High levels of anti-factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors.

Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

Oral mucormycosis associated with COVID-19 and diabetes mellitus: Case report and literature review / Mucormicosis oral asociada a COVID-19 y diabetes mellitus: descripción de un caso.

Mucormycosis is an invasive opportunistic fungal infection with high mortality, mainly detected in people with COVID-19, especially those with underlying diseases such as diabetes mellitus. Mucormycosis prevalence is 0.005 to 1.7 cases per million inhabitants, and it has been increasing in countries like India and Pakistan. This mycosis can affect different organs, and clinical manifestations reflect the transmission mechanism. Frequent forms are rhino-orbital-cerebral and pulmonary. This disease should be suspected in patients with necrotic injuries on mucous membranes or skin. We present a case of a patient with diabetes mellitus and diagnosed with oral mucormycosis associated with COVID-19.

La mucormicosis es una infección fúngica oportunista e invasiva, con una elevada tasa de mortalidad. Se ha detectado principalmente en pacientes con COVID-19, especialmente en personas con enfermedades concomitantes como la diabetes mellitus. La prevalencia de las mucormicosis es de 0,005 a 1,7 casos por millón de habitantes y ha ido en aumento en países como India y Pakistán; puede afectar diferentes órganos y su forma clínica refleja el mecanismo de transmisión. Entre las formas frecuentes están la rino-orbital-cerebral y la pulmonar, por ello, debe sospecharse mucormicosis en los pacientes con lesiones necróticas en mucosas o piel. Se presenta el caso de un paciente con antecedentes de diabetes mellitus que fue diagnosticado con mucormicosis oral asociada a la COVID-19.

Pregnancies through oocyte donation. A mini review of pathways involved in placental dysfunction.

Pregnancies resulting from assisted reproductive techniques (ART) are increasingly prevalent worldwide. While most pregnancies conceived through in-vitro fertilization (IVF) progress without complications, mounting evidence suggests that these pregnancies are at a heightened risk of adverse perinatal outcomes. Specifically, IVF pregnancies involving oocyte donation have garnered attention due to numerous reports indicating an elevated risk profile for pregnancy-related complications within this subgroup of patients. The precise mechanisms contributing to this increased risk of complications remain incompletely understood. Nonetheless, it is likely that they are mediated by an abnormal immune response at the fetal-maternal interface. Additionally, these outcomes may be influenced by baseline patient characteristics, such as the etiology of infertility, absence of corpus luteum, and variations in endometrial preparation protocols, among other factors. This review aims to succinctly summarize the most widely accepted mechanisms that potentially contribute to the onset of placental dysfunction in pregnancies conceived through oocyte donation.

Clinical and molecular impact of concurrent thyroid autoimmune disease and thyroid cancer: From the bench to bedside.

The recent incorporation of immune checkpoint inhibitors targeting the PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways into the therapeutic armamentarium of cancer has increased the need to understand the correlation between the immune system, autoimmunity, and malignant neoplasms. Both autoimmune thyroid diseases and thyroid cancer are common clinical conditions. The molecular pathology of autoimmune thyroid diseases is characterized by the important impact of the PD-1/PD-L1 axis, an important inhibitory pathway involved in the regulation of T-cell responses. Insufficient inhibitory pathways may prone the thyroid tissue to a self-destructive immune response that leads to hypothyroidism. On the other hand, the PD-1/PD-L1 axis and other co-inhibitory pathways are the cornerstones of the immune escape mechanisms in thyroid cancer, which is a mechanism through which the immune response fails to recognize and eradicate thyroid tumor cells. This common mechanism raises the idea that thyroid autoimmunity and thyroid cancer may be opposite sides of the same coin, meaning that both conditions share similar molecular signatures. When associated with thyroid autoimmunity, thyroid cancer may have a less aggressive presentation, even though the molecular explanation of this clinical consequence is unclear. More studies are warranted to elucidate the molecular link between thyroid autoimmune disease and thyroid cancer. The prognostic impact that thyroid autoimmune disease, especially chronic lymphocytic thyroiditis, may exert on thyroid cancer raises important insights that can help physicians to better individualize the management of patients with thyroid cancer.

