pallidum is not helpful in evaluating the efficacy of treatment in secondary, early latent, late latent and reinfected syphilis. However, serum IgG antibodies to treponemal antigens of molecular weights 68,500 and 47,000 could possibly be useful in the assessment of the efficacy of treatment in primary syphilis.
PMCID: PMC3053684  PMID: 2688687
12.  Tumour-like pulmonary lesion in secondary syphilis: a case report 
Radiographic studies have rarely identified tumours of purely syphilitic origin, which are more often present in tertiary syphilis. In this study, a pseudo-neoplastic lesion was detected in a patient with secondary syphilis and rapidly cured by penicillin.
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PMCID: PMC1045976  PMID: 7326550
13.  Evaluation of a New Competitive Immunoassay (BioElisa Syphilis) for Screening for Treponema pallidum Antibodies at Various Stages of Syphilis 
Journal of Clinical Microbiology  1998;36(2):358-361.
The BioElisa Syphilis, a new competitive enzyme immunoassay (EIA) for Treponema pallidum whole antigen that uses specific human immunoglobulin G (IgG) antibodies as the competitor, was evaluated for potential use in screening for syphilis at various stages. The results obtained by this competitive EIA were compared with those obtained by the fluorescent treponemal antibody absorption (FTA-abs) test and the T. pallidum hemagglutination assay (TPHA). Serum samples from 434 patients with positive TPHA and FTA-abs test results, including patients with primary, latent, secondary, and tertiary syphilis and neurosyphilis, were investigated. Two samples tested negative by competitive EIA but were weakly reactive by the TPHA and the FTA-abs test. Sixteen serum samples from patients with clinically documented active syphilis, including several patients infected with human immunodeficiency virus, tested positive by the competitive EIA. There was a direct inverse correlation between EIA indices and titers in the TPHA and the FTA-abs test for all samples that tested positive. Specificity was assessed by testing 358 serum samples which tested negative for syphilis by TPHA and the FTA-abs test, including 100 serum samples from patients with documented infectious or autoimmune diseases. Only two serum samples gave a weakly positive EIA result. Thus, competitive EIA had a sensitivity of 99.5% and a specificity of 99.4% relative to the results of the FTA-abs test and TPHA. Our evaluation shows that BioElisa Syphilis is a sensitive, specific, and simple assay for screening for syphilis.
PMCID: PMC104542  PMID: 9466741
14.  Impact of on-site testing for maternal syphilis on treatment delays, treatment rates, and perinatal mortality in rural South Africa: a randomised controlled trial 
Sexually Transmitted Infections  2003;79(3):208-213.
Background: Syphilis remains a significant cause of preventable perinatal death in developing countries, with many women remaining untested and thus untreated. Syphilis testing in the clinic (on-site testing) may be a useful strategy to overcome this. We studied the impact of on-site syphilis testing on treatment delays and rates, and perinatal mortality.
Methods: We conducted a cluster randomised controlled trial among seven pairs of primary healthcare clinics in rural South Africa, comparing on-site testing complemented by laboratory confirmation versus laboratory testing alone. Intervention clinics used the on-site test conducted by primary care nurses, with results and treatment available within an hour. Control clinics sent blood samples to the provincial laboratory, with results returned 2 weeks later.
Results: Of 7134 women seeking antenatal care with available test results, 793 (11.1%) tested positive for syphilis. Women at intervention clinics completed treatment 16 days sooner on average (95% confidence interval: 11 to 21), though there was no significant difference in the proportion receiving adequate treatment at intervention (64%) and control (69%) clinics. There was also no significant difference in the proportion experiencing perinatal loss (3.3% v 5.1%; adjusted risk difference: -0.9%; 95% CI -4.4 to 2.7).
