RESUMEN
The aim of this study is to investigate salivary gland involvement in patients with anti-centromere antibody (ACA)-positive primary Sjögren's syndrome (pSS). We retrospectively evaluated 134 patients with pSS. Patients were divided into four groups based on the results of ACA and SSA antibodies. We compared clinical manifestations, laboratory findings, salivary gland shear wave elastography, minor salivary gland biopsy results, and EULAR Sjögren's syndrome disease activity index (ESSDAI) scores among the four groups. A total of 134 patients were classified as having pSS and divided into three groups based on serum ACA and anti-SSA antibody status: ACA + SSA + , ACA + SSA-, ACA-SSA + , and seronegative. The primary analysis focused on comparing the clinical and SWE findings between the ACA + SSA + and ACA + SSA- groups. In the double-positive group, SWE revealed fewer minor salivary glands along with higher mean (Emean) and maximum (Emax) values of Young's moduli than those in the ACA-negative group. Patients in the positive group had increased occurrence of Raynaud's phenomenon, liver involvement, and a higher incidence of malignancy (P < 0.05). ACA-positive pSS patients are a subgroup with different clinical manifestations and more pronounced involvement of the minor salivary glands. SWE findings revealed that ACA-positive patients exhibit significantly higher mean and maximum stiffness values compared to ACA-negative patients, indicating more extensive glandular fibrosis and involvement. These results underscore the utility of SWE as a valuable method for evaluating salivary gland pathology and supporting the stratification of pSS patients.
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Anticuerpos Antinucleares , Diagnóstico por Imagen de Elasticidad , Glándulas Salivales Menores , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico por imagen , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Estudios Retrospectivos , Femenino , Diagnóstico por Imagen de Elasticidad/métodos , Persona de Mediana Edad , Masculino , Glándulas Salivales Menores/patología , Glándulas Salivales Menores/diagnóstico por imagen , Anticuerpos Antinucleares/sangre , Adulto , Anciano , Centrómero/inmunología , BiopsiaAsunto(s)
Anticuerpos Antinucleares/sangre , Proteína A Centromérica/administración & dosificación , Infertilidad Femenina/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Antinucleares/inmunología , Línea Celular Tumoral , Centrómero/inmunología , Centrómero/ultraestructura , Proteína A Centromérica/genética , Proteína A Centromérica/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Tolerancia Inmunológica , Inmunización/métodos , Infertilidad Femenina/sangre , Ratones , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Especificidad de la EspecieRESUMEN
OBJECTIVES: Anti-centromere antibodies (ACAs) are detected in patients with various autoimmune diseases such as Sjögren's syndrome (SS), systemic sclerosis (SSc) and primary biliary cholangitis (PBC). However, the targeted antigens of ACAs are not fully elucidated despite the accumulating understanding of the molecular structure of the centromere. The aim of this study was to comprehensively reveal the autoantigenicity of centromere proteins. METHODS: A centromere antigen library including 16 principal subcomplexes composed of 41 centromere proteins was constructed. Centromere protein/complex binding beads were used to detect serum ACAs in patients with SS, SSc and PBC. ACA-secreting cells in salivary glands obtained from patients with SS were detected with green fluorescent protein-fusion centromere antigens and semiquantified with confocal microscopy. RESULTS: A total of 241 individuals with SS, SSc or PBC and healthy controls were recruited for serum ACA profiling. A broad spectrum of serum autoantibodies was observed, and some of them had comparative frequency as anti-CENP-B antibody, which is the known major ACA. The prevalence of each antibody was shared across the three diseases. Immunostaining of SS salivary glands showed the accumulation of antibody-secreting cells (ASCs) specific for kinetochore, which is a part of the centromere, whereas little reactivity against CENP-B was seen. CONCLUSIONS: We demonstrated that serum autoantibodies target the centromere-kinetochore macrocomplex in patients with SS, SSc and PBC. The specificity of ASCs in SS salivary glands suggests kinetochore complex-driven autoantibody selection, providing insight into the underlying mechanism of ACA acquisition.
