Medico - Scientific Background

The concept of autoinflammatory/autoimmune disease continuum (AADC)

Chronic inflammation, a condition present in various diseases including those with an immune component, is an important cause of morbidity/mortality in the developed world. Recent advances in the pathophysiology of autoinflammatory/autoimmune diseases have led to a re-examination of their nosology. It now appears that autoinflammatory and autoimmune diseases do not represent two distinct categories of disorders. Rather, they form a disease continuum ranging from pure autoinflammatory disorders to pure autoimmune diseases, encompassing a large panel of inflammatory diseases with some autoimmune component, and vice versa. A wide range of disorders fall into this disease category. These are rare or common disorders, whose management requires an integrated approach in which clinicians from internal medicine or medical specialties and research teams collaborate closely in translational research programs.

Aims

WP1: Patient care, Cohorts, Deep phenotyping & Clinical trials

• Aim 1: Refine the clinical and biological phenotype of patients
  

  This includes the establishment of a dedicated database common to a series of diseases of the AADC and the creation of biobanks with links between deep phenotyping and available biobanks for each disease.

• Aim 2: Establish a common panel of investigations
  • This includes the creation of a workforce of clinical and basic science investigators to support patient care and research programs through:
    • consultations for the child-to-adult transition in pulmonology and nephrology, and
    • specialized consultations giving patients rapid access to the different medical departments of i2B.

WP2: Basic and translational research

• Aim 1: Identify new genetic factors in autoinflammatory syndromes
  • Our aim is to identify new genes by means of complementary approaches to decipher underlying networks in well-characterized cohorts of patients.
  • In addition, pathophysiology will be explored through the study of the unfolded protein response (UPR) pathway and the comparison of signaling pathways involved in chronic and acute episodes of inflammation.

• Aim 2: Identify new molecules/pathways in organ-specific and systemic inflammation
  

  Several i2B teams are involved in deciphering pathways implicated in organ-specific inflammation (joints, kidney, lung, intestine, muscle). They have established a number of animal and cell models as well as tissue explants, that have led to the identification of major mediators of inflammation. Three common themes are being explored in WP2:

  • The role of endoplasmic reticulum (ER) stress, UPR pathway and autophagy
  • The role of mechanical stress in inflammation
  • The role of collagen receptors in inflammation

• Aim 3: Identify new target antigens in autoimmune diseases
  

  A major goal is the identification of pathogenic B- and T-cell antigens/epitopes by using a combination of approaches including high-throughput sequencing of T- and B-cell receptors in phenotyped patients. Gene variants will also be studied by exome sequencing and next generation sequencing of specific loci to understand disease predisposition.

• Aim 4: Investigate Treg/Teff/Th17 balance in selected inflammatory and autoimmune disorders
  

  Our expertise in T-cell biology is applied to in-depth studies of a group of autoimmune diseases. Based on large, deeply phenotyped cohorts, we are currently investigating T-cell regulation in relation with epitope presentation to explore the mechanisms responsible for disease triggering and remission. We will also determine whether clinical heterogeneity is reflected by different patterns of T-cell response as well as potential commonalities among different diseases.

• Aim 5: Investigate the role of intestinal microbiota dysbiosis in inflammatory and autoimmune disorders
  

  Dysbiosis seems to play a major role not only in inflammatory bowel disease (IBD), but also in other inflammatory diseases. A main project is aimed at deciphering the anti-inflammatory properties of Faecalibacterium prausnitzii. The findings recorded in IBD will be applied to selected diseases of the AADC.

WP3: Translational medicine and biotherapy

• Aim 1: Assess new biomarkers for diagnosis and/or prognosis
  

  Biomarkers are key molecular or cellular indicators used to (i) refine diagnosis and to identify subgroups of patients that are at increased risk for disease or disease progression and (ii) to evaluate response to treatments​. Based on current knowledge and on the results of WP2, the diagnostic or prognostic value of identified biomarkers will be assessed in specific clinical trials.

• Aim 2: Evaluate Treg-based therapies in immunopathology and inflammation
  

  Partners of i2B have a leading position in the investigation of IL-2, a molecule which specifically activates / expands regulatory T cells (Tregs). They have notably performed the first worldwide clinical trial aimed at inducing Tregs with IL-2 in patients with (i) HCV-vasculitis (Saadoun, 2011; NCT00574652​​) and (ii) type 1​ diabetes (Hartemann, 2013; NCT01353833​)​. The results of these trials show that IL-2 is safe, specifically ​expands Tregs and provide clinical improvements. Hence there is a strong rationale for the use of T-reg based therapies in autoimmune diseases. TRANSREG a clinical trial evaluating the efficacy of low-dose Il-2 in 11 autoimmune diseases of the AADC is ongoing with i2B clinicians (​NCT01988506​​).

• Aim 3: Evaluate other targeted biotherapies
  

  Collectively, i2B can call upon extensive expertise in clinical trials in the AADC. The therapeutic potential of new drugs and novel indications for existing drugs are being tested in specific diseases. For instance, rituximab is currently being investigated in inflammatory myopathies. Rapamycine is being evaluated in a phase II clinical trial in inclusion body myositis and eculizumab is being assessed in genetic and infectious inflammatory nephritis.