Ethnological aspects of COVID-19

Abstract Within recent past, coronavirus has shaken the whole world. The world faced a new pandemic of novel coronavirus 2019 (SARS-CoV-2/ COVID-19).It has socioeconomically impacted world population a lot in terms of education, economy as well as physical and mental health. This novel coronavirus is notorious enough that put human health at a great risk. Currently, researchers all over the world aretrying hard to develop a new drug/vaccine for its treatment. In past decades, the world population has faced various viral infectious illness outbreaks. Influenza A, Ebola, Zika, SARS and MERS viruses had whacked public health and economy. Medical science technology achieved the landmark in developing coronavirus (SARS-CoV-2) vaccines that are approved currently for emergency use. Some of the recently approved vaccines are developed by Pfizer and Moderna, Johnson and Johnson, Gam-COVID-vac (Sputnik V), Bharat Biotech (covaxin) andOxford-AstraZeneca vaccines (covishield) (Badenet al., 2021). Here, a short review is drafted focusingon infection, immune system, pathogenesis, phylogenesis, mode of transmission and impact of coronavirus on health and economy and recent developments in treating COVID-19

Specific Susceptibility to COVID-19 in Adults with Down Syndrome.

The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.

Free Light Chains as a Novel Diagnostic Biomarker of Immune System Abnormalities in Multiple Sclerosis and HIV Infection.

INTRODUCTION: Immunoglobulins are molecules composed of two heavy and two light chains. Light chains are produced by B lymphocytes during the synthesis of immunoglobulins, and physiologically light chains are generally produced in excess compared to heavy chains. Light chains that are not combined to heavy chains in a whole immunoglobulin are called free light chains (FLCs). B-cell abnormalities are associated with disorders leading to an abnormal concentration of free light chains. In this study, we focus on the described changes of serum and cerebrospinal fluid concentration of free light chains in inflammatory disorders: multiple sclerosis, HIV infection, and HIV-associated lymphomas. METHODS: We performed broad research of the literature pertaining to our investigation via the MEDLINE/PubMed database. RESULTS: It has been proven that FLC determination can provide rapid information about intrathecal inflammation in patients with multiple sclerosis. Moreover, literature data suggest that free light chain determination is the most interesting alternative for oligoclonal band analysis. In the present review, we also described that HIV-related immune system dysfunction is associated with an elevated concentration of serum-free light chains. Additionally, FLCs are potentially a strong and sensitive predictor of the risk of developing HIV-associated lymphomas. CONCLUSION: Based on these published findings, we suggest that free light chains have high diagnostic sensitivity, which probably enables application in laboratory diagnostics.

Evaluación infectológica inicial y seguimiento prospectivo de una cohorte de pacientes sometidos a inmunosupresión inducida / Initial assessment and prospective follow-up of a cohort of patients with immunosuppressive therapy by an infectious diseases physician

El uso de inmunosupresores generó una población creciente de pacientes con defectos en el sistema inmune. Creamos un consultorio especializado en la atención infectológica de dichos pacientes. Objetivos: Describir los antecedentes clínicos y la prevalencia de infecciones latentes, evaluar el estado de vacunación, determinar la necesidad de profilaxis antimicrobiana. Describir la frecuencia de aparición infecciones oportunistas (IO). Materiales y métodos: estudio descriptivo, prospectivo de pacientes atendidos en un consultorio que estuvieran bajo tratamiento inmunosupresor (noviembre 2015-enero 2017). Se recolectaron datos demográficos, clínicos y factores de riesgo para IO. Se realizó pesquisa de tuberculosis (TB), serologías para HIV, hepatitis A, B y C, sífilis, toxoplasmosis, Chagas, búsqueda de Strongyloides spp. Se indicaron vacunas de acuerdo con las recomendaciones actuales. Se realizó seguimiento para detección de IO. Resultados: n=197, media de edad 50,7 años (DE 14), mujeres 79,7%. Enfermedades de base: artritis reumatoidea 52%, lupus 12%. Drogas inmunosupresoras: metotrexato 45%, corticoides 16%, biológicos anti-TNF 15%, micofenolato 10%, ciclofosfamida 4%. Se diagnosticaron 49 (25%) infecciones: 15 Chagas, 15 anti-HBc positivo aislado, 7 sífilis, 4 HIV, 4 TB latentes, 2 HBV, 1 HCV, 1 estrongiloidiosis. Se indicó profilaxis antimicrobiana en 27 (14%) pacientes. En todos se intervino indicando o completando los esquemas de vacunación. Se detectaron 7 IO. Conclusiones: En el 39% de los pacientes, la evaluación sistematizada arrojó hallazgos que motivaron intervenciones, ya sea terapéuticas o de monitoreo. En el 100% fue necesaria la prescripción de vacunas. Esto pone en evidencia la importancia de evaluar sistemáticamente en consultorios especializados a estos pacientes

