Allergic Contact Dermatitis of the Anogenital Region in Men and Women.

OBJECTIVES: Allergic contact dermatitis is an uncommon but important cause of skin disease in the anogenital region. Relevant allergens are described in women and less commonly in men. The aim of this study was to describe outcomes of patch testing in men and women presenting with anogenital dermatoses. MATERIALS AND METHODS: Cases patch tested for anogenital conditions at 2 patch test clinics in Sydney, Australia, from 2002 to 2017 were reviewed. Positive and relevant patch test reactions were recorded. RESULTS: Thirty-seven women and 27 men were included. Dermatitis was the most common diagnosis, followed by psoriasis and lichen sclerosus. Thirty percent had a final diagnosis of allergic contact dermatitis. The most frequent relevant allergens were fragrance mix I (9%), patients own products (9%), Myroxylon pereirae (8%), cocamidopropyl betaine (3%), and benzocaine (3%). CONCLUSIONS: The top positive and relevant allergens seen were in concordance with other reports from Australia and the rest of the world. Fragrances and medicaments are common allergens, and it is recommended that products used on anogenital skin be fragrance free. Testing patients own products is imperative.

Bivalent Vaccine Effectiveness Against Anal Human Papillomavirus Positivity Among Female Sexually Transmitted Infection Clinic Visitors in the Netherlands.

Human papillomavirus (HPV) vaccines are indicated for anal cancer prevention, but evidence for vaccine effectiveness (VE) against anal HPV infections among women is limited. We estimated the VE (≥1 dose) against anal HPV positivity of the bivalent vaccine, whose target types HPV-16/18 are associated with approximately 90% of HPV-related anal cancers. Among 548 female STI clinic visitors 16-24 years old who provided an anal swab sample as part of a repeated cross-sectional survey, VE against HPV-16/18 was 89.9% (95% confidence interval, 63.0%-97.2%). Type-specific VE correlated well with VE against cervicovaginal HPV (Spearman ρ = 0.76), suggesting comparable effectiveness of HPV-16/18 vaccination against genital and anal infections.

Prevalence of N. gonorrhoeae, C. trachomatis, M. genitalium, M. hominis and Ureaplasma spp. in the anus and urine among Japanese HIV-infected men who have sex with men.

The present study investigated the prevalence of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, M. hominis, and Ureaplasma spp. (biovars 1 and 2) in Japanese HIV-positive men who have sex with men (MSM). One-hundred-and-six Japanese HIV-infected MSM patients were enrolled. Anal and urine samples were collected and DNA testing for each microorganism was performed. Questionnaires regarding lifestyle habits and sexual behavior were administered. The prevalence of N. gonorrhoeae, C. trachomatis, M. genitalium, M. hominis, and Ureaplasma spp. in the anus was 5.6%, 8.9%, 4.4%, 5.6%, and 8.9%, respectively. A history of genital warts was an independent risk factor for detection of Mycoplasma spp. and Ureaplasma spp. The prevalence of these microorganisms in the anus of asymptomatic Japanese HIV-positive MSM was relatively high in agreement with previous reports from other countries.

Diagnostic accuracy of faecal calprotectin in patients with active perianal fistulas.

Background: Faecal calprotectin (FC) is a marker of mucosal inflammation. Objective: The aim of this study was to determine the diagnostic accuracy of FC to (a) differentiate between perianal fistulizing Crohn's disease (pCD) and cryptoglandular perianal fistulas; and (b) detect mucosal inflammation in pCD. Methods: Patients with active perianal fistulas who had FC measured and a complete ileocolonoscopy within 10 weeks were retrospectively included. Results: Fifty-six patients were included (pCD, n = 37) of whom 19 pCD patients exhibited ulcers. FC was significantly higher in pCD compared to cryptoglandular fistulas (µg/g) (708.0 (207.0-1705.0) vs 32.0 (23.0-77.0), p < 0.001). Area-under-the-curve (AUC) value for FC receiver operating characteristic (ROC) statistics was 0.900. Optimal FC cut-off was ≥ 150 µg/g. To differentiate pCD from cryptoglandular fistulas in the absence of luminal inflammation, optimal cut-off remained ≥ 150 µg/g (AUC = 0.857, sensitivity = 0.81, specificity = 0.89, positive predictive value (PPV) = 93.8% and negative predictive value (NPV) = 70.8%). In pCD, FC was significantly increased in the presence of ulcers (1672.0 vs 238.0, p = 0.004). Optimal cut-off was ≥ 250 µg/g (AUC = 0.776; sensitivity = 0.89, specificity = 0.56, PPV - 68.0% and NPV = 83.0%). Conclusion: FC discriminates pCD from cryptoglandular fistulas, even in the absence of intestinal ulcers. In active pCD, an elevated FC does not accurately predict the presence of ulcers and should be interpreted with caution.

