CD20, generalidades básicas-moleculares y su posible relación como marcador de mal pronóstico en leucemia / CD20, basic-molecular generalities, and its possible relationship as a marker of poor prognosis in leukemia

CD20 es una proteína transmembranal expresada en la superficie del linfocito B y desempeña un papel muy importante en su desarrollo y diferenciación. Se expresa en la gran mayoría de neoplasias de células B, como en la leucemia linfoblástica aguda (LLA). Se recopiló información sobre la estructura biológica y molecular del marcador CD20 y su mecanismo de regulación, para mejorar el entendimiento sobre su función dentro de la célula, el efecto que ejerce como marcador de mal pronóstico cuando se encuentra expresado en pacientes adultos diagnosticados con LLA y las ventajas de ser utilizado como blanco terapéutico en esta patología.

CD20 is a transmembrane protein expressed on the surface of the B lymphocyte and plays a significant role in its development and differentiation. It is expressed in most B-cell neoplasms, such as Acute Lymphoblastic Leukemia (ALL). Information was collected on the biological and molecular structure of the CD20 marker and its regulation mechanism to improve the understanding of its function within the cell, the effect it exerts as a marker of poor prognosis when expressed in adult patients diagnosed with ALL, and the advantages of being used as a therapeutic target in this pathology.

Proliferative verrucous leukoplakia mimicking oral lichen planus: case report and literature review

This report presents the clinical, microscopic and immunohistochemical aspects of a case of proliferative verrucous leukoplakia (PVL) mimicking oral lichen planus (OLP) in a 66-year-old woman. We also review the literature reporting cases of PVL mimicking OLP, where we found a higher prevalence in women who do not consume tobacco or alcohol. The initial manifestation of lichenoid areas was around the age of 59, with the diagnosis of PVL being established on average 6 years later, while malignant transformation occurred in 8 of the 22 cases at an average of 3.7 years after the final diagnosis of PVL. We emphasize the need for a close follow-up of any patient presenting white lesions of the oral mucosa. Lesions that are clinically and microscopically compatible with lichenoid reactions or OLP must be investigated and differentiated from PVL, which has a worse prognosis.

Este relato apresenta os aspectos clínicos, microscópicos e imuno-histoquímicos de um caso de leucoplasia verrucosa proliferativa (LPV) mimetizando líquen plano oral (LPO) em uma paciente do sexo feminino de 66 anos. Também revisamos a literatura relatando casos de LPV mimetizando LPO, onde encontramos maior prevalência em mulheres que não consomem tabaco ou álcool, com manifestação inicial de áreas liquenoides por volta dos 59 anos, sendo estabelecido o diagnóstico de LPV em média 6 anos depois, enquanto a transformação maligna ocorreu em 8 dos 22 casos em média 3,7 anos após o diagnóstico final de LPV. Ressaltamos a necessidade de acompanhamento rigoroso de qualquer paciente que apresente lesões brancas da mucosa oral, devendo ser investigadas lesões clinicamente e microscopicamente compatíveis com reações liquenóides ou LPO e diferenciadas da LPV, que tem pior prognóstico

Este reporte presenta los aspectos clínicos, microscópicos e inmunohistoquímicos de un caso de leucoplasia verrugosa proliferativa (LVP) simulando liquen plano oral (LPO) en una paciente de 66 años. También revisamos la literatura reportando casos de LVP simulando LPO, donde encontramos una mayor prevalencia en mujeres que no consumen tabaco ni alcohol, con una manifestación inicial de áreas liquenoides alrededor de los 59 años, estableciéndose el diagnóstico de LVP en promedio 6 años después, mientras que la transformación maligna ocurrió en 8 de los 22 casos en un promedio de 3,7 años después del diagnóstico final de LVP. Resaltamos la necesidad de un seguimiento estrecho de todo paciente que presente lesiones blanquecinas de la mucosa oral, que las lesiones clínica y microscópicamente compatibles con reacciones liquenoides o LPO deben ser investigadas y diferenciadas de la LVP, que tienen peor pronóstico.

Efecto del Rituximab sobre los niveles circulantes de citocinas y quimiocinas producidas o no por los linfocitos B en pacientes con Artritis Reumatoide

La Artritis Reumatoide (AR) es una enfermedad autoinmune frecuente, caracterizada por inflamación crónica en las articulaciones que puede progresar a la destrucción ósea. Aunque la fisiopatología de la AR no es clara, se ha visto que las células T y las células B desempeñan un importante papel en la misma. Estudios con Rituximab (RTX), un fármaco que elimina las células B CD20+, han contribuido a esclarecer y destacar la participación de las células B en la AR. Las células B pueden contribuir a la autoinmunidad de manera dependiente de la producción de los anticuerpos e independiente de esta producción. Esta última función puede ser debida al papel de las células B como presentadoras de antígeno para las células T y productoras de citocinas y quimiocinas. Para contribuir a entender este último mecanismo, se revisaron los artículos donde se evidenciaron los efectos del tratamiento con RTX sobre la citocinas y quimiocinas circulantes en pacientes con AR. Se encontró que la mayoría de las citocinas estudiadas disminuyeron sus niveles en circulación luego del tratamiento con RTX. La IL-10 y la IL-6 se vieron consistentemente disminuidas en los pacientes que respondieron al tratamiento y podrían ser marcadores del tratamiento con Rituximab.

Summary Rheumatoid Arthritis (RA) is a common autoimmune disease characterized by chronic inflammation in the joints that can progress to bone destruction. Although the pathophysiology of RA is unclear, T cells and B cells are though to be involved. Rituximab (RTX), a drug that eliminates CD20 + B cells, has helped to clarify and highlight the role of B cells in RA. B cells can contribute to autoimmunity by mechanisms dependent on the production of antibodies and independent of this production. The latter may depend on the role of B cells as antigen-presenting cells for T cells and their capacity to produce cytokines and chemokines. To contribute to our understanding of this mechanism, studies that evaluated levels of circulating cytokines and chemokines in patients with RA after treatment with RTX were reviewed. Most cytokines studied decreased their levels in circulation after treatment with RTX. IL-10 and IL-6 consistently were decreased in patients responding to treatment and maybe markers of Rituximab treatment.