Introduction: The extensive use of immunosuppressive drugs resulted in a growing population of patients with defects in the immune system. We opened an infectious diseases practice focused on the attention of these patients. Our objectives were to describe the clinical history and prevalence of latent infections, evaluate the vaccination status, determine the need for antimicrobial prophylaxis and describe the frequency of opportunistic infections (OI). Methods: We performed a descriptive and prospective study of patients seen at a medical practice who were under immunosuppressive therapy (November 2015-January 2017). Demographic and clinical history, as well as risk factors for OI were collected. Tuberculosis (TB) screening, serologies for HIV, hepatitis A, B and C, syphilis, toxoplasmosis, Chagas and Strongyloides spp. screening were performed. Vaccines were indicated according to current recommendations. Follow-up was performed for IO detection. Results: n=197. Mean age: 50.7 years (SD 14). Female 79.7%. Underlying diseases: rheumatoid arthritis 52%, 12% lupus. Immunosuppressive drugs: methotrexate 45%, corticoids 16%, biological anti-TNF agents 15%, mycophenolate 10%, cyclophosphamide 4%. Forty-nine (25%) infections were diagnosed: 15 Chagas, 15 anti-HBc positive isolated, 7 syphilis, 4 HIV, 4 latent TB, 2 HBV, 1 HCV, 1 strongyloidiosis. Antimicrobial prophylaxis was indicated in 27 (14%) patients. In all cases, vaccination schemes were indicated or completed. Seven IO were detected. Conclusions: In 39% of the patients, the systematized evaluation revealed findings that motivated interventions, either therapeutic or monitoring. In 100% the prescription of vaccines was necessary. These findings highlight the importance of a systematically evaluation of these patients in specialized care centers.

Gut microbiota and mTOR signaling: Insight on a new pathophysiological interaction.

The gut microbiota plays a substantial role in regulating the host metabolic and immune functions. Dysbiosis, resulting from disruption of gut microbiota, predisposes many morbid pathologies like obesity and its associated comorbidities, diabetes and inflammatory conditions including some types of cancer. There are numerous proposed signaling pathways through which alterations in gut microbiota and its metabolites can disturb the host's normal physiological functions. Interestingly, many of these processes happen to be controlled by the mammalian target of rapamycin (mTOR). The mTOR pathway responds to environmental changes and regulates accordingly many intracellular processes such as transcription, translation, cell growth, cytoskeletal organization and autophagy. In this review, we aim to highlight the cross-talk between the gut microbiota and the mTOR pathway and discuss how this emerging field of research gives a beautiful insight into how the mentioned cross-talk impacts the body's homeostasis thus leading to undesirable complications including obesity, diabetes, colon and pancreatic cancer, immune system malfunctioning and ageing. Although there are a limited number of studies investigating the crosstalk between the gut microbiota and the mTOR pathway, the results obtained so far are enough to elucidate the key role of the mTOR signaling in microbiota-associated metabolic and immune regulations.

