Osteomielite maxilar associada ao COVID-19: mucormicose ou não? Uma série de casos / Maxillary osteomyelitis associated with COVID-19: mucormycosis or not? A series of cases

Aim: A series of cases have been presented involving the oral cavity focusing on the presentation, diagnosis and treatment of mucormycosis that can form a basis for successful therapy. Background: The management of severe coronavirus disease (COVID-19) in conjunction with comorbidities such as diabetes mellitus, hematological malignancies, organ transplants, and immunosuppression have led to a rise of mucormycosis which is an opportunistic infection. Cases Description: The various forms that have been enlisted till date are rhino-cerebral, rhino-orbital, gastrointestinal, cutaneous, and disseminated mucormycosis. From the dentistry and maxillofacial surgery perspective, the cases depicting extension of mucormycosis into the oral cavity have been less frequently recorded and thus, require a detailed study. The patients that reported to our private practice had non-tender swelling, draining sinuses and mobility of teeth. A similarity was observed in the clinical signs both in osteomyelitis and mucormycosis. Thus, a histopathological examination was used to establish the definitive diagnosis. Conclusion: Mucormycosis is a life threatening pathology that requires intervention by other branches to make an early diagnosis and commence the treatment. The characteristic ulceration or necrosis is often absent in the initial stage and thus, histopathological examination and radiographic assessment are required to formulate a definitive diagnosis. Early intervention is a necessity to avoid morbidity. The treatment involves surgical debridement of the necrotic infected tissue followed by systemic antifungal therapy. Mucormycosis has recently seen a spike in its prevalence, post the second-wave of coronavirus pandemic in India. It was seen commonly in patients with compromised immunity, diabetes mellitus, hematological malignancies, or on corticosteroid therapy. Mucormycosis invading the palate mostly via maxillary sinus has been less frequently described. In the post-COVID era the features associated with mucormycosis involving oral cavity, should warrant a possible differential diagnosis and managed appropriately. (AU)

Objetivo: Apresentar uma série de casos com enfâse na apresentação, diagnóstico e tratamento da mucormicose oral, assim como uma revisão sistemática que sirva como base para estabelecimento de terapias de sucesso. Introdução: A forma severa da infecção por coronavirus (COVID-19) associada a diabetes mellitus, doenças hematológicas malignas, transplante de órgãos e imunossupressão levaram a um aumento das infecções oportunistas de mucormicose. Descrição dos Casos: As diversas apresentações clínicas que foram descritas até o momento são a rinocerebral, rino-orbital, gastrointestinal, cutânea e mucormicose disseminada. No que concerne a odontologia e a cirurgia maxillofacial, os casos que apresentam extensão de mucormicose para cavidade oral tem sido menos reportados e assim requerem mais estudos. Os pacientes que compareceram a nossa clínica apresentavam aumento de volume endurecido, drenagem de fluidos dos seios maxilares e mobilidade dentária. Clinicamente tanto a osteomielite quanto a mucormicose apresentaram-se de forma semelhante. Assim, análise histopatológica foi utilizada para estabelecimento do diagnóstico definitivo. Conclusão: A mucormicose é uma patologia grave que requer intervenção precoce para estabelecimento do tratamento. A ulceração e necrose características usualmente estão ausentes nos estágios iniciais da lesão, assim análise histopatológica e radiográfica são necessárias para o diagnóstico final. Intervenção precoce é necessária para diminuir a morbidade. O tratamento envolve o debridamento cirúrgico da área necrosada seguida de terapia antifúngica sistêmica. Recentemente, houve um aumento nos casos de mucormicose, após a Segunda onda da pandemia de COVID-19 na índia. Os casos acometiam principalmente pacientes imunocomprometidos, com diabetes mellitus, doenças hematológicas malignas e em uso de corticosteróides. A mucormicose invadindo o palato pelos seios maxilares foi raramente descrita. Na era pós-COVID a mucormicose envolvendo a cavidade oral deve entrar no painel de diagnósticos diferenciais para que o tratamento adequado possa ser instituído precocemente.(AU)

Humoral and Cellular Immunology in Human Prostate Cancer: Plasma Cells and T and B Lymphocytes / Inmunología Humoral y Celular en el Cáncer de Próstata Humano: Células Plasmáticas y Linfocitos T y B

SUMMARY: In solid and malignant tumors, innate and adaptive immunity are combined in antitumor responses. This study aimed to analyze the activation of plasma cells and the correlation between the infiltration of B and T lymphocytes with the degree of malignancy or Gleason grade in human prostate biopsies diagnosed with cancer. Prostate cancer biopsies were obtained from the Clinical Hospital of Universidad de Chile (n=70), according to the bioethical norms of the institution. Histological sections of 5µm thickness were processed for immunohistochemistry with primary antibodies against BL and total TL (HRP/DAB). Recognition and quantification were performed under a Leica DM750 optical microscope. Microsoft Excel and GraphPad software were used for the statistical study. Correlation coefficient (Pearson) and mean comparison tests (Kruskal-Wallis and Dunn) and p≤ 0.05 were developed. B and T lymphocyte populations were inversely interregulated in prostate cancer (Gleason) (r= -0.46). Their relationship with Gleason grade is variable according to lymphocyte type (LB vs. Gleason r= -0.0.47 and LT vs. Gleason r= -0.21). Histological diagnosis of prostate cancer correlates with a predominance of LT. The malignancy of the pathology correlates with a predominance of LTs, according to the Gleason grade. The increased knowledge of B and T lymphocyte infiltration and plasma cell activation could be used to better target clinical trials on treatments based on immune system responses. Immunotherapy could be a new paradigm to apply better antitumor therapy strategies.

