Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.

Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders.

Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs.

Translational research in immune and inflammatory diseases; what are the challenges, expected advances, and innovative therapies?

Despite very different aetiologies and clinical expressions, advancing knowledge in the physiopathology and treatment of immune and inflammatory diseases (IID) prompts us to consider them as a whole. These are chronic, often incapacitating and painful illnesses that progress and destroy organs. Management by discipline too often leads to erroneous diagnoses and sometimes inappropriate treatment. More integrated translational research would further understanding of the complex relationships between cytokines and organ damage, which vary with the conditions and patients, making it possible to develop new biomarkers and personalize treatment. The research in France has very many strengths but its organization is fragmented. Better coordinated research into IID, which could be based on creating a strategic valorization field (domaine de valorisation stratégique, DVS) and thematic multi-organization institute (Institut thématique multi-organismes ITMO), would advance patient management.

[Mastocytosis--diagnostic criteria and treatment]. / Mastocytoza--rozpoznawanie i leczenie.

Mastocytosis is a heterogeneous group of rare diseases characterized by the proliferation and accumulation of mast cells in one or more organs such as the skin, bone marrow, liver, spleen, and lymph nodes. According to the WHO classification, mastocytosis is divided into seven subvariants. The symptoms are associated with mediator release and impaired organ function due to infiltration by neoplastic mast cells. There is a higher risk of anaphylactic shock; therefore education of the patients is very important. Patients may be asymptomatic. Symptomatic treatment is used in cutaneous mastocytosis and in indolent systemic mastocytosis. More aggressive subvariants of mastocytosis are treated with chemotherapy, targeted therapy, and bone marrow transplantation.

[Immunologic diseases and hepatitis C virus]. / Maladies immunologiques et virus de l'hépatite C.

Active chronic hepatitis may be associated with various immunologic diseases. In the Mediterranean area and to a lesser extent elsewhere, hepatitis C virus, has often been detected in patients affected by mixed cryoglobulinemia, membranoproliferative glomerulonephritis, polyarteritis nodosa autoimmune type 2b hepatitis, Hashimoto's disease, Sjögren's syndrome and lichen ruber planus. These findings should not be considered fortuitous due to the elevated prevalence of autoantibodies and immunologic abnormalities observed in hepatitis C patients compared with subjects presenting other liver diseases. The pathogenetic evaluation of the association between these immunologic diseases and chronic hepatitis C has led us to suggest that diverse virus C and host induced factors may play a fundamental role in determining these immunologic diseases.

[Mechanisms and classification of immunological diseases]. / Mehanizmi nastanka i klasificacija imunskih bolesti.

Immunological diseases comprise a clinically heterogenous group of disorders that result either from defects in one or more compartmens of the immune system or from aberrant, excessive or uncontrolled immune reactions. Immunodeficiency disaeses are caused by congenital or acquired defects in lymphocytes, phagocytes or other mediators of specific or natural immunity. The second group of immunological diseases result from the failure to control physiological immune response against foreign antigens or to maintain self-tolerance. The two principal factors that determine the clinical and pathological manifestation of such diseases are 1. the type of immune response that leads to tissue injury, and 2. the nature and location of antigen that initiates or is a target of this response. The most frequently used classification of immunological diseases is based on the principal pathogenic mechanism responsible for cell and tissue injury. Immunological diseases can also be subdivided based on the source of antigen against which the immune responses are directed. Mechanisms implicated in the pathogenic immune response to foreign and self antigens are discussed.

[Abortions of immunologic origin. A trial of etiologic classifications and therapeutic consequences]. / Avortements d'origine immunologique. Tentative de classifications étiologiques et conséquences thérapeutiques.

Repeated unintentional abortions are an agonizing problems for many couples. When the cause is unexplained an immunological reason is often invoked. There have been many theories, but none have been able to be proven. Progress in immunology makes it possible to predict that these mechanisms will become better understood. At the present time the most recent work presented by the authors underlines the fact that there are probably several different immunological mechanisms causing abortion. When the mechanisms can be identified using current techniques, it may be possible to suggest the treatment suited to each one of these situations and to abandon empirical treatment as is at present used in these repeated abortions.

Phagocytic dysfunctions: a proposal for classification.

The classification presented here is designed to help clinicians make therapeutic and diagnostic decisions. It is based on the modern view of the phagocytosis process as events involving ligand-receptor interaction, transmission of signal through second messenger systems and activation of effector mechanisms leading to specific cell behaviour. According to the classification proposed here, phagocytic disorders can be divided into extracellular disorders which are caused by abnormalities affecting ligands and cellular disorders caused by a pathological disturbance affecting the phagocytic cell. These cellular disorders are subdivided into defects of membrane receptors, defects of enzymatic equipment and defects of subcellular structures. Laboratory investigations of phagocytic cells make it possible to classify inborn, acquired, permanent and transient disorders into these groups. Examples of disorders in each of these groups are presented.