Ocular cicatricial pemphigoid: is there an association with autoimmune diseases?

PURPOSE: To assess the prevalence of autoimmune diseases (ADs) associated with ocular cicatricial pemphigoid (OCP) and analyze clinical, laboratory, and treatment associations between these entities. METHODS: A multicentre cross-sectional study of patients with an OCP diagnosis. The population was divided into two groups according to their association with other ADs or not. Clinical, laboratory and treatment variables were described and compared between groups. A multivariable logistic regression analysis was performed to identify variables that could suggest the association between OCP and ADs. RESULTS: Eighty-eight patients were recruited, with a mean age at diagnosis of 64.3 years (SD 11.9). Biopsy was performed in 86.8% of the patients. There was a median delay of 2 years from the onset of symptoms to diagnosis. Extraocular involvement was evidenced in 11.5%. The group associated with ADs included 24 patients (27.3%). The most prevalent diagnosis was Sjögren´s syndrome. Hypergammaglobulinemia was associated with ADs and OCP, adjusted for age, sex, smoking, skin and mucosal involvement, and erythrocyte sedimentation rate (OR 8.7; 95%CI 1.6-46.8; p = 0.012). CONCLUSIONS: Due to OCP's autoimmune nature, it could coexist with other ADs. This study observed that more than a quarter of the population presented with this association, and hypergammaglobulinemia could suggest it.

Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency.

OBJECTIVE: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. METHODS: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. RESULTS: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. CONCLUSIONS: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.

Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency / Enfermedad de Behçet en países de Latinoamérica: Revisión sistemática de la literatura sobre datos demográficos, hallazgos clínicos y frecuencia del alelo HLA-B*51

Objective: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. Methods: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. Results: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. Conclusions: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.(AU)

Objetivo: Describir las características demográficas, clínicas y la frecuencia del alelo HLA-B*51 en pacientes con enfermedad de Behçet (EB) en países de América Latina. Métodos: Se llevó a cabo una revisión sistemática de la literatura (RSL) según la guía PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) sin realizar un metaanálisis final. Se incluyeron estudios observacionales (transversales o de cohortes) de pacientes con EB que cumplieron con los criterios de clasificación del Grupo Internacional de Estudio de la EB e informaron las características demográficas, clínicas y de laboratorio en pacientes adultos con EB. Resultados: Doce estudios fueron incluidos para la RSL. La información de 532 pacientes provenientes de 5 países de América Latina se incluyó para el análisis. La edad media al diagnóstico fue de 33 años, el 58,3% fueron mujeres y el 41,7% hombres; la mayoría de los pacientes fueron no caucásicos. Las manifestaciones clínicas más comunes fueron las úlceras orales y genitales recurrentes, seguidas del compromiso cutáneo, ocular, articular, neurológico, gastrointestinal, vascular y cardíaco. La prevalencia de la EB fue descrita en 2 estudios, uno realizado en Brasil que reportó una prevalencia de 0,3/100.000 habitantes, y otro en Colombia con una prevalencia de 1,1/100.000 habitantes. La frecuencia del HLA-B*51 en pacientes con EB fue del 38%, 30,1% y 9% en Argentina, Brasil y México, respectivamente. Conclusiones: La prevalencia de la EB en los países latinoamericanos parece ser baja, así como la frecuencia del alelo HLA-B*51. Sin embargo, la fuerza de asociación entre el HLA-B*51 y la EB sigue siendo alta en nuestra población. Las características clínicas claves de la EB son similares a las reportadas en países/regiones donde es endémica.(AU)

Significance of HLA-B[*]51 allele expression in Crohn's disease: a case-control study.