Murciélagos como vectores de enfermedades virales e impacto en la salud humana

Introducción: Los murciélagos se destacan por ser los únicos mamíferos voladores, con alrededor de 1 400 especies que cumplen un rol fundamental como controladores de plagas y polinizadores de plantas nocturnas. Sin embargo, su influencia sobre la salud humana se ha evidenciado cada vez más, en particular después del surgimiento de brotes epidémicos de enfermedades virales asociadas a estos mamíferos. Objetivo: Analizar la influencia de los murciélagos en la salud humana, centrándose en su papel como portadores de enfermedades virales y su potencial como reservorios y vectores de enfermedades. Métodos: Se realizó una revisión bibliográfica de la literatura utilizando descriptores MeSH y términos como: Animals, Wild Chiroptera, Virus Diseases, Zoonoses, Disease Vectors, Disease Reservoirs, Public Health, bats, Communicable Disease Control, Disease Outbreaks, Prevention and Control. Se revisaron 1 442 artículos en bases de datos y documentos oficiales, se seleccionaron las fuentes relevantes con Mendeley Desktop 1.19.4. y se obtuvieron al final 47 artículos. Resultados: Existen varias especies de murciélagos que pueden afectar la salud del ser humano y que albergan en especial virus de las familias Filoviridae, Coronaviridae y Paramixoviridae. Los murciélagos se consideran incubadoras óptimas para la propagación de virus debido a su sistema inmune único que lo hace resistente a estos agentes infecciosos. Conclusiones: La vigilancia y monitoreo de los murciélagos, junto con acciones de educación pública y una gestión adecuada de sus hábitats, son fundamentales para la detección temprana y prevención de la transmisión de nuevos virus de estos mamíferos a los humanos.

Introduction: Bats are the only flight mammals, with around 1,400 species playing critical roles as pest controllers and nocturnal plant pollinators. However, its impact on human health has become increasingly evident, especially after the appearance of epidemic outbreaks of viral diseases related to these mammals. Objetive: To analyze the influence of bats on human health, focusing on their role as carriers of viral diseases and their potential as reservoirs and vectors of diseases. Methods: A literature bibliographical review was conducted using MeSH descriptors and keywords such as: Animals, Wild Chiroptera, Virus Diseases, Zoonosis, Disease Vectors, Disease Reservoirs, Public Health, bats, Communicable Disease Control, Disease Outbreaks, Prevention and Control. 1442 articles in databases and official documents were reviewed, selecting the relevant sources with Mendeley Desktop 1.19.4., obtaining 47 articles at the end. Results: There are several species of bats that can affect human health and that mainly harbor viruses from the Filoviridae families, Coronaviridae and Paramyxoviridae. Bats are considered optimal incubators for the spread of the virus due to their unique immune system that makes them particularly resistant to these infectious agents. Conclusions: Surveillance and monitoring of bats, together with public education actions and proper management of their habitats, are essential for early detection and prevention of transmission of new viruses from these mammals to humans.

Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance.

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing "idiotypic network theory" and "Treg cell theory" into an "anti-idiotypic Treg cell theory." Based on this hypothesis, an "active anti-idiotypic therapy" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.

Molecular Mimicry between SARS-CoV-2 Proteins and Human Self-Antigens Related with Autoimmune Central Nervous System (CNS) Disorders.

