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- ÍtemAcceso Abierto
Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome(2015) Johar, Angad S; Mastronardi, Claudio; Rojas-Villarraga, Adriana; Patel, Hardip R; Chuah, Aaron; Peng, Kaiman; Higgins, Angela; Milburn, Peter; Palmer, Stephanie; Silva‑Lara, Maria Fernanda; Velez, Jorge I; Andrews, Dan; Field, Matthew; Huttley, Gavin; Goodnow, Chris; Anaya, Juan-Manuel; Arcos-Burgos, MauricioBackground: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. Methods: The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. Results: Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. Conclusions: Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity. © Johar et al. - ÍtemAcceso AbiertoPrimary immunodeficiency and autoimmunity: A comprehensive review(2019) Amaya-Uribe L.; Rojas M.; Azizi G.; Anaya, Juan-Manuel; Gershwin M.E.The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented. © 2019 Elsevier Ltd
- ÍtemAcceso AbiertoDepresión y familia en pacientes con artritis reumatoide(2002) Cadena, José; Cadavid, Martha; Ocampo, Maria Victoria; Vélez Ángel, María Clara; Anaya, Juan-ManuelObjetivos: Estudiar la prevalencia de depresión y las características de las relaciones familiares en pacientes con artritis reumatoide (AR). Métodos: Estudio transversal y descriptivo. La depresión fue evaluada mediante la escala de Zung. El estado de salud de los pacientes y las características familiares fueron evaluados por encuesta dirigida. Resultados: Se incluyeron 107 pacientes. Se observó una alta tasa de depresión (58%), y una baja proporción de satisfacción con el entorno laboral (40%) y con la situación del país (7%). La relación con el núcleo familiar fue considerada buena en la mayoría de los casos, con una proporción importante de satisfacción (60%). Dentro del núcleo familiar, quienes más colaboran con el paciente son la pareja (53%) y los hijos (63%), quienes, a través de una actitud de escucha, logran que el paciente con AR se sienta apoyado. Conclusión: La depresión es frecuente en los pacientes con AR, a pesar de tener un buen entorno familiar, el cual parece actuar ejerciendo un efecto amortiguador en el impacto de la enfermedad sobre la calidad de vida.
- ÍtemAcceso AbiertoSTAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians(2008) Palomino-Morales, R J; Rojas-Villarraga, A; González, C I; Ramírez, G; Anaya, Juan-Manuel; Martín, JThe aim of this study was to determine the influence of STAT4 (rs7574865) and TRAF1/C5 (rs10818488 and rs2900180) gene polymorphisms on the risk of developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Colombian population. This was a case-control study in which 839 individuals with RA (N = 274) and SLE (N = 144) and matched healthy controls (N = 421) were included. Genotyping was performed by using a polymerase chain reaction system with pre-developed TaqMan allelic discrimination assay. STAT4 rs7574865T allele disclosed a significant influence on the risk of developing SLE (P = 0.0005; OR 1.62, 95% CI 1.22-2.16) and RA (P = 0.008; OR 1.36; 95% CI 1.08-1.71), whereas no effect on these autoimmune diseases was observed for the TRAF1/C5 polymorphisms examined. Our data strengthen STAT4 rs7574865 polymorphism as a susceptibility factor for RA and SLE and provide further evidence for a common origin of autoimmune diseases.
