The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1ß.

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1ß reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1ß. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.

Polydioxanone-Based Membranes for Bone Regeneration.

Resorbable synthetic and natural polymer-based membranes have been extensively studied for guided tissue regeneration. Alloplastic biomaterials are often used for tissue regeneration due to their lower immunoreactivity when compared with allogeneic and xenogeneic materials. Plenum® Guide is a synthetic membrane material based on polydioxanone (PDO), whose surface morphology closely mimics the extracellular matrix. In this study, Plenum® Guide was compared with collagen membranes as a barrier material for bone-tissue regeneration in terms of acute and subchronic systemic toxicity. Moreover, characterizations such as morphology, thermal analysis (Tm = 107.35 °C and crystallinity degree = 52.86 ± 2.97 %, final product), swelling (thickness: 0.25 mm ≅ 436% and 0.5 mm ≅ 425% within 24 h), and mechanical tests (E = 30.1 ± 6.25 MPa; σ = 3.92 ± 0.28 MPa; ε = 287.96 ± 34.68%, final product) were performed. The in vivo results revealed that the PDO membranes induced a slightly higher quantity of newly formed bone tissue than the control group (score: treated group = 15, control group = 13) without detectable systemic toxicity (clinical signs and evaluation of the membranes after necropsy did not result in differences between groups, i.e., non-reaction -> tissue-reaction index = 1.3), showing that these synthetic membranes have the essential characteristics for an effective tissue regeneration. Human adipose-derived stem cells (hASCs) were seeded on PDO membranes; results demonstrated efficient cell migration, adhesion, spread, and proliferation, such that there was a slightly better hASC osteogenic differentiation on PDO than on collagen membranes. Hence, Plenum® Guide membranes are a safe and efficient alternative for resorbable membranes for tissue regeneration.

The development of erythema elevatum diutinum in a patient with juvenile idiopathic arthritis under treatment with abatacept.

In this case report, we present the first report of erythema elevatum diutinum after treatment of juvenile idiopathic arthritis with abatacept. Although it could also be coincidental, in our case, the appearance of vasculitis was not blocked by the simultaneous administration of a stimulation inhibitor, and alerts to the fact that as effective as a abatacept may be to control of the inflammatory articular symptoms, this might not translate into control of the disease.

Ganciclovir-resistant, cytomegalic interstitial lung disease in a patient with systemic lupus erythematosus.

A patient with systemic lupus erythematosus developed interstitial lung disease initially felt to be a manifestation of the disease but that, on further workup, proved to be a manifestation of cytomegalic disease resistant to ganciclovir. Treatment with foscarnet was associated with prompt improvement.

HLA-A*31 as a marker of genetic susceptibility to sepsis.

OBJECTIVE: The HLA haplotype has been associated with many autoimmune diseases, but no associations have been described in sepsis. This study aims to investigate the HLA system as a possible marker of genetic sepsis susceptibility. METHODS: This is a prospective cohort study including patients admitted to an intensive care unit and healthy controls from a list of renal transplant donors. Patients with less 18 years of age; pregnant or HIV positive patients; those with metastatic malignancies or receiving chemotherapy; or with advanced liver disease; or with end-of-life conditions were excluded. The DNA was extracted from the whole blood and HLA haplotypes determined using MiliPlex® technology. RESULTS: From October 2010 to October 2012, 1,121 patients were included (1,078 kidney donors, 20 patients admitted with severe sepsis and 23 with septic shock). HLA-A*31 positive subjects had increased risk of developing sepsis (OR 2.36, 95%CI 1.26-5.35). Considering a p value <0.01, no other significant association was identified. CONCLUSION: HLA-A*31 expression is associated to risk of developing sepsis.

Thermodynamics as the driving principle behind the immune system.

