Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases.

PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein-protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions.

Epigenetic Therapy as a Putative Molecular Target to Modulate B Cell Biology and Behavior in the Context of Immunological Disorders.

Histone Deacetylase- (HDAC-) dependent epigenetic mechanisms have been widely explored in the last decade in different types of malignancies in preclinical studies. This effort led to the discovery and development of a range of new HDAC inhibitors (iHDAC) with different chemical properties and selective abilities. In fact, hematological malignancies were the first ones to have new iHDACs approved for clinical use, such as Vorinostat and Romidepsin for cutaneous T cell lymphoma and panobinostat for multiple myeloma. Besides these promising already approved iHDACs, we highlight a range of studies focusing on the HDAC-dependent epigenetic control of B cell development, behavior, and/or function. Here, we highlight 21 iHDACs which have been studied in the literature in the context of B cell development and/or dysfunction mostly focused on B cell lymphomagenesis. Regardless, we have identified 55 clinical trials using 6 out of 21 iHDACs to approach their putative roles on B cell malignancies; none of them focuses on peritoneal B cell populations. Since cells belonging to this peculiar body compartment, named B1 cells, may contribute to the development of autoimmune pathologies, such as lupus, a better understanding of the HDAC-dependent epigenetic mechanisms that control its biology and behavior might shed light on iHDAC use to manage these immunological dysfunctions. In this sense, iHDACs might emerge as a promising new approach for translational studies in this field. In this review, we discuss a putative role of iHDACs in the modulation of peritoneal B cell subpopulation's balance as well as their role as therapeutic agents in the context of chronic diseases mediated by peritoneal B cells.

[A medical biography of Ludwig van Beethoven]. / Ludwig van Beethoven, el genio de Bonn atormentado por sus enfermedades: su historia médica.

Much emphasis has been given to the deafness of Ludwig van Beethoven and its potential causes. However, when analyzing several symptoms reported by himself throughout his life in many letters and his final illness, a common etiology emerges. This article reports the medical history of this artist, based on authoritative scientific sources.

De Novo Allergy and Immune-Mediated Disorders Following Solid-Organ Transplantation-Prevalence, Natural History, and Risk Factors.

OBJECTIVES: To describe the prevalence, natural course, outcome, and risk factors of post-transplant de novo allergy and autoimmunity. STUDY DESIGN: A cross-sectional, cohort study of all children (<18 years) who underwent a solid-organ transplantation, between 2000 and 2012, in a single transplant center, with a follow-up period of 6 months or more post-transplant and without history of allergy or immune-mediated disorder pretransplant. RESULTS: A total of 626 eligible patients were screened, and 273 patients (160 males; 59%) met the inclusion criteria; this included 111 liver, 103 heart, 52 kidney, and 7 multivisceral recipients. Patients were followed for a median period of 3.6 years. A total of 92 (34%) patients (42 males, 46%) developed allergy or autoimmune disease after transplantation, with a high prevalence among liver (41%), heart (40%), and multivisceral (57%) transplant recipients compared with kidney recipients (4%; P < .001). Post-transplant allergies included eczema (n = 44), food allergy (22), eosinophilic gastrointestinal disease (11), and asthma (28). Autoimmunity occurred in 18 (6.6%) patients, presenting mainly as autoimmune cytopenia (n = 10). In a multivariate analysis, female sex, young age at transplantation, family history of allergy, Epstein-Barr virus infection, and elevated eosinophil count >6 months post-transplantation were associated with an increased risk for allergy or autoimmunity. Two patients (0.7%) died from autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis, and 52 episodes of post-transplant allergy, autoimmunity, and immune-mediated disorders (37%) did not improve over time. CONCLUSIONS: Allergy and autoimmunity are common in pediatric liver, heart, and multivisceral transplant recipients and pose a significant health burden. Further studies are required to clarify the mechanisms behind this post-transplant immune dysregulation.