- ÍtemAcceso AbiertoLatent Autoimmune Thyroid Disease(2020) Rodríguez Velandia, Yhojan Alexis; Rojas Quintana, Manuel Eduardo; Monsalve Carmona, Diana Marcela; Acosta Ampudia, Yeny Yasbleidy; Pacheco Nieva, Yovana; Rodríguez Jiménez, Mónica María del Pilar; Ramírez Santana, Heily Carolina; Anaya, Juan-ManuelObjetivo Determinar la prevalencia de autoanticuerpos tiroideos y los factores asociados en sujetos eutiroideos. Métodos Se incluyeron 300 sujetos eutiroideos, elegidos por muestreo estratificado de una cohorte inicial de 1335 individuos. La función tiroidea se evaluó midiendo los niveles séricos de TSH (0.3–4.5 ?IU / mL) y FT4 (5.2–12.7?g / dL). Los anticuerpos anti-peroxidasa (TPOAbs), anti-tiroglobulina (TgAbs) y anti-receptor de TSH (TrAbs) se evaluaron con 23 autoanticuerpos adicionales, así como con niveles de vitamina D (VitD). El análisis incluyó características sociodemográficas, clínicas y ambientales. Los datos se analizaron mediante pruebas bivariadas y multivariadas. Resultados Se observó autoinmunidad tiroidea en el 15,3% de los sujetos (TPOAbs 11,3% y TgAbs 2,0%). En seis individuos, ambos autoanticuerpos fueron positivos. Los TrAbs no se detectaron en ningún individuo. Enfermedad tiroidea familiar (? = 3.4, IC 95%: 1.2–9.5, P = 0.021), la presencia de otras enfermedades autoinmunes (? = 10.8, IC 95%: 1.6–72.9, P = 0.014) Insuficiencia de VitD ( P = 0.030), nunca fume (? = 6.9, IC 95%: 1.6–30.4, P = 0.010), beba más de 4 tazas de café (? = 3.8, IC 95%: 1.1–13.1, P = 0.036), y un mayor número de años expuestos al humo de leña ( P = 0.04) se asociaron con autoinmunidad tiroidea. En el caso de TPOAbs, enfermedad de tiroides familiar (CI ? = 4,9, 95%: 1,7 a 14,0, P = 0,003), nunca fume (? = 5,7, IC 95%: 1,4 a 21,0, P = 0.002), y beber más de 4 tazas de café (? = 3.6, IC 95%: 1.1–13.1, P = 0.047) se asociaron con su positividad. Además, la presencia de anti – SS – A / Ro52 (? = 36.7, IC 95%: 2.5–549.9, P = 0.009) y anticuerpos anti-Ku (? = 10.2, IC 95%: 1.1–100.7, P = 0.046) también se asoció con TPOAbs. La presencia de ascendencia africana (? = 10.5, IC 95%: 1.7–63.2, P = 0.01), anti – SS – A / Ro52 (? = 15.8, IC 95%: 1.2–198.6, P = 0,03), y los anticuerpos anti-CENP-B (? = 31,2, IC 95%: 1,8 a 565,9 P = 0,02) se asociaron con TgAbs. Conclusión La autoinmunidad tiroidea latente no es rara. Los factores ambientales, genéticos e inmunológicos, así como los ancestros, son factores de riesgo asociados. Estos resultados facilitarían la implementación de estrategias de detección para proporcionar un diagnóstico y tratamiento oportunos.
- ÍtemAcceso AbiertoAutoclinimetría : no más esperas para el paciente con artritis reumatoide . ¡Autoexamínese!(2012) Anaya, Juan-Manuel; Rojas-Villarraga, Adriana; Mantilla, Rubén D.; Amaya-Amaya, JennyLa artritis reumatoide es la enfermedad inflamatoria y crónica más frecuente. Afecta más a las mujeres que a los hombres. Luego del diagnóstico, el paciente debe ser sometido a un proceso de seguimiento, que incluye un correcto examen clínico, pruebas de laboratorio, seguimiento radiográfico y cuestionarios que evalúan su calidad de vida y su aspecto funcional. Como sucede con otras enfermedades, se ha demostrado que el paciente con artritis reumatoide puede realizar un autoexamen y ser un agente activo en su consulta médica. Esta autorrevisión se conoce como autoclinimetría, herramienta útil para el seguimiento y la valoración de la capacidad funcional y la calidad de vida del paciente.
