Fundamentos fisiopatológicos para el diagnóstico de la anemia hemolítica autoinmune / Pathophysiological basics for the diagnosis of autoimmune hemolytic anemia

RESUMEN Introducción: la anemia hemolítica autoinmune es producida por anticuerpos que reaccionan con los eritrocitos propios del paciente, demostrables a través de la positividad del test de antiglobulina o prueba de Coombs directa. La clasificación de la enfermedad se basa en dos parámetros fundamentales: su etiología y las características térmicas del funcionamiento de los autoanticuerpos. Objetivo: actualizar la información científica sobre las causas y la fisiopatología de la anemia hemolítica autoinmune. Métodos: se realizó una revisión de los principales libros de texto y los artículos más recientes publicados en las principales revistas hematológicas e inmunológicas, para lograr una guía práctica del diagnóstico de la enfermedad. Discusión: debido a que existe una amplia gama de protocolos para su diagnóstico basados en parámetros no siempre coincidentes, se expone una metodología para el trabajo de los médicos que atienden enfermos con diferentes tipos de anemia hemolítica autoinmune, sobre la base de los conocimientos acerca de las causas y la fisiopatología de la enfermedad. Conclusiones: la comprensión de la fisiopatología y los criterios de clasificación de la anemia hemolítica autoinmune es un requisito para el diagnóstico de este trastorno, y la utilización de las nuevas opciones terapéuticas en el manejo de estos enfermos.

ABSTRACT Introduction: autoimmune hemolytic anemia is produced by antibodies that react with the patient's own erythrocytes provable through the positivity of the antiglobulin test or direct Coombs test. The classification of the disease is based on two fundamental parameters: its etiology and the thermal characteristics of the functioning of the auto antibodies accounts. Objective: to update scientific information on the causes and pathophysiological autoimmune hemolytic anemia. Methods: a review of the main textbooks and the most recent articles published in the main hematological and immunological journals was carried out, bringing together the knowledge to achieve a practical guide to the diagnosis of this disease. Discussion: due to the fact that there is a wide range of protocols for its diagnosis, based on parameters that do not always coincide, a methodology is presented for the work of physicians who treat patients with different types of autoimmune hemolytic anemia based on knowledge about the causes and the pathophysiological characteristics of this disease. Conclusions: understanding the physiopathology and classification criteria of autoimmune hemolytic anemia is a requirement for the diagnosis of this disorder and the use of new therapeutic options in the management of these patients.

Systemic Lupus Erythematosus, Ten years of follow up / Lupus Eritematoso Sistémico. 10 años de Seguimiento

ABSTRACT Introduction: Systemic Lupus Erythematosus is a relatively frequent disease of universal distribution. Its incidence varies according to the characteristics of the studied population such as age, gender and ethno. It is a chronic and autoimmune disease, which cause is not clear at all. Objective: to characterize clinically and epidemiologically the patients with systemic lupus erythematosus. Methods: A descriptive investigation of 112 patients with diagnosis of systemic lupus erythematosus assisted at Arnaldo Milián Castro University Hospital was carried out from January 2008 to December 2017. Results: patients between 30 and 39 years of age were the most representative with a higher incidence in the female sex. High blood pressure prevailed as previous history and coffee as toxic habit. There was a higher affection of the osteomyoarticular system followed by skin and mucosa. The combination of Prednisone and Azathioprine was the most used treatment. Infections were the main cause of death. Conclusions: systemic Lupus Erythematosus is present with major frequency in female young patients, with a high risk of systemic affection as well as presenting a life-threatening evolution secondary to infections(AU)

Introducción: el lupus eritematoso sistémico, es una enfermedad relativamente frecuente y de distribución universal. La incidencia varía según las características de la población estudiada, como la edad, el género y la etnia. Es una enfermedad crónica y autoinmune, cuya causa no está esclarecida del todo. Objetivo: caracterizar clínica y epidemiológicamente a los pacientes con lupus eritematoso sistémico. Métodos: se realizó una investigación descriptiva de 112 pacientes con diagnóstico de lupus eritematoso sistémico, atendidos en el Hospital Universitario Clínico Quirúrgico Arnaldo Milián Castro, entre enero del 2008 y diciembre del 2017. Resultados: los pacientes entre 30 y 39 años de edad fueron los más representativos, con mayor incidencia en el sexo femenino. Predominó la hipertensión arterial como antecedente patológico personal y el café como hábito tóxico. Existió mayor afectación del sistema osteomioarticular seguido por piel y mucosas. La combinación de prednisona y azatioprina fue el tratamiento más usado. La principal causa de muerte fueron las infecciones. Conclusiones: el lupus eritematoso sistémico se presenta con mayor frecuencia en pacientes jóvenes y del sexo femenino, con alto riesgo de afectación sistémica así como a presentar evolución tórpida secundaria a infecciones(AU)