Conclusions: Despite reducing treatment delays, the addition of on-site syphilis testing to existing laboratory testing services did not lead to higher treatment rates or reduce perinatal mortality. However on-site testing for syphilis may remain an important option for improving antenatal care in settings where laboratory facilities are not available.
doi:10.1136/sti.79.3.208
PMCID: PMC1744662  PMID: 12794203
15.  Serological Response to Treatment of Syphilis According to Disease Stage and HIV Status 
The serological response to treatment was studied in 264 syphilis patients; it was influenced by syphilis stage but not by human immunodeficiency virus infection and reinfection. Some of the recommendations of current guidelines are critically discussed, and amendments are proposed.
Background. Serology is the mainstay for syphilis diagnosis and treatment monitoring. We investigated serological response to treatment of syphilis according to disease stage and HIV status.
Methods. A retrospective cohort study of 264 patients with syphilis was conducted, including 90 primary, 133 secondary, 33 latent, and 8 tertiary syphilis cases. Response to treatment as measured by the Venereal Disease Research Laboratory (VDRL) test and a specific IgM (immunoglobulin M) capture enzyme-linked immunosorbent assay (ELISA; Pathozyme-IgM) was assessed by Cox regression analysis.
Results. Forty-two percent of primary syphilis patients had a negative VDRL test at their diagnosis. Three months after treatment, 85%–100% of primary syphilis patients had reached the VDRL endpoint, compared with 76%–89% of patients with secondary syphilis and 44%–79% with latent syphilis. In the overall multivariate Cox regression analysis, serological response to treatment was not influenced by human immunodeficiency virus (HIV) infection and reinfection. However, within primary syphilis, HIV patients with a CD4 count of <500 cells/μL had a slower treatment response (P = .012). Compared with primary syphilis, secondary and latent syphilis showed a slower serological response of VDRL (P = .092 and P < .001) and Pathozyme-IgM tests (P < .001 and P = .012).
Conclusions. The VDRL should not be recommended as a screening test owing to lack of sensitivity. The syphilis disease stage significantly influences treatment response whereas HIV coinfection only within primary syphilis has an impact. VDRL test titers should decline at least 4-fold within 3–6 months after therapy for primary or secondary syphilis, and within 12–24 months for latent syphilis. IgM ELISA might be a supplement for diagnosis and treatment monitoring.
doi:10.1093/cid/cis757
PMCID: PMC3501331  PMID: 22955437
16.  Clinical Value of Treponema pallidum Real-Time PCR for Diagnosis of Syphilis▿  
Journal of Clinical Microbiology  2009;48(2):497-502.
The diagnosis of syphilis can be complicated when it is based on diverse clinical manifestations, dark-field microscopy, and serology. In the present study, therefore, we examined the additional clinical value of a Treponema pallidum real-time TaqMan PCR for the detection of primary and secondary syphilis. The additional value of the T. pallidum real-time PCR for the diagnosis of primary syphilis was evaluated by the use of three different algorithms: (i) a head-to-head comparison of the dark-field microscopy result and the T. pallidum real-time PCR result, (ii) comparison of the clinical diagnosis made in a sexually transmitted infection clinic (STI) (including by dark-field microscopy) and the T. pallidum real-time PCR result, and (iii) comparison of the clinical diagnosis made in a general practitioner's office (without dark-field microscopy) and the T. pallidum real-time PCR result. A fourth algorithm was used to determine the performance of the T. pallidum real-time PCR regarding the detection of secondary syphilis. From December 2006 to April 2008, 716 patients with suspected cases of primary syphilis and 133 patients with suspected cases of secondary syphilis were included in the study. A kappa value of 0.601 was found for the agreement between dark-field microscopy and the T. pallidum real-time PCR. Good agreement was found between the T. pallidum real-time PCR and both the diagnosis of the general practitioner (kappa = 0.745) and the diagnosis of the STI clinic (kappa = 0.769). The sensitivity with respect to the STI clinic diagnosis was 72.8%, the specificity was 95.5%, the positive predictive value was 89.2%, and the negative predictive value was 95.0%. The T. pallidum real-time PCR is a fast, efficient, and reliable test for the diagnosis of primary syphilis in an STI outpatient clinic and a general practitioner setting, but it has no added diagnostic value for the diagnosis of secondary syphilis.
doi:10.1128/JCM.00720-09
PMCID: PMC2815629  PMID: 20007388
17.  Primary syphilis cases in Guangdong Province 1995-2008: Opportunities for linking syphilis control and regional development 
BMC Public Health  2010;10:793.