Characterization of HIV-1 gp120 antibody specificities induced in anogenital secretions of RV144 vaccine recipients after late boost immunizations.

Sexual transmission is the principal driver of the human immunodeficiency virus (HIV) pandemic. Understanding HIV vaccine-induced immune responses at mucosal surfaces can generate hypotheses regarding mechanisms of protection, and may influence vaccine development. The RV144 (ClinicalTrials.gov NCT00223080) efficacy trial showed protection against HIV infections but mucosal samples were not collected, therefore, the contribution of mucosal antibodies to preventing HIV-1 acquisition is unknown. Here, we report the generation, magnitude and persistence of antibody responses to recombinant gp120 envelope and antigens including variable one and two loop scaffold antigens (gp70V1V2) previously shown to correlate with risk in RV144. We evaluated antibody responses to gp120 A244gD and gp70V1V2 92TH023 (both CRF01_AE) and Case A2 (subtype B) in cervico-vaginal mucus (CVM), seminal plasma (SP) and rectal secretions (RS) from HIV-uninfected RV144 vaccine recipients, who were randomized to receive two late boosts of ALVAC-HIV/AIDSVAX®B/E, AIDSVAX®B/E, or ALVAC-HIV alone at 0 and 6 months. Late vaccine boosting increased IgG geometric mean titers (GMT) to gp120 A244gD in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (28 and 17 fold, respectively), followed by SP and RS. IgG to gp70V1V2 92TH023 increased in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (11-17 fold) and SP (2 fold) two weeks post first boost. IgG to Case A2 was only detected in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM. Mucosal IgG to gp120 A244gD (CVM, SP, RS), gp70V1V2 92TH023 (CVM, SP), and Case A2 (CVM) correlated with plasma IgG levels (p<0.001). Although the magnitude of IgG responses declined after boosting, anti-gp120 A244gD IgG responses in CVM persisted for 12 months post final vaccination. Further studies in localization, persistence and magnitude of envelope specific antibodies (IgG and dimeric IgA) in anogenital secretions will help determine their role in preventing mucosal HIV acquisition.

Regenerating the Anal Sphincter: Cytokines, Stem Cells, or Both?

BACKGROUND: Healing of an anal sphincter defect at a time distant from injury is a challenge. OBJECTIVE: We aimed to investigate whether re-establishing stem cell homing at the site of an anal sphincter defect when cytokine expression has declined using a plasmid engineered to express stromal derived factor 1 with or without mesenchymal stem cells can improve anatomic and functional outcome. DESIGN: This was a randomized animal study. SETTINGS: Thirty-two female age- and weight-matched Sprague Dawley rats underwent 50% excision of the anal sphincter complex. Three weeks after injury, 4 interventions were randomly allocated (n = 8), including no intervention, 100-µg plasmid, plasmid and 800,000 cells, and plasmid with a gelatin scaffold mixed with cells. MAIN OUTCOME MEASURES: The differences in anal sphincter resting pressures just before and 4 weeks after intervention were used for functional analysis. Histology was analyzed using Masson staining. One-way ANOVA followed by the Tukey post hoc test was used for pressure and histological analysis. RESULTS: All 3 of the intervention groups had a significantly greater change in resting pressure (plasmid p = 0.009; plasmid + cells p = 0.047; plasmid + cells in scaffold p = 0.009) compared with the control group. The plasmid-with-cells group showed increased organization of muscle architecture and increased muscle percentage, whereas the control group showed disorganized architecture at the site of the defect. Histological quantification revealed significantly more muscle at the site of defect in the plasmid-plus-cells group compared with the control group, which had the least muscle. Quantification of connective tissue revealed significantly less fibrosis at the site of defect in the plasmid and plasmid-plus-cells groups compared with the control group. LIMITATIONS: Midterm evaluation and muscle morphology were not defined. CONCLUSIONS: At this midterm follow-up, local delivery of a stromal derived factor 1 plasmid with or without local mesenchymal stem cells enhanced anal sphincter muscle regeneration long after an anal sphincter injury, thereby improving functional outcome. See Video Abstract at http://links.lww.com/DCR/A324.