Artritis reumatoide, autoanticuerpos y enzimas PADs / Rheumatoid arthritis, autoantibodies, and PAD enzymes

Resumen: La artritis reumatoide es una enfermedad inflamatoria sistémica que se caracteriza por sinovitis crónica y producción de autoanticuerpos. Los factores de riesgo incluyen genes HLA-DRῘβ1 con epítope compartido, periodontitis y tabaquismo. Al menos cinco diferentes sistemas de anticuerpos contra autoantígenos están implicados en la patogénesis de la enfermedad: 1) el factor reumatoide; 2) los anticuerpos a péptidos/proteínas citrulinadas (ACPAs); 3) los anticuerpos a proteínas carbamiladas (anti-Pcar); 4) los anticuerpos contra enzimas peptidilarginina desaminasas (anti-PAD2/4) y 5) los anticuerpos contra fibrinógeno citrulinado. La existencia de ACPA ha dividido a los sujetos con artritis reumatoide en dos subclases: artritis reumatoide positiva a ACPA y negativa a ACPA. Solamente los pacientes con artritis reumatoide positiva a ACPA están estrechamente relacionados con alelos HLA-DRβ1 con epítope compartido y son reconocidos por antígenos específicos de células T y células B.

Abstract: Rheumatoid arthritis is a systemic, inflammatory disease characterized by chronic synovitis and presence of autoantibodies. Risk factors include HLA-DRβ1 genes, periodontal disease and smoking. At least 5 different autoantibodies to autoantigens are implicated in the pathogenesis of this disorder: 1) rheumatoid factor; 2) autoantibodies directed against citrullinated peptides/proteins (ACPA); 3) anti-carbamilated protein antibody (anti-carP); 4) anti-peptidylarginine deiminase antibody (anti-PAD2/4), and 5) anti-citrullinated fibrinogen antibody. Patients with rheumatoid arthritis have been divided into two disease subsets: ACPA-positive rheumatoid arthritis and ACPA- negative rheumatoid arthritis. ACPA-positive rheumatoid arthritis is associated with HLA-DRβ1 shared epitope alleles and is recognized by antigen-specific T cells and B cells.

Alopecia areata difusa e a teoria dos autoantígenos associada a melanogênese / Diffuse alopecia areata and the autoantigens-melanogenesis association theory

A alopecia areata é afecção crônica dos folículos pilosos e das unhas, de etiologia desconhecida, que determina queda dos cabelos e/ou pelos. Apresenta-se sob diversas formas clínicas, sendo atípica a forma difusa, em que há perda aguda e difusa de cabelos. Aceita-se que exista uma base autoimune órgão-específica mediada por células T na alopecia areata, e estudos apontam que o autoantígeno é associado ao melanócito. Relatamos o caso de paciente que apresentou a forma difusa com preservação dos fios em canície.

Alopecia areata is a chronic condition of hair follicles and nails with unknown etiology, which causes hair loss. It emerges in several clinical types, with the diffuse form, where there is acute and diffuse hair loss, being atypical. It is generally accepted that there is a T-cell mediated, organ-specific autoimmune base in alopecia areata and studies indicate that the autoantigen is associated with melanocytes. The authors of the present paper report the case of a patient who had the diffuse form of alopecia areata, with preservation of the gray hair strands

Enfermedades autoinmunesreumáticas: de la clínica al laboratorio / Autoimmune rheumatic diseases: from clinic to the laboratory

La autoinmunidad es la pérdida de la tolerancia de un organismo a los antígenos propios, lo que genera la producción de autoanticuerpos; sin embargo, su presencia no siempre indica la existencia de una enfermedad. Las enfermedades autoinmunes reumáticas son un grupo de condiciones crónicas que comparten características clínicas y de laboratorio. Para hacer un diagnóstico correcto se debe partir de la identificación de los síntomas y hallazgos clínicos del paciente, y correlacionarlos con los exámenes de laboratorio, los cuales ayudan a confirmar o descartar la enfermedad, estimar su gravedad, pronóstico y dar seguimiento a su evolución.