Human follicular helper T lymphocytes critical players in antibody responses / Linfócitos T auxiliares foliculares humanos: células essenciais para a resposta de anticorpos

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes' antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

RESUMO Linfócitos T auxiliares foliculares são uma subpopulação de linfócitos T CD4+ identificada inicialmente nos centros germinativos dos folículos dos órgãos linfoides secundários. Sua função primordial é auxiliar os linfócitos B na produção de anticorpos. A mudança de classe e de afinidade dos anticorpos, a diferenciação das células B e a geração de memória dependem da cooperação entre os linfócitos T auxiliares foliculares e as células B. No sangue, recebem o nome de linfócitos T auxiliares circulantes. Considera-se que possuem especificidades semelhantes às desenvolvidas nos órgãos linfoides secundários. O fenótipo dos linfócitos T auxiliares humanos é dado pela expressão conjunta dos marcadores CXCR5, Bcl-6, CD40L, PD-1 e ICOS. Nos folículos, linfócitos T auxiliares sintetizam a interleucina 21 como citocina predominante. No sangue, são descritas várias subpopulações de linfócitos T auxiliares circulantes com expressões variadas dos marcadores clássicos de linfócitos T auxiliares, além de poderem agregar outros, como CXCR3 e CCR6. Existe um enorme interesse no estudo de linfócitos T auxiliares e linfócitos T auxiliares circulantes, para a avaliação de eficácia de vacinação. São também investigados como possíveis marcadores de atividade em muitas doenças e potenciais intervenções terapêuticas. Esta breve revisão descreve aspectos da imunobiologia e da quantificação de linfócitos T auxiliares humanos e linfócitos T auxiliares circulantes, além de apresentar alguns achados relacionados em lúpus eritematoso sistêmico, artrite reumatoide, infecção por HIV e vacinação.

COVID-19: fisiopatología e inmunopatología / Physiopathology and immunopathology of COVID-19: narrative review

La fisiopatología y la inmunopatología del COVID-19 están íntimamente relacionadas entre sí y son dependientes la una de la otra. La complejidad de ambos procesos puede desencadenar daños multiorgánicos, producto de la toxicidad viral directa (la cual es dependiente de la expresión del receptor de enzima convertidora de angiotensina 2 o ACE2), del daño de las células endoteliales y tromboinflamación (induciendo endotelitis en múltiples lechos vasculares), y de la desregulación de la respuesta inmune y del sistema reninaangiotensina-aldosterona (SRAA), lo que se traduce en efectos citopáticos virales con daños en órganos diana. La enfermedad se caracteriza por presentar reacciones hiperinflamatorias que pueden desencadenar una liberación exacerbada de citoquinas proinflamatorias, proceso denominado "tormenta de citoquinas". La desregulación de la respuesta inmune produce linfopenia (de los linfocitos T CD4,+ CD8+, y B) así como un aumento de la relación neutrófilos-linfocitos. También se evidencia un claro incremento de marcadores inflamatorios, como los reactantes de fase aguda(AU)

The physiopathology and immunopathology of COVID-19 are both related and dependent on each other, The complexity of both processes has the potential to unfold multi-organ failure, product of the endothelium inflammation in multiple vascular beds, also viral toxicity (which depends, as well, on the expression of the angiotensin-converting enzyme 2 or ACE2), the damage on endothelial cells and thrombo-inflammation (inducing a dysregulation of the immune response and the renin-angiotensin-aldosterone system (RAAS), with cytopathic viral effects and damage on target organs. This disease also presents hyperinflammatory reactions that can lead to the exacerbated release of proinflammatory cytokines, a process known as "cytokine storm". The dysregulation of the immune response also generates lymphopenia, and a higher ratio of the neutrophils-lymphocytes ratio. There is a clear increase of the inflammatory markers, including the acute phase reactants. The understanding of the physiopathology and immunopathology is crucial in order to comprehend the bases of COVID-19, its treatment and prevention(AU)

Diseño y optimización de un tubo policromático de citometría de flujo para inmunofenotipo linfocitario periférico / Design and optimization of a polychromatic tube of flow cytometry for peripheral lymphocyte immunophenotype

Introducción: La citometría de flujo permite la cuantificación de las subpoblaciones de linfocitos con una elevada sensibilidad, especificidad y objetividad. Estas ventajas solo se logran con un proceso laborioso de diseño individualizado y controlado para cada experimento. Objetivo: Diseñar un protocolo de un solo tubo policromático de citometría flujo para inmunofenotipo linfocitario periférico. Métodos: Se realizó un estudio experimental in vitro con muestras de sangre periférica obtenidas de tres voluntarios sanos, en el Centro Nacional de Genética Médica, en marzo de 2019. El tubo se compuso de seis marcadores de linaje para identificar linfocitos B, T, natural killer y natural killer T. Se desarrolló un protocolo de lisis de hematíes sin lavado. Se emplearon anticuerpos monoclonales conjugados con fluorocromos. El punto óptimo de concentración correspondió al mayor índice de tinción y conservación de los porcentajes de positividad de cada población. Se realizó la construcción progresiva del tubo y se propuso una estrategia lógica de secuencia de ventanas para el análisis de datos. Resultados: Los marcadores seleccionados permitieron realizar correctamente el inmunofenotipo linfocitario periférico. En los cinco puntos de titulación se observaron buenas discriminaciones entre las señales positivas y negativas, excepto para el anti-CD56 que presentó una tendencia decreciente del índice de tinción. El volumen total de conjugados requeridos para la determinación de los 6 antígenos fue de 3,75 μL por tubo. Conclusiones: Se obtuvo un tubo policromático que permite el inmunofenotipo periférico de forma rápida y precisa por seis antígenos linfocitarios simultáneamente, con el empleo de pequeños volúmenes de conjugado y sangre(AU)

Introduction: Flow cytometry allows quantification of lymphocyte subpopulations with high sensitivity, specificity and objectivity. These advantages are only achieved through the hardworking process of individualized and controlled design for each experiment. Objective: To design a flow cytometry protocol of a single polychromatic tube for peripheral lymphocyte immunophenotype. Methods: An experimental in vitro study was carried out, in March 2019, with peripheral blood samples obtained from three healthy volunteers, at the National Center for Medical Genetics. The tube was made up of six lineage markers for identifying natural B and T lymphocytes, natural killers and natural killer T cells. A protocol was developed for red blood cell lysis without washing. Fluorochrome-conjugated monoclonal antibodies were used. The optimal point of concentration corresponded to the highest staining index and preservation of the positivity percentages of each population. Progressive tube construction was performed and a logical window sequence strategy was proposed for data analysis. Results: The chosen markers allowed to carry out correct peripheral lymphocyte immunophenotype. Good discriminations between positive and negative signals were observed at the five titration points, except for anti-CD56, which presented a decreasing trend in the staining index. The total volume of conjugates required for determination of the six antigens was 3.75 μL per tube. Conclusions: A polychromatic tube was obtained that allows to carry out peripheral immunophenotype quickly and precisely by six lymphocyte antigens simultaneously, with the use of small volumes of conjugate and blood(AU)

