Project GIAS – Università La Sapienza – Roma (Italy) – Research Group Prof.ssa Rosa Sorrentino

GIAS= Genetics and Immunobiology of Ankylosing Spondylitis

Rationale:
Ankylosing Spondylitis (AS) is a chronic, immune-mediated rheumatic disease, representing the prototypic member of a group of disorders known as Spondyloarthropathies. Patients with AS share clinical features such as spinal and pelvic joint dysfunction as well as genetic associations, primarily with genes involved in the antigen processing and presentation: the Human Leukocyte Antigen B*27 (HLA-B*27) and the Endoplasmic Reticulum Amino Peptidase 1 (ERAP1). In spite of the intense investigations, the AS pathogenic molecular mechanisms are still poorly elucidated. Noteworthy, the HLA-B*27 includes a family of more than one hundred and forty alleles not all of them equally predisposing to AS. This is the case of HLA-B*2709 described for the first time by our group and frequent in Sardinia Island but absent in patients. The HLA-B*2709 differs from the B*2705, the worldwide more common and strongly AS-associated allele, uniquely for the His116Asp substitution. We and other research groups have shown how important is the residue 116 in determining the structure, the flexibility and the immunological properties of the HLA-B*27 molecules. We believe that comparing the B*2705/B*2709 pair of alleles could give a clue to the understanding of the molecular mechanisms of AS. Moreover, it has been shown the ERAP1 is a risk factor for AS only in patients carrying the HLA-B*27 alleles, indicating a strong gene-gene interaction. Therefore, it is crucial to understand how the ERAP1 polymorphisms can influence the immunological properties of HLA-B*27 molecules.

Main goals of the project:

  • Comparative analysis of the presentation of atypical peptides by HLA-B*27 alleles. By this study we will highlight the peculiarity of AS-associated B*27 molecules to present to CD8+ T cells antigens that do not have the optimal binding motif. This functional analysis will be correlated with structural studies and the pathogenic relevance of these observations will be evaluated.
  • Deep characterization of HLA-B*2705 and HLA-B*2709 peptidome from immune and non-immune cells in order to refine the knowledge on the peptide repertoire of these molecules and to extend this analysis to cell types involved in the inflammatory process.
  • Analysis of ERAP1 polymorphisms. Genotype analysis of ERAP1 will be performed and correlated with T cell functional data in B*27 carriers either patients with AS or healthy individuals.
  • Analysis of the features of HLA-B*27-restricted CD8+ T cell responses. The main role of B*27 alleles is the antigen presentation to CD8+ T cells that, if dysfunctional, could be pathogenic. We want to assess if the HLA-B*27-restricted virus-specific CD8+ T cells, taken as "experimental cellular model", possess specific properties in terms of polyfunctionality, cell migration, TCR repertoire, cytokine profile, response to regulatory feedbacks that make them different from T cells restricted for other HLA-alleles.

TEAM

Rosa Sorrentino

Professor of Pathology, Sapienza University, Rome (Italy) Scientific career and experience: In 1980, she joined as postdoctoral fellow the team leaded by Dr. Roberto Tosi focusing on the genetics of the human leucocyte antigen (HLA) region. She therefore moved to the Dept. of Biochemistry and Molecular Biology, Harvard University, MA, USA in the group directed by Prof. Jack L Strominger that was investigating the gene organization of the HLA region. She is the author of more than 100 peer-reviewed scientific publications and book chapters, many of which focused on the genetics and molecular basis of autoimmune diseases. Since 1992, one of the main topics of investigation has been the genetics of Ankylosing Spondylitis, a rheumatic disease strongly associated with the HLA-B27 family of alleles. These studies have allowed the identification of a novel member of the family, HLA-B*2709, frequent in Sardinia and differing from HLA-B*2705, the most common allele, for a single amino acid position. HLA-B*2709 is not present in patients thus representing a powerful tool for the understanding of the molecular basis of the disease.

Maria Teresa Fiorillo

Maria Teresa Fiorillo is Assistant Professor of General Pathology at "Sapienza" University of Rome, teaching courses in Molecular Pathology and Immunology for BSc master students. She graduated in Biological Sciences at the University of Naples "Federico II" and, in 1996, she obtained a PhD in Biotechnology at the University of L'Aquila. She started her scientific career at IRBM (Istituto di Ricerche di Biologia Molecolare, Pomezia, Rome, Italy) focusing on the cloning and characterization of the mouse interleukin-6 receptor. In 1994, she was visiting scientist at the National Cancer Institute, NIH, Bethesda, (MD), USA. Her current research work is mainly devoted to the understanding of the molecular and functional mechanisms underlying the association between human leukocyte antigen (HLA) genes and autoimmune diseases. She is the author of more than 40 peer-reviewed scientific publications and book chapters.

Research Interest
Autoimmune diseases; Role of HLA-B27 alleles in Spondyloarthropathies; Multiple Sclerosis; Antigen presentation; CD8+ T cells; Chronic Inflammation.