Over the last 120 years, few things contributed more to our understanding of immune system than the study of its behavior in the host/parasite relationship. Despite the advances though, a few questions remain, such as what drives the immune system? What are its guiding principles? If we ask these questions randomly, most will immediately answer "defend the body from external threats," but what exactly do we defend ourselves from? How do these threats harm us? What criteria define what constitutes a threat? On the other hand, if the immune system evolved to defend us against external threats, how does its action against "internal" processes, such as neoplasms, qualify? Why do we die from cancer? Or from infection? Or even, why do we die at all? These apparently obvious questions are nor simple neither trivial, and the difficulty answering them reveals the complex reality that the immune system handles. The objective of this article is to articulate for the reader something that he instinctively already knows: that the decisions of the immune system are thermodynamically driven. Additionally, we will discuss how this apparent change in paradigm alters concepts such as health, disease, and therapeutics.

HLA-A*31 como marcador de suscetibilidade genetica em sepse / HLA-A*31 as a marker of genetic susceptibility to sepsis

Objetivo: Haplótipos do HLA têm sido associados a muitas doenças autoimunes, mas não foi descrita qualquer associação na sepse. O objetivo desse estudo é investigar o sistema HLA como um possível marcador de suscetibilidade genética à sepse. Métodos: Estudo prospectivo de coorte, incluindo pacientes admitidos em unidade de terapia intensiva e controles-saudáveis obtidos em lista de doadores de transplante renal. Foram excluídos pacientes abaixo dos 18 anos de idade, gestantes ou HIV positivos, pacientes com doença maligna metastática ou sob quimioterapia, pacientes com hepatopatia avançada, com condições de fim de vida. O DNA foi extraído de sangue total, e a haplotipagem de HLA foi realizada com a tecnologia MiliPlex®. Resultados: Foram incluídos 1.121 pacientes (1.078 doadores de rim, 20 pacientes com sepse grave e 23 pacientes admitidos por choque séptico) entre outubro de 2010 e outubro de 2012. Os participantes positivos para HLA-A*31 tiveram risco aumentado de desenvolver sepse (OR: 2,36 IC95%: 1,26-5,35). Não foi identificada outra associação significativa, quando considerado como nível de significância o valor de p<0,01. Conclusão: A expressão de HLA-A*31 está associada ao risco de desenvolvimento de sepse. .

Objective: The HLA haplotype has been associated with many autoimmune diseases, but no associations have been described in sepsis. This study aims to investigate the HLA system as a possible marker of genetic sepsis susceptibility. Methods: This is a prospective cohort study including patients admitted to an intensive care unit and healthy controls from a list of renal transplant donors. Patients with less 18 years of age; pregnant or HIV positive patients; those with metastatic malignancies or receiving chemotherapy; or with advanced liver disease; or with end-of-life conditions were excluded. The DNA was extracted from the whole blood and HLA haplotypes determined using MiliPlex® technology. Results: From October 2010 to October 2012, 1,121 patients were included (1,078 kidney donors, 20 patients admitted with severe sepsis and 23 with septic shock). HLA-A*31 positive subjects had increased risk of developing sepsis (OR 2.36, 95%CI 1.26-5.35). Considering a p value <0.01, no other significant association was identified. Conclusion: HLA-A*31 expression is associated to risk of developing sepsis. .

A termodinâmica como princípio motriz do sistema imune / Thermodynamics as the driving principle behind the immune system

Nos últimos 120 anos, poucas coisas contribuíram tanto para a compreensão do funcionamento do sistema imune quanto o estudo de seu comportamento na relação hospedeiro/parasita. Apesar do avanço, algumas questões permanecem sem resposta clara, como, por exemplo: qual o objetivo do sistema imune? Qual o princípio de sua atuação? Se perguntarmos aleatoriamente, a maioria imediatamente responderá: "defender o organismo contra invasores externos", mas exatamente do que nos defendemos? Como esses invasores nos prejudicam? Quais critérios determinam o que é um invasor? Por outro lado, se o sistema imune existe para nos defender de invasores externos, como qualificar sua atuação contra processos "internos", como as neoplasias? Por que morremos de câncer? Ou de infecção? Ou mesmo: por que morremos? Essas perguntas aparentemente óbvias não são simples nem triviais e a dificuldade em respondê-las revela a complexa realidade que o sistema imune administra. O objetivo deste artigo foi articular, para o leitor, algo que ele instintivamente já sabe: que as decisões do sistema imune são tomadas segundo princípios termodinâmicos. Adicionalmente, discutiremos como esta aparente mudança de paradigma altera conceitos como saúde, doença e terapêutica.