Colecalciferol regula os parâmetros hematológicos e a produção de citocinas pró-inflamatórias renais em camundongos diabéticos e nas células RAW 264. 7 / Colecalciferol regulates haematological parameters and the production of renal proinflammatory cytokines in diabetic mice and RAW 264. 7 cells

Os efeitos causados pelo tratamento em conjunto da insulina e do colecalciferol em indivíduos diabéticos não estão completamente elucidados. O presente trabalho avaliou o efeito de ambos os hormônios nos rins, no fígado, no coração e nos parâmetros hematológicos de camundongos machos (C57BL/6) sadios e diabéticos, bem como a ação do colecalciferol (in vitro) na resposta imunológica desenvolvida pelas células RAW 264.7 e pelos macrófagos peritoneais (MP) após estímulo com lipopolissacarídeo (LPS). Após dez dias da administração da aloxana (60 mg/kg), animais diabéticos exibiram redução do ganho de peso corporal e hiperglicemia quando comparados aos animais que receberam salina. No sétimo dia do período experimental, foi verificado que animais diabéticos que não receberam nenhum hormônio, em relação aos não diabéticos, exibiram redução do peso corporal, dos níveis de hemoglobina (Hb), hematócrito, hematimetria, insulina, TNF-α e IL-6 (coração) e aumento da glicemia, da relação peso corpóreo/peso rim esquerdo, das concentrações séricas de ureia, creatinina, Fosfatase Alcalina (FAL), Lactato desidrogenase (LDH) e lactato, fator de necrose tumoral (TNF)-α, interleucina (IL)-6 e IL-10 (no rim); o tratamento com insulina (1 UI/300 mg/dL glicemia), em relação aos animais diabéticos não tratados, promoveu aumento do peso corporal, das concentrações séricas de insulina e redução da glicemia, das concentrações séricas de ureia e da razão TNF-α/IL-10 (coração); o tratamento com colecalciferol (800 UI/dia), em relação aos animais diabéticos não tratados, promoveu aumento das concentrações séricas de 25-hidroxicolecalciferol [25(OH)D], Hb, hematócrito, hematimetria, IL-10 (coração) e reduziu IL-6, IL-10, TNF-α e EPO (rim); os animais diabéticos tratados com insulina, em relação aos animais diabéticos suplementados com colecalciferol apresentaram aumento do peso corpóreo, de ureia sérica, IL-6 e TNF-α (coração) e redução da glicemia, das concentrações séricas de lactato, de IL-6, TNF-α, IL-10 e EPO (rim); os animais -que receberam ambos os hormônios, em relação aos animais tratados com insulina, apresentaram aumento sérico de insulina e lactato; os animais diabéticos que receberam ambos os hormônios, em relação aos animais diabéticos tratados com colecalciferol, exibiram aumento sérico de 25(OH)D, de insulina, além da redução das concentrações de IL-10, da razão de TNF-α/IL-10 e TNF-α/IL-6 (coração); animais diabéticos que receberam ambos os hormônios, em relação aos diabéticos não suplementados com colecalciferol, exibiram: aumento de insulina sérica e redução das concentrações séricas de ureia e das razões renal e hepática de TNF-α/IL-6; células RAW 264.7 estimuladas pelo LPS e tratadas com 100 nM colecalciferol exibiram maior expressão da CYP27B1 e redução na liberação de mediadores inflamatórios quando comparadas ao grupo estimulado pelo LPS. Entretanto, não foi observado o mesmo efeito nos MP. Em conjunto, os resultados sugerem que: 1) em animais diabéticos, o colecalciferol pode modular parâmetros hematológicos e que a insulina pode melhorar a função renal, bem como a recuperação do peso corporal; 2) o colecalciferol pode ser metabolizado pelas células RAW 264.7 e modular a resposta imunológica desencadeada pelo LPS