En tumores sólidos y malignos, la inmunidad innata y adaptativa se combinan en respuestas antitumorales. Este estudio tuvo como objetivo analizar la activación de células plasmáticas y la correlación entre la infiltración de linfocitos B y T con el grado de malignidad o grado de Gleason en biopsias de próstata humana diagnosticadas con cáncer. Las biopsias de cáncer de próstata se obtuvieron del Hospital Clínico de la Universidad de Chile (n=70), de acuerdo con las normas bioéticas de la institución. Secciones histológicas de 5 µm de espesor fueron procesadas para inmunohistoquímica con anticuerpos primarios contra LB y LT total (HRP/DAB). El reconocimiento y las cuantificaciones se realizaron bajo un microscopio óptico Leica DM750. Para el estudio estadístico se utilizaron los programas Microsoft Excel y GraphPad. Se desarrollaron pruebas de coeficiente de correlación (Pearson) y comparación de medias (Kruskal-Wallis y Dunn) y p≤ 0.05. Los resultados muestran que las poblaciones de linfocitos B y T están inversamente interreguladas en el cáncer de próstata (r= -0,4578). Su relación con el grado de Gleason es variable según el tipo de linfocito (LB vs Gleason r= -0,47* y LT vs Gleason r= -0,21). Se concluye que la malignidad del cáncer de próstata se correlaciona con un predominio de LT, versus el grado de Gleason. El mayor conocimiento de la infiltración de linfocitos B y T y la activación de células plasmáticas podría aprovecharse para una mejor orientación de ensayos clínicos en tratamientos basados en las respuestas del sistema inmunitario. La inmunoterapia podría ser un nuevo paradigma para aplicar mejores estrategias de terapias antitumorales.

Papel inmunomodulador de la vitamina D y los ácidos grasos poliinsaturados omega-3 en trastornos autoinmunes: Revisión de la Literatura / Immunomodulatory role of vitamin D and omega-3 polyunsaturated fatty acids in autoinmune disorders: Literature Review

Los trastornos autoinmunes representan una familia de al menos 80 condiciones diferentes que surgen de una respuesta aberrante del sistema inmunológico resultando finalmente en la destrucción de tejidos y órganos específicos del cuerpo. Es importante destacar que durante las últimas tres décadas los estudios epidemiológicos han proporcionado evidencia de un aumento constante en la incidencia y prevalencia de trastornos autoinmunes. En los últimos años, varios estudios han demostrado que la vitamina D y los ácidos grasos poliinsaturados (AGPs) omega-3 ejercen propiedades inmunomoduladoras y antiinflamatorias sinérgicas que pueden aprovecharse positivamente para la prevención y el tratamiento de trastornos autoinmunes. En este sentido, el reciente ensayo clínico denominado VITAL (ensayo de vitamina D y omega 3); un estudio a gran escala, aleatorizado, doble ciego, controlado con placebo encontró que la suplementación conjunta de vitamina D y AGPs omega-3 (VIDOM) puede reducir la incidencia de enfermedades autoinmunes. En esta revisión de la literatura, resumimos los mecanismos moleculares detrás de las propiedades inmunomoduladoras y antiinflamatorias de la vitamina D y los AGPs omega-3, así como la posible interacción bidireccional entre el metabolismo de la vitamina D y el metabolismo de los AGPs omega-3 que justifica la co- suplementación VIDOM en trastornos autoinmunes(AU)

Autoimmune disorders represent a family of at least 80 different conditions that arise from an aberrant immune system response, which ultimately results in the destruction of specific body tissues and organs. It is important to highlight that during the last three decades epidemiological studies have provided evidence of a steady increase in the incidence and prevalence of autoimmune disorders. In recent years, several studies have shown that vitamin D and omega-3 polyunsaturated fatty acids (PUFAs) exert synergistic immunomodulatory and anti-inflammatory properties that can be positively harnessed for the prevention and treatment of autoimmune disorders. In this sense, the recent clinical trial called VITAL (Vitamin D and Omega 3 trial) - a large, randomized, double-blind, placebo- controlled study - found that co-supplementation of vitamin D and omega-3 PUFAs (VIDOM) can reduce the incidence of autoimmune diseases. In this literature review, we summarize the molecular mechanisms behind the immunomodulatory and anti-inflammatory properties of vitamin D and omega-3 PUFAs, as well as the possible bidirectional interaction between vitamin D metabolism and omega-3 PUFA metabolism that justifies VIDOM co- supplementation in autoimmune disorders(AU)

Terapia de REGEN COV como base de terapia inmunomoduladora mixta en pacientes hospitalizados por neumonía por SARS-CoV-2: Serie de casos / REGEN COV Therapy as the Basis of Mixed Immunomodulatory Therapy in Patients Hospitalized for SARS- CoV-2 Pneumonia: Case Series

Los países en desarrollo con sistema de salud de baja inversión encuentran un reto en priorizar el tratamiento de COVID-19 según su eficacia y sus costos. Materiales y métodos: se explora la utilidad hospitalaria de una intervención segura con eficacia ambulatoria comprobada. Se describe la administración de un tratamiento inmunomodulador combinado a base de imdevimab y casirivimab (REGEN COV). Resultados: los resultados individualizados apuntan a resultados prometedores en pacientes de alto riesgo a progresión y mortalidad. Conclusión: se ha demostrado que REGEN COV es eficiente para tratar dicha enfermedad. Sin embargo, se necesitan ensayos clínicos aleatorizados para comprobar su eficacia en combinación. (AU)

Developing countries with low-investment health systems find it challenging to prioritize COVID-19 treatment according to its efficacy and affordability. Materials and methods: therefore, the in-hospital utility of a safe intervention with outpatient efficacy is explored. We describe the administration of immunomodulatory combination therapy based on imdevimab and casirivimab (REGEN COV). Results: individualized results point to promising outcomes in patients at high risk of progression and mortality. Conclusion: REGEN COV has been shown to be efficient in treating said disease. However, randomized clinical trials are needed to verify their efficacy in combination. (AU)

