Polymorphism of the IgH Locus Regulatory Region as a Prognostic Factor During Immune Pathologies.

Overview

The investigators previously showed that both antibody class switching (from IgM to IgG, IgA or IgE) and antibody secretion are controlled by a polymorphic "3' regulatory region" (3'RR) of the immunoglobulin heavy chain (IgH) locus. Alleles of the 3'RR have shown influences on the severity and progression of IgA nephropathy (IgAN) (with an over-representation of the B allele among patients with severe kidney IgA deposits). Allele B also constitutes a risk factor for celiac disease, herpetiform dermatitis, psoriasis and rheumatoid arthritis. Since the 3'RR now appears as a crucial regulator of Ig production, we wish to check whether its genetic polymorphism might influence not only the occurrence of immunopathologic processes involving class-switched antibody deregulated production but also the severity of such diseases or the time course of their progression. We wish to focus on two conditions involving class-switched antibodies: on one hand the severe forms of IgE hypersensitivities, and on the other hand a disease involving pathogenic IgA and for which the prognosis is currently very difficult to predict at the onset of the disease: Henoch-Schonlein purpura (HSP). Regarding hypersensitivities, the diversity of their clinical manifestations prompt us to focus on homogeneous groups of patients and we thus wish to concentrate on two groups of patients who are frequently referred to the hospital: severe allergies to Hymenoptera venoms and severe food allergies related to peanut allergens sensitization. These groups will be built by considering multiple clinical criteria (clinical history, severity of the manifestations, positive skin tests, and positive oral provocation tests for peanut allergens…) and biological criteria authenticating the mechanisms of the disease (high specific serum IgE, demonstration of specific basophil activation by the allergen…). In parallel to the study in patients, we will include a large cohort of healthy controls (400 individuals), in order to be able to decipher whether correlations can be seen between: * IgH 3'RR genotypes * The serum accumulation of the various Ig classes, including IgG subclasses, IgA (which are sometimes depicted as protective, sometimes as tolerogenic and anti-inflammatory) and IgE (highly pro-inflammatory and responsible for hypersensitivities) * IgG allotypes (with 6 frequent IgG haplotypes known in human and previously reported as correlated with varying levels of IgG and IgE production in normal individuals).

This study should thus finally provide answers to 5 questions which are currently un-addressed: * How the 3'RR alleles are linked to IgG allotypes and corresponding IgH haplotypes? * Is there a physiological link between 3'RR alleles and production of the various Ig classes and sub-classes? * Is the 3'RR polymorphism connected with the risk of more severe forms of allergic diseases? * Is the 3'RR polymorphism connected with the risk of occurrence and/or severe evolution of HSP? * Is the oncogenicity of translocations affecting the IgH locus connected to the strength of the 3'RR allelic variants?