Human papillomavirus 16-specific T-cell responses and spontaneous regression of anal high-grade squamous intraepithelial lesions.

BACKGROUND: Most anal cancers are attributable to persistent human papillomavirus type 16 (HPV-16) infection. The anal cancer precursor, high-grade squamous intraepithelial lesion (HSIL), frequently regresses spontaneously. We hypothesized that T-cell responses are associated with HSIL regression. METHODS: In men who have sex with men undergoing anal cytology and high-resolution anoscopy, we measured responses to HPV-16 oncogenic proteins E6 and E7, using the CD25/CD134 assay for CD4(+) antigen-specific T cells and intracellular cytokine staining for CD4(+) and CD8(+) antigen-specific T cells. RESULTS: Of 134 participants (mean [SD] age, 51 [9.3] years; 31 [23.1%] infected with human immunodeficiency virus), 51 (38.1%) had HSIL. E6- and E7-specific CD4(+) T-cell responses were detected in 80 (59.7%) and 40 (29.9%) of the participants, respectively, and E6- and E7-specific CD8(+) T-cell responses were each detected in 25 (18.7%). HSIL was significantly associated with E7-specific CD8(+) T-cell responses (odds ratio, 4.09 [95% confidence interval, 1.55-10.77], P = .004), but not with any CD4(+) T-cell response (P ≥ .09). Twenty-six participants had HSIL a mean of 1 year before measurement of T-cell responses, and 6 (23%) of them were regressors. Five regressors (83%) had E6-specific CD4(+) T-cell responses vs 7 of 20 (35%) nonregressors (Pexact = .065). CONCLUSIONS: Systemic HPV-16 E6- and E7-specific T-cell responses were common in men who have sex with men. E6-specific CD4(+) T-cell responses may be associated with recent HSIL regression. CLINICAL TRIALS REGISTRATION: NCT02007421.

Topical application of trichloroacetic acid is efficacious for the treatment of internal anal high-grade squamous intraepithelial lesions in HIV-positive men.

OBJECTIVES: To assess the efficacy of topical 80% trichloroacetic acid (TCA) to treat internal anal high-grade squamous intraepithelial lesions (HSILs) in HIV-positive individuals. METHODS: All patients who attended the University of Pittsburgh Anal Dysplasia Clinic for treatment of biopsy-proven internal anal HSIL with topical TCA between July 1, 2009, and June 30, 2012, and who had 1 or more follow-up visits to assess treatment efficacy were included in the analysis. Recurrence of HSIL was assessed in July 1, 2013. RESULTS: A total of 98 HSILs from 72 patients were treated, and 77 (78.6%) resolved to normal epithelium or low-grade SIL during follow-up. Forty-eight (49.0%) and 27 (27.6%) of lesions resolved with 1 and 2 TCA treatments, respectively, whereas 1 lesion (1%) each resolved with 3 and 4 TCA treatments. Twenty-one (21.4%) lesions in 20 patients remained without resolution after TCA treatments. These patients were offered an alternative treatment. During follow-up, 8 (15.1%) of 53 patients had a lesion that recurred at the index site (11/53 [20.8%], inclusive of adjacent lesions) and 17 patients had new lesions diagnosed. CONCLUSIONS: Topical TCA is an efficacious treatment of internal anal HSIL in an anal dysplasia clinic setting with high-resolution anoscopy capacity. Advantages of TCA for this recurrent disease process include the following: low cost, no requirement for special equipment beyond that for high-resolution anoscopy, and painless application procedure. A larger prospective comparative study would better define efficacy and patient acceptability between treatment methods.

