Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia patients after clearance of HCV viremia with direct-acting antivirals

Introduction Type II Mixed cryoglobulinemia (MC) is an autoimmune and benign lymphoproliferative disorder caused by Hepatitis C virus (HCV) and characterized by the expansion of monoclonal CD27+ IgM+ B cells producing a rheumatoid factor often encoded by the VH1-69 and VK3-20 genes. These cells display peculiar phenotypic and functional features: in particular, they commonly express low levels of CD21 (CD21low B cells), an array of inhibitory and apoptosis-related genes and a distinctive pattern of homing receptors, fail to proliferate in response to the stimulation of BCR or of TLR9 and, similarly to murine B cells made anergic by continual antigenic stimulation, overexpress pERK and are prone to apoptosis. Usually MC regresses after eradication of HCV with interferon (IFN), whose immunomodulatory activity might contribute to this effect; the newly available direct-acting antivirals (DAAs) rapidly suppress HCV viremia in HCV+MC patients and lack the immunomodulatory properties of IFN. Aim To investigate phenotypic and functional changes in clonal B cells of MC patients with sustained virologic response to DAAs, untangling the effects of BCR disengagement in a human model of virus-driven anergy and exhaustion. Results In patients treated with DAA, B cell phenotype, constitutive and BCR-induced ERK signaling, spontaneous apoptosis and cell proliferation were analyzed before and after HCV eradication, using healthy donors as control. Immunophenotyping studies were performed with combinations of fluorochrome-labeled monoclonal antibodies, using the VH1-69-specific G6 mAb (which recognize an epitope of the VH1-69-encoded protein) to identify VH1-69+ B cells; spontaneous apoptosis was assessed by staining cells with annexin V and 7- aminoactinomycin D; the intracellular pERK content was measured by the BD PhosFlow system and represented as pERK-specific Mean Fluorescence Intensity (MFI); finally, cell proliferation was evaluated at day 5 of in vitro culture by the carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay. All these experiments have been done by flow cytometry. Phenotypic and functional analyses in untreated patients were in agreement with previous data showing an anergic status and an exhausted behavior of VH1-69+ CD21low B cells. After treatment with DAA, when all patients were negative for HCV RNA, it was observed a slow reduction of VH1-69+ CD21low B cells in peripheral blood; moreover, these cells showed a significantly reduced constitutive ERK phosphorylation and a significative decrease in spontaneous apoptosis after eradication of the virus. To investigate whether reduced lifespan was related to ERK signaling, MC B cells were treated with the MEK/ERK inhibitor U0126; no effect on spontaneous in vitro apoptosis was observed, suggesting that ERK signaling is not directly involved in the pro-apoptotic pathway of these cells. Despite phenotypic changes, clonal B cells failed to restore their capacity to proliferate in response to TLR9 stimulation. Conclusions Clonal B cells of HCV+MC display signatures of anergy induced by continual BCR occupancy and of exhaustion driven by chronic viral infection. Anergy features (pERK overexpression and accelerated apoptosis) rapidly revert after disengagement from HCV; phenotypic and functional features of exhaustion persist for several months. The rapid clearance of HCV viremia with DAAs offers a unique model for untangling the interplay of virus-driven anergy and exhaustion in human B cells

A Sublimação Como Finalidade do Trabalho em Saúde Mental

Faz-se a articulação entre o material bibliográfico psicanalítico referente à sublimação e experiências já publicadas da prática em instituições de saúde mental, que utilizam recursos artísticos no plano terapêutico dos pacientes atendidos. Pôde-se constatar que a sublimação tem sido compreendida na teoria como objetivo do processo de análise, visto que possibilita novas construções simbólicas ao sujeito que se encontra em sofrimento psíquico. A utilização de recursos artísticos nos atendimentos de saúde mental, quando imbuídos de boa sustentação teórica e do desejo dos profissionais atuantes, tem trazido resultados interessantes, no que diz respeito à retificação do posicionamento subjetivo de alguns pacientes

Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia.

Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of IgM+CD27+ B cells. These cells display both the features of anergy induced by continual engagement of the B cell receptor (BCR), such as high expression of phosphorylated extracellular signal regulated kinase (pERK) and reduced lifespan, and of virus-specific exhaustion such as CD21low phenotype and defective response to ligation of BCR and Toll-like receptor 9 (TLR9). Usually MC regresses after eradication of HCV with interferon, whose immunomodulatory activity might contribute to this effect. We investigated phenotypic and functional changes in clonal B cells of MC patients with sustained virologic responses to direct-acting antivirals (DAA), which lack immunomodulatory properties. We found that high pERK expression and accelerated apoptosis revert within 4 weeks after beginning therapy, whereas clonal B cells unresponsive to TLR9 stimulation persist for at least 24 weeks although they may partially rescue normal CD21 expression. Thus, similar to mouse models, features of anergy in MC B cells rapidly revert after disengagement from HCV, whereas virus-specific exhaustion imparts a durable inhibitory imprint on cell function. Treatment of HCV+ MC with DAA provides a valuable tool for untangling the molecular mechanisms of anergy and exhaustion in human B cells