Afectación de parámetros inmunológicos en un caso de leishmaniasis visceral autóctono del Noroeste Argentino / Alterations of immunological parameters in an autochthonous case of visceral leishmaniasis from the Northwest of Argentina

Resumen En el presente trabajo informamos la afectación de parámetros inmunológicos durante la etapa grave de la infección y luego de alcanzar la recuperación clínica en un paciente autóctono del Noroeste argentino con leishmaniasis visceral causada por Leishmania (Leishmania) infantum. Detectamos concentraciones plasmáticas elevadas de interferón-γ, interleuquina 10, IgG y BAFF (B-cell activating factor) durante la enfermedad activa, que se normalizaron luego de la recuperación clínica. En relación al perfil de diferenciación y memoria de las células T, clasificamos las células según la expresión de CD27, CD28, CD45RO, CD57 y perforina. Encontramos un fenotipo altamente diferenciado analizando la población de linfocitos T CD8+, con porcentajes aumentados de células T de diferenciación tardía y efectoras terminales. Si bien el fenotipo T CD8+ persistió luego de la recuperación clínica, pudimos observar un claro aumento de células T de memoria central en ese punto de estudio, sugiriendo signos de una posible reversión hacia un perfil T menos avanzado. El compartimiento de células B CD19+ mostró cambios más leves en la composición de las subpoblaciones de memoria. Documentamos el compromiso global de parámetros inmunológicos en la etapa grave de la leishmaniasis visceral que tienden a revertir luego de la recuperación, sugiriendo posibles signos de reconstitución inmune acompañando a la mejoría clínica. Los parámetros evaluados podrían ser útiles como biomarcadores de la evolución clínica de la enfermedad.

Abstract We report the alterations of immunological parameters of a patient with visceral leishmaniasis caused by Leishmania (Leishmania) infantum from the Northwest of Argentina during active disease and after achieving clinical recovery. We first demonstrated elevated amounts of IFN-γ, IL-10, B-cell activating factor (BAFF) and IgG in plasma during active disease, which returned to control values after recovery. In relation to T cell profile, we measured CD27, CD28, CD45RO, CD57 and perforin. We found a highly differentiated phenotype, preferentially in active disease and among CD8+ T cells, consisting in increased numbers of late differentiated and terminal effector cells. Although this highly differentiated CD8+ T cell phenotype persisted after recovery, a clear increase of central memory cells was recorded for both T subsets at that point, suggesting signs of reversion toward a less differentiated profile. The composition of the B cell compartment was slightly modified during active disease. Herein wedocument the global impact of severe visceral leishmaniasis on immunological parameters, which tend to revert upon clinical recovery, suggesting signs of immune restoration accompanying clinical improvement. The evaluated parameters could eventually be used as biomarkers of clinical evolution of visceral leishmaniasis.

Linfoma linfoblástico cutáneo de células precursoras B: una presentación infrecuente de linfomas en niños / Cutaneous lymphoblastic lymphoma of precursor B cells: An infrequent presentation of lymphomas in children

Resumen Los linfomas linfoblásticos primarios cutáneos son una enfermedad infrecuente que ocurre predominantemente en la edad pediátrica y al momento del diagnóstico se presentan con lesiones cutáneas sin enfermedad sistèmica identificable. La enfermedad tiene un comportamiento agresivo y el tratamiento debe basarse en protocolos derivados de manejo de las leucemias linfoblásticas agudas con lo que se ha demostrado buenas tasas de supervivencia. Los autores presentan el caso de una niña con un linfoma linfoblástico de células precursoras B primario cutáneo localizado en cara manejado con protocolo basado en BFM para leucemias linfoblásticas con buena evolución.

Abstract Primary cutaneous lymphoblastic lymphomas are an infrequent disease that occurs predominantly in the pediatric age; and they present with cutaneous lesions without identifiable systemic disease at the time of diagnosis. The disease has an aggressive behavior and the treatment must be based on protocols derived from the management of acute lymphoblastic leukemia, which has shown good survival rates. The authors present the case of a girl with a lymphoblastic lymphoma of cutaneous primary precursor B cells localized on the face managed with a BFM-based protocol for lymphoblastic leukemia with good evolution.

Pénfigo vulgar refractario a tratamientos convencionales, con respuesta positiva a Rituximab: presentación de 5 casos / Positive Outcome in Treatment of Patients with Pemphigus Vulgaris Refractory to Conventional Treatments: A Report of Five Cases

Resumen El pénfigo vulgar es una enfermedad ampollar crónica de etiología autoinmune, en la cual el diagnóstico y tratamiento precoz disminuye la morbimortalidad de los pacientes. Actualmente se utilizan corticosteroides de primera línea asociados a inmunosupresores. Sin embargo,se ha visto que el uso de Rituximab como terapéutica de primera elección en los países desarrollados ha disminuido las reacciones adversas, con lo que mejora la calidad de vida de los pacientes. Se presentan cinco pacientes con diagnóstico de pénfigo vulgar refractario a tratamientos convencionalesque requirieron tratamiento con Rituximab.

Abstract Pemphigus vulgaris is an autoimmune chronic blistering disease. Its early diagnosis and treatment help reduce patient mortality and morbidity. Corticosteroids associated with immunosuppressants remain the standard treatment for pemphigus vulgaris. However, the use of Rituximab as first-line therapy in developed countries has been effective in reducing adverse effects improving the quality of life of patients. We report five patients with a diagnosis of pemphigus vulgaris refractory to conventional treatments requiring treatment with Rituximab.

Demencia Rápidamente Progresiva Como Manifestación De Recaída En Linfoma De Células Del Manto: Experiencia En Diagnóstico Y Tratamiento / Rapidly Progressive Dementia As A Manifestation Of Relapse In Mantle Cell Lymphoma: Experience In Diagnosis And Treatment

Resumen Introducción: La demencia rápidamente progresiva es una entidad que tiene una etiología múltiple y heterogénea. Se caracteriza por la alteración de dos o más dominios cognitivos en un periodo menor de 1 a 2 años. El compromiso del sistema nervioso central por el linfoma de células del manto es poco frecuente, de mal pronóstico y debuta principalmente en las fases tardías de la enfermedad como una recaída. Caso Clínico: Varón de 61 años con antecedente de linfoma de células del manto quien presenta una recaída asociada al sistema nervioso central que debuta como demencia rápidamente progresiva y se confirma por estudios de citometría de flujo en líquido cefalorraquídeo. Presenta una adecuada respuesta al manejo con un inhibidor de la tirosina quinasa (Ibrutinib), resolviendo la sintomatología clínica y los hallazgos imagenológicos. Discusión: El compromiso del sistema nervioso central secundario al linfoma de células del manto es una complicación poco frecuente y debuta como una recaída con manifestaciones clínicas variables que requieren de una intervención oportuna con el objetivo de mejorar la supervivencia del paciente. La terapia con un agente único como el Ibrutinib parece ser una buena opción en casos de refractariedad y compromiso neurológico.