Inmunomodulación con bióticos y alergia alimentaria en pediatría / Immunomodulation properties of biotics and food allergy in pediatrics

El parto prematuro, la cesárea, el uso de antibióticos y la lactancia materna limitada son señalados como responsables en parte del aumento de enfermedades crónicas no transmisibles en niños, como las alergias, principalmente la alergia a la proteína de la leche de vaca (APLV). Quienes desarrollan enfermedades alérgicas muestran diferencias en la composición de su microbiota intestinal durante los primeros meses de vida, en comparación con los que no lo hacen. Las intervenciones tempranas para modular la microbiota intestinal y el sistema inmunológico pueden ser herramientas claves para el abordaje y tratamiento de la APLV. El criterio clínico y el trabajo interdisciplinario de alergólogos, gastroenterólogos, inmunólogos, microbiólogos y nutricionistas le permitirá al pediatra lograr un adecuado diagnóstico y un tratamiento oportuno. En este contexto, el empleo de bióticos (prebióticos, probióticos, sinbióticos y posbióticos) como herramientas nutricionales complementarias tiene un presente con sustento científico y un futuro promisorio para la prevención y tratamiento de estas patologías.

Preterm birth, C-section, antibiotic use, and limited breastfeeding are blamed in part for the increasing incidence of chronic noncommunicable diseases among children, such as allergies, mainly cow's milk protein allergy (CMPA). Those who develop allergic diseases, against those who do not, show differences in the composition of their gut microbiota during the first months of life. Early interventions to modulate the intestinal microbiota and the immune system may be the key tools for the management of CMPA. Clinical judgment and the interdisciplinary work of allergists, gastroenterologists, immunologists, microbiologists, and nutritionists will allow pediatricians to achieve an adequate diagnosis and a timely treatment. In this setting, the use of biotics (prebiotics, probiotics, synbiotics, and postbiotics) as supplementary dietary tools is scientifically supported at present and seems to be very promising for the prevention and treatment of these conditions.

Imunização de camundongos LDLr-/- com peptídeo mimético da LDL eletronegativa: uma potencial estratégia terapêutica para a ateroscleros / Immunization of LDLr - / - mice with electronegative LDL mimetic peptides: a potential therapeutic strategy for atherosclerosis

Introdução: A aterosclerose é uma doença inflamatória crônica decorrente de alterações na parede das artérias de médio e grande calibre e associadas a diversos fatores de risco, dentre os quais destaca-se as hiperlipidemias, ou seja, o aumento plasmático das lipoproteínas, mas também outras comorbidades, como a Síndrome Metabólica. Entre as lipoproteínas, a lipoproteína de baixa densidade (LDL) é de grande relevância na aterosclerose. Diferentes espécies de LDL modificada (LDLm) são originadas através de lipólise, glicação e proteólise, além da oxidação, variando em densidade e eletronegatividade, sendo melhor denominada LDL eletronegativa [LDL (-)]. Considerando as diferenças conformacionais entre a estrutura da ApoB-100 da LDL nativa e da LDL (-), em um estudo inicial, nosso grupo desenvolveu um anticorpo monoclonal (2C7) a partir da imunização de camundongos Balb/c com a LDL (-) humana. Em uma etapa seguinte foi mapeado o epítopo reconhecido pelo anticorpo monoclonal anti-LDL (-) através de phage display. O peptídeo ligante do anticorpo monoclonal anti-LDL (-) foi nomeado p2C7. Esse peptídeo não representa regiões da sequência linear da ApoB-100 humana, mas microdomínios conformacionais de epítopos da ApoB-100 da LDL (-), tornando-os candidatos para a imunomodulação da aterogênese. Portanto, investigar a imunomodulação induzida pelos peptídeo p2C7 miméticos da LDL (-), por representar um epítopo imunodominante da LDL (-), poderá abrir novas perspectivas terapêuticas futuras para a imunomodulação da aterosclerose. Objetivo: Avaliar a imunomodulação promovida pelo p2C7 in vivo, utilizando camundongos C57BL/6 LDLr -/- e amostras de plasma humano. Adicionalmente, no estágio (BEPE) realizado no Instituto Karolinska (dezembro de 2019 a março de 2021), investigou-se o imunometabolismo como mediador nas doenças cardiovasculares. Na parte II-A, estão descritos os resultados do estudo inicialmente proposto. Na parte II-B, apresenta-se os resultados que foram desenvolvidos posteriormente, com ampliação do escopo do projeto, abordando-se a inflamação vascular envolvida no aneurisma de aorta abdominal através de ferramentas de bioinformática. Na parte II-C, são apresentados os resultados do estudo do envolvimento da enzima indolamina 2,3 dioxigenase (IDO) na esteatohepatite não-alcoólica (NASH) e aterosclerose em camundongos ApoE-/- and ApoE/IDO/double-knockout. Metodologia: Foi avaliada a presença de anticorpos anti-p2C7 em amostras de plasma humano de indivíduos com ou sem síndrome metabólica. Realizamos a determinação de TNF circulante nas mesmas amostras e prosseguimos com regressões lineares associando os parâmetros inflamatórios com os níveis de anticorpos anti-p2C7. Camundongos C57BL/6 LDLr -/- foram imunizados com p2C7 e os adjuvantes Alum ou Montanide ISA 720, analisando-se os títulos de anticorpos contra p2C7 e LDL (-), a produção de citocinas (IL-10, IL-4, IL-2, IL-6, IFNγ, IL-17, TNFα) e células secretoras de anticorpos. Camundongos C57BL/6 LDLr -/- foram tolerizados contra os peptídeos mimotopos, com injeções intravenosas (veia caudal) e desafiados com a imunização contendo LDL (-) + Alum. Avaliou-se os títulos de anticorpos contra p2C7 e LDL (-) e a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Os camundongos foram mantidos em dieta hipercolesterolêmica por 3 meses para formação da placa aterosclerótica. Após este período, os camundongos foram eutanasiados, avaliando-se a formação de placa aterosclerótica na artéria abdominal e arco aórtico, assim como a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Camundongos C57BL/6 LDLr -/- foram imunizados com OVA-p2C7 e, após dieta hipercolesterolêmica de 3 meses para formação de placa aterosclerótica, foram avaliados os parâmetros inflamatórios e avaliada a captação de 18F-FDG no arco aórtico através de PET/CT. Resultados: A imunização com o p2C7 (livre) não foi capaz de induzir resposta humoral, não se observando títulos detectáveis de anticorpos reativos à p2C7 ou LDL (-) em nenhum camundongo imunizado, assim como não foram detectadas células secretoras de anticorpos específicos para a LDL (-). O grupo imunizado com Alum ou Montanide + p2C7 teve aumento significativo na produção de TNF- quando comparado com os demais grupos. O protocolo de tolerização foi realizado com sucesso, visto que os camundongos tolerizados apresentaram títulos de anticorpos inferiores aos controles para o epítopo utilizado. Apenas os camundongos tolerizados com o p2C7 apresentaram aumento significativo na produção de IL-6, IL-12, IL-10, TNF-α, IFNγ e MCP 1 após dieta hipercolesterolêmica. A imunização ativa com OVA-p2C7 foi capaz de reduzir a produção de TNF induzida pela dieta hipercolesterolêmica, assim como reduzir a captação de 18F-FDG. Conclusão: o epítopo p2C7 é altamente expresso na LDL (-) de pacientes com maior risco cardiovascular. Além disso, a imunização ativa com p2C7 também se mostra uma ferramenta promissora para prevenir e regular a inflamação causada pela LDL (-) no curso da aterosclerose