SARS-CoV-2 can trigger autoimmune central nervous system (CNS) diseases in genetically susceptible individuals, a mechanism poorly understood. Molecular mimicry (MM) has been identified in other viral diseases as potential triggers of autoimmune CNS events. This study investigated if MM is the process through which SARS-CoV-2 induces the breakdown of immune tolerance. The frequency of autoimmune CNS disorders was evaluated in a prospective cohort with patients admitted to the COVID-19 Intense Care Unity (ICU) in Rio de Janeiro. Then, an in silico analysis was performed to identify the conserved regions that share a high identity between SARS-CoV-2 antigens and human proteins. The sequences with significant identity and antigenic properties were then assessed for their binding capacity to HLA subtypes. Of the 112 patients included, 3 were classified as having an autoimmune disorder. A total of eleven combinations had significant linear and three-dimensional overlap. NMDAR1, MOG, and MPO were the self-antigens with more significant combinations, followed by GAD65. All sequences presented at least one epitope with strong or intermediate binding capacity to the HLA subtypes selected. This study underscores the possibility that CNS autoimmune attacks observed in COVID-19 patients, including those in our population, could be driven by MM in genetically predisposed individuals.

Does SARS-CoV-2 Induce IgG4 Synthesis to Evade the Immune System?

SARS-CoV-2, the virus that causes the COVID-19 disease, has been shown to cause immune suppression in certain individuals. This can manifest as a reduced ability of the host's immune system to effectively control the infection. Studies have reported that patients with COVID-19 can exhibit a decline in white blood cell counts, including natural killer cells and T cells, which are integral components of the immune system's response to viral pathogens. These cells play critical roles in the immune response to viral infections, and their depletion can make it harder for the body to mount an effective defense against the virus. Additionally, the virus can also directly infect immune cells, further compromising their ability to function. Some individuals with severe COVID-19 pneumonia may develop a "cytokine storm", an overactive immune response that may result in tissue damage and organ malfunction. The underlying mechanisms of immune suppression in SARS-CoV-2 are not entirely understood at this time, and research is being conducted to gain a more comprehensive understanding. Research has shown that severe SARS-CoV-2 infection promotes the synthesis of IgG4 antibodies. In this study, we propose the hypothesis that IgG4 antibodies produced by B cells in response to infection by SARS-CoV-2 generate immunological tolerance, which prevents its elimination and leads to persistent and chronic infection. In summary, we believe that this constitutes another immune evasion mechanism that bears striking similarities to that developed by cancer cells to evade immune surveillance.

COVID-19 en las embarazadas. Riesgo de las complicaciones durante el embarazo y en el neonato / COVID-19 in pregnant women. Risk of complications during pregnancy and in the newborn

Sobre el tema COVID-19 se han publicado múltiples estudios que reflejan su elevada incidencia, transmisibilidad, morbilidad y mortalidad, con gran repercusión y severidad en los grupos poblacionales de riesgo. El embarazo no escapa a ello, y la inmunosupresión fisiológica que se presenta en esta condición, hace a la gestante y al neonato, ser más susceptibles a las enfermedades infecciosas. El objetivo de esta comunicación es profundizar en la fisiopatología y la repercusión de la enfermedad COVID-19 en las gestantes y el neonato, para mejorar el conocimiento relacionado con el tema, el cual repercutirá en un mejor manejo de estos pacientes. Para ello, se realizó una revisión de investigaciones publicadas en el período comprendido entre enero y diciembre de 2021, en las bases de datos: SciELO, SCOPUS, Medline, Dialnet, Cumed y Lilacs. De los 44 artículos obtenidos inicialmente, 33 cumplieron los criterios de inclusión.

Several studies on COVID-19 have been published reflecting its high incidence, transmissibility, morbidity and mortality, with great repercussions and severity in population groups at risk. Pregnancy does not escape from this, and the physiological immunosuppression that occurs in this condition makes the pregnant woman and the newborn more susceptible to infectious diseases. The objective of this communication is to deepen the pathophysiology and the repercussion of the COVID-19 disease in pregnant women and the newborn in order to improve knowledge related to the subject, which will have an impact on better management of these patients. For this, a review of research published between January and December 2021 was carried out in the databases such as SciELO, SCOPUS, Medline, Dialnet, Cumed and Lilacs. A number of 33 articles met the inclusion criteria from 44 initially obtained.

Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia.

Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from the spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen, promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-ß secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.

[Development of autoimmunity in patients with primary immunodeficiencies]. / Desarrollo de autoinmunidad en pacientes con inmunodeficiencias primarias.