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Complejo Antígeno-Anticuerpo/inmunología , Autoanticuerpos/inmunología , Centrómero/inmunología , Cirrosis Hepática Biliar/inmunología , Esclerodermia Sistémica/inmunología , Síndrome de Sjögren/inmunología , Anciano , Anticuerpos Antinucleares/inmunología , Células Productoras de Anticuerpos/inmunología , Autoantígenos/inmunología , Femenino , Humanos , Cinetocoros/inmunología , Cirrosis Hepática Biliar/sangre , Masculino , Persona de Mediana Edad , Glándulas Salivales/inmunología , Esclerodermia Sistémica/sangre , Síndrome de Sjögren/sangreRESUMEN
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. METHODS: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. RESULTS: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. CONCLUSION: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.
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Centrómero/genética , Centrómero/inmunología , Cara/anomalías , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/inmunología , Humanos , Mutación/genética , Enfermedades de Inmunodeficiencia Primaria/diagnósticoRESUMEN
PURPOSE: To examine the long-term clinical outcomes of patients with anti-centromere antibody (ACA)-positive critical limb-threatening ischemia (CLTI) who were treated with endovascular therapy (EVT). MATERIALS AND METHODS: This was a retrospective analysis using a database of 423 consecutive CLTI patients (543 limbs, Rutherford class 4-6) who underwent EVT between January 2011 and March 2013. The patients were divided into 2 groups: an ACA-positive group (10 limbs, 8 patients) and a control group (46 limbs, 43 patients). The control group was defined as female, non-dialysis, and those who were able to obtain a below-knee angiogram. RESULTS: None of the 8 ACA-positive CLTI patients had previously been diagnosed as ACA positive. No significant difference was observed in the below-the-knee lesion distribution and severity between the ACA-positive group and the control group. The median observational period was 51 months. The survival rate was 54% in the ACA-positive group and 76% in the control group at 5 years after EVT (P = .732). The freedom from major amputation rate was 60% in the ACA-positive group and 91% in the control group at 5 years after EVT (P = .029). The technical EVT success rate in the ACA-positive group was 70% (7/10). Of the successful EVT cases, 71% (5/7) of patients achieved complete wound healing or rest pain relief; however, 60% (3/5) had a recurrence of wounds. CONCLUSIONS: In a series of ACA-positive patients with CLTI, successful EVT had acceptable outcomes with respect to wound healing with short-term results. However, the major amputation rate for ACA-positive patients was high in long-term follow-up.
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Anticuerpos Antinucleares/sangre , Centrómero/inmunología , Procedimientos Endovasculares , Isquemia/terapia , Enfermedad Arterial Periférica/terapia , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Biomarcadores/sangre , Enfermedad Crítica , Bases de Datos Factuales , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Femenino , Humanos , Isquemia/sangre , Isquemia/diagnóstico por imagen , Isquemia/mortalidad , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/mortalidad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Cicatrización de HeridasRESUMEN
BACKGROUND: Anti-centromere auto-antibodies (ACA) have been described as a marker in Systemic sclerosis (SSc) disease. CENP-B is the major centromere auto-antigen recognized by SSc patients with positive ACA. Our aim was to characterize the major epitope involved in the anti-CENP-B immune response of Moroccan SSc patients. PATIENTS AND METHOD: For identification of SSc biomarkers, 80 sera from patients with SSc and systemic lupus erythematosus (SLE) were screened by indirect immunofluorescence test (IIF) to assess the presence of ANA reactivity. Immunoblotting analysis was performed for 11 sera with positive ACA using the N-terminal and C-terminal region of CENP-B protein as antigens. RESULTS: 29 out of 30 (96, 66 %) patients with SSc had positive ANA. 11 out of 30 (36, 67 %) patients were ACA positive and 6 of them produced auto-antibodies against Nt-CENPB antigen. Two of these 6 Nt-CENPB positive sera produced also other auto-antibodies associated to primary biliary cirrhosis. None of all sera tested showed reactivity against Ct-CENPB. CONCLUSION: Our data showed, for the first time in Morocco, that the Nt-CENPB contains a major epitope for Moroccan SSc patients. These findings could provide additional information that would contribute to improving the diagnosis and management of these patients.