OBJECTIVES: Crohn's disease (CD) and Behçet's disease (BD) are two autoinflammatory diseases that share clinical and pathogenic features. Furthermore, when BD involves the gastrointestinal tract, it is extremely difficult to distinguish endoscopic lesions from CD lesions. HLA-B*51 allele expression is highly associated with BD diagnosis. In this study we analysed HLA-B*51 status in 70 Argentine patients with confirmed CD diagnosis and compared it to our previous Argentine BD cohort, with the aim of finding similarities or differences between these two diseases regarding HLA-B*51 status. METHODS: This is a multi-centre case-control study, including 70 patients with confirmed CD diagnosis, who underwent HLA-B*51 allele status testing; the results were compared to our previous BD cohort of 34 patients. RESULTS: Among patients with CD, 12.85% were positive for the HLA-B*51 allele, compared with 38.24% patients with BD (OR=0.238; 95% CI=0.089-0.637; p=0.004). CONCLUSIONS: Our finding suggests that determination of HLA-B*51 allele status may contribute to the differential diagnosis between CD and BD.

Recomendaciones de la Sociedad Argentina de Reumatología en el manejo de la arteritis de células gigantes / Recommendations of the Argentine Society of Rheumatology in the management of giant cell arteritis

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

Giant cell arteritis (GCA) is a systemic vasculitis affecting adult patients and involving large and medium vessels. Potential serious complications as blindness may occur and it is considered a medical emergency. The objective of elaborating this guideline was to develop first Argentinian GCA treatment recommendations using GRADE methodology. An expert panel generated clinically meaningful questions addressing aspects of the treatment of GCA in the Population, Intervention, Comparator and Outcome (PICO) format and then a group of methodology experts reviewed and extracted data from literature summarizing available evidence. A patient's focus group discussion took place gathering information on their preferences and experiences. Finally, the vasculitis expert panel, with all the information obtained, voted recommendations here presented.

Guías Argentinas de Vasculitis Suplemento. Tablas arteritis de células gigantes / Argentine Vasculitis Guidelines Supplement. Giant cell arteritis tables

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

Patients of 75 years and over with ANCA-associated vasculitis have a lower relapse risk than younger patients: A multicentre cohort study.

BACKGROUND: Little is known about antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years. METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively. RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65-75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause-specific hazards ratio [CSHR] 0.54, 95% CI [0.33-0.89], p = 0.016, Cox model; subdistribution hazard ratio [SHR] 0.46, 95% CI [0.29-0.74], p = 0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI [0.11-0.68], p = 0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95% [CI 0.24-0.67], p < 0.001). CONCLUSIONS: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen.

The HLA-B*51 allele is strongly associated with Behçet Disease in an Argentinean population / El alelo HLA-B*51 se asoció fuertemente a la Enfermedad de Behçet en la población argentina

OBJECTIVE: To assess the association between the HLA-B*51 allele and Behçet Disease (BD) in Argentinean patients. METHODS: We enrolled 34 consecutive Argentinean patients with definitive diagnosis of BD between October 2016 and March 2017. None of the patients had the HLA-B*51 allele determined at study entry. Unrelated controls (n=240) were randomly obtained from the national cadaveric donor database. Demographic and clinical features of the patients were recorded by attending physicians through a questionnaire. RESULTS: Mean age of cases was 42 years old. Nineteen (55.8%) were male, and the mean age at diagnosis was 35 years old; twenty (58.8%) were Mestizos, 8 (23.5%) were Caucasian, and 6 (17.6%) were Amerindians. Thirteen (38.2%) of 34 cases were HLA-B*51 allele positive; 11 were heterozygous and 2 homozygous for the allele. Thirty-four (14.2%) of 240 controls were positive for the HLA-B*51 allele. The association between BD and HLA-B*51 allele was greater than that of control group (OR=3.75; p = 0.0012). CONCLUSIONS: The HLA-B*51 allele is strongly associated with BD in Argentinean patients. Our finding is consistent with previous studies indicating that the HLA-B*51 allele is an important susceptibility gene in BD regardless the geographical region and ethnicity