Introduction: Atherosclerosis is a chronic inflammatory disease resulting from changes in the wall of medium and large-caliber arteries and associated with several risk factors, among which hyperlipidemias stand out, ie, the increase in plasma lipoproteins, but also other comorbidities, such as Metabolic Syndrome. Among the lipoproteins, low-density lipoprotein (LDL) is of great relevance in atherosclerosis. Different isoforms of modified LDL (LDLm) are originated through lipolysis, glycation and proteolysis, in addition to oxidation, varying in density and electronegativity, being better called electronegative LDL [LDL (-)]. Considering the conformational differences between the ApoB-100 structure of native LDL and LDL (-), in an initial study, our group developed a monoclonal antibody (2C7) from the immunization of Balb/c mice with human LDL (-). In a next step, the epitope recognized by the anti-LDL monoclonal antibody (-) was mapped using phage display. The binding peptide of anti-LDL monoclonal antibodies (-) was named p2C7. This peptide does not represent linear sequence regions of human ApoB-100, but conformational microdomains of LDL (-) ApoB-100 epitopes, making them candidates for the immunomodulation of atherogenesis. Therefore, investigating the immunomodulation induced by p2C7 peptide mimetics of LDL (-) as it represents an immunodominant epitope of LDL (-) could open new future therapeutic perspectives for the immunomodulation of atherosclerosis. Objective: To evaluate the immunomodulation promoted by p2C7 in vivo, using C57BL/6 LDLr -/- mice, and human plasma samples. In addition, in the internship (BEPE), held at the Karolinska Institute (December 2019 to March 2021), immunometabolism as a mediator of Cardiovascular Diseases was studied. In part II-A, the results of the initially proposed study are described. In part II-B, the results that were developed later are presented, expanding the scope of the project, approaching the vascular inflammation involved in the abdominal aortic aneurysm through bioinformatics tools. In part II-C, the results of the study of the involvement of the enzyme indoleamine 2,3 dioxygenase (IDO) in non-alcoholic steatohepatitis (NASH) and atherosclerosis in ApoE-/- and ApoE/IDO/double mice are presented -knockout. Methodology: The presence of anti-p2C7 antibodies in human plasma samples with or without Metabolic Syndrome was evaluated. We measured circulating TNF in the same samples and proceeded with linear regressions associating inflammatory parameters with levels of anti-p2C7 antibodies. C57BL/6 LDLr -/- mice were immunized with p2C7 and the adjuvants Alum or Montanide ISA 720, analyzing the antibody titers against p2C7 and LDL (-), the production of cytokines (IL-10, IL-4, IL -2, IL-6, IFNγ, IL-17, TNFα) and antibody-secreting cells. C57BL/6 LDLr -/- mice were tolerized against mimotope peptides with intravenous injections (caudal vein) and challenged with immunization containing LDL (-) + Alum. Antibody titers against p2C7 and LDL (-) and cytokine production (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP-1) were evaluated. The mice were kept on a hypercholesterolemic diet for 3 months for atherosclerotic plaque formation. After this period, the mice were euthanized, evaluating the formation of atherosclerotic plaque in the abdominal artery and aortic arch, as well as the production of cytokines (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP -1). C57BL/6 LDLr -/- mice were immunized with OVA-p2C7 and, after a 3-month hypercholesterolemic diet for atherosclerotic plaque formation, inflammatory parameters were evaluated and 18F-FDG uptake was evaluated by PET/CT. Results: Immunization with p2C7 (free) was not able to induce a humoral response, with no detectable titers of antibodies reactive to p2C7 or LDL (-) being observed in any immunized mouse, as well as no detectable antibody-secreting cells for the LDL (-). The group immunized with Alum or Montanide + p2C7 had a significant increase in TNF-α production when compared to the other groups. The tolerance protocol was successfully performed, as the tolerized mice had lower antibody titers than controls for the epitope used. Only mice tolerated with p2C7 showed a significant increase in the production of IL-6, IL-12, IL-10, TNF-α, IFNγ and MCP 1 after a hypercholesterolemic diet. Active immunization with OVA-p2C7 was able to reduce TNF production induced by the hypercholesterolemic diet, as well as to reduce 18F-FDG uptake. Conclusion: the p2C7 epitope is highly expressed in LDL (-) of patients with higher cardiovascular risk. Furthermore, active immunization with p2C7 is also a promising tool to prevent and regulate inflammation caused by LDL (-) in the course of atherosclerosis