Ludwig van Beethoven, el genio de Bonn atormentado por sus enfermedades: su historia médica / A medical biography of Ludwig van Beethoven

Much emphasis has been given to the deafness of Ludwig van Beethoven and its potential causes. However, when analyzing several symptoms reported by himself throughout his life in many letters and his final illness, a common etiology emerges. This article reports the medical history of this artist, based on authoritative scientific sources.

Immune dysfunction in bipolar disorder and suicide risk: is there an association between peripheral corticotropin-releasing hormone and interleukin-1ß?

OBJECTIVE: The aim of the present study was to investigate the relationship between peripheral levels of corticotropin-releasing hormone (CRH) and interleukin-1ß (IL-1ß) in individuals with bipolar disorder (BD) with and without suicide risk (SR), and controls. METHODS: A total of 120 young adults (40 controls, 40 subjects with BD without SR, and 40 subjects with BD with SR) were enrolled from a population-based study carried out in the city of Pelotas, Brazil. BD and SR were assessed through the Mini International Neuropsychiatric Interview (MINI 5.0), and peripheral markers were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Levels of CRH were significantly lower both in subjects with BD without SR (p = 0.04) and subjects with BD with SR (p = 0.02) when compared to controls. However, levels of IL-1ß were increased in subjects with BD with SR (p = 0.05) when compared to controls. Sociodemographic and clinical variables, current mood episode, and use of psychiatric medications were not associated with changes in these markers. No correlation was found between peripheral levels of CRH and IL-1ß (p = 0.60) in the population or in the BD with SR group (p = 0.88). CONCLUSIONS: These results suggest that peripheral mechanisms linking stress hormones and the immune system might be critical patterns involved in suicidal behavior associated with BD.

Curso de atualização em cardiologia: aula 10. Miocardite como modelo de doença imunológica: aspectos clínicos e diagnósticos / Cardiology updating course: class 10. Miocardite as model of disease imunológica: clinical aspects and diagnoses

Miocardites são um grupo de doenças heterogêneas que podem ser compreendidas com uma fisiopatologia imunológica. Os autores discutem aspectos históricos e a imunologia dessas doenças, correlacionando o trabalho de cientistas como Carlos Chagas, Noel Rose e Nelson Vaz. Levam em consideração a evolução histórica do conhecimento científico e a mudança de paradigma em andamento na imunologia. Também analisam as principais manifestações clínicas e estratégias para o diagnóstico e abordam novas propostas para investigação clínica dessas síndromes.

Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation.

STAT5 proteins are components of the common growth hormone and interleukin 2 family of cytokines' signaling pathway. Mutations in the STAT5b gene, described in 2 patients, lead to growth hormone insensitivity that resembles Laron syndrome. Clinical immunodeficiency was also present, although immunologic defects have not been well characterized thus far. Here we describe a 16-year-old girl who suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis. Clinical features of congenital growth hormone deficiency were observed, such as persistently low growth rate, severely delayed bone age, and postnatal growth failure resulting from growth hormone resistance. This combined phenotype of growth hormone insensitivity and immunodeficiency was attributable to a homozygous C-->T transition that resulted in a nonsense mutation at codon 152 in exon 5 of the STAT5b gene. This novel mutation determined a complete absence of protein expression. The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio, and very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells. T cells presented a chronically hyperactivated phenotype. In vitro T-cell proliferation and interleukin 2 signaling were impaired. CD4+ and CD25+ regulatory T cells were significantly diminished, and they probably contributed to the signs of homeostatic mechanism deregulation found in this patient. This new case, in accordance with 2 previously reported cases, definitely demonstrates the significant role of the STAT5b protein in mediating growth hormone actions. Furthermore, the main immunologic findings bring about an explanation for the clinical immunodeficiency features and reveal for the first time the relevant role of STAT5b as a key protein for T-cell functions in humans.