The effects caused by the treatment of insulin and cholecalciferol in diabetic subjects are not completely elucidated. The present study evaluated the effect of both hormones on the kidneys, liver, heart and hematological parameters of healthy and diabetic male mice (C57BL/6), as well as the action of cholecalciferol (in vitro) on the immune response developed by the cells RAW 264.7 and peritoneal macrophages (MP) after stimulation with lipopolysaccharide (LPS). After ten days of alloxan administration (60 mg/kg), diabetic animals exhibited a reduction in body weight gain and hyperglycemia when compared to animals that received saline. On the seventh day of the experimental period, it was verified that diabetic animals that did not receive any hormones, in relation to non-diabetics, showed reduction of body weight, hemoglobin (Hb), hematocrit, hematimetry, insulin, TNF-α and IL- 6 (heart) and increased glycemia, body weight / left kidney weight, serum urea, creatinine, Phosphatase Alkaline, lactate dehydrogenase (LDH) and lactate levels, tumor necrosis factor (TNF) interleukin (IL) -6 and IL-10 (in the kidney); diabetic mice treated with insulin (1 IU / 300 mg/dL glycemia) in relation to untreated diabetic animals promoted increased body weight, serum insulin levels and blood glucose lowering, serum urea levels and TNF-α ratio / IL-10 (heart); diabetic animals treated with cholecalciferol (800 IU/day), in relation to untreated diabetic animals, exhibited increased serum levels of 25-hydroxycholecalciferol [25 (OH) D], Hb, hematocrit, hematimetry, IL-10 (heart) and reduced IL-6, IL-10, TNF-α and EPO (kidney);insulin-treated diabetic animals compared to diabetic animals supplemented with cholecalciferol exhibited an increase of body weight, serum urea, IL-6 and TNF-α (heart) and a reduction of glycaemia, serum lactate levels, IL-6, TNF- α, IL-10 and EPO (kidney); animals that received both hormones, compared to animals treated with insulin exhibited an increase of insulin and lactate serum levels; diabetic animals that received both hormones, compared to diabetic animals treated with cholecalciferol, exhibited an increase of 25(OH)D and insulin serum levels, and a reduction of IL-10, TNF-α/IL-10 and TNF-α/IL-6 ratios (heart); diabetic animals that received both hormones, compared to diabetic animals not supplemented with cholecalciferol, exhibited an increase of insulin and reduced urea serum levels and reduced renal and hepatic TNF-α/IL-6 ratios; LPS-stimulated RAW 264.7 cells and treated with 100 nM cholecalciferol exhibited greater CYP27B1 expression and reduced release of inflammatory mediators when compared to the LPS-stimulated group. However, the same effect was not observed in PM. Taken together, the results suggest that: 1) in diabetic animals, cholecalciferol may modulate hematological parameters and that insulin may improve renal function as well as recovery of body weight; 2) cholecalciferol can be metabolized by RAW 264.7 cells and modulate the immune response triggered by LPS

Acción inmunomoduladora de las células madre mesenquimales en las enfermedades autoinmunitarias / Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases

Las enfermedades autoinmunitarias son un grupo de trastornos en los que existe un fallo en la tolerancia inmunitaria y, con ello, una hiperactivación del sistema inmunológico, de lo que se deriva un estado de inflamación crónica y un potencial daño multiorgánico. Los fármacos empleados en la actualidad para el tratamiento de este grupo de enfermedades son agentes con mayor o menor efecto inmunodepresor, con importante toxicidad sistémica y potencial riesgo de infecciones oportunistas. Se han descrito, en distintos estudios, las propiedades inmunomoduladoras de las células madre mesenquimales, características que las hacen candidatas a ser empleadas en el tratamiento de las enfermedades autoinmunitarias. Realizamos una revisión de la situación actual de esta línea terapéutica en lupus eritematoso sistémico, síndrome de Sjögren, esclerosis sistémica, enfermedad de Crohn y esclerosis múltiple, así como de los potenciales riesgos derivados de su empleo (AU)

Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use (AU)

Glomerulonefritis lúpica y otras glomerulopatías autoinmunes / Lupus glomerulonephritis and other autoimmune glomerulonephritis