Hemolymph of triatomines presents fungistatic activity against Cryptococcus neoformans and improves macrophage function through MCP-I/TNF-α increase

Triatomines are blood-feeding arthropods belonging to the subfamily Triatominae (Hemiptera; Reduviidae), capable of producing immunomodulatory and water-soluble molecules in their hemolymph, such as antimicrobial peptides (AMPs). In this work, we evaluated the antifungal and immunomodulatory activity of the hemolymph of Meccus pallidipennis (MPH) and Rhodnius prolixus (RPH) against Cryptococcus neoformans. Methods: We assessed the activity of the hemolymph of both insects on fungal growth by a minimum inhibitory concentration (MIC) assay. Further, RAW 264.7 macrophages were cultivated with hemolymph and challenged with C. neoformans. Then, their phagocytic and killing activities were assessed. The cytokines MCP-1, IFN-γ, TNF-α, IL-10, IL-12, and IL-6 were measured in culture supernatants 4- and 48-hours post-infection. Results: Both hemolymph samples directly affected the growth rate of the fungus in a dose-dependent manner. Either MPH or RPH was capable of inhibiting fungal growth by at least 70%, using the lowest dilution (1:20). Treatment of RAW 264.7 macrophages with hemolymph of both insects was capable of increasing the production of MCP-I and TNF-α. In addition, when these cells were stimulated with hemolymph in the presence of C. neoformans, a 2- and a 4-fold increase in phagocytic rate was observed with MPH and RPH, respectively, when compared to untreated cells. For the macrophage killing activity, MPH decreased in approximately 30% the number of viable yeasts inside the cells compared to untreated control; however, treatment with RPH could not reduce the total number of viable yeasts. MPH was also capable of increasing MHC-II expression on macrophages. Regarding the cytokine production, MCP-I and TNF-α, were increased in the supernatant of macrophages treated with both hemolymphs, 4 and 48 hours after stimulation. Conclusion: These results suggested that hemolymph of triatomines may represent a source of molecules capable of presenting antifungal and immunomodulatory activity in macrophages during fungal infection.(AU)

Mechanical circulatory support combined with immunomodulation treatment for patients with fulminant myocarditis: a single-center real-world study / 中华心血管病杂志

Objective: To investigate the relationship between the mechanical circulatory support (MCS) combined with immunomodulation and the prognosis of patients with fulminant myocarditis. Methods: This is a retrospective study. A total of 88 patients with fulminant myocarditis admitted to Dongguan Kanghua hospital from Aug. 2008 to Dec. 2020 were included. Medical histories, results of laboratory tests, treatment regimens and clinical outcomes of these patients during their hospitalization were collected from the medical record system. According to the treatment methods, the patients were divided into MCS+immunomodulation group (38 cases), MCS group (20 cases) and traditional treatment group (30 cases). Patients in the MCS+immunomodulation group received intra-aortic balloon pump (IABP) or IABP combined with extracorporeal membrane oxygenation (ECMO) and immunoglobulin or glucocorticoid. Patients in the MCS group only received mechanical circulatory support. Patients in the traditional treatment group received neither mechanical circulatory support nor immunomodulatory therapy, and only used vasoactive drugs and cardiotonic drugs. The in-hospital mortality and length of stay were compared among the three groups. Results: A total of 88 patients with fulminant myocarditis aged (35.0±10.8) years were included, and there were 46 males (52.3%). The mortality of MCS+immunomodulation group (7.9% (3/38) vs. 56.7% (17/30), P=0.001 2) and MCS group (30.0% (6/20) vs. 56.7% (17/30), P=0.002 8) were lower than that of traditional treatment group. Compared with the MCS group, the in-hospital mortality in the MCS+immunomodulation group was lower (P=0.005 4). The most common cause of death was multiple organ dysfunction syndrome (MODS). The constituent ratios of death in MCS+immunomodulation group, MCS group and traditional treatment group were 3/3, 4/6 and 12/17, respectively. The incidence of MODS in the MCS group (20% (4/20)) and the traditional treatment group (40% (12/30)) was significantly higher than that in the MCS+immunomodulation group (7.9% (3/38)) (both P<0.01). In discharged patients, the hospitalization time of MCS+immunomodulation group was shorter than that of traditional treatment group ((13.4±5.5)d vs. (18.5±7.4)d, P<0.05) and MCS group ((13.4±5.5)d vs. (16.9±8.5)d, P<0.05). Conclusion: MCS combined with immunomodulatory therapy is associated with lower in-hospital mortality and shorter hospital stay in patients with fulminant myocarditis.