Background
Syphilis cases have risen in many parts of China, with developed regions reporting the greatest share of cases. Since syphilis increases in these areas are likely driven by both increased screening and changes in sexual behaviours, distinguishing between these two factors is important. Examining municipal-level primary syphilis cases with spatial analysis allows a more direct understanding of changing sexual behaviours at a more policy-relevant level.
Methods
In this study we examined all reported primary syphilis cases from Guangdong Province, a southern province in China, since the disease was first incorporated into the mandatory reporting system in 1995. Spatial autocorrelation statistics were used to correlate municipal-level clustering of reported primary syphilis cases and gross domestic product (GDP).
Results
A total of 52,036 primary syphilis cases were reported over the period 1995-2008, and the primary syphilis cases increased from 0.88 per 100,000 population in 1995 to 7.61 per 100,000 in 2008. The Pearl River Delta region has a disproportionate share (44.7%) of syphilis cases compared to other regions. Syphilis cases were spatially clustered (p = 0.01) and Moran's I analysis found that syphilis cases were clustered in municipalities with higher GDP (p = 0.004).
Conclusions
Primary syphilis cases continue to increase in Guangdong Province, especially in the Pearl River Delta region. Considering the economic impact of syphilis and its tendency to spatially cluster, expanded syphilis testing in specific municipalities and further investigating the costs and benefits of syphilis screening are critical next steps.
doi:10.1186/1471-2458-10-793
PMCID: PMC3022862  PMID: 21192782
18.  Immunoglobulin-bearing lymphoid cells in primary syphilis. Quantitative and elution studies. 
The delay in antibody production in response to infection with Treponema pallidum may be caused by a block in the differentiation of antigen-stimulated B (Bursa-dependent) lymphoid cells towards plasma cells. This hypothesis was tested by a study to detect clonal expansion of immunoglobulin-bearing B lymphoid cells by in-vitro immunofluorescence tests in patients with primary syphilis. In addition, antibodies eluted from circulating lymphoid cells were investigated for treponemal binding by the enzyme-linked immunosorbent assay, the T pallidum immobilisation test, and the immunoglobulin class-specific FTA-ABS test. Results indicated that the number of IgG-bearing lymphoid cells were increased in patients with primary syphilis. However, in only a few cases could antitreponemal antibodies be eluted from isolated lymphoid cells. For this reason, the original hypothesis was rejected.
PMCID: PMC1045734  PMID: 6992939
19.  Immune Evasion and Recognition of the Syphilis Spirochete in Blood and Skin of Secondary Syphilis Patients: Two Immunologically Distinct Compartments 
Background
The clinical syndrome associated with secondary syphilis (SS) reflects the propensity of Treponema pallidum (Tp) to escape immune recognition while simultaneously inducing inflammation.
Methods
To better understand the duality of immune evasion and immune recognition in human syphilis, herein we used a combination of flow cytometry, immunohistochemistry (IHC), and transcriptional profiling to study the immune response in the blood and skin of 27 HIV(-) SS patients in relation to spirochetal burdens. Ex vivo opsonophagocytosis assays using human syphilitic sera (HSS) were performed to model spirochete-monocyte/macrophage interactions in vivo.