Abstract Introduction: Rapidly progressive dementia is an entity that has a multiple and heterogeneous etiology. It is characterized by the alteration of two or more cognitive domains in a period of less than 1 to 2 years. The involvement of the central nervous system attributed to mantle cell lymphoma is rare with a poor prognosis and mainly debuts in the late stages of the disease as a relapse. Case Report: A 61-year-old male with a history of mantle cell lymphoma who presents a relapse of the central nervous system, given by a clinical course compatible with a rapidly progressive dementia and which is confirmed by flow cytometry studies in cerebrospinal fluid. It presents an adequate response to management with a tyrosine kinase inhibitor (Ibrutinib), resolving clinical symptoms and imaging findings. Discussion: The involvement of the central nervous system secondary to mantle cell lymphoma is a rare complication and debuts as a relapse with variable clinical manifestations that requires a timely intervention with the aim of improving patient survival. Therapy with a single agent such as Ibrutinib seems to be a good alternative in cases of refractoriness and neurological involvement.

Agammaglobulinemia ligada al cromosoma X, lo crucial del diagnóstico y tratamiento oportunos / Agammaglobulinemia linked to the X chromosome, the crucial of timely diagnosis and treatment

INTRODUCCIÓN. La Agammaglobulinemia ligada al cromosoma X es un tipo de inmunodeficiencia primaria originada por una mutación en el gen que codifica a la proteína responsable del proceso madurativo de los linfocitos B, provocando la disminución o ausencia de inmunoglobulinas en sangre periférica y la predisposición a procesos infecciosos a repetición, sobre todo a nivel del tracto respiratorio y digestivo. La sospecha clínica orienta la solicitud de pruebas complementarias de forma secuencial. El tratamiento consiste en la administración sustitutiva de por vida de inmunoglobulina humana. CASO CLÍNICO. Se presentó el caso de un niño de 8 años de edad con infecciones respiratorias altas y bajas a repetición, con estudios radiográficos de tórax que revelaron una atelectasia persistente, en quien la sospecha clínica dio paso a los evaluativos inmunológico y genético. RESULTADOS. El diagnóstico fue realizado a los 6 años de edad con recuento sérico de inmunoglobulinas por debajo del rango para la edad, citometría de flujo con CD19+ del 0,08% y genética con mutación del gen BTK. Se instauró tratamiento con Inmunoglobulina humana a 400 mg/Kg cada 4 semanas, se monitorizó los niveles de IgG antes de cada infusión. DISCUSIÓN. La Agammaglobulinemia ligada al cromosoma X constituye una enfermedad poco prevalente e infradiagnosticada en la que la sospecha clínica representa la base del abordaje, lo que permitió el tratamiento sustitutivo apropiado. CONCLUSIÓN. El diagnóstico y tratamiento oportunos permitieron evitar el desarrollo de infecciones respiratorias graves, mejorar la calidad de vida del niño y el asesoramiento genético familiar.

INTRODUCTION. X-linked Agammaglobulinemia is a type of primary immunodeficiency caused by a mutation in the gene that encodes the protein responsible for the maturation process of B lymphocytes, causing the decrease or absence of immunoglobulins in peripheral blood and the predisposition to repeated infectious processes, especially at the level of the respiratory and digestive tracts. Clinical suspicion guides the request for complementary tests sequentially. The treatment consists of lifelong substitute administration of human immunoglobulin. CASE REPORT. The case of an 8-year-old boy with repeated high and low respiratory infections was presented, with chest radiographic studies that revealed persistent atelectasis, in whom clinical suspicion gave way to immunological and genetic evaluations. RESULTS. The diagnosis was made at 6 years of age with serum immunoglobulin counts below the age range, flow cytometry with CD19 + of 0,08% and genetics with BTK gene mutation. Treatment with human Immunoglobulin at 400 mg / Kg every 4 weeks was initiated, IgG levels were monitored before each infusion. DISCUSSION. X- linked Agammaglobulinemia is a rare and underdiagnosed disease in which clinical suspicion represents the basis of the approach, which allowed for appropriate replacement. CONCLUSION. Timely diagnosis and treatment allowed to avoid the development of serious respiratory infections, improve de child ́s quality of life and family genetic couseling.

Abnormal expression of b10 cell frequencies: possible relation to pathogenesis and disease severity of aplastic anemia

SUMMARY OBJECTIVE: Aplastic anemia (AA) is an immune-mediated disease that destroys hematopoietic cells through activated T lymphocytes. B lymphocyte-mediated humoral immunity also plays an important role in the pathogenesis of AA. Regulatory B cell (Breg) subpopulation, which is defined as "B10", secretes interleukin 10 (IL-10). The objective of our experiment was to investigate whether the scale-down proportion of B10 cells in AA patients may play a key role in the pathogenesis. METHODS: A total of 38 AA patients (14 SAA patients and 24 NSAA patients) and 20 healthy control subjects were included. All subjects did not suffer from autoimmune diseases or any other diseases affecting the immune system, such as infectious diseases. Bone marrow mononuclear cells (PBMCs) were isolated and analyzed by Flow cytometry (FCM) and Immunofluorescence double-labeling assay. The relationship between the relative proportions of B10 and ProB10 and their associations to AA, as well as disease severity, were assessed by common clinical indicators and then examined. RESULTS: Our analyses revealed AA patients had significantly lower proportions of peripheral B10 and B10pro compared to healthy controls. SAA patients had a substantially lower percentage of B10 cells and B10pro cells compared to NSAA patients. In addition, B10 cells and B10pro cells were negatively correlated with absolute neutrophil counts, hemoglobin levels and platelet, and absolute reticulocyte counts in AA patients. CONCLUSIONS: The present study attempted to elucidate the potential role of the scale-down proportion of B10 cells in the pathogenesis of AA.