La glomerulonefritis es un término empleado para expresar la proliferación e inflamación endocapilar del glomérulo renal, que clínicamente puede manifestarse de numerosas formas e incluso permanecer asintomática. En su etiología se encuentran múltiples mecanismos, como la participación de microorganismos y parásitos, aunque es destacable el mecanismo autoinmune en el que se identifican varios componentes del sistema inmune, entre ellos el sistema del complemento. Un ejemplo de este último mecanismo es la glomerulonefritis secundaria al Lupus Eritematoso Sistémico (LES), que ha sido objeto de investigación en los últimos años, y en la que se han hecho importantes avances en cuanto al descubrimiento de nuevas moléculas implicadas en el proceso etiopatogénico. Esto ha conseguido abrir una puerta a nuevas terapias que reduzcan la mortalidad y mejoren la calidad de vida. Se ha revisado la fisiopatología, clínica, diagnóstico, pronóstico y tratamientos, incluyendo los emergentes, en cuanto a glomerulonefritis haciendo hincapié en la glomerulonefritis lúpica y otras glomerulonefritis de mecanismo igualmente autoinmune.

The syndrome of degenerative calcific aortic stenosis: prevalence of multiple pathophysiologic disorders in association with valvular stenosis and their implications.

BACKGROUND: We hypothesized that degenerative calcific aortic stenosis (DCAS) is a syndrome influenced by factors beyond aortic valve stenosis (AS). The aim of this study was to assess how frequently DCAS is complicated by increased vascular load, systolic and/or diastolic left ventricular (LV) dysfunction, and comorbid disorders. METHODS: In 215 consecutive patients > 60 years of age with severe and moderate AS, we analyzed systemic arterial compliance, global hemodynamic load, LV ejection fraction (EF), the presence of diastolic dysfunction, and other valvular or systemic disorders. RESULTS: A total of 164 patients had severe AS and 51 had moderate AS. In patients with severe AS, the prevalence of increased vascular load was 42%; LV systolic and diastolic dysfunction was present in 27% and 42%; other valve diseases in 23%; and comorbid disorders in 82%. In the moderate AS group, abnormal vascular load was found in 52%; LV systolic and diastolic dysfunction was prevalent in 26% and 31%; other valve diseases in 17%; and comorbid disorders in 78% patients. More than half the patients in both groups had symptoms. In both severe and moderate AS groups, the prevalence of increased vascular load and systolic dysfunction was higher in the symptomatic group. CONCLUSION: Considerable number of patients with DCAS have abnormal vascular load, abnormal LV function, and significant coexisting disorders. These could influence the total pathophysiologic burden on the heart and symptom expression. Thus, DCAS should not be considered just as valvular stenosis, but a syndrome of DCAS because of the diagnostic, prognostic, and therapeutic implications of various factors associated with it.

Efeito da suplementação com L-glutamina livre e na forma de dipeptídeo sobre eixo glutamina-glutationa, sistema imune, sistema inflamatório e vias de sinalização proteica em camundongos submetidos à endotoxemia / Effects of dietary supplementation with L-glutamine in the free and dipeptide forms on glutamine-glutathione axis, immune system, inflammatory system and protein signaling pathwaysin mice submitted to endotoxemia