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Autoanticuerpos/inmunología , Proteína B del Centrómero/inmunología , Centrómero/inmunología , Mapeo Epitopo , Epítopos/inmunología , Proteoma , Proteómica , Esclerodermia Sistémica/etiología , Anticuerpos Antinucleares/inmunología , Autoantígenos/inmunología , Mapeo Epitopo/métodos , Técnica del Anticuerpo Fluorescente , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Proteómica/métodosRESUMEN
OBJECTIVES: Recent evidences have revealed that anti-SSA/SSB antibodies, the major autoantibodies in Sjögren's syndrome (SS), are produced in salivary glands. This study aims to clarify overall of autoantibody production at lesion site, including anti-centromere antibody (ACA)-positive SS. METHODS: Antibodies of antibody-secreting cells in human salivary glands were produced as recombinant antibodies. The reactivity of these antibodies and their revertants were investigated by ELISA and newly developed antigen-binding beads assay, which can detect conformational epitopes. The target of uncharacterised antibodies was identified by immunoprecipitation and mass spectrometry. Autoantibody-secreting cells in salivary gland tissue were identified by immunohistochemistry using green fluorescent protein-autoantigen fusion proteins. RESULTS: A total of 256 lesion antibodies were generated, and 69 autoantibodies including 24 ACAs were identified among them. Beads assay could detect more autoantibodies than ELISA, suggesting autoantibodies target to antigens with native conformation. After somatic hypermutations were reverted, autoantibodies drastically decreased antigen reactivity. We showed that MIS12 complex, a novel target of ACA, and CENP-C are major targets of ACA produced in salivary glands by examining cloned antibodies and immunohistochemistry, whereas few anti-CENP-B antibodies were detected. The target profiling of serum ACA from 269 patients with SS, systemic sclerosis (SSc), primary biliary cirrhosis (PBC) and healthy controls revealed that ACA-positive patients have antibodies against various sites of centromere complex regardless of disease. CONCLUSION: We showed direct evidences of antigen-driven maturation of anti-SSA/SSB antibody and ACA in SS lesion. ACA recognises centromere 'complex' rather than individual protein, and this feature is common among patients with SS, SSc and PBC.
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Anticuerpos Antinucleares/inmunología , Formación de Anticuerpos/inmunología , Centrómero/inmunología , Proteínas Asociadas a Microtúbulos/inmunología , Glándulas Salivales/inmunología , Síndrome de Sjögren/inmunología , Adulto , Anciano , Células Productoras de Anticuerpos , Autoanticuerpos/inmunología , Proteína A Centromérica/inmunología , Proteína B del Centrómero/inmunología , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/inmunología , Femenino , Humanos , Cirrosis Hepática Biliar/inmunología , Masculino , Persona de Mediana Edad , Glándulas Salivales/citología , Esclerodermia Sistémica/inmunologíaRESUMEN
Oikopleura dioica is a ubiquitous marine tunicate of biological interest due to features that include dioecious reproduction, short life cycle, and vertebrate-like dorsal notochord while possessing a relatively compact genome. The use of tunicates as model organisms, particularly with these characteristics, offers the advantage of facilitating studies in evolutionary development and furthering understanding of enduring attributes found in the more complex vertebrates. At present, we are undertaking an initiative to sequence the genomes of Oikopleura individuals in populations found among the seas surrounding the Ryukyu Islands in southern Japan. To facilitate and validate genome assemblies, karyotyping was employed to count individual animals' chromosomes in situ using centromere-specific antibodies directed against H3S28P, a prophase-metaphase cell cycle-specific marker of histone H3. New imaging data of embryos and oocytes stained with two different antibodies were obtained; interpretation of these data lead us to conclude that the Okinawan Oikopleura dioica has three pairs of chromosomes, akin to previous results from genomic assemblies in Atlantic populations. The imaging data have been deposited to the open-access EBI BioImage Archive for reuse while additionally providing representative images of two commercially available anti-H3S28P antibodies' staining properties for use in epifluorescent and confocal based fluorescent microscopy.