RESUMO OBJETIVO: A anemia aplástica (AA) é uma doença imunomediada que destrói células hematopoiéticas por meio dos linfócitos T ativados. A imunidade humoral mediada por linfócitos B também desempenha um papel importante na patogênese da AA. A subpopulação de células B reguladoras (Breg), que é definida como "B10", secreta interleucina 10 (IL-10). No experimento, investigou-se se a proporção reduzida de células B10 nos pacientes de AA pode desempenhar um papel-chave na patogênese. MÉTODOS: Um total de 38 pacientes de AA (14 pacientes de anemia aplástica grave e 24 pacientes de anemia aplástica não grave) e 20 indivíduos de controle saudáveis foram incluídos. Todos os indivíduos não sofriam de doenças autoimunes ou de quaisquer outras doenças que afetam o sistema imunológico, tais como doenças contagiosas. As células mononucleares da medula óssea (PBMCs) eram isoladas e analisadas por citometria de fluxo (FCM) e ensaio de dupla marcação por imunofluorescência. A relação entre as proporções relativas de células B10 e as células ProB10 e as suas associações à AA, assim como a gravidade da doença avaliada por indicadores clínicos comuns, foram examinadas. RESULTADOS: Nossas análises revelaram que os pacientes de AA têm proporções significativamente menores de células B10 e células ProB10 periféricas em comparação com indivíduos de controle saudáveis. Os pacientes de anemia aplástica grave tiveram uma percentagem substancialmente menor de células B10 e células B10pro em comparação com pacientes de anemia aplástica não grave. Além disso, as células B10 e B10pro foram negativamente correlacionadas com contagens absolutas de neutrófilos, níveis de hemoglobina e plaquetas e contagem de reticulócitos absolutos nos pacientes de AA. CONCLUSÕES: Além disso, o estudo presente tentou elucidar o papel imunorregulatório potencial das células B10 na patogênese da AA e fornecer uma nova estratégia para a aplicação de imunoterapia baseada na célula B para tratar a AA no futuro.

Evaluation of immunological parameters in pregnant women: low levels of B and NK cells / Avaliação dos parâmetros imunológicos em mulheres gestantes: baixos níveis de células B e NK

Abstract Objective To describe the immunological and hematological reference intervals of low-risk pregnant women. Methods A cross-sectional retrospective database analysis of a basic and translational study analyzing the hematological evaluation blood counts and immunophenotyping of TCD3 + , TCD4 + , TCD8 + , B, and natural killer (NK) cells of the peripheral blood in 79 low-risk pregnant women and of 30 control women from the state of Pernambuco, Brazil, was performed. Results No significant differences were detected between the hematological profiles of the 2nd and 3rd trimesters. Nevertheless, the median level of B cells decreased significantly in the 2nd (174 x 103 μL; p < 0.002) and 3rd trimesters (160 x 103 μL; p < 0.001), compared with the control group (296 x 103 μL). Similarly, the median level of NK cells was lower in the 2nd (134 x 103 μL; p < 0.0004) and 3rd trimesters (100 x 103 μL, p < 0.0004), compared with the control group (183 x 103 μL). In contrast, relative TCD4+ and TCD8+ levels increased in the 2nd and 3rd trimesters compared with the controls (TCD4 + : 2nd trimester = 59%; p < 0.001; 3rd trimester = 57%; p < 0.01; control = 50%; and TCD8 + : 2nd trimester = 31%; p < 0.001; 3rd trimester = 36%; p < 0.01; control = 24%). Conclusion Low-risk pregnant women have ~ 40% less B and NK cells in the peripheral blood, compared with non-pregnant women. These parameters may improve health assistance for mothers and contribute to define reference values for normal pregnancies.

Resumo Objetivo Descrever o intervalo de referência imunológico e hematológico de gestantes de baixo risco. Métodos Realizou-se uma análise retrospectiva, de um estudo básico e translacional, analisando o perfil hematológico e a imunofenotipagem das células TCD3 + , TCD4 + , TCD8 + , B e natural killer (NK) do sangue periférico de 79 gestantes de baixo risco e de 30 mulheres (controles) do estado de Pernambuco, Brasil. Resultados Não observamos diferenças significativas entre os perfis hematológicos do 2° e 3° trimestres. No entanto, houve redução das células B no 2° (média = 174 x 103 μL; p < 0,002) e no 3° trimestres (160 x 103 μL; p < 0,001), comparado como grupo controle (296 x 103 μL). A mediana das células NK foi menor no 2° (134 x 103 μL; p < 0,0004) e no 3° trimestres (100 x 103 μL; p < 0,0004), comparado com o grupo controle (183 x 103 μL). Porém, o percentual de TCD4+ e de TCD8+ aumentou no 2° e 3° trimestres em relação aos controles (TCD4 + : 2° trimestre = 59%; p < 0,001; 3° trimestre = 57%; p < 0,01; controle = 50%; e TCD8 + : 2° trimestre = 31%; p < 0,001; 3° trimestre = 36%; p < 0,01; controle = 24%). Conclusão Mulheres grávidas de baixo risco têm ~ 40% menos células B e NK no sangue periférico em comparação com mulheres não grávidas. Estes parâmetros podem melhorar a assistência à saúde das mães e contribuir para a definição de valores de referência para gestações normais.

El caseinato de sodio incrementa número de linfocitos B en ratones / Sodium caseinate increases the number of B lymphocytes in mouse

Introducción. El caseinato de sodio, una sal de la caseína utilizada como agente proinflamatorio en ratones, es capaz de inducir granulopoyesis en vivo e incrementar la producción de citocinas esenciales en dicho evento. Objetivo. Evaluar si el caseinato de sodio es capaz de inducir un efecto biológico en células de origen linfoide y la producción de citocinas involucradas con este linaje. Materiales y métodos: Se utilizaron ratones hembra BALB/c de 8 a 12 semanas de edad. Los animales se inyectaron cuatro veces, con intervalos de 48 horas, por vía intraperitoneal con 1 ml de caseinato de sodio (10 % de SFB p/v). La población de linfocitos B y la incorporación de bromodesoxiuridina (BrdU) se analizaron mediante citometría de flujo. La detección de la interleucina 7 se evaluó mediante la técnica de ELISA. Resultados. Tras la inyección por vía intraperitoneal, el número de linfocitos B 220+ provenientes del bazo de ratones tratados con caseinato de sodio aumentó comparados con los que solo recibieron el vehículo como tratamiento (89,01±1,03 Vs. 75,66±2,08), así como la incorporación de BrdU en células B220+ (38,59±4,48 Vs. 11,82±1,04). Se evidenció, asimismo, el incremento en la concentración de la interleucina 7 (IL-7) en el suero de los ratones tratados con caseinato de sodio, comparados con los que solo recibieron el vehículo (62,1±17,5 Vs. 26,9±4,4 pg/ml). Conclusión. El caseinato de sodio fue capaz de aumentar el número de linfocitos B en bazo de ratones, así como inducir la producción de IL-7, citocina clave para la linfopoyesis B.