Over the last 120 years, few things contributed more to our understanding of immune system than the study of its behavior in the host/parasite relationship. Despite the advances though, a few questions remain, such as what drives the immune system? What are its guiding principles? If we ask these questions randomly, most will immediately answer "defend the body from external threats," but what exactly do we defend ourselves from? How do these threats harm us? What criteria define what constitutes a threat? On the other hand, if the immune system evolved to defend us against external threats, how does its action against "internal" processes, such as neoplasms, qualify? Why do we die from cancer? Or from infection? Or even, why do we die at all? These apparently obvious questions are nor simple neither trivial, and the difficulty answering them reveals the complex reality that the immune system handles. The objective of this article is to articulate for the reader something that he instinctively already knows: that the decisions of the immune system are thermodynamically driven. Additionally, we will discuss how this apparent change in paradigm alters concepts such as health, disease, and therapeutics.

Development of serum sickness-like symptoms after rituximab infusion in two patients with severe hypergammaglobulinemia.

Rituximab is a monoclonal antibody that depletes B cells and is commonly used for the treatment of autoimmune diseases. In this report, we describe 2 patients with autoimmune diseases and marked hypergammaglobulinemia attending at a tertiary care hospital, who, following treatment with rituximab, developed a severe serum-sickness-like reactions. Both patients were treated with intravenous corticosteroids, recovered well, and on follow-up, were negative for the development of human antichimeric antibodies. Based on these and other similar cases in the literature, we propose that severe hypergammaglobulinemia due to autoimmune conditions may be a predisposing factor for the development of a serum sickness-like reaction after treatment with Rituximab, which can sometimes occur without prior exposure to this antibody. Rheumatologists should be aware of this possible association when prescribing this medication.

Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis.

The hepatic immunopathology in schistosomiasis mansoni is mediated by CD4 T cells specific for egg antigens and varies considerably among mouse strains. Previous studies in high pathology C3H mice suggested that a strong T cell response was due to the recognition of an immunodominant epitope within the major egg antigen Sm-p40 (Sm-p40(234-246)). Using a panel of T cell hybridomas, we have now examined the egg antigen-specific TCR repertoire in two high pathology strains, C3H and CBA. We found that nearly half of the hybridomas responded to the Sm-p40(234-246 )epitope and, of these, nearly all expressed Valpha11.3 associated with Vbeta8. Furthermore, in response to egg antigen stimulation, transcript levels of Valpha11.3J36 (the most prevalent rearrangement expressed by Sm-p40(234-246)-specific hybridomas), increased in high pathology (CBA) but not in low pathology BALB/c strains. Our findings suggest that exacerbated schistosome egg-induced immunopathology can be driven by T cells expressing a highly restricted TCR structure specific for a single parasite epitope.

Enhanced egg-induced immunopathology correlates with high IFN-gamma in murine schistosomiasis: identification of two epistatic genetic intervals.

The genetic basis of dissimilar immunopathology development among mouse strains infected with Schistosoma mansoni is not known. We performed a multipoint parametric linkage analysis on a cohort of F(2) mice, offspring of brother-sister mating between (high pathology CBA x low pathology BL/6)F(1) mice, to examine whether the observed differences in the type of immune response or the extent of hepatic immunopathology are linked to any particular genomic intervals. The F(2) mice exhibited cytokine responses and immunopathologies that revealed a statistically significant correlation between prominent egg Ag-stimulated IFN-gamma production by mesenteric lymph node cells and hepatic egg granuloma size. Increased IFN-gamma production showed suggestive linkage to a dominant CBA locus on chromosome 1 and a recessive CBA locus on chromosome 5; significantly, there was an epistatic interaction between the two IFN-gamma loci. An additional locus with suggestive linkage to granuloma formation and a CBA-recessive mode of inheritance was mapped to centromeric chromosome 13. Our analysis identified the first three genetic regions that appear to influence the immunopathology in murine schistosomiasis; however, further congenic dissection studies will furnish a more precise understanding of the genetic control of this disease.