Terapias usuales y emergentes en colangitis biliar primaria / Conventional and emerging therapies in primary biliary cholangitis

La colangitis biliar primaria (CBP) es una enfermedad autoinmune caracterizada por daño de los conductos biliares intrahepáticos, que hasta ahora tiene mecanismos poco claros de respuesta celular inflamatoria, con la mitocondria como orgánulo blanco. Durante varias décadas han sido el control de los ácidos biliares y el tratamiento de la colestasis lo que ha permitido el manejo médico de los pacientes, logrando un impacto parcial en el curso y la progresión de la enfermedad, mejorando además la sobrevida de los individuos. Con el hallazgo de nuevos mecanismos fisiopatológicos se han iniciado estudios con terapias inmunomoduladoras, que podrían ser prometedoras en el mejoramiento de la calidad de vida de los pacientes que padecen la enfermedad. Aún los resultados son inciertos, y se hacen necesarios más estudios para aclarar el papel de los nuevos tratamientos en el arsenal terapéutico disponible para la CBP.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by damage of intrahepatic bile ducts, so far with unclear mechanisms of inflammatory cellular response with the mitochondria as the target organelle. For several decades it has been the control of bile acids and the treatment of cholestasis what has allowed the management of patients, achieving a partial impact on the course and progression of the disease, also improving the survival of individuals. With the discovery of new pathophysiological mechanisms, studies have been initiated with new immunomodulatory therapies that could be promising in improving the quality of life of patients suffering from the disease. The results are still uncertain and further studies are needed to clarify the role of the new treatments in the therapeutic arsenal available for PBC.

Evaluation of the immunomodulatory activity of thalidomide on tumor-associated macrophages in the 4T1 murine metastatic breast cancer model / [Avaliação do efeito imunomodulador da talidomida em macrófagos associados a tumores no modelo murino de câncer de mama metastático 4T1]

The present work evaluated the immunomodulatory effect of thalidomide (Thal) at different doses on tumor-associated macrophages (TAMs) using a mouse model of human breast cancer. Mice were inoculated with 4T1 cells in the left flank and treated with Thal once a day at concentrations of 50, 100, and 150mg/kg body weight from the 5th day until the 28th day of tumor inoculation. The tumors were sized, proliferation index and TAMs count were evaluated in primary tumors and metastatic lungs. In addition, the metastasis rate was evaluated in the lungs. Thal at 150mg/kg significantly decreased tumor growth, proliferation index, and TAMs infiltration in primary tumors. Conversely, a higher number of TAMs and lower proliferation index were observed in metastatic lungs in mice treated with 150mg/kg of Thal. Furthermore, Thal at 150mg/kg significantly decreased the metastatic nodules in the lungs. Our findings demonstrated that Thal treatment considerably decreased the primary tumor and lung metastasis in mice associated with different TAM infiltration effects in these sites.(AU)

No presente trabalho, foi avaliado o efeito imunomodulador de diferentes doses de talidomida em macrófagos associados ao tumor (TAMs), em um modelo murino de câncer de mama. Camundongos foram inoculados com células 4T1, na região do flanco esquerdo, e tratados com talidomida, uma vez ao dia, nas doses de 50, 100 e 150mg/k, por massa corporal, do quinto dia ao 28º dia de inoculação tumoral. Os tumores foram medidos, o índice de proliferação celular e a contagem de TAMs foram avaliados nos tumores primários e nos pulmões com metástases. Além disso, a taxa de metástases pulmonares também foi avaliada. A talidomida na dose de 150mg/kg diminuiu significativamente o crescimento tumoral, o índice de proliferação celular e a infiltração de TAMs nos tumores primários. Por outro lado, maior número de TAMs e menor índice de proliferação celular foram observados nos pulmões metastáticos, em camundongos tratados com 150mg/kg de talidomida. Ademais, a talidomida na dose de 150mg/kg diminuiu significativamente os nódulos metastáticos nos pulmões. Os resultados demonstraram que o tratamento com talidomida diminuiu o crescimento tumoral e as metástases pulmonares em camundongos, associado com diferentes efeitos na infiltração de TAMs nesses locais.(AU)

Candidiasis y Candida albicans / Candidiasis and Candida albicans

La candidiasis es una enfermedad micótica debida a levaduras pertenecientes al género Candida. Dentro del gran conjunto de microorganismos que colonizan al ser humano, Candida albicans es el agente etiológico más comúnmente detectado ya que habita como comensal en las superficies mucosas y la piel. C. albicans participa en procesos de fermentación de azúcares y asimilación de nutrientes, pero, en algunas ocasiones se relaciona con procesos patológicos. En los últimos años los avances tecnológicos y médicos; así como el aumento en la incidencia de infecciones por el virus de la inmunodeficiencia humana, el auge creciente de la terapia inmunomoduladora y el uso de antibióticos de amplio espectro durante largos períodos de tiempo se han convertido en los factores de riesgo más importantes para la creciente incidencia de infecciones por microorganismos del género Candida. Debido a esto, resulta imperativo el conocimiento de esta enfermedad y sus formas clínicas más importantes, así como el abordaje diagnóstico y el tratamiento actual; información que recolectamos en este documento para brindar una visión general sobre esta patología(AU)

Candidiasis is a fungal disease caused by yeasts belonging to the genus Candida. Within the large group of microorganisms that colonize humans, candida albicans is the most commonly detected etiological agent since it inhabits mucosal surfaces and skin as a commensal. C. albicans participates in sugar fermentation processes and assimilation of nutrients but, on some occasions, it is related to pathological processes. In recent years, technological and medical advances; As well as the increase in the incidence of human immunodeficiency virus infections, the growing boom in immunomodulatory therapy and the use of broad-spectrum antibiotics for long periods of time have become the most important risk factors for the increasing incidence of infections by microorganisms of the genus Candida. Due to this, knowledge of this disease and its most important clinical forms, as well as the current diagnostic approach and treatment, is imperative; information that we collect in this document to provide an overview of this condition(AU)

Microbiota intestinal y su relación con agentes oportunistas vinculados a las epidemias / Gut microbiota and its relationship with opportunistic agents linked to epidemics