Introduction: Sodium caseinate, a casein salt, is a proinflammatory agent in mice, and it is able to induce granulopoiesis in vivo and to increase the production of cytokines, which is key for this biological process. Objective: To assess whether sodium caseinate is able to induce a biological effect on cells from lymphoid origin and the production of cytokines involved in this lineage in vivo. Materials and methods: We used female BALB /c mice from 8 to 12 weeks old. The animals were injected intraperitoneally (IP) with 1 ml of sodium caseinate (10% PBS w/v) four times every 48 hours. The B cell populations and the incorporation of BrdU were analyzed by flow cytometry. Detection of interleukin-7 was assessed by ELISA (Enzyme-Linked ImmunoSorbent Assay). Results: We established that after intraperitoneal injection, the number of B lymphocytes 220+ from the spleen of mice treated with sodium caseinate increased compared to those that only received the vehicle (89.01±1.03 vs 75.66 ± 2.08), and the same was observed with the incorporation of BrdU in B220 + cells (38.59±4.48 vs 11.82±1.04 respectively). We also established that the concentration of interleukin-7 (IL-7) in the serum of mice treated with sodium caseinate increased compared to those that only received the vehicle (62.1 ± 17.5 vs 26.9 ± 4.4 pg/ml). Conclusion: Sodium caseinate was able to increase the number of B lymphocytes in the spleen; it also induced IL-7 production, a cytokine that is key for the B cell lymphopoiesis.

Mecanismos da imunoterapia alérgeno-específica / Mechanisms of allergen-specific immunotherapy

A imunoterapia alérgeno-específica tem sido usada há mais de 100 anos como um tratamento de dessensibilização para doenças alérgicas, representando um método potencialmente curativo e específico. O presente estudo tem como objetivo revisar os mecanismos da imunoterapia alérgeno-específica, através de revisão bibliográfica com base em artigos publicados entre 1998 e 2016, disponíveis no banco de dados PubMed. Os mecanismos de ação da imunoterapia incluem modulação de linfócitos T e B, produção de IgG4 alérgeno-específica e redução de IgE alérgenoespecífica, migração de eosinófilos, basófilos e mastócitos nos tecidos, bem como a liberação de seus mediadores. As células T reguladoras (Treg) suprimem as células dendríticas responsáveis pela geração de células T efetoras, inibindo TH1, TH2 e TH17. As células Treg foram identificadas como peças-chave no processo de indução de tolerância periférica aos alérgenos.

Allergen-specific immunotherapy has been used for more than 100 years as a desensitizing therapy for allergic diseases, representing a potentially curative and specific method. The aim of the present study was to review the mechanisms of allergenspecific immunotherapy based on papers published between 1998 and 2016 and available in the PubMed database. The mechanisms of action of immunotherapy include modulation of T-and B-cell responses, induction of allergen-specific IgG4 and suppression of allergen-specific IgE production, migration of eosinophils, basophils, and mast cells to tissues, as well as release of their mediators. Regulatory T cells (Treg) suppress dendritic cells that support the generation of effector T cells, inhibiting TH1, TH2, and TH17 cells. Treg cells have been identified as key regulators of the induction process of peripheral allergen tolerance.

Small clonal B-cell population in the bone marrow as a possible tool in the diagnosis of occult primary parotid lymphoma / Pequeña población de células B monoclonales en medula ósea como posible herramienta diagnóstica en el linfoma oculto primario de parótida

Case Description: An 82-years old Hispanic woman with a past medical history significant for pulmonary thromboembolism on oral anticoagulation, rheumatoid arthritis, and hypertension developed a new onset thrombocytopenia. Clinical Findings: Small clonal B-cells populations (SCBP) also known as monoclonal B-cell lymphocytosis was found as part of the workup for an idiopathic thrombocytopenia and lead ultimately to the diagnosis of parotid primary follicular lymphoma coexisting with Warthin tumor involving the bone marrow in a small extent and oncocytic papilloma located in the maxillary sinus. Treatment and Outcome: Patient was treated with Rituximab monotherapy with improvement on her platelet count. Clinical relevance: Although it is unclear the role of this clonal cells, they may work as a possible diagnostic tool for occult lymphomas. Further prospective studies are needed to confirm this possible association.

Descripción de caso: Mujer hispana de 82 años con una historia médica significativa de tromboembolismo pulmonar en anticoagulación, artritis reumatoide e hipertensión, la cual desarrolló recientemente una trombocitopenia. Hallazgos clínicos: Una pequeña población de células B monoclonales también conocida como linfocitosis monoclonal de células B fue encontrado dentro del estudio de una trombocitopenia idiopática que conllevó al diagnóstico de un linfoma folicular primario de parótida coexistiendo con un tumor de Warthin y un papiloma oncocítico localizado en el seno maxilar. Tratamiento y resultado: La paciente fue tratada con monoterapia de Rituximab con una mejoría en su conteo de plaquetas. Relevancia clínica: Aunque el rol de las pequeñas poblaciones B monoclonales no está completamente dilucidado, podrían tener una aplicación como herramienta diagnóstica. Futuros estudios prospectivos son necesarios para confirmar esta posible asociación.