OBJETIVO: Evaluar la asociación entre el alelo HLA-B*51 y la enfermedad de Behçet (EB) en pacientes argentinos. MÉTODOS: Incluimos en forma consecutiva 34 pacientes argentinos con diagnóstico definitivo de EB entre los meses de octubre de 2016 y marzo de 2017. Ninguno de los pacientes tenía el alelo HLA-B*51 determinado al inicio del estudio. Los controles no relacionados (n=240) se obtuvieron al azar de la base nacional de datos de donantes cadavéricos. Las características demográficas y clínicas de los pacientes fueron registradas por los médicos asistentes a través de un cuestionario. RESULTADOS: La edad promedio de los casos fue de 42 años. Diecinueve (55,8%) fueron varones, y la edad promedio en el momento del diagnóstico fue de 35 años; 20 (58,8%) fueron mestizos, 8 (23,5%) caucásicos y 6 (17,6%) amerindios. Trece (38,2%) de los 34 casos fueron positivos para el alelo HLA-B*51; 11 de ellos fueron heterocigotas y 2 homocigotas para dicho alelo. Treinta y cuatro (14,2%) de los 240 controles fueron positivos para el alelo HLA-B*51. La asociación entre la EB y el alelo HLA-B*51 fue mayor que en el grupo control (OR=3,75; p = 0,0012). CONCLUSIONES: El alelo HLA-B*51 está fuertemente asociado con la EB en pacientes argentinos. Nuestro hallazgo es consistente con estudios previos que indican que el alelo HLA-B*51 es un gen de susceptibilidad importante en la EB independientemente de la región geográfica y la etnia

[Anatomoclinical results of temporal artery biopsies at a university hospital in Argentina] / Resultados anatomoclínicos de las biopsias de arteria temporal realizadas en un hospital universitario de Argentina.

Introduction: Giant cell arteritis (GCA) is the most frequent systemic vasculitis in patients older than 50 years. The diagnosis is based on the clinical history, laboratory findings and imaging studies associated with a temporal artery biopsy (TAB). However, the biopsy result could be inconclusive in up to 40% of the cases. The aim of this study was to review the current management of the patients with clinical suspect of GCA in the university hospital CEMIC in Buenos Aires, Argentina, and correlate the disease behavior with the TAB result. Methods: Retrospective study that reviewed consecutive patients to whom a TAB was made in an 11-year period (2005-2016). Clinical and pathology reports were reviewed. Descriptive statistics were performed. Quantitative variables were described as mean (S.D.) or median [range or inter- quartile range (IQR)] and qualitative variables as number (%). To compare the characteristics of the groups, bivariate analyzes were performed using contingency tables and logistic regression models if necessary. Results: Sixty three patients were included, 68% women. The mean age was 72 years old (SD 8.4). Seventeen biopsies (26.9%) were positive for GCA. The average post fixation length was 1.68 cm (SD 1.2). Patients were divided into 3 groups taking into account the result of the TAB, the ACR criteria and the imaging studies. We could not identify predictors of biopsy positivity. The group of patients with GCA and negative TAB showed a higher percentage of patients with abnormal temporal artery at physical examination. Conclusion: The TAB positive percentage (26.9%) was similar to the reported in other series as well as the post fixation length. We could not identify predictors of biopsy positivity.