A sepse é a principal causa de morte em unidades de terapia intensiva (UTIs) no mundo. A reduzida disponibilidade do aminoácido mais abundante do organismo, a glutamina contribui para o complicado estado catabólico da sepse. No presente estudo investigamos os efeitos da suplementação oral com L-glutamina e L-alanina (GLN+ALA), ambos na norma livre e como dipeptídeo, L-alanil-L-glutamina (DIP), sobre o eixo glutamina-glutationa (GSH), sistema imune, inflamação, proteínas de choque térmico (HSPs) e expressão de genes envolvidos com vias de sinalização proteica em animais endotoxêmicos. Camundongos C57/B6 foram submetidos à endotoxemia (Escherichia coli LPS, 5 mg.kg-1, grupo LPS) e suplementados por 48 horas com L-glutamina (1 g.kg-1) e L-alanina (0,61 g.kg-1, grupo GLN+ALA-LPS) ou 1,49 g.kg-1 de DIP (grupo DIP-LPS). A endotoxemia promoveu depleção da concentração de glutamina no plasma (71%), músculo esquelético (50%) e fígado (49%), quando comparado ao grupo CTRL, sendo restauradas nos grupos DIP-LPS e GLN+ALA-LPS (P<0,05), fato que atenuou a redução da GSH e o estado redox (taxa GSSG/GSH) em eritrócitos circulantes, musculo e fígado (P<0,05). A suplementação em animais endotoxêmicos resultou em uma upregulation dos genes GSR, GPX1 e GCLC no músculo e fígado. A concentração das citocinas plasmáticasTNF-α, IL-6, IL-1ß e IL-10 foi atenuada pelas suplementações, bem como a expressão de mRNAs envolvidos com a resposta inflamatória, ativadas pela via do NF-κB(P<0,05). Concomitantemente, verificou-se aumento da capacidade proliferativa de linfócitos T e B circulantes nos grupos GLN+ALA-LPS e DIP-LPS. A expressão de mRNAs e a concentração de HSPs no tecido muscular foi restabelecida pelas suplementações, contudo, a expressão mRNAs relacionados às vias de síntese e degradação proteica foi somente estimulada no tecido hepático(P<0,05). Os resultados do presente estudo demonstram que a suplementação por via oral com GLN+ALA ou DIP podem ser utilizados clinicamente como métodos nutricionais em reverter o quadro de depressão da disponibilidade de glutamina corporal da sepse induzida por LPS, tendo impacto no eixo glutamina-glutationa, sistema imune e inflamatório

Sepsis is the leading cause of death inintensive care units (ICUs) in the world.The availability ofthe most abundant amino acid in the body, glutamine, is reduced in this situation, fact that contribute to the complicated catabolic state of sepsis. In the present study, we investigated the effects of oral supplementation with L-glutamine and L-alanine (GLN+ALA), both in their free form and as a dipeptide, L-alanyl-L-glutamine (DIP) on glutamine-glutathione axis (GSH), immune and inflammatory system, heat shock proteins (HSPs) expression and gene expressions involved in protein signaling pathways during endotoxemia. C57/B6 mice were subjected to endotoxemia (Escherichia coli LPS, 5 mg.kg-1, LPS group) and supplemented for 48 hours with L-glutamine (1 g.kg-1) plus L-alanine(0.61 g.kg-1, GLN+ALA-LPS group) or 1.49 g.kg-1of DIP (DIP-LPS group). Endotoxemia promoted depletion glutamine concentration in plasma (71%), skeletal muscle (50%) and liver (49%), when compared to the CTRL group, and was restored in the DIP-LPS e GLN+ALA-LPS (P<0.05), fact that attenuate the reduction of GSH and the redox state (GSSG/GSH rate) in circulating erythrocytes, liver and muscle (P<0.05). Supplementations in endotoxemic mice resulted in upregulation of GSR, GCLC and GPX1 genes in muscle and liver. Plasma concentration of TNF-α, IL-6, IL-1ß and IL-10 were attenuated by supplementation as well as the expression of mRNAs involved in the inflammatory response, activated by NFκ-B pathway (P <0.05). At the same time, high proliferative capacity of circulating T and B lymphocytes GLN+ALA-LPS e DIP-LPS were observed. HSPs (protein and mRNAs) and in muscle were restored by the supplements, however, the mRNAs expression related to the synthesis and degradation of protein pathways was only stimulated in the liver (P <0.05). Our results demonstrate that oral supplementation with GLN+ALA or DIP can be used as clinically nutritional methods to reverse the depression of body glutamine availability during sepsis induced by LPS, impacting on the glutamine-glutathione axis, immune and inflammatory system

Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment. METHODS: We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8(+) T cells. RESULTS: KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4(+)CD25(+)FoxP3(+) Treg cells and the contraction of NY-ESO-1-specific CD8(+) T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4(+) T cells into bona fide CD4(+)CD25(hi)FoxP3(hi) Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by D,L-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO(+) myeloma disease compared with patients having IDO(-) MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity. CONCLUSIONS: These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.

Pno1 tissue-specific expression and its functions related to the immune responses and proteasome activities.