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Centrómero/inmunología , Cromosomas/genética , Urocordados , Animales , Anticuerpos Monoclonales , Femenino , Japón , Cariotipificación , Masculino , Coloración y Etiquetado , Urocordados/genéticaRESUMEN
OBJECTIVE: The Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in North Africa. Our objective was to describe a SSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies with other international SSc populations. METHODS: In this retrospective observational study, Folders of patients with SSc seen in the internal medicine section of the Hedi Chaker Hospital between 2000 and 2013 were retrospectively analyzed. The diagnosis of SSc was retained according to ACR/EULAR 2013 criteria. Patients were classified into diffuse cutaneous SSc and limited cutaneous SSc subsets. Comparison with other cohorts was made based on published information. RESULTS: A higher female: male ratio (8:1) and a higher diffuse subset prevalence (82%) was found in this Tunisian cohort comparing with others. We also found a lower prevalence of calcinosis and anticentromere antibodies. Within each subset, diffuse cutaneous and limited cutaneous scleroderma clinical findings were similar with other systemic sclerosis populations except for a very low prevalence in renal crisis and pulmonary hypertension. Our results indicate overlap syndrome defined as scleroderma associated with others connective tissue disorder's is a relatively common condition. CONCLUSION: With slight variations, perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other part of the world.
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Esclerodermia Limitada , Esclerodermia Sistémica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Calcinosis/epidemiología , Centrómero/inmunología , Estudios Transversales , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Esclerodermia Limitada/complicaciones , Esclerodermia Limitada/diagnóstico , Esclerodermia Limitada/inmunología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/inmunología , Túnez , Adulto JovenRESUMEN
BACKGROUND: Rhombencephalitis (RE) is a serious condition of the brain with multiple etiologies. We report a unique case of recurrent, postpartum RE that is associated with positive anti-centromere antibody (ACA). A discussion of the case, current literature on autoimmune RE and related autoantibodies are reviewed. CASE PRESENTATION: A healthy 33-year-old Caucasian patient (gravida 2, para 2) had two episodes of progressive focal neurological deficits during postpartum periods. Signs and symptoms included right-sided dysmetria, adiadochokinesia, weakness, ataxia, and photophobia. MRI revealed rhombencephalitis involving the mesencephalon of the brainstem. Extensive and comprehensive investigations using blood and cerebrospinal fluid (CSF) were consistently positive only for ACA. The first episode was successfully treated with empiric antimicrobial agents and steroid. Given the negative infectious work up with the prior episode and the nearly identical clinical presentations, the second episode was treated with corticosteroid only. This led to complete resolution of her symptoms and reversal of the brain magnetic resonance imaging (MRI) lesions. CONCLUSION: To the author's knowledge, this is the first report of a primary autoimmune RE during postpartum period that is associated with ACA. Immunologic causes should be considered early with any encephalitis. Given the risk of recurrence, relapse, and neurologic deterioration, regular monitoring is recommended, especially for female patients of child-bearing age. Consistent with the current literature on autoimmune RE, steroid seems to be an effective treatment for ACA-associated RE.
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Anticuerpos Antinucleares/inmunología , Enfermedades Autoinmunes/inmunología , Encefalitis/inmunología , Corticoesteroides/uso terapéutico , Adulto , Autoantígenos/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Centrómero/inmunología , Encefalitis/diagnóstico , Encefalitis/tratamiento farmacológico , Femenino , Humanos , Imagen por Resonancia Magnética , Periodo Posparto/inmunologíaRESUMEN
INTRODUCTION: Our objective was to evaluate the pulmonary hypertension (PH) data for Spanish patients with systemic sclerosis (SSc), define the PH types and determine the associated factors. METHOD: Descriptive study of PH-related data from the multicentre RESCLE registry. Estimated systolic pulmonary artery pressure (esPAP), measured via echocardiogram was considered elevated if ≥ 35 mmHg. Left heart disease (LHD) and interstitial lung disease (ILD) were identified. When performed, data from right heart catheterisation (RHC) were collected. RESULTS: esPAP was elevated in 350 of 808 patients (43.3%). One hundred and forty-four patients (17.8%) were considered to have PH (88 via RHC and the rest due to elevated esPAP along with evidence of significant LHD or ILD): PAH 3.7%, secondary to ILD 8.3%, secondary to LHD 2.8% and unclassified 3%. Prevalence of elevated esPAP was greater in diffuse SSc (dSSc) than in limited scleroderma (lSSc) (50.5 vs. 42.2%, p 0.046). In the group with elevated esPAP, a lower prevalence of anti-centromere antibodies (41.9% vs. 52.3%, p 0.006) and a greater prevalence of anti-topoisomerase-1 antibodies (ATA) (25.1% vs. 18.6%, p 0.04) were observed compared to the group with normal esPAP. Patients with elevated esPAP had a lower rate of digital ulcers (50.6% vs. 60.2%, p 0.007) and esophageal involvement (83.6% vs. 88.7%, p 0.07) and higher rate of renal crisis (4.6% vs. 1.8%, p 0.066). CONCLUSIONS: Prevalence of PAH was lower than expected (3.7%). Probability of having elevated esPAP was higher among patients with dSSc and among those with ATA.