The autoimmune diseases include many in which the immune system is directed against the host, leading to life-threatening destruction of organs. The origin of autoimmune disorders can be multifactorial and, there are no specific therapy for these diseases. Primary immunodeficiencies are a group of immune disorders that affect different components of the innate and adaptive responses. Interestingly, patients with primary immunodeficiencies have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies, and autoimmune diseases. The molecular mechanism for development of autoimmunity in immunodeficiencies is unclear. The study of the complex immune regulatory and signaling mechanisms is revealing the relationships between primary immunodeficiency syndromes and autoimmune diseases. Newly, it has been demonstrated that a deficient maturation of immune cells; the deficiency of proteins important for T and B lymphocyte function and impaired signally pathways that include key molecules in regulation and activation of immune cells are associated with the development of autoimmunity in patients with primary immunodeficiencies. The aim of the present work is to review the evidence available to date regarding the cellular and molecular mechanisms involved in the development of autoimmunity in patients with primary immunodeficiencies.

Las enfermedades autoinmunes constituyen un grupo de trastornos del sistema inmunológico en dónde este ataca a las células propias del organismo. Las causas pueden ser multifactoriales y no hay tratamientos específicos contra estas enfermedades. Por su parte, las inmunodeficiencias primarias (IDP) son un grupo de alteraciones originadas por defectos genéticos que tienen como consecuencia la deficiencia en la función del sistema inmunológico. Actualmente, se han descrito algunos mecanismos celulares y moleculares por los cuales se desarrollan trastornos autoinmunes en pacientes con inmunodeficiencias, sin embargo, dichos mecanismos no se han descrito con exactitud. Lo anterior, representa uno de los principales retos de las personas que lo padecen. De manera interesante, diversos reportes indican que la autoinmunidad secundaria a la inmunodeficiencia sigue algunos mecanismos celulares y moleculares como: una deficiente maduración de células inmunológicas; deficiencia de proteínas importantes para la función de los linfocitos T y B y; fallas en la función de moléculas de señalización intracelular importantes para la regulación inmunológica. En conjunto, estos mecanismos se relacionan con el desarrollo de autoinmunidad en pacientes con IDP. El objetivo del presente trabajo fue realizar una revisión de la evidencia disponible hasta la fecha respecto a los mecanismos celulares y moleculares implicados en el desarrollo de autoinmunidad en pacientes con IDP.

[Basophil activation test to follow-up of patients treated with hymenoptera venom immunotherapy: a review of current evidence]. / Prueba de activación de basófilos en el seguimiento de pacientes que reciben inmunoterapia con veneno de himenópteros: revisión de la evidencia actual.

Hymenoptera venom immunotherapy (HVI) is a long-term effective treatment to avoid new systemic reactions in patients with Hymenoptera allergy. The sting challenge test is considered the gold standard to confirm the tolerance. However, the use of this technique is not generalized in clinical practice, being the basophil activation test (BAT), which functionally explores allergen response, an alternative that does not entail any of the provocation risks associated with the sting challenge test. This study reviews the publications that used the BAT to follow up and evaluate the success of the HVI. Studies assessing the changes between a baseline BAT before the start and BATs performed between the starting and maintenance phases of the HVI were selected. Ten articles were found, comprising information from 167 patients, of which 29% used the sting challenge test. The studies concluded the importance of evaluating the responses with submaximal allergen concentrations, which reflect basophil sensitivity, to monitor the HVI using the BAT. It was also observed that changes in the maximum response (reactivity) could not reflect the clinical status of tolerance, particularly in the initial phases of HVI.