A six-year experience with anal cytology in women with HPV in the lower genital tract: utility, limitations, and clinical correlation.

This study assessed the utility and limitations of anal cytology as a screening method for women infected with human papilloma virus (HPV) in the lower genital tract. Furthermore, this study aimed to establish risk factors for pathological anal cytology/biopsy findings, the prevalence of anatomopathological lesions associated with positive anal brushings, and the frequency of concomitant lesions of the lower genital tract. A cross-sectional, retrospective, descriptive study in 207 women with HPV-associated lesions of the lower genital tract and 25 women with immunosuppression was carried out. Anal cytology, high resolution anoscopy, and biopsy of suspicious lesions were performed. In total, 232 anal brushings were performed: 184 (79.3%) were negative, 24 (10.34%) showed atypical squamous cells of undeterminated significance, 18 (7.7%) showed low-grade squamous intraepithelial lesions, and 6 (2.6%) showed high-grade squamous intraepithelial lesion. Cytohistological correlation was obtained for 70 cases. The sensitivity of anal cytology in detecting intraepithelial lesions was 70%, whereas the specificity was 93%. The sensitivity of the method for detecting high-grade lesions (84%) was higher, than that for detecting low-grade lesions (66%). The most frequently associated pathology was vulvar lesion. It is important to perform anal brushings in women who have had lower genital tract biopsies for HPV-associated lesions due to the high prevalence of anal lesions in such patients. Anal cytology is useful for detecting high-grade lesions but the sensitivity for detecting low-grade lesions is low. It is of the utmost importance to perform high-resolution anoscopy and biopsy in women with suspicious lesions in order to confirm the pathology.

Linfocitos CD4 como factor protector frente a la infección por genotipos oncogénicos del virus del papiloma humano en la mucosa del canal anal de varones que tienen sexo con varones infectados por el virus de la inmunodeficiencia humana / CD4 lymphocytes as a protective factor against infection by oncogenic genotypes of human papilloma virus in the anal mucosa of men who have sex with human immunodeficiency virus positive men

Fundamento y objetivos: Analizar la prevalencia de los genotipos del virus del papiloma humano (VPH) y de displasia de canal anal en una cohorte prospectiva de pacientes infectados por el virus de la inmunodeficiencia humana (VIH) que mantienen relaciones sexuales con varones (HSH) del sur de España, así como las variables que se asocian con la aparición de lesiones displásicas y genotipos de VPH oncogénicos. Pacientes y método: Estudio transversal compuesto por pacientes HSH-VIH positivos procedentes de una cohorte prospectiva de seropositivos atendidos en una Unidad de Enfermedades Infecciosas, incluidos de forma consecutiva tras firma de consentimiento informado. En la visita se recogían datos epidemiológicos, clínicos, analíticos, y se tomaban 2 muestras de la mucosa del canal anal: una para realización de polymerase chain reaction (PCR, «reacción en cadena de la polimerasa») de VPH, y otra para citología. La clasificación citológica empleada fue la de Bethesda. Resultados: Un total de 134 pacientes fueron incluidos de forma consecutiva, con edad media (DE) de 35,97 (9,5) años. El 16,4% (22/134) de las muestras procedentes de la mucosa anal para estudio de PCR de VPH no fueron válidas por falta de ADN en el material. Un total de 102/112 (91,1%) pacientes estaban colonizados por VPH; 73/112 (65,1%) por genotipos de bajo grado (VPH-BR), 74/112 (66,1%) por genotipos de alto grado (VPH-AR) y 51/112 (41,5%) de alto y bajo grado de malignidad. Los genotipos más prevalentes fueron el 6 (16/112), 11 (15/112), 16 (27/112), 18 (16/112), 51 (16/112) y 53 (17/112). De las 134 muestras enviadas para citología, en 8/134 (5,9%) hubo falta de muestra y en 91/126 (72,2%) eran displásicas, de las que 65/91 (71,4%) correspondían a lesiones intraepiteliales escamosas de bajo grado, 26/91 (23,1%) a células escamosas atípicas, y ninguna lesión intraepitelial escamosa de alto grado. En el análisis multivariante que analizaba los factores de riesgo asociados con la aparición de displasia en la mucosa anal encontramos asociación estadística con el tabaco (odds ratio [OR] 3,336; intervalo de confianza del 95% [IC 95%] 1,196-9,303; p = 0,02) y número de genotipos de VPH-AR (OR 2,229; IC 95% 1,387-3,811; p = 0,001). En cuanto a la presencia de genotipos oncogénicos de VPH, en el análisis multivariante encontramos que cifras de CD4 más bajas (OR 2,48; IC 95% 1,098-5,58; p = 0,029) se asociaban con la infección por tales virus. Conclusiones: La prevalencia de displasia en el canal anal de pacientes VIH-HSH de nuestra área es muy alta, presentándose fundamentalmente en fumadores y con mayor número de genotipos de VPH oncogénicos. La presencia de VPH-AR se asociaba con menores cifras de linfocitos CD4 (AU)