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Hipertensión Pulmonar/epidemiología , Esclerodermia Sistémica/epidemiología , Adulto , Anciano , Anticuerpos Antinucleares , Centrómero/inmunología , Comorbilidad , Femenino , Humanos , Hipertensión Pulmonar/inmunología , Masculino , Persona de Mediana Edad , Prevalencia , Sistema de Registros , Esclerodermia Sistémica/inmunología , España/epidemiologíaRESUMEN
AIM: Anti-centromere antibody (ACA) is often detected in patients with autoimmune diseases, including limited cutaneous systemic sclerosis (SSc), Sjögren's syndrome (SS), and primary biliary cholangitis (PBC). The association between autoimmune disease and ACA positivity remains unclear. We sought to clarify the clinical features of ACA-positive patients and their association with autoantibodies. METHOD: A total of 309 cases of a discrete-speckled pattern anti-nuclear antibody (ANA) test and/or positive ACA who visited our department were retrospectively enrolled. Clinical and immunological data were collected and statistically analyzed. RESULT: A proportion of second and/or third ANA patterns were speckled (16%), homogenous (7%), cytoplasmic (3%) and/or nucleolar (3%). Of the 309 patients, 186 had Raynaud's phenomenon, 149 had sclerodactyly, and 162 had oral and/or ocular dryness. A total of 214 patients were classified into 17 autoimmune diseases based on their symptoms at the initial visit, while the other 95 patients did not meet any criteria. Most of the 214 patients were diagnosed with SSc and/or SS; 25 and 22 additional patients were diagnosed with rheumatoid arthritis and PBC, respectively. Higher titers of immunoglobulins were observed in patients diagnosed with autoimmune disease compared to patients without a diagnosis. The mean observation period was 80 months. Three additional patients received interim diagnoses based on new symptoms or organ involvement. In the other patients, the diagnosis made at the first visit was not changed over the observation period. CONCLUSION: Our study confirmed that many ACA-positive cases can be classified into an autoimmune disease type on presentation.
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Anticuerpos Antinucleares/inmunología , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Centrómero/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Biomarcadores/sangre , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Pruebas Serológicas , Adulto JovenRESUMEN
Four killer cell Ig-like receptor (KIR) genes, collectively referred to as framework genes, characterize almost all KIR haplotypes. In particular, KIR3DL3 and KIR3DL2 mark the ends of the locus, whereas KIR3DP1 and KIR2DL4 are located in the central part. A recombination hot spot, mapped between KIR3DP1 and KIR2DL4, splits the haplotypes into two regions: a centromeric (Cen) region (spanning from KIR3DL3 to KIR3DP1) and a telomeric region (from KIR2DL4 to KIR3DL2), both varying in KIR gene content. In this study, we analyzed KIR3DP1 polymorphism in a cohort of 316 healthy, unrelated individuals. To this aim, we divided KIR3DP1 alleles into two groups by the use of a sequence-specific primer- PCR approach. Our data clearly indicated that KIR3DP1 alleles present on haplotypes carrying Cen-A or Cen-B1 regions differ from those having Cen-B2 motifs. Few donors (â¼3%) made exceptions, and they were all, except one, characterized by uncommon haplotypes, including either KIR deletions or KIR duplications. Consequently, as KIR2DL1 is present in Cen-A and Cen-B1 regions but absent in Cen-B2 regions, we demonstrated that KIR3DP1 polymorphism might represent a suitable marker for KIR2DL1 gene copy number analysis. Moreover, because Cen-B1 and Cen-B2 regions are characterized by different KIR3DP1 alleles, we showed that KIR3DP1 polymorphism analysis also provides information to dissect between Cen-B1/Cen-B1 and Cen-B1/Cen-B2 donors. Taken together, our data suggest that the analysis of KIR3DP1 polymorphism should be included in KIR repertoire evaluation.