Síndrome de activación macrofagico en pediatría: a propósito de cuatro casos / Activated macrophage syndrome in paediatrics: 4 clinical cases

Introducción: El Síndrome de Activación Macrofágico (SAM) es una entidad poco frecuente en la práctica pediátrica que se caracteriza por una excesiva activación del sistema macrofágico y por una liberación exagerada de citoquinas por parte de los linfocitos T, y que clínicamente se manifiesta como un síndrome semejante a una falla orgánica múltiple. Existe actualmente disparidad en la nomenclatura de este síndrome, y es así como a nivel de la reumatología pediátrica se mantiene el término de SAM, mientras que para los hemato-oncólogos esta enfermedad está incluida dentro de las diferentes variedades de histiocitosis. Objetivo: Actualizar el conocimiento respecto de la etiología, clínica y tratamiento del SAM, enfermedad de baja frecuencia y alta mortalidad, en relación al análisis de 4 casos clínicos. Casos clínicos: 2 pacientes eran portadores de una enfermedad reumatológica, Artritis Idiopática Juvenil, el tercer paciente presentaba elementos de Inmunodeficiencia, y el último niño de linfohistiocitosis familiar congénita. Los factores desencadenantes del SAM fueron fármacos en dos pacientes y una posible causa infecciosa en los dos restantes. Los cuatro pacientes sobrevivieron al proceso inicial después de recibir una terapia agresiva inmunosupresora con esteroides en altas dosis y ciclosporina intravenosa. Conclusión: La importancia de dar a conocer este síndrome, radica en que un diagnóstico precoz y una terapia agresiva, preferentemente con ciclosporina y pulsos de esteroides en altas dosis, puede mejorar significativamente el pronóstico de esta enfermedad.

What causes pre-eclampsia?

Pre-eclampsia remains a leading cause of maternal and fetal morbidity and mortality. Despite extensive research, the mechanisms that cause pre-eclampsia are unknown and it has been considered to be the 'disease of theories'. Hippocrates wrote in one of his Aphorisms that 'convulsions take place from either repletion or depletion'. Since then, obstetricians have been divided on the question of which factor accounted for the convulsions observed during childbirth. Some considered that a sudden reduction in intra-abdominal pressure at delivery led to a pooling of blood diverted from the brain, causing collapse of the cerebral blood vessels and convulsions. Others postulated that cerebral congestion, secondary to compression of the abdominal organs by the large uterus, diverted blood to the brain, causing eclamptic convulsions. It is the purpose of this review to examine those theories about the cause of pre-eclampsia for which modern evidence is available. At present, it is believed that the pathological chain of events leading to pre-eclampsia is scheduled in two steps: an absolute or relative placental ischaemia is followed by a diffuse endothelial cell activation, which causes the clinical features of the disease.

[Superantigens in human disease]. / Superantígenos en la enfermedad humana.

Superantigens include viral and bacterial products, mainly of streptococci, staphylococci that stimulate T cells to proliferate nonspecifically through interaction with class II major histocompatibility complex products on antigen-presenting cells and then with variable regions on the beta chain of T cell receptor complex. Superantigens cause symptoms via release of immune cytokines. These proteins should be considered potential cause of illnesses such as rheumatic fever, arthritis. Kawasaki syndrome, atopic dermatitis, and guttate psoriasis because of their potent immune system-altering capacity.

Anormalidades imunologicas e susceptibilidade a infeccoes na anemia ferropriva / Imunological abnormalities and susceptibility the infections in hypochromic anemia

A relacao entre a incidencia de infeccoes e o estado nutricional de ferro e bastante controvertida, sendo relatados tanto maioir susceptibilidade como maior resistencia a infeccoes na anemia ferropriva. O ferro e essencial para o cresciemnto de mocroorganismos e a sua carencia ao lado de limitar a proliferacao dos mesmos determina alteracoes imunologicas no hospedeiro. Estas anormalidades caracterizam uma imunodeficiencia multifatorial, porem parcial. Assim, a susceptibilidade a infeccoes nos pacientes com anemia ferropriva seria determinada pelo balanco entre as alteracoes imunologicas e a limitacao do crescimento dos microorganismos condicionada pela carencia de ferro. Variacoes do equilibrio deste binomio poderiam explicar os resultadosdiscrepantes assinaladosna literatura