Background and objectives: To analyze the prevalence of human papillomavirus (HPV) genotypes and anal dysplasia in a cohort of human immunodeficiency virus (HIV) infected men who have sex with men (MSM) from southern Spain, and the variables associated with the appearance of dysplastic lesions and oncogenic HPV genotypes. Patients and methods: A cross-sectional study involving a prospective cohort of HIV-positive MSM included consecutively after signing an informed consent form. During the consultation 2 samples were taken from the anal mucosa: one for HPV detection using polymerase chain reaction (PCR), and the other for cytological evaluation; the Bethesda system was used to classify the cytology. Results: One hundred and thirty-four consecutive patients were included. 91.1% patients were colonized by HPV, 66.1% by high-grade types and 41.52% by genotypes of low and high-grade malignancy. The most prevalent genotypes were: 6, 11, 16, 18, 51 and 53. 72.2% samples sent for cytology showed dysplasia, of which 71.4% were low-grade squamous intraepithelial lesions, 23.1% were atypical squamous cell, and 0% was high-grade squamous intraepithelial lesions. The multivariate analysis of risk factors associated with the appearance of dysplasia revealed association with smoking (95% confidence interval [95% CI] 1.196-9.303; odds ratio [OR] 3.336; P = .02) and number of oncogenic HPV types (95% CI 1.387-3.811; OR 2.229; P = .001). With regard to the presence of oncogenic HPV genotypes the multivariate analysis showed a high CD4 cell count was a protective factor against infection by these viruses (95% CI 1.098-5.58; OR 2.48; P = .029).Conclusions: The prevalence of anal dysplasia among HIV-positive MSM in this study is very high, fundamentally in smokers and a high number of oncogenic HPV genotypes. The presence of oncogenic HPV genotypes was associated with a lower CD4 cell count (AU)

Lack of regression of anal squamous intraepithelial lesions despite immune restoration under cART.

BACKGROUND: A high prevalence of anal squamous intraepithelial lesions (ASIL) and human papillomavirus (HPV) infections were observed in HIV-infected men who have sex with men (MSM) in the precART (combined antiretroviral therapy) era. The impact of cART on the natural history of HPV infection and ASIL is poorly documented. METHODS: Ninety-four HIV-infected MSM naive of cART were enrolled in a longitudinal study before starting cART. Patients were evaluated for anal cytology, histology and anal HPV DNA at baseline, month 12 and month 24 of cART. HPV DNA genotyping was performed by Linear Array assay. Anal cytologic samples were processed by the Thin Prep method. RESULTS: Analyses included 76 patients with at least two visits with available cytology. The median age was 39.4 years. The median (interquartile range) CD4 cell count was 301 cells/µl (242-339) at baseline and 545 cells/µl at month 24, when 93% of patients had plasma HIV-RNA 50 copies/ml or less. An abnormal result was observed in 45 of 76 patients at baseline (59%) with prevalent low-grade squamous intraepithelial lesion (LSIL) in 27 patients (36%) and high-grade squamous intraepithelial lesion (HSIL) in seven patients (9%) and in 36 of 69 patients assessed at month 24 (52%) with LSIL in 23 patients (33%) and HSIL in six patients (9%). At month 24, regression of the severity of lesions was observed in 44% of patients, whereas a lesion occurred in 37% of patients. CONCLUSION: Our results show a high prevalence and incidence of ASIL in HIV-infected MSM despite immune restoration under cART. These data emphasize that HIV-positive MSM although receiving effective cART remain at high risk of anal squamous intra-epithelial lesions.