Inmunodeficiencia común variable: caracterización clínica e inmunológica de pacientes e identificación de subgrupos homogéneos con base en la tipificación de subpoblaciones de linfocitos B / Common variable immunodeficiency: Clinical and immunological characterization of patients and homogeneous subgroup definition by means of B lymphocyte subpopulation typing

Introducción. La inmunodeficiencia común variable es un síndrome heterogéneo caracterizado por infecciones recurrentes, hipogammaglobulinemia y producción deficiente de anticuerpos específicos. Las anormalidades en subpoblaciones de linfocitos en sangre periférica, particularmente de linfocitos B, permiten la clasificación de los pacientes en grupos homogéneos. Objetivo. Caracterizar clínica e inmunológicamente los linfocitos B y tipificar sus subpoblaciones en doce pacientes colombianos con inmunodeficiencia común variable, para clasificarlos en grupos homogéneos. Materiales y métodos. Se revisaron las historias clínicas de los pacientes y se evaluaron las inmunoglobulinas séricas, la proliferación de linfocitos y la hipersensibilidad retardada, así como las subpoblaciones de linfocitos y de linfocitos B mediante citometría de flujo. Resultados. Todos los pacientes presentaron infecciones respiratorias o gastrointestinales recurrentes y, algunos, infecciones en otros sistemas. Además, todos presentaban disminución de la IgG, en tanto que la IgA y la IgM fueron bajas en nueve y diez pacientes, respectivamente. En todos hubo disminución de la proliferación de linfocitos inducida por mitógenos, pero fue normal frente a antígenos específicos. La tipificación de subpoblaciones reveló valores elevados de linfocitos T en tres pacientes; siete presentaron disminución en la relación CD4+/CD8+ y, cuatro, linfocitos NK bajos. El conteo de linfocitos B fue normal en once pacientes, ocho de los cuales presentaron linfocitos B de memoria bajos, en tanto que cuatro presentaron aumento de linfocitos B de transición o de linfocitos B CD21 low . Conclusión. La tipificación de subpoblaciones de linfocitos solo permitió asignar a 11 de los pacientes a grupos homogéneos según los esquemas de clasificación internacionales, lo que indica la necesidad de agregar más criterios hasta lograr una clasificación ideal. Este estudio permitirá establecer mejores seguimientos médicos para pacientes con inmunodeficiencia común variable en grupos con alto riesgo de desarrollar complicaciones clínicas.

Introduction: Common variable immunodeficiency is a heterogeneous syndrome characterized by recurrent infections, hypogammaglobulinemia and defective production of specific antibodies. Abnormalities in peripheral blood lymphocyte subpopulations, in particular of B lymphocytes, allow the classification of patients into homogeneous groups. Objective: To perform a clinical and immunological characterization and to evaluate lymphocyte subpopulations of twelve Colombian patients with common variable immunodeficiency in order to define homogeneous groups. Materials and methods: We reviewed medical records and evaluated serum immunoglobulins (Ig), lymphoproliferation, delayed hypersensitivity and used flow cytometry to quantify peripheral blood total lymphocyte and B cell populations. Results: All patients had recurrent respiratory and/or gastrointestinal infections, while some also had infections affecting other systems. All patients had abnormally low serum IgG levels, while IgA and IgM levels were reduced in nine and ten patients, respectively. Lymphoproliferation to mitogen was lower in patients than in healthy controls but lymphoproliferation to specific antigen was normal in all. Flow cytometry revealed high numbers of T cells in three patients, while seven had a low CD4+/CD8+ ratio and four had reduced NK cells . Eleven patients had normal B cell counts, and eight of them also showed decreased memory B lymphocytes, and four had increased transitional or CD21 low B lymphocytes. Conclusion: Lymphocyte typing allowed assigning all but one patient to homogeneous groups according to international classification schemes, indicating the necessity of including more criteria until an ideal classification is achieved. This study will lead to a better medical monitoring of common variable immunodeficiency patients in groups at high risk of developing clinical complications.

IgE sérica e IgA salival, total y específica para Dermatophagoides pteronyssinus y subpoblaciones leucocitarias en niños atópicos y no atópicos con asma y/o rinitis / Total and Dermatophagoides pteronyssinus specific IgE and salivary IgA and leukocyte populations in atopic and nonatopic children with asthma and/or rhinitis

Objetivo. Investigar inmunológicamente niños con problemas respiratorios de asma y/o rinitis (atópicos o no atópicos) en la búsqueda de evidencias que permitan una mejor comprensión del desbalance que padecen estos niños en su sistema inmune. Materiales y métodos. Se estudiaron 47 niños de ambos sexos, con edades comprendidas entre los 6 y 15 años, que concurrieron a la consulta por afecciones respiratorias compatibles con asma y/o rinitis a la División de Alergia e Inmunología del Hospital de Niños de la Santísima Trinidad de la Ciudad de Córdoba. Según la información obtenida en la anamnesis, examen físico y prick tests, fueron divididos en dos grupos: atópicos (n=25) y no atópicos (n=22). Luego que los padres firmaron el consentimiento informado y los niños mayores a 7 años dieron su asentimiento para participar del trabajo de investigación, se tomaron muestras de sangre y saliva, para determinar concentración y actividad específica en inmunoglobulinas (Igs) así como estudiar poblaciones leucocitarias y subpoblaciones linfocitarias. Resultados. Como era previsible, los niveles de IgE sérica total y los porcentajes relativos de eosinófilos sanguíneos se mostraron significativamente elevados en el grupo de los niños atópicos (A) con respecto a los no atópicos (NA). El estudio de IgE sérica específica para Dermatophagoides pteronyssinus solo arrojó resultados positivos en los pacientes A y se observó una correlación significativa entre los niveles de IgE total y específica para dicho alérgeno, y entre los niveles de prick y RAST. Los niveles séricos de IgG e IgA no demostraron diferencias de significación entre ambos grupos. El estudio de la IgA salival (IgAs) total permitió observar en el grupo de los niños NA concentraciones significativamente mayores que las correspondientes al grupo de pacientes A. Sin embargo, al estudiar la IgAs específica para el D. pteronyssinus, se observó lo inverso: los pacientes A tienen casi el doble de IgAs específica para el alérgeno respecto del grupo NA. En el estudio de subpoblaciones de células T (CD3, CD4 y CD8), no se observaron diferencias significativas entre ambos grupos. Las subpoblaciones de linfocitos B CD27-y linfocitos B CD27+ tuvieron valores similares en ambos grupos (aproximadamente 80% y 20%, respectivamente). En ambos grupos, alrededor de un 50% de los linfocitos B CD27+ expresaron IgD y el 50% restante fueron IgD­. Sin embargo, el grupo de niños A tuvo dos veces menos de linfocitos B que expresan alta densidad de la molécula CD27 (CD27+++) con respecto a los niños NA (p=0,044). Conclusión. Entre los parámetros inmunológicos investigados encontramos diferencias significativas entre niños A y NA en las concentraciones totales y específicas para el D. pteronyssinus en los isotipos de IgE e IgAs, y en una subpoblación de linfocitos B CD27+++. Dichos hallazgos son analizados en la discusión del manuscrito. (AU)