Introducción: La arteritis de células gigantes (ACG) es la vasculitis sistémica primaria más frecuente en pacientes mayores de 50 años. El diagnóstico de ACG se basa en la evaluación clínica, de laboratorio y estudios por imágenes, asociados a una biopsia. Sin embargo, el resultado de la biopsia puede no ser concluyente en más del 40% de los casos. El objetivo de este estudio fue revisar el manejo de los pacientes con sospecha de ACG en el hospital universitario CEMIC en Buenos Aires, Argentina, y correlacionar el comportamiento de la enfermedad con el resultado de la biopsia de arteria temporal (BAT). Métodos: Estudio retrospectivo que analizó pacientes consecutivos a los cuales se les realizó BAT en un período de 11 años (2005-2016). La información recolectada se obtuvo a partir de las historias clínicas y de los informes de anatomía patológica. Se realizó estadística descriptiva. Para las variables cuantitativas se estimaron medias y sus respectivos desvíos estándar o medianas y percentil 25-75, y para las variables cualitativas, la cantidad y el porcentaje. Para comparar las características de los grupos se realizaron análisis bivariados mediante tablas de contingencia y modelos de regresión logística de ser necesario. Resultados: Sesenta y tres pacientes fueron incluidos, 68% mujeres, con una edad media de 72 años (DS 8,4). Diecisiete biopsias (26,9%) fueron positivas. La longitud media posfijación fue de 1,68 cm (DS 1,2). La población se dividió en 3 grupos según la BAT, los criterios ACR y los estudios por imágenes. No se identificaron factores predictores de positividad de la BAT. El grupo con ACG y BAT negativa presentó mayor porcentaje de pacientes con arteria temporal anormal al examen físico. Conclusión: El porcentaje de positividad de las biopsias (26,9%) fue similar al reportado por otras series, así como la longitud de la biopsia luego de la fijación (1,68 cm). No identificamos factores predictores de positividad de la BAT.

The HLA-B*51 Allele is strongly associated with Behçet Disease in an Argentinean population.

OBJECTIVE: To assess the association between the HLA-B*51 allele and Behçet Disease (BD) in Argentinean patients. METHODS: We enrolled 34 consecutive Argentinean patients with definitive diagnosis of BD between October 2016 and March 2017. None of the patients had the HLA-B*51 allele determined at study entry. Unrelated controls (n=240) were randomly obtained from the national cadaveric donor database. Demographic and clinical features of the patients were recorded by attending physicians through a questionnaire. RESULTS: Mean age of cases was 42 years old. Nineteen (55.8%) were male, and the mean age at diagnosis was 35 years old; twenty (58.8%) were Mestizos, 8 (23.5%) were Caucasian, and 6 (17.6%) were Amerindians. Thirteen (38.2%) of 34 cases were HLA-B*51 allele positive; 11 were heterozygous and 2 homozygous for the allele. Thirty-four (14.2%) of 240 controls were positive for the HLA-B*51 allele. The association between BD and HLA-B*51 allele was greater than that of control group (OR=3.75; p=0.0012). CONCLUSIONS: The HLA-B*51 allele is strongly associated with BD in Argentinean patients. Our finding is consistent with previous studies indicating that the HLA-B*51 allele is an important susceptibility gene in BD regardless the geographical region and ethnicity.

Immunogenicity and safety of seasonal and 2009 pandemic A/H1N1 influenza vaccines for patients with autoimmune diseases: a prospective, monocentre trial on 199 patients.

OBJECTIVES: The 2009 pandemic A/H1N1 influenza outbreak represented a theoretical risk for patients with autoimmune diseases (AID), especially those immunosuppressed. This study was undertaken to evaluate immunogenicity and tolerance of seasonal (SFV) and A/H1N1 flu vaccines (HFV) in AID patients. METHODS: This prospective, open, monocentre, vaccine phase-III study on 199 patients with AID (systemic necrotising vasculitides, progressive systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome and others), treated or not with immunosuppressants, was conducted from September 2009 to June 2010, to evaluate SFV and HFV efficacy and safety. Subjects received SFV (1 dose, Mutagrip®) and/or non-adjuvant HFV (Panenza®, 2 doses at a 3-week interval). The primary judgment criterion was the seroprotection rate. Secondary outcome measures were seroconversion rates, vaccine tolerance, and numbers of flu syndromes, and AID flares and relapses throughout the 6 month observation period. RESULTS: After SFV inoculation, 1% of the patients became febrile, 18% developed local reactions, 80% were seroprotected and 38% seroconverted. After HFV immunisation, 4% of the patients developed a fever, 23% had local reactions, 65% were seroprotected and 83% seroconverted. Twelve patients developed 15 flu syndromes (3 patients developed 2 syndromes each); 2 of these episodes were temporally consistent with vaccination; 1 patient died of septic shock unrelated to vaccination. Nineteen mild AID flares occurred during follow-up, only 6 being temporally consistent with HFV and SFV. CONCLUSIONS: Our findings demonstrated the safety and efficacy of SFV and HFV in AID patients.