Results
Despite the presence of low-level spirochetemia, as well as immunophenotypic changes suggestive of monocyte activation, we did not detect systemic cytokine production. SS subjects had substantial decreases in circulating DCs and in IFNγ-producing and cytotoxic NK-cells, along with an emergent CD56−/CD16+ NK-cell subset in blood. Skin lesions, which had visible Tp by IHC and substantial amounts of Tp-DNA, had large numbers of macrophages (CD68+), a relative increase in CD8+ T-cells over CD4+ T-cells and were enriched for CD56+ NK-cells. Skin lesions contained transcripts for cytokines (IFN-γ, TNF-α), chemokines (CCL2, CXCL10), macrophage and DC activation markers (CD40, CD86), Fc-mediated phagocytosis receptors (FcγRI, FcγR3), IFN-β and effector molecules associated with CD8 and NK-cell cytotoxic responses. While HSS promoted uptake of Tp in conjunction with monocyte activation, most spirochetes were not internalized.
Conclusions
Our findings support the importance of macrophage driven opsonophagocytosis and cell mediated immunity in treponemal clearance, while suggesting that the balance between phagocytic uptake and evasion is influenced by the relative burdens of bacteria in blood and skin and the presence of Tp subpopulations with differential capacities for binding opsonic antibodies. They also bring to light the extent of the systemic innate and adaptive immunologic abnormalities that define the secondary stage of the disease, which in the skin of patients trends towards a T-cell cytolytic response.
Author Summary
Syphilis, a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum, affects close to 10 million people per year worldwide. Despite the robust nature of the humoral and cellular immune responses associated with the disease, weeks to months may elapse before the host gains control of the infection. Moreover, in the absence of antibiotic treatment, containment is often incomplete and relapses are common. Herein we studied aspects of the immune response in the blood and skin of patients with secondary syphilis to better understand the factors that determine whether the bacterium evades host defenses or is cleared in its natural human host. Our findings support the importance of the macrophage as a primary means of bacterial killing in the skin, while suggesting that the extent of bacterial clearance is determined by the bacterial loads present in either the blood or skin of patients and the appearance of spirochetes which are resistant to uptake (phagocytosis) by the macrophages. Study results underscore the extent of the systemic immunologic abnormalities triggered by the bacterium and provide new insights regarding the complexity of the immune response in the skin of untreated patients.
doi:10.1371/journal.pntd.0001717
PMCID: PMC3398964  PMID: 22816000
20.  Unheated serum reagin test as a quantitative test for syphilis. 
Journal of Clinical Microbiology  1982;15(2):238-242.
The unheated serum reagin (USR) test, a standard qualitative test for syphilis, was evaluated for use as a quantitative test for the serodiagnosis of syphilis and as a means of determining the effectiveness of treatment. Tests were performed on 664 syphilitic sera from treated and untreated patients in the primary, secondary, and latent stages of the disease. Also included were 95 false-positive sera and 36 sera from presumably normal donors. The Venereal Disease Research Laboratory slide and rapid plasma reagin 18-mm circle card tests were used as a basis for comparison with the USR test. Results of the USR quantitative test paralleled the Venereal Disease Research Laboratory and rapid plasma reagin card quantitative tests with approximately 84% agreement. The advantages of the USR test make the findings of this study significant in that: (i) less technical manipulation is required to perform the USR test than the Venereal Disease Research Laboratory slide test; (ii) no labor cost is incurred for daily Venereal Disease Research Laboratory antigen preparation; and (iii) the USR antigen is less expensive than the rapid plasma reagin card tests antigen.