Resumen Existen epidemias silenciosas asociadas al estrés y a los malos hábitos de alimentación, tan importantes como las epidemias tradicionales asociadas a la pobreza, a problemas geográficos y climáticos. Numerosos estudios se suman al importante papel de un patrón estable de la microbiota intestinal que favorece el estado saludable en los seres humanos y por lo tanto, su posible implicación en la incidencia y prevalencia de enfermedades que pueden convertirse en epidémicas. En esta revisión se analiza el estado actual de la relación entre los factores demográficos, geográficos, ambientales, patrones de consumo de alimentos con la microbiota intestinal y la aparición de epidemias de origen microbiano, metabólico e inmunológico. Se apoya la iniciativa promovida internacionalmente para la creación de plataformas metagenómicas que contribuyan al estudio del patrón de la microbiota intestinal, el seguimiento epidemiológico y la prevención de las enfermedades epidémicas asociadas con su alteración, así como el diseño de métodos rápidos y económicos para la complementación de estos estudios.

Abstract Silent epidemics associated with stress and unhealthy eating habits are as important as traditional epidemics related to poverty, geographical and climate problems. Many studies incorporate the important role of a stable pattern of gut microbiota that favours the human health status and therefore, its possible implication in incidence and prevalence of diseases that can become epidemics. In this review, the current state-of-art is analysed in terms of relationship between demographic, geographic, environmental factors, and habits with the gut microbiota pattern and the onset of epidemics of microbial, metabolic and immunological origin. The internationally promoted initiative for the creation of metagenomic platforms contributing to studies of the gut microbiota pattern for the epidemiological monitoring and prevention of epidemic diseases associated with its alteration is fostered, as well as the design of rapid and economic methods to complement these studies.

Resumo Existem epidemias silenciosas associadas ao estresse, maus hábitos alimentares, tão importantes quanto as epidemias tradicionais associadas à pobreza, problemas geográficos e climáticos. Numerosos estudos contribuem para o importante papel de um padrão estável de microbiota intestinal que favorece o estado saudável em seres humanos e, portanto, sua possível comprometimento na incidência e prevalência de doenças que podem se tornar epidêmicas. Esta revisão analisa o estado atual da relação entre fatores demográficos, geográficos, ambientais, padrões de consumo de alimentos com a microbiota intestinal e o aparecimento de epidemias de origem microbiana, metabólica e imunológica. É fornecido apoio à iniciativa promovida internacionalmente para a criação de plataformas metagenômicas que contribuam para o estudo do padrão da microbiota intestinal, monitoramento epidemiológico e prevenção de doenças epidêmicas associadas à sua alteração, bem como o desenho de métodos rápidos e baratos para a complementação desses estudos.

Imunomodulação causada por parasitoses oportunistas em casos de COVID-19: um breve estudo / Immunomodulation caused by opportunistic parasites in COVID-19 cases: a brief report

Até o presente momento, foram notificadas mais de 550 mil mortes causadas por COVID-19 no Brasil. Estimulada pelo SARS-Cov-2, a formação de um inflamassoma causa um processo inflamatório sistêmico, responsável pela progressão da enfermidade, e ainda favorece o surgimento de doenças oportunistas, como as parasitoses, que são excelentes moduladoras do sistema imunológico, induzindo uma tolerância do organismo através do equilíbrio entre as respostas pró-inflamatórias e anti-inflamatórias. A partir disso, um levantamento bibliográfico foi realizado com o objetivo de avaliar a possível relação imunomoduladora das infecções parasitárias na COVID-19. Há uma extensa discussão quanto à presença de parasitoses concomitantes a esta coronavirose, devido à possibilidade de modulação do sistema imunológico, que pode ser capaz de refrear ou intensificar a progressão da COVID-19, bem como interferir na soroconversão pós-vacina dos indivíduos afetados, uma vez que doenças diretamente relacionadas aos processos inflamatórios, como Diabetes mellitus do tipo 2, tornam estes indivíduos mais susceptíveis às formas mais graves desta pandemia. Sendo assim, ainda que alguns autores sugiram a possibilidade da helmintíase experimental como uma alternativa para a imunomodulação, trata-se de uma ideia controversa, que necessita de maiores estudos para avaliar se tal procedimento seria seguro e viável de ser aplicado ou não.

Until now, more than 550,000 deaths caused by COVID-19 have been reported in Brazil. Stimulated by Sars-Cov-2, the formation of an inflammasome causes a systemic inflammatory process, responsible for the progression of the disease, and favors the emergence of opportunistic diseases, such as parasitosis, which are excellent modulators of the immune system, inducing a tolerance of the organism through the balance between pro-inflammatory and anti-inflammatory responses. From this, a bibliographical survey was carried out with the aim of evaluating the possible immunomodulatory relationship of parasitic infections in COVID-19. There is an extensive discussion regarding the presence of parasitic diseases concomitant to this coronavirus, due to the possibility of modulation of the immune system, which may be able to curb or intensify the progression of COVID-19, as well as interfere with the post-vaccine seroconversion of affected individuals, a since diseases directly related to inflammatory processes, such as type 2 diabetes mellitus, make these individuals more susceptible to the more severe forms of this pandemic. Thus, although some authors suggest the possibility of experimental helminthiasis as an alternative to immunomodulation. This is a controversial idea, which needs further studies to assess whether such a procedure would be safe and viable to apply or not.