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Alelos , Centrómero/genética , Haplotipos , Polimorfismo Genético , Receptores KIR2DL4/genética , Receptores KIR3DS1/genética , Centrómero/inmunología , Femenino , Eliminación de Gen , Duplicación de Gen , Humanos , Masculino , Receptores KIR2DL4/inmunología , Receptores KIR3DS1/inmunologíaRESUMEN
OBJECTIVES: ACA-positive/primary Sjögren's syndrome (pSS) represents a distinct overlapping entity with intermediate features in between limited systemic sclerosis (lSSc) and pSS. Few data are available on their general risk for lymphoproliferative complications, specifically regarding adverse predictors at the level of minor salivary gland (MSG) histology. The objectives of this work are: a) to characterise, through a detailed immunohistochemistry study, the organisation of the lymphomonocitic infiltrates in ACA-positive/pSS patient vs. ACA-negative/pSS patients focusing on the presence of GC-like structures in minor salivary gland biopsies; b) to compare the frequency of traditional clinical and serological risk factors for lymphoma between the two subgroups. METHODS: We analysed 28 MSG samples from ACA-positive/pSS patients and 43 consecutive MSGs from ACA-negative/pSS, using sequential IHC staining for CD3, CD20 and CD21 in order to define the T/B cell segregation within the periductal infiltrates and presence of ectopic GC-like on the detection of GC-like structures. Clinical and serological data of all the patients were retrieved and analysed. RESULTS: Ectopic lymphoid structures (ELS) with GC-like structures were observed in 7 out of 28 ACA-positive/pSS patients (25%) and in 13 out of 43 ACA-negative/pSS patients (30.2%). Similarly, no statistical significant difference was found between the two groups as far as the classical pSS risk factors for lymphoproliferative complications was concerned (i.e. salivary gland enlargement, purpura, low C4, leukocytopenia, clonal gammopathy). Finally, the 3 cases of non-Hodgkin's lymphoma observed were equally distributed between the two subsets. CONCLUSIONS: Overall, this study indicates that ACA-positive/and ACA-negative pSS patients apparently present a similar risk for lymphoproliferative complications as suggested indirectly by the analogies between the two groups observed at the histopathology level.
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Anticuerpos Antinucleares/inmunología , Centrómero/inmunología , Trastornos Linfoproliferativos/inmunología , Glándulas Salivales Menores/patología , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Adulto , Anciano , Anticuerpos Antinucleares/sangre , Antígenos CD20/análisis , Biomarcadores/sangre , Biopsia , Complejo CD3/análisis , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Italia , Londres , Linfoma/inmunología , Linfoma/patología , Trastornos Linfoproliferativos/sangre , Trastornos Linfoproliferativos/patología , Persona de Mediana Edad , Fenotipo , Receptores de Complemento 3d , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de las Glándulas Salivales/inmunología , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales Menores/inmunología , Síndrome de Sjögren/sangreRESUMEN
OBJECTIVES: We aimed to assess the clinical significance of Krebs von den Lungen-6 (KL-6) in the diagnosis and severity of interstitial lung disease (ILD) in a French cohort of patients with systemic sclerosis (SSc). METHODS: Serum KL-6 concentrations were measured with chemiluminescent enzyme immunoassay (CLEIA) in 75 SSc patients. Patients were divided into two groups according to the presence of interstitial lung disease (SSc-ILD versus SSc-without ILD) on chest High-Resolution Computed Tomography. Pulmonary function tests, main manifestations and severity of the lung disease (Medsger's severity scale) were collected. RESULTS: KL-6 serum concentrations were significantly higher in SSc-ILD patients than in those without ILD (p < 10-4) and were inversely correlated with forced vital capacity, total lung capacity and diffuse lung capacity of carbon monoxide. Serum KL-6 level superior to 872 U/ml appeared as the optimal cut-off value associated with ILD. Patients with a restrictive pulmonary syndrome and dyspnoea had significant higher KL-6 serum concentrations. SSc patients with anti-topoisomerase 1 antibodies had higher KL-6 serum levels than patients with anti-centromere antibodies (p < 10- 4). ILD and anti-topoisomerase 1 antibodies were independent factors associated with KL-6 in multivariate analysis. Interestingly, KL-6 serum concentrations positively increased with the patient lung severity. CONCLUSIONS: Our study confirms that KL-6 is an accurate biomarker for the diagnosis of SSc-ILD in a French cohort of patients. High KL-6 levels should prompt physicians to assess ILD with pulmonary imaging and pulmonary functions tests. Prospective clinical studies are still required to determine whether levels of KL-6 might predict progression of ILD as well as its usefulness in the timing of therapeutic intervention.