A perspective on progress and gaps in HIV prevention science.

In the past few years, the transdisciplinary field of HIV prevention has reached several milestones. Topically applied tenofovir gel provided significant protection from sexual transmission of HIV in a large-scale clinical trial and oral Truvada (emtricitabine/tenofovir disoproxil fumarate) was recently approved for preexposure prophylaxis (PrEP) following two successful clinical trials in men and women. These achievements are tempered by the disappointing results of other clinical trials, which highlight the complexities of prevention research. In this perspective, we discuss scientific and developmental gaps for topical chemoprophylaxis of the sexual transmission of HIV, which depends on the complex interactions between the pharmacokinetics and pharmacodynamics of drugs, formulation and delivery systems, anatomic site of transmission, and host mucosal immune defenses. Despite the considerable time and resources devoted to unraveling the initial steps in sexual transmission of HIV, current knowledge is based on animal models and human explanted tissue, which may not fully recapitulate what happens clinically. Understanding these events, including the role that sex hormones, semen, and mucosal secretions play in transmission, and the interplay between innate immunity, the mucosal environment, and drug efficacy is paramount. This drives some of the most pressing questions in the field.

Immunophenotype of cells within cervine rectoanal mucosa-associated lymphoid tissue and mesenteric lymph nodes.

Rectoanal mucosa-associated lymphoid tissue (RAMALT) is a part of the lymphoid system that can be sampled easily in live animals, especially ruminants. RAMALT biopsy is useful for the diagnosis of transmissible spongiform encephalopathies, including scrapie in sheep and goats and chronic wasting disease (CWD) in cervids. Diagnosis is reliant on detection of abnormal prion protein (PrP(d)), which is associated with lymphoid follicles. For enzyme linked immunosorbent assays (ELISAs) detecting PrP(d) it is necessary to ensure that lymphoid follicles are present in biopsy samples to avoid false-negative results. Monoclonal antibodies known to recognize specific immune cell subsets present in lymphoid tissues of sheep were tested for cross-reactivity with cervine RAMALT and mesenteric lymph nodes (MLNs) preserved in zinc salts fixative. The distribution of cells expressing CD3, CD4, CD79, CD21 and class II molecules of the major histocompatibility complex was determined in these tissues. Cells of each immunophenotype had similar distributions in RAMALT and MLNs and these distributions were similar to those reported previously for sheep and cattle. The identification and validation of cervine lymphoid follicle cell markers (CD79 and CD21) may allow reduction in false-negative results during diagnosis of CWD by ELISA.

Mucosal junctions: open doors to HPV and HIV infections?

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies.

FoxP3 overexpression and CD1a+ and CD3+ depletion in anal tissue as possible mechanisms for increased risk of human papillomavirus-related anal carcinoma in HIV infection.

AIM: We analysed local cellular and humoral immunity factors in the anal mucosa in an attempt to explain how HIV infection increases the risk of anal cancer in HPV-infected patients. METHOD: HIV-positive cases and matched HIV-negative controls with more than one recurrence of condylomas were included in a prospective study following treatment of the initial lesions. Patients were followed every 3 to 6 months for the development of anal intraepithelial neoplasia (AIN3) and cancer for up to 60 months. Tissue CD1a(+), CD3(+), CD4(+), CD8(+) cells and mRNAs of selected cytokines and chemokines were quantified and compared in patients with or without AIN3 or cancer using morphometric or immunohistochemistry analysis and qRT-PCR. RESULTS: Sixty-six individuals (22 patients and 44 controls) were included. In the case group, CD1a(+) and CD3(+) cell counts were significantly lower in biopsies from AIN3 and cancer specimens compared with those from AIN 1-2 or normal biopsies (P < 0.0001). A CD1a(+) count of < 10/mm was predictive of AIN3 and cancer (Odds ratio = 9.4, 95% CI: 5.4-18.3, P < 0.0001). IL-8 and IL23 levels were significantly higher in cancer than in non-cancer tissues regardless of HIV status (P = 0.02). FoxP3 expression was significantly higher in HIV-infected cases than in controls with AIN3/cancer (P < 0.04). CONCLUSION: Depletion of CD1a(+) and CD3(+) cells and overexpression of FoxP3 in the anal mucosa appear likely to contribute to the risk of HPV-related anal cancer in HIV-infected patients. Furthermore, overexpression of IL-8 and IL-23 in the anal mucosa might be responsible for the development of this cancer regardless of HIV status.