Purpose. To perform an immunologically investigation in children with respiratory problems of asthma and/or rhinitis (atopic or non atopic) in order to get a better understanding of the immune system imbalance in these patients. Materials and methods. 47 children of both sexes, aged between 6 and 15 years, who were attended for respiratory diseases at the Division of Allergy and Immunology at Children's Hospital de la Santísima Trinidad from Córdoba city were studied. According to information obtained on clinical history, physical examination and prick tests they were divided into two groups: Atopics (n=25) and non-atopic (n=22). After parents signed informed consent and children over 7 years assent to participate in the research work, samples of blood and saliva were taken to determine immune globulins concentrations and specific activities as well as to study leukocyte populations and lymphocytes subpopulations. Results. As expected, levels of total serum IgE and the relative percentages of blood eosinophils were significantly higher in the group of atopic (A) children with regard to non¬atopic (NA) children. The study of specific serum IgE for Dermatophagoides pteronissynus only showed positive results in the A group, and positive correlations between the levels of total and specific IgE, as well as prick and RAST values. Serum IgG and IgA levels showed no significant differences between both groups. Total salivary IgA concentrations were significantly higher in the group of NA children than in the group of A patients. Surprisingly, when specific salivary IgA for D. pteronyssinus was studied, the opposite was observed: Atopic patients have nearly twice specific salivary IgA for this allergen than the NA children. In the study of T cells subpopulations (CD3, CD4 and CD8), no significant differences between groups were observed. The subpopulations of CD27-B cells and CD27+ B cells were similar in both groups (roughly 80% and 20%, respectively). In both groups, approximately 50% of CD27+ B cells expressed IgD and the remaining 50% were IgD­. However, atopic children had less than half B cells expressing high density of CD27 molecule (CD27+++) with respect to the NA children (p=0.044). Conclusion: Among the immunological parameters investigated, we found significant differences between A and NA children in the concentrations of total and specific IgE and salivary IgA to the allergen, and in a subpopulation of CD27+++ B cells. These findings are debated in the discussion of the manuscript(AU)

Waldenström's macroglobulinemia - a review / Macroglobulinemia de Waldenström - uma revisão

Waldenström's macroglobulinemia (WM) is a lymphoproliferative disease of B lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone marrow and by IgM monoclonal hypergammaglobulinemia. It was first described in 1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and serum viscosity, normal radiography and bone marrow infiltrated by lymphoid cells. The WM is a rare disease with a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. Most patients have clinical signs and symptoms related to hyperviscosity resulting from IgM monoclonal gammopathy, and/or cytopenias resulting from bone marrow infiltration by lymphoma. The differential diagnosis with other lymphomas is essential for the assessment of prognosis and therapeutic approach. Treatment of patients with asymptomatic WM does not improve the quality of life of patients, or increase their survival, being recommended, therefore, their follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used. However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising results with bortezomib, an inhibitor of proteasomes, and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may be indicated. The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical manifestations, diagnosis, prognosis and treatment.

A macroglobulinemia de Waldenström (MW) é uma doença linfoproliferativa dos linfócitos B, caracterizada por um linfoma linfoplasmocítico na medula óssea e por hipergamaglobulinemia monoclonal de tipo IgM. Foi descrita pela primeira vez em 1944, por Jan Gösta Waldenström, que descreveu dois doentes com hemorragia oronasal, adenopatias, anemia, trombocitopenia, velocidade de sedimentação eritrocitária e viscosidade sérica elevadas, radiografia óssea normal e medula óssea infiltrada por células linfoides. A MW é uma doença rara com um percurso clínico normalmente indolente, atingindo principalmente os indivíduos com idades entre 63 e 68 anos. A maioria dos doentes apresenta sintomas e manifestações clínicas relacionadas com a hiperviscosidade, resultante da gamopatia monoclonal IgM e/ou com as citopenias, resultantes da infiltração medular pelo linfoma. O diagnóstico diferencial com outros linfomas é essencial para a avaliação do prognóstico e a abordagem terapêutica. O tratamento dos doentes com MW assintomática não melhora a qualidade de vida do doente nem aumenta a sua sobrevivência, recomendando-se o acompanhamento clínico. Para o tratamento dos doentes sintomáticos, são usados agentes alquilantes, análogos das purinas e anticorpos monoclonais anti-CD20. No entanto, a doença é incurável e a resposta à terapêutica nem sempre é favorável. Estudos relativamente recentes mostram resultados promissores com o bortezomibe, um inibidor dos proteossomas, e alguns doentes respondem à talidomida. Nos doentes com recidivas ou refratários à terapêutica, pode-se indicar o transplante autólogo. O objetivo deste trabalho é descrever, de forma detalhada, o conhecimento atual sobre a fisiopatologia da MW, as principais manifestações clínicas, o diagnóstico, o prognóstico e o tratamento.

Doença de Castleman multicêntrica não associada aos vírus HHV-8 e HIV / Multicentric Castleman disease not associated with HHV-8 and HIV viruses

A doença de Castleman (DC) é uma desordem linfoproliferativa policlonal, também conhecida como hiperplasia nodular gigante ou hiperplasia angiofolicular linfoide. Esta é uma doença rara que está frequentemente associada ao vírus da imunodeficiência humana (HIV) e ao herpes vírus 8 (HHV-8). Os achados histopatológicos encontrados na DC sugerem uma intensa resposta aos estímulos antigênicos observada em várias doenças associadas com ativação imune, como a artrite reumatoide. Um fator importante implicado na patogênese da DC é a produção autônoma da interleucina-6 (IL-6). Nessa doença, as manifestações clínicas estão relacionadas aos níveis de IL-6, e a remoção cirúrgica dos linfonodos acometidos ou a utilização de anticorpos anti-IL-6 fazem regredir os sintomas. Descrevemos um caso da DC multicêntrica em uma mulher jovem, não associada à infecção pelo vírus HHV-8 ou à imunossupressão. Uma breve revisão da literatura se segue à descrição do caso clínico.

Castleman's disease (CD) is a polyclonal lymphoproliferative disorder also known as giant nodular hyperplasia or angiofollicular lymph node hyperplasia. It is a rare disease often associated to human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8). Histopathological findings in Castleman's disease suggest an exaggerated response to antigenic stimuli seen in other diseases associated with immune activation, such as rheumatoid arthritis. An important aspect of its pathogenesis is the autonomous production of interleukin-6 (IL-6). In this disease, the clinical manifestations are associated to IL-6 serum levels, and surgical removal of the compromised lymph nodes or use of anti-IL-6 antibodies can slow down the symptoms. We describe a multicentric Castleman's disease in a young woman not associated to HHV-8 virus infection or immunosuppression. A short review of the literature follows the description of this clinical case.