Pno1 is a protein that plays a role in proteasome and ribosome neogenesis in yeast. So far, its functions in mammalian cells have not been investigated. To understand its function in mammals, we performed in situ hybridization analysis of Pno1 expression in different development stages and generated Pno1 gene knockout (KO) and transgenic (Tg) mice lineages. The results showed early lethality of homozygous Pno1 KO lineage caused, as demonstrated in parallel by ex vivo experiments, by arrest of embryo development before compaction stage. Though, heterozygous (HET) mice with 50% of normal Pno1 mRNA concentration were fertile and showed no obvious anomalies. The lymphoid organs of HET mice were normal in size, weight and cellularity, with normal T and B cell subpopulations. TCR-triggered activation and proliferation of HET T cells were normal. Proteasome activities in HET organs were uncompromised. Tg mice with actin promoter-driven Pno1 expression were also fertile, with no apparent anomalies, although they expressed 2-5-fold higher Pno1 mRNA levels. The lymphoid organs of Tg mice were of normal size, weight and cellularity with normal T and B cell sub-populations. TCR-triggered activation and proliferation of Tg T cells were normal. Tg organs and tissues presented normal proteasome activity as did their wild type counterparts. Tagged Pno1 over-expression in L cells and density gradient fractionation established that Pno1 existed in large complexes with sedimentation rates between 20S and 26S, bigger than mature 26S proteasomes. Pno1 in fractions did not coincide with 40S or 60S ribosome subunits. Our study indicates that Pno1 is essential for cellular functions, but only a small percentage of its normal level is sufficient, and excessive amounts are neither harmful nor useful. The nature of the large complexes it associates with remains to be identified, but it is certain that they are not mature proteasomes or ribosomes.

Hematopoietic stem cell transplantation for profound T-cell deficiency (combined immunodeficiency).

Typical cases of severe combined immunodeficiency present at infancy (most frequently at 6 months of age) with repeated opportunistic infections; failure to thrive; and scarcity of lymphoid tissues, including undetectable lymph nodes and a small dysplastic thymus. Patients with profound T-cell dysfunction (PTD)/combined immunodeficiency (CID) have moderate to large numbers of circulating autologous lymphocytes with variable residual function. These cells may interfere with proper engraftment and may complicate the procedure of HSCT, hence the need for conditioning. There is no immediate explanation for the excellent outcome of hematopoietic stem cell transplantation (HSCT) for PTD/CID. Historically, protocols for mismatched related donor HSCT did not include conditioning regimens, which could jeopardize engraftment. Careful studies on the role of conditioning, especially myeloablative conditioning, should be conducted in the future. It is possible that in some genotypes, related identical donor can be accepted by the recipient with little or no conditioning. Until such studies become instructive, the protocols in current use seem to provide excellent, although not perfect, outcome in patients with PTD/CID.

Respuesta inmune contra antígenos menores de histocompatibilidad en el trasplante alogénico de progenitores hematopoyéticos / Immunologycal response under antigens hematopoietic stem cell transplantation

Patients who receive allo hematopoietic stem cell transplantation (SCT) could develop graft versus host disease and/or graft versus tumour effect. These immunological responses can happen even with perfect fully HLA matched haematopoietic stem cells. Moreover, the engraftment of the donor’s cells depends on the immunological conditions of both donor and recipient. The development of alloreactivity occurs in the context of the polymorphisms of the human genome, these genomic differences results in proteins with antigenic properties which trigger immune responses. Considering this, the SCT is a powerful tool to heal the patient disease, because all of them become chimeras. In other words, into individuals with two different genomic sets, which will develop a strong immunological response that cannot exist in natural conditions.

Translation elongation factor eEF1A2 is essential for post-weaning survival in mice.