Alveolar haemorrhage in ANCA-associated vasculitides: 80 patients' features and prognostic factors.

OBJECTIVES: Alveolar haemorrhage (AH) can be a mild or life-threatening manifestation of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), but its prognostic impact and specific characteristics remain controversial. Our objective was to determine the prognostic value of AH in this context. METHODS: AH episodes that occurred, between 1991 and 2010, in AAV patients entered in the FVSG database were retrospectively analysed. Data on AH characteristics and outcome measures were collected on a specific form. RESULTS: Among the 80 cases analysed, AAV were 61.25% granulomatosis with polyangiitis (GPA) (Wegener), 26.25% microscopic polyangiitis (MPA), 10% Churg-Strauss syndrome and 2 (2.5%) unclassified. Mild or severe haemoptysis alone, or together with other clinical symptoms was present in 77 (96.2%) patients before AAV diagnosis. Among 10 (12.5%) patients requiring mechanical ventilation, 4 had prior minor haemoptysis before abundant AH. Sixty-one (76.3%) patients had concomitant active rapid crescentic glomerulonephritis causing renal insufficiency (pulmo-renal syndrome): 37/49 GPA (Wegener) (75.5% of all GPA (Wegener)), 19/21 MPA (90.4% of all MPA), 3/8 had CSS and 2/2 had unclassified vasculitis. The mean AH-to-treatment-onset interval was 5.9 days. Mean follow-up was 7.3 years. Forty-seven (58.8%) patients relapsed: 23 with AH and with (13) or without (10) other organ involvement, 24 with non-AH manifestation(s). Three patients underwent kidney transplantation. Sixteen (20%, 8 GPA (Wegener) and 8 MPA) patients died. No death resulted directly from the initial AH; 14 (87.5%) patients with pulmo-renal syndrome died. CONCLUSIONS: As previously demonstrated by the Five-Factor Score, AH alone is not predictive of poor prognosis, unlike kidney involvement, which dictates a poor outcome.

Acute demyelinating disease after oral therapy with herbal extracts.

Central nervous system demyelinating processes such as multiple sclerosis and acute disseminated encephalomyelitis constitute a group of diseases not completely understood in their physiopathology. Environmental and toxic insults are thought to play a role in priming autoimmunity. The aim of the present report is to describe a case of acute demyelinating disease with fatal outcome occurring 15 days after oral exposure to herbal extracts.

Astrocytic regulation of human monocytic/microglial activation.

Recent reports have described reduced immunological responsiveness and stimulatory capacity among monocytes/microglia that infiltrate malignant human gliomas. Herein, we demonstrate that culture of ex vivo human monocytes or primary human microglia with tumor cells isolated from glioblastoma multiforme (GBM) specimens renders them tolerogenic, capable of suppressing the function of ex vivo monocytes in the absence of tumor cells or their soluble factors. We demonstrate that the tolerance induced in monocytes/microglia by GBM tumor cells is not associated with interference with the signaling cascade associated with TLR- or CD40-induced monocyte activation. Rather, these tumor cells appear to up-regulate pathways that antagonize positive signaling pathways, including but not limited to STAT3 and STAT5. Finally, we demonstrate that the tolerogenic properties of GBM tumor cells amplify properties inherent to nontransformed astrocytes. Future studies that identify all of the molecular mechanisms by which astrocytes and malignant gliomas suppress monocyte/microglial function will have dual therapeutic benefits: suppressing these pathways may benefit patients with astrocytic tumors, while enhancing them may benefit patients with autoimmune processes within the CNS, such as multiple sclerosis.

Up-regulation of gene related to anergy in lymphocytes is associated with Notch-mediated human T cell suppression.

A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.