La inmunoterapia con veneno de himenópteros (IVH) es, a largo plazo, un tratamiento eficaz para evitar nuevas reacciones sistémicas en pacientes con alergia a este tipo de insectos. La prueba de repicadura controlada es el estudio de referencia para confirmar la tolerancia del individuo. Sin embargo, no se ha generalizado su indicación clínica, por lo que la prueba de activación de basófilos (TAB) resulta una buena alternativa, pues valora de manera funcional la respuesta al alérgeno y está exenta de los riesgos asociados con la provocación. En esta revisión se explora la utilidad de la TAB en el seguimiento y valoración del éxito de la IVH. Se seleccionaron estudios que evalúan los cambios entre una TAB basal y en otro momento de la fase de inicio o mantenimiento de la IVH. Se incluyeron 10 estudios con datos de 167 pacientes, de los que el 29% había tenido prueba de repicadura controlada. Para vigilar la eficacia de la IVH debe explorarse la respuesta del basófilo, con la determinación de las concentraciones submáximas del alérgeno, que reflejan la sensibilidad del basófilo. Los cambios en la respuesta máxima (reactividad) no pueden aportar información del estado de tolerancia, especialmente en las fases iniciales de la IVH.

Anemia hemolítica autoinmune: mecanismos de inducción de autoinmunidad e inmunobiología / Autoimmune hemolytic anemia: mechanisms of autoimmunity induction and immunobiology

Introducción: La patogénesis de la anemia hemolítica autoinmune es un proceso complejo en el que muchos elementos tienen una función esencial que repercuten en la gran heterogeneidad clínica de la enfermedad, pero los mecanismos involucrados en su inducción se desconocen en gran medida. Objetivo: Explicar los principales mecanismos propuestos en el inicio y aparición de la anemia hemolítica autoinmune y su contribución a la fisiopatología de la enfermedad. Métodos: Se realizó una revisión de la literatura en los idiomas inglés y español, de artículos publicados en los últimos 10 años sobre mecanismos propuestos en el inicio de la anemia hemolítica autoinmune. Análisis y síntesis de la información: Los mecanismos propuestos en la inducción de la autoinmunidad contra los eritrocitos incluyen el mimetismo molecular entre antígenos endógenos y antígenos exógenos, el procesamiento desregulado de autoantígenos influenciado por factores adquiridos y la disfunción de los linfocitos B y T. Conclusiones: Los mecanismos propuestos en la aparición de la anemia hemolítica autoinmune brindan información valiosa para mejorar la comprensión de los mecanismos moleculares involucrados y subrayan la complejidad de los fenómenos involucrados en la perdida de la tolerancia hacia los eritrocitos autólogos y el delicado equilibrio entre factores genéticos y ambientales(AU)

Introduction: The pathogenesis of autoimmune hemolytic anemia is a complex process in which many elements play an essential role and have an impact on the great clinical heterogeneity of the disease, but the mechanisms involved in its induction are largely unknown. Objective: To explain the main mechanisms proposed in the initiation and occurrence of autoimmune hemolytic anemia and its contribution to the pathophysiology of the disease. Methods: A review of the literature, in English and Spanish languages, of articles published in the last 10 years on proposed mechanisms in the initiation of autoimmune hemolytic anemia was carried out. Analysis and synthesis of information: Proposed mechanisms for the induction of autoimmunity against erythrocytes include molecular mimicry between endogenous and exogenous antigens, deregulated processing of autoantigens influenced by acquired factors, and B and T cells dysfunction. Conclusions: The proposed mechanisms in the occurrence of autoimmune hemolytic anemia provide valuable information to improve the understanding of the mechanisms involved and underline the complexity of the phenomena involved in the loss of tolerance towards autologous erythrocytes and the delicate balance between genetic and environmental factors(AU)

Time between inhibitor detection and start of immune tolerance induction: Association with outcome in the BrazIT study.

BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.

