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Primary Immunodeficiencies and early-onset Autoimmunity

Mardi 14 novembre 2017 11:00 - Duree : 1 heure
Lieu : Salle de Conférence de l’IAB - Rond Point de La Chantourne, 38700 La Tronche (arrêt de tram Grand Sablon, ligne B)

Orateur : Frédéric RIEUX-LAUCAT (Hôpital Necker, Paris)

Primary immunodeficiencies (PIDs) are usually seen as monogenic predispositions to common pathogens infections. However, autoimmune manifestations are frequent features in PIDs and can even be a presenting feature. For example, based on a registry of more than 5000 cases of PIDs followed at the Necker hospital, the relative risk of developing autoimmune cytopenia is 120 times higher in PID patients than in the general population. There are numerous examples of autoimmune diseases developing in the adaptive immune system deficiencies such as hypomorphic RAG-1/2 mutations, AID and WASP mutations or even thymus developmental defect in Di George Syndrome. Historically, monogenic predisposition to autoimmunity has been first described with the discovery of the FAS mutations, impairing lymphocyte apoptosis and leading to Autoimmune Lymphoproliferative Syndrome (ALPS). The genetic basis of the ALPS-FAS comes in several flavors. Whereas most mutations are heterozygous dominant mutations, that can be inherited (in familial cases) or acquired in hematopoietic progenitors (in sporadic cases), mutations leading to haplo-insufficiency are associated with partial clinical penetrance. In these families, healthy carriers and patients are carrying the same germline mutations, but acquired mutations of the second FAS allele are found only in patients. This discovery shows that predisposition to autoimmunity can be the consequence of a monogenic trait and that non-mendelian expression of the disease can be explained by the stochastic occurrence of somatic mutations. This may well account for the discordance of monozygotic tweens sometimes observed in autoimmune diseases. More recently, inborn errors of immune checkpoints have been described as recessive mutations of LRBA or heterozygous haplo-insufficient CTLA-4 mutations in patients variably presenting with tumoral syndrome, organ-lymphocyte infiltrations and autoimmunity, and progressive loss of IgGs. CTLA-4 is a well characterized inhibitor of lymphocyte activation, and its membrane expression is regulated by LRBA, an intracellular trafficking protein of the BEACH family (including LYST and NBEAL2), thereby explaining the overlapping clinical phenotype observed in these two genetic deficiencies. The clinical onset of these patients can be quite variable and may lead to erroneous diagnosis of ALPS-FAS, Combined Immunodeficiency or even IPEX syndrome. If the final diagnosis consists in the identification of causal mutations of these genes, an in depth immuno phenotype of B and T cell subsets, including Tregs, is very helpful to orientate the genetic screening. With the development of targeted-new generation sequencing or whole exome sequencing, we found, in a cohort of more than 160 patients referred for Evans syndrome, that at least a third of these patients could be diagnosed for known PID genes (FAS, KRAS, NRAS, RAG-1, IKAROS, NFKB1, PIK3CD, CTLA-4, LRBA, STAT3 gain of function, del 22q, ) or for new genetic deficiencies (RELB, IkBa, JAK1). Therefore, an early-onset (< 2years) severe autoimmune cytopenia should prompt the clinicians to investigate towards a genetic diagnosis of PID. Finally, by performing the same type of genetic screening in Systemic Lupus Erythematous with juvenile onset we found monogenic deficiencies affecting genes related to PIDs (IKAROS, TAP1, NLRP3 or FOXP3) or new genetic causes (TMEM173/STING, ERN1 or RELA), suggesting that pediatric onset of SLE could reveal an underlying PID. Overall, these examples are demonstrating that early-onset autoimmunity is a frequent manifestation in PIDs and is probably the consequence of a monogenic cause in most cases.

Contact : karin.sadoul@univ-grenoble-alpes.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (IAB)
Nature évènement : (Séminaire)
Evènement répétitif : (Mardis de l’IAB)
Site de l'évènement : Pôle Santé / La Tronche

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