Autoimmunity is the loss of tolerance to self-antigens in an organism, which generates the production of autoantibodies; however, their presence does not always indicate the existence of disease. Rheumatic autoimmune diseases are a group of chronic conditions that share clinical and laboratory features. The correct diagnosis of these diseases are based on the symptoms and clinical findings of patients and their correlation with laboratory tests to confirm or rule out the disease, estimate its severity, prognosis and monitoring the evolution.

Autoinmunidad y receptores tipo Toll / Autoimmunity and toll-like receptors

La respuesta inmune innata está conformada por un conjunto de mecanismos que permiten reconocer los componentes propios del organismo y diferenciarlos de los microorganismos invasores para generar una primera línea de defensa. Este reconocimiento está mediado por diferentes receptores presentes en la superficie y en el interior de células inmunes y no inmunes; entre ellos se encuentran los siguientes: receptores tipo Toll (RTT), receptores de lectinas tipo C, receptores tipo GIR (genes inducibles por ácido retinoico) y receptores tipo Nod y NALP, que reconocen patrones moleculares asociados a microorganismos (PMAM). Gracias a esta capacidad de discriminación, adquirida evolutivamente por la inmunidad innata, se ha aceptado tradicionalmente que los procesos autoinmunes no están relacionados con esta sino con la inmunidad adquirida. Sin embargo, varios estudios han demostrado que esa teoría no es totalmente cierta y que algunos mecanismos efectores de la inmunidad innata participan en la generación de las enfermedades autoinmunes o en la potenciación de su fisiopatología. En esta revisión se estudia la contribución de la inmunidad innata a la autoinmunidad con énfasis en el papel de los receptores tipo Toll.

Autoimmunity and toll-like receptors Innate immune response consists of a set of mechanisms allowing the body to recognize its own components and to differentiate them from invasive microorganisms in order to generate a first line of defense. Such recognition is mediated by several receptors present both on the surface and inside immune and non-immune cells, among them: Toll-like receptors, C-type lectin receptors, RIG receptors (retinoic acid induciblegenes), and Nod-like and NALP receptors, all of which recognize microbe-associated molecular patterns (MAMP). Due to this discriminative ability, acquired by innate immunity in the course of evolution, it has been traditionally accepted that autoimmune processes are not related to innate immunity but to the acquired one. However, several studies have demonstrated that this theory is not entirely true and that some mechanisms of innate immunity either participate in the generation of autoimmune diseases or enhance its physiopathology. This review examines the contribution of innate immunity to autoimmunity emphasizing on the role of Toll-like receptors.

Immune system markers of neuroinflammation in patients with clinical diagnose of neuromyelitis optica / Marcadores imunológicos em pacientes com diagnóstico de neuromielite óptica

Neuromyelitis optica (NMO) is an inflammatory, demyelinating disease of the central nervous system characterized by the association of a serious myelitis and unilateral or bilateral optic neuritis. The present study aimed to analyze the immunological parameters of NMO patients with diagnosis established based on Wingerchuck et al. (1999) criteria. Production of IgG and IgA antibodies to antigens of MBP, PLP 95-116, MOG 92-106, and the cytokines interleukin-4 (IL-4) and interferon-γ (INF-γ) were assessed by Elisa assay. The cohort was formed by 28 NMO patients and a matched healthy control group. NMO patients had significant high levels of IgG to MOG (p<0.0001), PLP (p=0.0002) and MBP (p<0.0001), and solely IgA to MBP (p<0.0001). INF-γ (p=0.61) levels were similar to healthy controls. Increased production of IL-4 (p=0.0084) indicates an important role for this cytokine in the activation of Th2 regulatory cells and of the IgA producers B lymphocyte indicating activation of humoral immunity.