The distribution of T lymphocytes, B lymphocytes, and dendritic-like cells of the anal tonsil in the laboratory shrew, Suncus murinus.

We investigated the distribution of T lymphocytes, B lymphocytes, and S-100 protein-immunoreactive dendritic-like in the anal tonsil of the laboratory shrew, Suncus murinus. In adult animals, T lymphocytes were located mainly at the periphery of the anal tonsil, especially around small blood vessels. B lymphocytes were located in the central and subepithelial region of the anal tonsil, which includes primary lymphoid follicles, and in which there are small numbers of scattered T lymphocytes. B and T lymphocytes were distributed over 72.7 and 27.3% of the tonsillar area, respectively. However, their areas of distribution were not clearly distinguished. The areas containing B lymphocytes were enriched in S-100 protein antibody-immunoreactive cells, which exhibited a dendritic shape. These S-100-positive cells appeared to be identical to the follicular dendritic cells (FDC) seen in the follicles of lymphoid organs. These results suggest that the anal tonsils constitute one of the gut-associated lymphoid tissues (GALT), and that a function of the anal tonsil includes the capture of intruding antigens that would generate protective antibody responses.

Immunization via the anal mucosa and adjacent skin to protect against respiratory virus infections and allergic rhinitis: a hypothesis.

Exposure of the immune system to environmental antigens and infectious agents by way of the anal mucosa and perianal skin could play an important role in protecting the respiratory tract against allergic conditions and virus infections. Hygienic practices that have reduced exposure of the immune system to such agents include the use of modern toiletry, disposable diapers and clothes dryers. Historically, the anal region was cleansed following defecation with natural materials that would have brought antigens and infectious agents from the environment into frequent contact with the perianal skin and anal mucosa. This practice was a crude form of transcutaneous and mucosal vaccination, whereby antigenic agents that are topically applied to skin or mucosal surfaces, penetrate into the tissues and stimulate immune responses that can extend to the respiratory tract. Furthermore, until the 1960s, diapers and other cloth items were often dried outdoors where they would have collected environmental antigens that, when applied to the body, could have made contact with the immune system in the skin. Herein, it is hypothesized that prevention of allergic rhinitis and possibly other disorders involving the immune system could be achieved by the daily application of preparations composed of environmental antigens and infectious agents to the anal mucosa and adjacent skin. In support of the proposal, immunotherapy for allergic rhinitis currently involves administration of specific allergens to subcutaneous tissue or to the sublingual mucosa. It is considered that superior protection could be achieved by applying the allergens to the anal region where they would target the immune system in both mucosal tissue and adjacent skin. It is also hypothesized that respiratory viruses applied to the anal region would infect tissues at that site and induce immune responses that would protect the respiratory tract against the common cold and influenza. This approach is supported by evidence that orally administered adenovirus vaccine can induce an infection in the intestinal mucosa that stimulates immunity to protect the respiratory tract. Although other respiratory viruses are unlikely to survive passage through the intestinal tract, rhinovirus has on rare occasion been detected in stool specimens, suggesting the possibility of an infection at the terminal end of the digestive tract. Respiratory syncytial viruses and influenza viruses are amenable to modification by reverse genetics and other techniques and it is expected that natural or modified viruses applied to the anal region could serve to immunize the respiratory tract.

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells.