Asunto(s)
Enfermedades Pulmonares Intersticiales/sangre , Pulmón , Mucina-1/sangre , Fibrosis Pulmonar/sangre , Esclerodermia Sistémica/sangre , Anciano , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Centrómero/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Francia , Humanos , Modelos Logísticos , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Capacidad de Difusión Pulmonar , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/fisiopatología , Factores de Riesgo , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Capacidad Pulmonar Total , Regulación hacia Arriba , Capacidad VitalRESUMEN
BACKGROUND: Previously, we found women with positive anticentromere antibody showed impaired potential of oocyte maturation and embryo cleavage; the possible mechanism behind this phenomenon was still unknown. OBJECTIVE: Thus, the present study aimed to preliminarily explore whether ACA could penetrate into the living embryos and impair their developmental potential via in vitro coculture with mouse embryos. METHODS: Mouse embryos were collected and used for in vitro culture with polyclonal anticentromere protein A (CENP-A) antibody; then, immunofluorescence assay was performed to determine the penetration of antibody into embryos, and embryo development potential was observed. RESULTS: All embryos cultured with anti-CENP-A antibody exhibited immunofluorescence on the nucleus, while none of the embryos from the control groups showed immunofluorescence. Additionally, embryos cultured with anti-CENP-A antibody experienced significant growth impairment compared with controls. CONCLUSION: Mouse embryos may be a direct target for ACA in vitro prior to implantation. However, the precise mechanism needs further clarification.
Asunto(s)
Autoanticuerpos/metabolismo , Proteína A Centromérica/inmunología , Centrómero/inmunología , Animales , Células Cultivadas , Técnicas de Cocultivo , Embrión de Mamíferos , Desarrollo Embrionario , Femenino , Edad Gestacional , Ratones , Ratones Endogámicos ICR , Oogénesis/inmunología , Circulación Placentaria , EmbarazoRESUMEN
OBJECTIVES: To assess the clinical manifestations and prognosis of Spanish patients with systemic sclerosis (SSc) according to their immunological profile. METHODS: From the Spanish Scleroderma Study Group or RESCLE (Registro de ESCLErodermia as Spanish nomenclature) Registry we selected those patients in which anti-centromere (ACA), anti-topoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies had been determined, and a single positivity for each SSc specific antibody was detected. Demographic, clinical, laboratory, and survival data were compared according to the serologic status of these antibodies. RESULTS: Overall, 209 SSc patients were included. In 128 (61%) patients ACA was the only positive antibody, 46 (22%) were only positive for ATA, and 35 (17%) for ARA. Of note, the three groups were mutually exclusive. In univariate analysis, patients with ACA presented more frequently limited cutaneous SSc (lcSSc) (p<0.001), whereas diffuse cutaneous SSc (dcSSc) was the most frequent subtype in patients with ATA (54%) and ARA (62%) (both p<0.001). Positive patients for ARA showed the highest prevalence of joint involvement (p<0.001) and those from ATA group had a higher prevalence of interstitial lung disease (ILD) (p<0.001). Scleroderma renal crisis was more frequent in the ARA group (p<0.001). In multivariate analysis, ACA were associated with female gender and were protective for dcSSc and ILD. ATA were found to be protective for lcSSc and they were independently associated with interstitial reticular pattern. ARA positivity was independently associated with dcSSc. We did not find differences in mortality between the three groups. CONCLUSIONS: In Spanish SSc patients, the presence of SSc specific antibodies conferred a distinctive clinical profile.
Asunto(s)
Autoanticuerpos/análisis , Esclerodermia Sistémica/inmunología , Adulto , Anciano , Centrómero/inmunología , Estudios de Cohortes , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , ARN Polimerasa III/inmunología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/mortalidadRESUMEN
Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9,575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3,353 RA patients and confirmed the findings. ACA was also associated with Raynaud's phenomenon (p = 6.8 × 10-11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.