Translation elongation factor eEF1A, formerly known as EF-1 alpha, exists as two variant forms; eEF1A1, which is almost ubiquitously expressed, and eEF1A2, whose expression is restricted to muscle and brain at the level of whole tissues. Expression analysis of these genes has been complicated by a general lack of availability of antibodies that specifically recognize each variant form. Wasted mice (wst/wst) have a 15.8-kilobase deletion that abolishes activity of eEF1A2, but before this study it was unknown whether the deletion also affected neighboring genes. We have generated a panel of anti-peptide antibodies and used them to show that eEF1A2 is expressed at high levels in specific cell types in tissues previously thought not to express this variant, such as pancreatic islet cells and enteroendocrine cells in colon crypts. Expression of eEF1A1 and eEF1A2 is shown to be generally mutually exclusive, and we relate the expression pattern of eEF1A2 to the phenotype seen in wasted mice. We then carried out a series of transgenic experiments to establish whether the expression of other genes is affected by the deletion in wasted mice. We show that aspects of the phenotype such as motor neuron degeneration relate precisely to the relative expression of eEF1A1 and eEF1A2, whereas the immune system abnormalities are likely to result from a stress response. We conclude that loss of eEF1A2 function is solely responsible for the abnormalities seen in these mice.

Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter.

Telomeres are gene rich regions with a high recombination rate. Cryptic subtelomeric rearrangements are estimated to account for 5% of mental retardation/malformation syndromes. Here we present the first patient with a deletion of 19p13.3, identified by subtelomeric FISH analysis. His features included a distinctive facial appearance, cleft palate, hearing impairment, congenital heart malformation, keloid scarring, immune dysregulation, and mild learning difficulties. Subtelomeric FISH analysis identified a deletion of 19p13.3-pter. The deletion size was determined to be 1.2 Mb by FISH analysis. It extended from within the chromosomal region covered by BAC RP11-50C6 to 19pter. The deleted area encompassed approximately 60 genes. Fifteen possible candidate genes were considered with respect to the phenotype, including follistatin-related precursor 3 (FSTL3) and serine-threonine kinase 11 (STK-11).

Further delineation of Kabuki syndrome in 48 well-defined new individuals.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Virus de inmunodeficiencia humana y síndrome de la inmunodeficiencia adquirida: (primera parte) / Human immunodeficiency virus and acquired immuno deficiency syndrome: (part one)

En esta primera entrega de EVIDENCIA, el autor describe el impacto mundial y local de la infección por el virus de la inmunodeficienciaadquirida a pesar de que existen medidas efectivas para evitar su diseminación y un tratamiento efectivo para controlarla(ambas estrategias con mala accesibilidad para las poblaciones de los países subdesarrollados); destaca la importanciadel trabajo en equipo para la atención de estos pacientes y algunos puntos de la interacción entre el especialista y el generalista;y se extiende en los principales puntos clínicos sobre el diagnóstico en individuos que están cursando una primoinfección,así como los asintomáticos.

Developmental atrazine exposure suppresses immune function in male, but not female Sprague-Dawley rats.

Each year, 75 million pounds of the broadleaf herbicide atrazine (ATR) are applied to crops in the United States. Despite limited solubility, ATR is common in ground and surface water, making it of regulatory concern. ATR suppresses the immunomodulatory hormones prolactin (PRL) and the thyroid hormones (THs), with developmental exposure to ATR permanently disrupting PRL regulation. We hypothesized that ATR may cause developmental immunotoxicity through its disruption of PRL or THs. To test this hypothesis, pregnant Sprague-Dawley (SD) rats were exposed to 35-mg ATR/kg/d from gestational day (GD) 10 through postnatal day (PND) 23. Separate groups were exposed to bromocryptine (BCR) at 0.2 mg/kg/2x/day to induce hypoprolactinemia or to propylthiouracil (PTU) at 2 mg/kg/day to induce hypothyroidism. After the offspring reached immunologic maturity (at least 7 weeks old), the following immune functions were evaluated: natural killer (NK) cell function; delayed-type hypersensitivity (DTH) responses; phagocytic activity of peritoneal macrophages; and antibody response to sheep erythrocytes (SRBC). ATR decreased the primary antibody and DTH responses in male offspring only. Neither PTU nor BCR caused immunosuppression in any measured variable, although PTU increased phagocytosis by peritoneal macrophages. These results demonstrate that developmental exposure to ATR produced gender-specific changes in immune function in adult rats and suggest that immune changes associated with ATR are not mediated through the suppression of PRL or THs.