PMCID: PMC272068  PMID: 7068819
21.  Rheumatoid factor in syphilis. 
Immunoglobulin M (IgM) antibodies directed against IgG antibodies (rheumatoid factor [RF]) are known to occur often in patients with syphilis and to interfere with serological tests measuring specific antibodies of the IgM class. In this study we examined the occurrence and specificity of the RF and demonstrated a simple method to detect and eliminate the RF for a specific Treponema pallidum IgM enzyme-linked immunosorbent assay. We measured the occurrence of the RF with a sensitive enzyme-linked immunosorbent assay and found that it increased with the duration of syphilitic disease: 1 of 13 primary syphilis serum specimens, 3 of 13 secondary syphilis serum specimens, and 10 of 27 latent syphilis serum specimens were reactive in this RF test. Those sera containing IgM RF were immunoprecipitated with anti-human gamma chain antibodies and 2% polyethylene glycol until the RF was removed. One serum specimen from a patient in the secondary stage of syphilis and eight serum specimens from patients with latent disease still presented the RF after immunoprecipitation. Removal of the IgG antibodies also improved the sensitivity of the treponemal IgM test, indicating competition of these antibodies for binding sites of the antigen. The enzyme-linked immunosorbent assays for detection of RF and antitreponemal IgM antibodies are performed on the same plate. Theoretically, only sera positive for both tests have to be immunoprecipitated. But our findings indicated an increase in sensitivity of the IgM enzyme-linked immunosorbent assay after removal of IgG antibodies responsible for competition at the binding sites.
PMCID: PMC268328  PMID: 3894413
22.  In Vitro Lymphocyte Response to Treponema refringens in Human Syphilis 
Infection and Immunity  1974;9(4):654-657.
The response of lymphocytes from patients with syphilis and normal subjects was studied in vitro by using phytohemagglutinin (PHA), pokeweed mitogen (PWM), streptolysin O (SLO), and a preparation of Treponema refringens. Normal lymphocytes exhibited a dose-response curve to treponemes. Although lymphocytes from patients with primary and secondary syphilis responded normally to PHA and PWM, their response to SLO was suppressed and they failed to show significant stimulation by treponemes. Serum from syphilitic patients did not affect normal lymphocytes, and culturing lymphocytes from patients with syphilis in normal serum did not restore their responsiveness. Six to 10 weeks after syphilitic patients had been treated, the degree of stimulation by treponemes was the same as for normal subjects. These data give indirect support to the hypothesis that immunological suppression occurs during active infection with T. pallidum.
PMCID: PMC414860  PMID: 4822867
23.  The erythrocyte sedimentation rate in syphilis. 
The erythrocyte sedimentation rate was studied in 520 men and 202 women with syphilis. It was raised in 66-6 per cent. of sero-negative primary cases, 80 per cent. of sero-positive cases, 100 per cent. of secondary cases, 80 per cent. of early latent cases, and 73-9 per cent. of late latent cases. It was also raised in sixteen out of seventeen cases of neurosyphilis and in all eleven cases of cardiovascular syphilis. It was concluded that the ESR had little place in the management of syphilis in general, but could be helpful in the post-treatment follow-up of late syphilis.
PMCID: PMC1045290  PMID: 990882
24.  Epidemiology of infectious syphilis in Singapore. 
Genitourinary Medicine  1986;62(2):75-77.
The incidence of early infectious syphilis in Singapore rose from 8.7 per 100,000 in 1980 to 25 per 100,000 in 1984. In this epidemiological study of 100 patients with early syphilis, 70 were men, the mean age was 31.7 (range 17 to 68) years, 25 patients had primary syphilis, 47 secondary syphilis, and the remaining 28 had early latent syphilis. Female prostitutes were cited as sources of infection by 46 and homosexual contacts by 11. Reduced herd immunity, decreased use of penicillin, greater population movement, and decreased surveillance and awareness have contributed to this rise in infectious syphilis.
PMCID: PMC1011902  PMID: 3721513
25.  How infectious is syphilis? 
In a study of the sexual contacts of patients with primary and secondary syphilis, 65 of 127 (51%) contacts at risk developed syphilis. There was no significant difference between figures for homosexuals (48/98, 49%) and for heterosexuals (17/29, 58%). Our findings are similar to those of the prepenicillin era, but the question, Why are so few contacts infected? remains unanswered.
PMCID: PMC1046186  PMID: 6871650

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