The immunobiology of Th1 polarization in high-pathology schistosomiasis.

Schistosomiasis is a serious global helminthic disease, in which the main immunopathology consists of a granulomatous and fibrosing reaction against tissue-trapped parasite eggs. The severity of this inflammatory process, the product of a CD4(+) T-cell-mediated immune response against parasite egg antigens, is, however, markedly uneven, both in human patients and among mouse strains in an experimental model. Severe schistosomiasis is associated with persistently elevated pro-inflammatory T-helper-1 (Th1)-type cytokines, whereas milder pathology is present when Th2 cytokines dominate. This scenario is supported by the pronounced pathology resulting from the obliteration of pathways that facilitate Th2 differentiation and by the development of more intense lesions in mouse strains that fail to downregulate the Th1 response. Genetically prone high-pathology mice have a higher proportion of CD4(+) T cells in lymph nodes and granulomas, in which the Th1 phenotype is driven by interleukin-12; they also develop a dominant repertoire against peptide 234-246 of the major Sm-p40 egg antigen, utilizing a strikingly restricted T-cell receptor structure that involves Valpha11.3beta8. In turn, low-pathology mice exhibit enhanced CD4(+) T-cell apoptosis, which contributes to limit pathology. The definition of distinctive immune profiles associated with polar forms of schistosomiasis opens opportunities for targeted immuno-intervention in individuals suffering from or at risk of severe disease.

Rituximab (Mabthera), uma nova abordagem para tratamento da artrite reumatóide. Uma revisãosistemática / Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

Rituximab é um anticorpo monoclonal quimérico capaz de reduziro repertório de linfócitos B que expressam CD20. Estudos clínicosrealizados em pacientes com diagnóstico definido de artrite reumatóideativa confirmaram que um ciclo único de rituximab aplicado por meiode duas infusões no intervalo de uma semana, associado a um regimesemanal de metotrexato, produz resposta clínica duradoura comparávelàquela observada com o bloqueio do TNF e pode reduzir a velocidadede dano estrutural nas articulações. Rituximab foi recentementeaprovado para tratamento de artrite reumatóide ativa não-responsivaao tratamento com agentes inibidores do TNF e apresenta um bom histórico de segurança, mas sua infusão pode gerar reações comfreqüência e gravidade variáveis que, na maior parte dos casos,podem ser evitadas com a administração intravenosa de corticóides eanti-histamínicos antes da infusão. O perfil de segurança do rituximaba longo prazo, a julgar pelo acompanhamento de pacientes tratadosem decorrência de linfomas não-Hodgkin, é favorável e motivador. Asdúvidas atuais sobre o uso do rituximab na artrite reumatóide são: a)como tratar falhas de resposta ao rituximab e b) falta de marcadoresconfiáveis para indicar de forma racional a melhor opção de agentebiológico a ser utilizado.

A imunofisiopatologia da autoimunidade / Immunophysiopathology of autoimmunity

Este artigo visa explicar conceitos básicos de imunologia de forma clara e sucinta para expor a fisiopatologia das síndromes autoimunes através de exemplos clínicos e/ou experimentais. Esperamos assim esclarecer pontos-chaves que contribuem para a instalação destas patologias.

Silicone breast implants, auto antibodies and rheumatic diseases

Objective: Systematic prospective study in six hundred and nineteen symptomatic woman with breast implants. Methods: To evaluate the symptoms and laboratory findings of patients with silicone breast implants. Results: The majority of the patients in our study presented with the atypical rheumatic syndrome (74,9 percent). A few with so called silicone disease. Various auto antibodies were found sometimes more than one in close to ten percent of the patients analysed. Conclusions: A systemic disease characterized by fatigue, cognitive dysfunction, muscle skeletal pain and the presence of auto antibodies in certain patients were observed in symptomatic brazilian woman with silicone breast implants.