Coinfección por Cryptococcus neoformans en paciente trasplantado renal con COVID-19 / Cryptococcus neoformans co-infection in a kidney transplant patient with COVID-19

Resumen La infección por el síndrome respiratorio agudo severo por coronavirus 2 (SARS-CoV-2), causante de la enfermedad COVID-19, representa una de las emergencias sanitarias más deletéreas de las últimas dos décadas; de la que aún existen innumerables incógnitas acerca del curso y manejo de presentaciones atípicas. Por lo anterior, resulta importante publicar casos clínicos de interés en población especial como lo son los pacientes receptores de trasplante renal, quienes pueden tener un mayor riesgo de contraer la enfermedad dado su estado de inmunosupresión, así como por el contacto frecuente con el sistema de atención médica. La coinfección con otros virus respiratorios no es infrecuente en población trasplantada con COVID-19, y la asociación con gérmenes oportunistas como Micobacterias, Citomegalovirus, Pneumocystis jirovecii y hongos, tal como el Cryptococcus neoformans es desconocida, pero es posible que dicha asociación pudiese empeorar la severidad del compromiso sistémico y pulmonar. Se presenta el caso de un hombre de 45 años, con antecedentes de trasplante renal de donante cadavérico, que ingresó al servicio de urgencias del Hospital de San José; el presentó síndrome de dificultad respiratoria aguda (SDRA) y falla ventilatoria por infección por SARS-CoV-2. Además, se confirmó infección sistémica por Cryptococcus neoformans sin compromiso del sistema nervioso central. Se inició manejo con ventilación mecánica invasiva, glucocorticoide, anfotericina B liposomal; fallece a los 12 días de su ingreso.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the disease COVID-19, represents one of the most deleterious health emergencies of the last two decades; of which there are still innumerable unknowns about the course and handling of atypical presentations. Therefore, it is important to publish clinical cases of interest in a special population, such as kidney transplant recipients, who may have a greater risk of contracting the disease due to their immunosuppression and frequent contact with the medical care system. Co-infection with other respiratory viruses is not uncommon in the transplanted population with COVID-19, and the association with opportunistic germs such as Mycobacteria, Cytomegalovirus, Pneumocystis jirovecii and fungi, such as Cryptococcus neoformans, is unknown, yet it is possible that this association could worsen the severity of the systemic and pulmonary involvement. We present the case of a 45-year-old deceased-donor kidney transplant recipient man who was admitted to the emergency service; he presented acute respiratory difficulty syndrome (ARDS) and ventilatory failure due to infection by SARS-CoV-2. It was also confirmed that he had systemic infection by Cryptococcus neoformans without compromise of the central nervous system. It was necessary to use invasive mechanical ventilation, glucocorticoid, liposomal amphotericin B; he died 12 days after admission.

Atherosclerosis: immunopathogenesis and strategies for immunotherapy.

Atherosclerosis, a chronic inflammatory condition in which atheroma accumulates within the intima of the arterial wall, is a life-threatening manifestation of cardiovascular disease, due to atheroma rupture, chronic luminal narrowing and thrombosis. Current knowledge of the role of a protective immune response in atherosclerotic lesions has provided promising opportunities to develop new immunotherapeutic strategies. In particular, Tregs exert an atheroprotective role by releasing anti-inflammatory cytokines (IL-10/TGF-ß) and suppressing autoreactive T lymphocytes. In vivo animal experiments have shown that this can be achieved by developing vaccines that stimulate immunological tolerance to atheroma antigens. Here, we present an overview of the current knowledge of the proatherogenic immune response, and we discuss the strategies currently used as immunoregulatory therapy.

Lay abstract Atherosclerosis is a chronic inflammatory disease in which the wall of the artery develops abnormalities, and can lead to serious problems, including heart attack, stroke, or even death. Scientific evidence has shown that the immune system is involved in the development and progression of atherosclerosis. Understanding the role of protective immune response in atherosclerosis provided promising opportunities to develop approaches for prevention and treatment.

Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing ß-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping ß-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.

