Antigen-Specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy

Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies

A Language-Independent Proof System for Mutual Program Equivalence

International audienceTwo programs are mutually equivalent if they both diverge or they end up in similar states. Mutual equivalence is an adequate notion of equivalence for programs written in deterministic languages. It is useful in many contexts, such as capturing the correctness of, program transformations within the same language, or capturing the correctness of compilers between two different languages. In this paper we introduce a language-independent proof system for mutual equivalence, which is parametric in the operational semantics of two languages and in a state-similarity relation. The proof system is sound: if it terminates then it establishes the mutual equivalence of the programs given to it as input. We illustrate it on two programs in two different languages (an imperative one and a functional one), that both compute the Collatz sequence.Deux programmes sont en équivalence mutuelle s'ils divergent tous les deux ou s'ils terminent dans des états similaires. L'équivalence mutuelle est une notion adéquate d'équivalence pour les programmes déterministes. Elle est utile dans divers contextes, parmi lesquels on peut citer la preuve de transformations de programmes dans un langage donné, et la preuve de compilateurs entre deux langages. Dans cet article nous introduisons un système déductif pour l'équivalence mutuelle, qui a comme paramètres les sémantiques opérationnelles de deux langages ainsi qu'une relation de similitude entre états des programmes. Le système déductif est correct: lorsqu'il termine, il démontre l'équivalence des programmes qui lui sont donnés en entrée. Nous l'illustrons sur deux programmes, appartenant à des langages différents : l'un impératif, l'autre fonctionnel, qui calculent la séquence de Collatz de deux manières différentes

On the Multi-Language Construction

Modern software is no more developed in a single programming language. Instead, programmers tend to exploit cross-language interoperability mechanisms to combine code stemming from different languages, and thus yielding fully-fledged multi-language programs. Whilst this approach enables developers to benefit from the strengths of each single-language, on the other hand it complicates the semantics of such programs. Indeed, the resulting multi-language does not meet any of the semantics of the combined languages. In this paper, we broaden the boundary functions-based approach a la Matthews and Findler to propose an algebraic framework that provides a constructive mathematical notion of multi-language able to determine its semantics. The aim of this work is to overcome the lack of a formal method (resp., model) to design (resp., represent) a multi-language, regardless of the inherent nature of the underlying languages. We show that our construction ensures the uniqueness of the semantic function (i.e., the multi-language semantics induced by the combined languages) by proving the initiality of the term model (i.e., the abstract syntax of the multi-language) in its category

Atopic dermatitis : a cutaneous or systemic disease? The search for answers in the history of Dermatology

A dermatite atópica é doença inflamatória cutânea associada à atopia, predisposição a produzir resposta IgE a alérgenos ambientais, constituindo uma das manifestações das doenças atópicas, junto com a asma e a rinite alérgica. A dermatite atópica é caracterizada por episódios recorrentes de eczema associado a prurido, acometendo superfície cutânea geneticamente alterada, induzindo, por fenômenos imunológicos, a presença de inflamação. Trata-se de doença multifatorial, com enfoque nas alterações sistêmicas e alérgicas ou nas manifestações cutâneas, de acordo com diferentes visões da doença. A conceituação da dermatite atópica é importante, porque a conduta terapêutica pode variar segundo essas duas formas diferentes de analisá-la. Autores modernos discutem extensivamente esses aspectos sem, contudo, alcançar uma conclusão sobre a dermatite atópica como doença sistêmica ou cutânea. A procura dos conceitos sobre a doença, desde os primeiros relatos, associada à evolução do pensamento na dermatologia, poderia esclarecer a origem dessas dúvidas. Uma análise histórica demonstra que a dermatite atópica tem seus conceitos atuais oriundos dos estudos de diversos pensadores, que, em diferentes momentos históricos, descreveram a doença, e que muito do que acreditamos atualmente tem, nesses escritos, seus fundamentos.Atopic dermatitis is an inflammatory disease associated to atopy, which is a predisposition to produce an IgE response to environmental allergens and considered one of the manifestations of the atopic diseases, including asthma and allergic rhinitis. Atopic dermatitis is characterized by recurrent eczema flares, associated to pruritus, affecting a genetically disrupted skin surface, inducing, by immunological phenomena, the onset of inflammation. It is a multifactorial disease, with an emphasis on systemic and allergic alterations or skin manifestations, according to different concepts. The definition of atopic dermatitis is important, since its management may vary according to these two different points of view. Modern authors have extensively discussed these concepts, though with no conclusion as to its nature - systemic or cutaneous disease. The search for concepts about the disease, since its first descriptions, associated to the evolution of the dermatology rationale through history, may help understand the origin of these doubts. A historical analysis demonstrates that the currently accepted concepts of atopic dermatitis have their background from different researchers, who, at different historical moments, described the disease, and a great part of our beliefs about atopic dermatitis are related to these ancient writings