Implications of perioperative allogeneic red blood cell transfusion on the immune-inflammatory response

ABSTRACT Background: The allogeneic transfusion-related immunomodulation (TRIM) may be responsible for an increase in survival of renal transplants but in contrast it could increase the rate of bacterial infections or the recurrence rate of tumors post-operatively. Objective: This review focuses in the implications of perioperative allogeneic transfusions on the immune-inflammatory response of surgical transfused patients. Results: ABTs modify immune functions in recipients including decrease of the number of lymphocytes; decrease the CD4 cells; decrease the CD4/CD8 T-cell ratio; decrease NK cells; and decrease the lymphocyte response to mitogens. TRIM effects may be mediated by allogeneic white cells present in blood products; soluble peptides present in transfused plasma; and/or biologic mediators released into the supernatant of blood units. A recent systematic review and meta-analysis including 36 clinical observational studies (n = 174,036) concluded that perioperative ABTs not only decreased overall survival and reduced colorectal cancer-specific survival. Furthermore ABTs increased the rate of infectious, cardiac, pulmonary and anastomotic complications in colorectal cancer patients undergoing surgery. Conclusions: It has been demonstrated by laboratory tests that TRIM is associated with transfusion recipient immune alterations but its influence in colorectal cancer recurrence after resection remains controversial though may exist. Surgical techniques reducing intraoperative blood loss have limited the number of ABTs perioperatively, however increase in mortality continues to be reported in literature after ABT in colorectal cancer surgery. Poor survival associated to TRIM in colorectal cancer might be due to higher number of allogeneic transfused units and/or prolonged length of blood storage.

Posicionamento da Associação Brasileira de Alergia e Imunologia sobre o manejo da imunoterapia específica com alérgenos (ITA) em pacientes vacinados contra COVID­19 / Position statement of the Brazilian Association of Allergy and Immunology on the management of allergen-specific immunotherapy (AIT) in patients vaccinated against COVID­19

A pandemia de COVID-19 representa um grande desafio para todas as especialidades médicas. A imunoterapia com alérgenos (ITA) é considerada o único procedimento terapêutico capaz de modificar a história natural das doenças alérgicas, e caracteriza o estado da arte na área de Alergia e Imunologia. Esta estratégia terapêutica de imunomodulação é capaz de promover a remissão e controle das doenças alérgicas por períodos prolongados, mesmo após o seu término. Existem poucos dados em relação ao emprego da ITA em pacientes vacinados contra COVID-19, e até o momento não há um posicionamento oficial das sociedades internacionais da área de Alergia e Imunologia Clínica. Este documento tem como objetivo estabelecer recomendações práticas para o manejo da ITA em pacientes que receberam a vacina contra COVID-19. Os fenômenos imunológicos envolvidos na imunoprofilaxia vacinal e no mecanismo de ação da ITA foram comparados, proporcionando o estabelecimento de recomendações precisas.

The COVID-19 pandemic represents a serious challenge for all medical specialties. Allergen-specific immunotherapy (AIT) is considered the only therapeutic procedure capable of modifying the natural history of allergic diseases and characterizes the state of the art in the field of allergy and immunology. This therapeutic strategy of immunomodulation is able to promote remission and control of allergic diseases for prolonged periods, even after cessation. There are few data regarding use of AIT in patients vaccinated against COVID-19 and, to date, there is no official position statement published by international allergy and clinical immunology societies. This document aims to establish practical recommendations for the management of AIT in patients who have received the COVID-19 vaccine. The immunological mechanisms involved in immunoprophylaxis with vaccines and the mechanism of action of AIT have been compared to provide a solid basis for establishing precise recommendations.

Facilitating the gut brain axis by probiotic bacteria to modulate neuroimmune response on lead exposed zebra fish models

Unravelling the efficacy of gut biome has a major impact on health. An unbalanced microbiome composition is linked to many common illnesses such as gut dysbiosis, mental deformities and immunological imbalance. An optimistic influence on the gut biome can be made by consumingprobiotics. This would stimulate neuroprotection and immunomodulation intended by heavy metals pollution. Lead is a major source of neurotoxin that can induce neural deformities. Lactobacillusspecies isolated from curd were characterized to confirm its specificity. Zebra fish was reared at standard conditions and preclinical assessment on the intensity of induced neurotoxin lead was performed. The embryo toxic assay, immunomodulation effects and animal behavioural models endorsed the consequence of neurotoxicity. Different concentrations of bacterial isolate with standard antidepressant was considered for analysing the vigour of toxicity and its influence on cognitive behaviour by novel tank diving method. The restrain in the animal behaviour was also conferred by all the test samples with a decreased bottom dwelling time which was authenticated with haematology and histopathological studies. The alterations in morphology of the lymphocytes were balanced by the treated test samples. This study paves a twofold potential of probiotic as neuroprotectant and immune modulator against heavy metal toxicity.

Methods of macrophages activation and their modulation for the prospection of new antileishmania drugs: a review

Leishmaniasis are a group of parasitic zoonoses provoked by protozoa from Leishmania genus and belonging to the group of neglected tropical diseases. The search and development for new drugs is necessary not only to investigate the activity against only the parasite, but also to investigate the possible synergistic effect of new drugs with the immune response of the host. In the present review, macrophages are pointed out as potential targets of the investigation of new antileishmanial drugs, and some methodologies in order to assess their activation as response to Leishmania-infected cells are presented. Macrophages are an important role in the cellular immune response, since they are cells from mononuclear phagocytic system, the first line of defense of the host, against parasites from Leishmania genus. Phagocytic capacity, lysosomal activity, increase of nitric oxide and intracellular calcium levels are parameters regarding assessment of macrophages activation which allow them to be more hostile in order to solve the infection and lead the patient to cure. In this context, we bring 19 substances already investigated and that activate macrophages, what makes them promising in the antileishmanial treatment. Therefore, assessment of macrophages activation, are important tools for discovery of immunomodulatory compounds which have potential to act in synergism with host immune response. Such compounds might be promising as monotherapy in the treatment of leishmaniasis, as well as being used as adjuvants in vaccines and/or in combination with conventional drugs.