A neuromielite óptica (NMO) é doença inflamatória do sistema nervoso central, caracterizada por mielite aguda ou subaguda grave e neurite óptica unilateral ou bilateral. Este estudo objetiva analisar parâmetros imunológicos de pacientes com critérios de Wingerchuck et al. (1999) para NMO. O método de ELISA avaliou a produção de IgG e IgA para antígenos da proteína básica da mielina (MBP), o proteolipídeo (PLP) 95-116, a glicoproteina associada ao oligodendrócito (MOG) 92-106 e as citocinas interleucina-4 (IL-4) e interferon-gama (INF-γ). Foram incluνdos 28 pacientes com NMO pareados com controles saudáveis. Pacientes com NMO apresentaram níveis significativamente elevados de imunoglobulinas reativas dos isotipos IgG para MOG (p<0,0001), PLP (p=0,0002) e MBP (p<0,0001) e IgA somente para MBP (p<0,0001). Os níveis de INF-γ (p=0,61) foram semelhantes aos controles. A produção elevada de IL-4 (p=0,0084) indica papel importante na ativação de células regulatórias Th2 e linfócitos B produtores de IgA e da ativação da imunidade humoral.

Sclera-Specific and non-sclera-specific autoantibodies in the serum of patients with non-infectious anterior scleritis

OBJECTIVES: to study the frequency and specificity of sclera-specific and non-sclera-specific autoantibodies in the sera of patients with anterior non-infectious scleritis. METHODS: prospective study involving 25 patients examined at the sector of Cornea and External Disease of the Department of Ophthalmology and Immuno-Rheumatology Laboratory at Federal University of São Paulo/Paulista Medicine School, during one year. The diagnosis of scleritis was according to Watson and Hayreh's (1976) classification criteria. The exclusion criterion was infectious scleritis. All the patients underwent a full clinical and ophthalmologic evaluation, including serological tests for syphilis and tuberculosis investigation. The following autoantibodies were tested: rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies, ANCA (anti-neutrophil cytoplasmic antibodies), anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-DNA and anti-APF (antiperinuclear factor). For sclera-specific autoantibodies, sera of all patients were subjected to indirect immunofluorescence and Western blot assays, using human sclera from eye banks as a substrate. Sera from 25 healthy individuals were used as a normal control in the immunologic assays. RESULTS: as non-sclera-specific autoantibodies we detected one patient with positive rheumatoid factor, two patients with positive antinuclear antibodies, two patients with positive anticardiolipin antibody and two patients with positive anti-APF. Sclera-specific autoantibodies were detected by Western blot and immunofluorescence in the serum of two patients with scleritis. The two patients with sclera-specific autoantibodies did not show non-sclera-specific autoantibodies and also presented no evidence of autoimmune rheumatic disease. Normal controls were negative for all tested autoantibodies. CONCLUSIONS: Sclera-specific autoantibodies were detected solely in the serum of patients with isolated non-infectious anterior scleritis. Non-sclera-specific...

OBJETIVOS: estudar a freqüência e especificidade de auto-anticorpos contra antígenos específicos e não específicos da esclera no soro de pacientes com esclerite anterior não infecciosa. MÉTODOS: foi realizado estudo prospectivo envolvendo 25 pacientes examinados no Setor de Córnea e Doenças Externas do Departamento de Oftalmologia da Unifesp-EPM e no Laboratório de Imuno-Reumatologia da Unifesp-EPM, durante um ano. Os critérios de esclerite foram estabelecidos conforme a classificação de Watson e Hayreh (1976). Os critérios de exclusão foram as esclerites infecciosas. Todos os pacientes tiveram avaliações clínica e oftalmológica completas, incluindo exames laboratoriais para afastar doenças infecciosas como a sífilis e a tuberculose. Os seguintes auto-anticorpos foram testados: fator reumatóide, anticorpos antinucleares, anticorpos anticardiolipina, ANCA (anticorpos anticitoplasmáticos de neutrófilos), anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-DNA e anti-APF (anticorpos antifator perinuclear). Para a pesquisa de auto-anticorpos contra antígenos específicos da esclera, o soro dos pacientes foi submetido à técnica de imunofluorescência indireta e Western-blot utilizando esclera humana obtida em banco de olhos, como substrato. Os soros de 25 pacientes hígidos foram utilizados como grupo controle nos testes imunológicos. RESULTADOS: auto-anticorpos contra antígenos não específicos da esclera foram detectados: um paciente com fator reumatóide positivo, dois pacientes com fator antinúcleo positivos, dois pacientes com anticorpos anticardiolipina positivos e dois pacientes com anti-APF. Auto-anticorpos contra antígenos específicos da esclera pela técnica de imunofluorescência indireta e Western-blot foram detectados no soro de dois pacientes com esclerite. Os dois pacientes com auto-anticorpos contra antígenos específicos da esclera não apresentavam auto-anticorpos contra antígenos não específicos da esclera nem tinham doença reumática auto-imune. Os controles...