O Silêncio na primeira tópica freudiana

Orientadora: Prof.a. Dra. Nadja Nara Barbosa PinheiroDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Humanas, Programa de Pós-Graduação em Psicologia. Defesa : Curitiba, 29/03/2019Inclui referências: p.98-106Resumo: A percepção de que o silêncio pode ser inquietante surgiu no âmbito da clínica musicoterapêutica, sustentada pela teoria psicanalítica. Assim, esta pesquisa se desenrola em torno da questão 'o que faz com que algumas vezes seja difícil sustentar o silêncio?'. Para tanto, tivemos como referência o método de pesquisa em psicanálise, que nos remeteu aos textos freudianos, para melhor entendermos o que nomeamos como 'natureza árdua do silêncio'. O ponto de partida da dissertação foi a apresentação da musicoterapia, com seus entrelaçamentos epistemológicos e, especificamente, da orientação da teoria psicanalítica para esta prática terapêutica. Pudemos notar que a musicoterapia com frequência se fundamenta sob o respaldo da combinação de mais de uma vertente teórica. Os textos pesquisados que se sustentam na teoria psicanalítica, apesar de apresentarem diferenças de leitura entre si, contemplam, também, características em comum, tal como o entendimento de que há similaridades entre os processos inconscientes e as manifestações sonoro-musicais. A imersão nos textos freudianos se deu com a realização de um estudo longitudinal que buscou conhecer as ocorrências do termo 'silêncio' e seus derivados na obra deste autor, bem como de situar cada uma delas com relação a noções e conceitos da psicanálise, ou a outras categorias. Com este estudo, localizamos que, diversas vezes, Freud fez uso da palavra 'silêncio' em analogia à repressão e à pulsão de morte, conceitos que, como hipótese, estariam ligados aos aspectos inquietantes do silêncio percebidos na clínica. A delimitação desta pesquisa na primeira tópica freudiana se mostrou pertinente à formação acadêmica e profissional da autora e, com os resultados do estudo longitudinal, decidimos iluminar a articulação entre silêncio e defesa, e silêncio e repressão. A pesquisa sobre a noção de defesa, centrada nos textos iniciais de Freud, propiciou que levantássemos a seguinte hipótese: mesmo quando se dá a operação de defesa, afastando os representantes ideativos inassimiláveis ao ego da consciência, o afeto permanece imutável e, portanto, não silenciado. Ou seja, o afeto seria o que não pode ser silenciado. Na sequência, o estudo da noção de repressão e seu uso em analogia ao silêncio, já no contexto da primeira tópica freudiana, permitiram que chegássemos a considerações parcialmente diferentes da anterior. Dos três tipos de neurose discutidos pelo autor no texto Repressão (1915d), dois deles indicavam que, com a operação de repressão, em que representantes ideativos são forçados a se manterem no inconsciente, os afetos permaneciam idênticos a si mesmos. Nesses casos, a hipótese de que o afeto é o que não pode ser silenciado se confirmaria, pois em ambos os casos restaria a angústia. Mas em outro tipo de neurose, a histeria de conversão, o afeto seria completamente silenciado. Sobre este tipo de neurose, permaneceram em aberto algumas indagações, instigadas tanto pelo texto freudiano, quanto pela clínica. Sobre a analogia do silêncio com a repressão, entendemos que se dá sempre contemplando um paradoxo. Pois ao mesmo tempo em que a repressão remete ao silenciamento de moções inaceitáveis para o ego, o reprimido que tenta retornar provoca efeitos ruidosos ao paciente. Trata-se, então, de uma operação sempre mal resolvida, já que este silenciamento parcial tenderá a caminhar lado a lado com a angústia. Palavras-chave: Silêncio. Repressão. Defesa. Afeto. Musicoterapia.Abstract: The perception that silence can be disquieting arose within the scope of the clinic Music Therapy, supported by the Psychoanalytic Theory. Thus, this research takes place around the question 'what makes it difficult to sometimes sustain the silence?'. For that, we had as reference the Psychoanalysis method of research - which referred us to the Freudian texts - to better understand what we call the 'arduous nature of silence'. The starting point of the dissertation was the presentation of Music Therapy, with its epistemological interlacings and, specifically, the orientation of Psychoanalytic theory to this therapeutic practice. We have noted that Music Therapy is often based on the combination of more than one theoretical aspect. The researched texts that are based on Psychoanalytic theory, although presenting differences of reading among themselves, also contemplate common characteristics, such as the understanding that there are similarities between the unconscious processes and the sonorous-musical manifestations. The immersion in the Freudian texts occurred with the realization of a longitudinal study that sought to know the occurrences of the term 'silence' and its derivatives in the work of this author, as well as to situate each of them in relation to notions and concepts of Psychoanalysis, or other categories. With this study we have observed that on several occasions, Freud used the word 'silence' in analogy to repression and death instinct. These concepts, as hypothesis, would be related to the inquieting aspects of the silence perceived in the clinic. The delimitation of this research in the first Freudian topical was pertinent to the author's academic and professional background and, with the results of the longitudinal study, we decided to illuminate the articulation between silence and defense, and silence and repression. The research on the notion of defense, centered on the initial texts of Freud, gave rise to the following hypothesis: even when the defense operation is carried out, distancing the ideal representatives that cannot be assimilated to the ego of consciousness, the affect remains unchanged and, therefore, muted. Hence, affect would be what cannot be silenced. The study of the notion of repression and its use in analogy to silence, already in the context of the first Freudian topical, allowed us to arrive at partially different considerations from the previous one. Of the three types of neurosis discussed by the author in the text "Repression" (1915d), two of them indicated that with the repressive operation, in which ideational representatives are forced to remain in the unconscious, the affects remained identical to themselves. In these cases, the hypothesis that affect is what cannot be silenced would be confirmed, since in both cases the anxiety would remain. But in another kind of neurosis, the conversion hysteria, the affect would be completely muted. On this type of neurosis, some questions remained open, instigated by both the Freudian and the clinical texts. On the analogy of silence with repression, we understand that it is always contemplating a paradox. For while repression refers to the silencing of motions unacceptable to the ego, the repressed who tries to return causes noisy effects to the patient. It is, then, an operation always badly resolved, since this partial silencing will tend to walk side by side with anxiety. Keywords: Silence. Repression. Defense. Affect. Music Therapy

¿Qué es canto gregoriano? : Su naturaleza è historia

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2009-201