- ÍtemAcceso AbiertoThe impact of rheumatoid foot on disability in Colombian patients with rheumatoid arthritis(2009) Rojas-Villarraga, Adriana; Bayona, Javier; Zuluaga, Natalia; Mejia, Santiago; Hincapie, Maria-Eugenia; Anaya, Juan-ManuelBackground. Alterations in the feet of patients with rheumatoid arthritis (RA) are a cause of disability in this population. The purpose of this research was to evaluate the impact that foot impairment has on the patients' global quality of life (QOL) based on validated scales and its relationship to disease activity. Methods. This was a cross-sectional study in which 95 patients with RA were enrolled. A complete physical examination, including a full foot assessment, was done. The Spanish versions of the Health Assessment Questionnaire (HAQ) Disability Index and of the Disease Activity Score (DAS 28) were administered. A logistic regression model was used to analyze data and obtain adjusted odds ratios (AORs). Results. Foot deformities were observed in 78 (82%) of the patients; hallux valgus (65%), medial longitudinal arch flattening (42%), claw toe (lesser toes) (39%), dorsiflexion restriction (tibiotalar) (34%), cock-up toe (lesser toes) (25%), and transverse arch flattening (25%) were the most frequent. In the logistic regression analysis (adjusted for age, gender and duration of disease), forefoot movement pain, subtalar movement pain, tibiotalar movement pain and plantarflexion restriction (tibiotalar) were strongly associated with disease activity and disability. The positive squeeze test was significantly associated with disability risk (AOR = 6,3; 95% CI, 1.2830.96; P = 0,02); hallux valgus, and dorsiflexion restriction (tibiotalar) were associated with disease activity. Conclusion. Foot abnormalities are associated with active joint disease and disability in RA. Foot examinations provide complementary information related to the disability as an indirect measurement of quality of life and activity of disease in daily practice. © 2009 Rojas-Villarraga et al; licensee BioMed Central Ltd.
- ÍtemAcceso AbiertoMedicina personalizada: La salud y la enfermedad sí se pueden predecir(2013-08) Anaya, Juan-Manuel; Sarmiento, Juan Camilo; Montoya Ortiz, Gladys; Molano González, Nicolás; Pérez Cristiano, Janeth; Rojas-Villarraga, AdrianaAños y años de constante investigación en busca del entendimiento y el tratamiento de las distintas enfermedades, han llevado a la conclusión de que la medicina debe ser tratada de manera individual, pues cada paciente es, por así decirlo, un universo distinto. La medicina personalizada es el campo de la salud que individualiza la atención médica, basándose en la información única que cada persona posee. Esta aproximación permite individualizar el cuidado de cada persona en el camino que existe entre la salud y la enfermedad.
- ÍtemAcceso AbiertoThe simultaneous presence of IL-1B and TNFA two-positions risk haplotypes enhances the susceptibility for celiac disease(2008) Cherñavsky, Alejandra Claudia; Páez, María Carolina; Periolo, Natalia; Correa, Paula; Guillén, Laura; Niveloni, Sonia Isabel; Mauriño, Eduardo; Bai, Julio César; Anaya, Juan-ManuelTo assess the joint contribution of interleukin 1 beta (IL-1B) and tumor necrosis factor alpha (TNF?) to the genetic risk of developing celiac disease (CD), we analyzed four biallelic polymorphisms of TNFA and IL-1B genes in 228 patients and 244 healthy controls. The individual contribution of TNFA -308A and IL-1B -511C alleles was weak (OR 1.47 and 1.66, respectively) and was null for TNFA -238 A/G and IL-1B +3953 C/T single nucleotide polymorphisms (SNPs). Due to the potential linkage disequilibrium between TNFA, human leukocyte antigen (HLA) -DQA1 and HLA-DQB1 genes, only individuals carrying DQ2 antigen (DQ2-positive) were considered to perform haplotype analyses. Two-position risk haplotypes were first defined by the combined presence of -511C and +3953T alleles for IL-1B (OR 9.402) or -308A and -238A alleles for TNFA (OR 15.389). The TNFA/IL-1B combined haplotype-stratified association analysis showed that the simultaneous presence of TNFA risk and IL-1B non-risk haplotypes (OR 13.32) but not TNFA non-risk and IL-1B risk haplotypes (OR 0.71) is associated with CD. Interestingly, our data suggest that the coexistence of both risk haplotypes seems to work synergistically (OR 29.59), which enhances the risk of developing CD. © 2008 Elsevier Ltd. All rights reserved.
- ÍtemAcceso AbiertoPrimary biliary cirrhosis and the nuclear pore complex(2012) Duarte-Rey, Carolina; Bogdanos, Dimitrios; Yang, Chen-Yen; Roberts, Krista; Leung, Patrick S.C.; Anaya, Juan-Manuel; Worman, Howard J.; Gershwin, M. EricExperimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry. © 2012 Elsevier B.V.