Papel de la alimentación en la respuesta a infecciones respiratorias altas en atletas de élite / Role of nutrition in the response to upper respiratory infections in elite athletes

Las infecciones de las vías respiratorios altas (IVRA), son debilitantes para el potencial deportivo de los atletas de élite. El ejercicio físico activa múltiples vías moleculares y bioquímicas relacionadas con el sistema inmune, sensibles a influencias nutricionales. Sobre este contexto, la inmunonutrición está adquiriendo una nueva dirección orientada a conseguir el equilibrio inmunológico, contraponiéndose con algunas de las teorías que han sentado las bases de la inmunología del ejercicio durante las últimas décadas. Objetivo. Investigar los aspectos nutricionales que puedan mejorar la respuesta inmunológica en deportistas de elite. Estudiar los posibles beneficios del equilibrio inmunológico para mejorar el rendimiento, analizar los factores nutricionales que contribuyan al equilibrio de la respuesta inmunológica y extrapolar la evidencia actual en recomendaciones prácticas de alimentación/suplementación para mejorar la homeostasis de la respuesta inmunológica en atletas de élite, teniendo en cuenta las limitaciones existentes.Resultados. La evidencia científica apunta que se puede potenciar el equilibrio inmunológico y la respuesta inmune a través de la modificación de factores nutricionales. Dentro de los cuales, la vitamina D, los probióticos, la vitamina C y el cinc son los que cuentan con mayor evidencia. Conclusión. Los avances científicos resultan prometedores y de interés para los atletas de élite, debido a que pueden disminuir la incidencia de IVRA, mejorando el éxito deportivo de los mismos. Se requieren más estudios para su validación y aplicación(AU)

Upper respiratory tract infections (URTI) are debilitating for the athletic potential of elite athletes. Physical exercise in elite athletes activates multiple molecular and biochemical pathways related to the immune system, which, at the same time, are sensitive to nutritional influences. Based on this context, immunonutrition is taking a new direction aimed at achieving the immunological balance. Objective. To investigate the nutritional aspects that can improve the immune response in elite athletes. To study the potential benefits of immune balance to improve performance, to analyse nutritional factors that contribute to the balance of the immune response and to extrapolate current evidence into practical dietary/supplementation recommendations to improve the homeostasis of the immune response in elite athletes, considering existing limitations. Results. Scientific evidence suggests that immune balance and immune response can be enhanced through the modification of nutritional factors. Among which, vitamin D, probiotics, vitamin C and zinc are the micronutrients with most evidence. Conclusion. Scientific advances in this field are promising and of great interest to elite athletes since it could decrease the incidence of URTI and, as a consequence, it could improve their sporting success. However, more studies are still required for its validation and application(AU)

Efficacy of Probiotics in Children and Adolescents With Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To evaluate the clinical efficacy of a mixture of probiotics (Lactobacillus and Bifidobacterium) in children and adolescents with atopic dermatitis (AD) and the effects on sensitization, inflammation, and immunological tolerance. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, we enrolled 60 patients aged between 6 months and 19 years with mild, moderate, or severe AD, according to the criteria proposed by Hanifin and Rajka. Patients were stratified to receive one gram per day of probiotics or placebo for 6 months. The primary outcome was a decrease in SCORing Atopic Dermatitis (SCORAD). Secondary outcomes were to assess the role of probiotics on the use of topical and oral medicines (standard treatment), serum IgE levels, skin prick test (SPT), and tolerogenic and inflammatory cytokines. Background therapy was maintained. RESULTS: Forty patients completed the study (24 probiotics, 16 placebo). After treatment for six months, the clinical response was significantly better in the probiotics group; the SCORAD decreased [mean difference (MD) 27.69 percentage points; 95% confidence interval (CI), 2.44-52.94], even after adjustment for co-variables (MD 32.33 percentage points; 95%CI, 5.52-59.13), especially from the third month of treatment on. The reduction of the SCORAD in probiotic group persisted for three more months after the treatment had been discontinued, even after adjustment for co-variables (MD 14.24 percentage points; 95%CI, 0.78-27.70). Patients in the probiotics group required topical immunosuppressant less frequently at 6 and 9 months. No significant changes were found for IgE levels, SPT and cytokines. CONCLUSIONS: Children and adolescents with AD presented a significant clinical response after 6 months with a mixture of probiotics (Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus paracasei, and Bifidobacterium lactis. However, this clinical benefit is related to treatment duration. Probiotics should be considered as an adjuvant treatment for AD.