Chronic auto-inflammatory and osteoarticular diseases represent a major socio-economic problem for our society. AIDs and systemic autoimmune diseases share some characteristics. They are systemic diseases, frequently involving musculoskeletal system; both include monogenic and polygenic diseases. They are characterized by a chronic activation of immune system, which eventually leads to tissue inflammation in genetically predisposed individuals (Doria et al, Autoimmun Rev 2012, PMID 22878274). Systemic autoinflammatory diseases (SAIDs) include a large group of syndromes characterized by recurrent attacks of fever, abdominal pain, arthritis and skin signs. Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are chronic, systemic inflammatory diseases that occur in multiple joints. Although very different in their manifestations, most of these diseases are considered a result of a deficiency in the self-regulatory mechanisms of the immune system, and their etiology of most of them remains to be elucidated.

Our project has two main objectives:

1) Identification of new genes by exome sequencing

The advent of Next Generation Sequencing (NGS) has revolutionized the genetic study of human diseases and the diagnosis of these diseases by making it possible to study the genome at the individual level by sequencing all exons.

• RA and JIA are considered as complex multifactorial genetic diseases. We propose that in some rare cases, patients with RA or JIA have an inherited form. In 2012, our group initiated an NGS project on multiplexed families with at least one member with JIA to identify potential genes.
• Some patients with SAID referred to our genetic diagnosis and clinical departments at the University Hospital of Montpellier (https://umai-montpellier.fr/) are genetically orphan. We propose to identify the causative genes in these families by NGS.

2) Identification of the physio-pathological basis of monogenic autoinflammatory diseases

Based on genetic models of definite SAIDs or on new candidate genes responsible for JIA, we propose to determine the pathogenic effect of the mutations found by using functional studies in order to clarify the role of these genes in the development of autoinflammation and autoimmunity.

• Methylation
  Gene expression in the immune system is tightly regulated by epigenetic processes, including DNA methylation (PMID 35268351). The increasing understanding of the importance of DNA methylation in disease causation, has contributed to efforts to develop DNA methylation testing as a clinical diagnostic tool. Within the past few years, genomic DNA methylation analysis, as peripheral blood episignatures using methylation microarrays, have proven useful in diagnosing patients with unclear developmental disability and intellectual disability disorders and in interpreting genetic variants of unknown clinical significance (VUS) (PMID 30875234). The functional consequences and clinical impacts of genomic variation or specific genetic condition may involve unique genomic DNA methylation episignatures, particularly in SAID, in which deregulation of innate immunity is mainly present in circulating cells. That’s why we aim to explore the complex biology underlying the monogenic autoinflammatory diseases and to identify DNA methylation patterns that could influence penetrance and subphenotypes.
• New JIA FR+ gene, CCP+.
  Considering JIA as monogenic rare disease, exome sequencing revealed several candidate genes.

  We have identified a new rare variant responsible for a stop codon mutation in exon 1 of a candidate gene associated with JIA. This gene encodes an endoplasmic reticulum protein specific to B lymphocytes. By assessing endoplasmic reticulum stress, we propose to study the functional consequences of the identified variant in order to clarify the pathophysiological pathways playing a key role in JIA.

  We also have identified compound heterozygous variations in a gene (so far not responsible for disease in human) in a girl with JIA, FR+ CCP+. This gene is a member of CARGO and is involved in lysosomal trafficking of CXCR4 and immune cells chimiotactism. We propose to study the functional variations in cells from the affected girl and their unaffected members in collaboration with other teams.

  We also identified compound heterozygous variations in an unreported gene in a boy with polyarticular JIA seronegative and immune deficiency. Based on a collaboration with other teams, we have studied immune function and unraveled physio pathological mechanisms responsible for clinical features.

• NLRP1, a new gene for systemic JIA
  In two independent families with a new syndrome combining arthritis, autoinflammation and autoimmunity, we have identified mutations in an inflammasome gene. We are developing in vitro and ex vivo functional assays to assess inflammasome formation and activity, with the aim of defining the pathogenic effect of these mutations on the secretion of pro-inflammatory cytokines IL-1β and IL-18 (PMID 27965258).
• PSMB10, the third and last immunoproteasome gene reported to be responsible for PRAAS
  we describe a patient exhibiting a PRAAS phenotype due to a homozygous mutation in PSMB10, which led to IFN type I dysregulation, PSMB10 maturation defect, and enzymatic impairment. Thus, the patient could benefit from anti-JAK 1/2 therapy (PMID 31783057)