Systemic sclerosis (SSc) IgGs affecting the M(3)-muscarinic receptor (M(3)-R) have been proposed to be responsible for the gastrointestinal (GI) dysmotility in this disease. However, the effect of SSc IgGs on smooth muscle cell (SMC) function has not been studied. We determined the effect of SSc IgGs on the muscarinic receptor activation by bethanechol (BeCh; methyl derivate of carbachol) in SMC and smooth muscle strips from rat internal anal sphincter. IgGs were purified from GI-symptomatic SSc patients and normal volunteers, with protein G-Sepharose columns. SMC lengths were determined via computerized digital micrometry. The presence of M(3)-R and IgG-M(3)-R complex was determined by Western blot. IgGs from SSc patients but not from normal volunteers caused significant and concentration-dependent inhibition of BeCh response (P < 0.05). The maximal shortening of 22.2 +/- 1.2% caused by 10(-4) M BeCh was significantly attenuated to 8.3 +/- 1.2% by 1 mg/ml of SSc IgGs (P < 0.05). Experiments performed in smooth muscle strips revealed a similar effect of SSc IgG that was fully reversible. In contrast to the effect on BeCh, the SSc IgGs caused no significant effect (P > 0.05) on K(+) depolarization and alpha(1)-adrenoceptor activation by phenylephrine. Western blot studies revealed the specific presence of SSc IgG-M(3)-R complex. SSc IgGs attenuated M(3)-R activation, which was reversible with antibody removal. These data suggest that SSc GI dysmotility may be caused by autoantibodies that inhibit the muscarinic neurotransmission. Future treatment of SSc patients may be directed at the removal or neutralization of these antibodies.

Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course.

OBJECTIVES: Crohn's disease (CD) is a complex genetic disease with multiple clinical patterns. Clinical classifications may help to identify subgroups of patients that have a distinct pattern of disease, and they are also a prerequisite for the conduction of genetic and therapeutic studies. The aim of this study was to determine the usefulness of the Vienna classification in patient care and clinical studies. METHODS: The clinical data of patients were carefully reviewed retrospectively. The behaviour and location of the disease were determined according to the Vienna classification and additional clinical characteristics including surgical data, vitamin B12 status and medication were also assessed. RESULTS: Data according to the Vienna classification of 292 CD cases were available. The mean age at diagnosis was 31.4 years. The operation rate was higher in patients with ileocolonic localization (P<0.05) and stricturing and penetrating disease behaviour (P<0.001). The incidence of vitamin B12 deficiency was 41.9% in cases with ileal involvement and 20.7% in cases with disease confined to the colon. In 187 cases (64.0%) an operation was performed because of CD-related complications, in a majority (126, 67.4%) this took place within 5 years after diagnosis. Intolerance of azathioprine occurred in 36 cases (22.0%). CONCLUSIONS: Ileocolonic disease localization is associated with a complicated course of disease. Vitamin B12 deficiency occurs frequently, also in patients with disease apparently confined to the colon. We propose that location parameters can be used for the prediction of disease course in clinical settings and in interventional studies.

Isopentenyl pyrophosphate-reactive Vgamma9Vdelta 2 T helper 1-like cells are the major gammadelta T cell subset recovered from lesions of patients with genital herpes.

Herpes simplex virus (HSV)-specific T cells are essential to control and resolve genital herpes (GH). To investigate the potential involvement of gamma delta T cells in GH, T cells were recovered and expanded, by mitogenic stimulation, to T cell lines from the genital lesions of 17 patients with GH and 5 control subjects who had other diseases. Relatively high numbers of gamma delta T cells--predominantly, V gamma 9V delta 2 T cells--were detected only in the T cell lines of the patients with GH. Intralesional V gamma 9V delta 2 T cell clones did not recognize HSV-infected cells, but they showed reactivity to isopentenyl pyrophosphate and Daudi cells. The T cell clones secreted interferon- gamma, tumor necrosis factor- alpha, interleukin (IL)-8, macrophage inflammatory protein-1 alpha, and RANTES (regulated on activation, normally T cell expressed or secreted), but they secreted no or limited IL-4. The results of the present study suggest the infiltration and putative involvement of isopentenyl pyrophosphate-reactive V gamma 9V delta 2 T helper 1-like cells in individuals with GH.