Progetto comune di ricerca

Ruolo di polimorfismi genetici nella suscettibilità e patogenesi della malattia celiaca e di spondiloartropatie autoimmuni in pazienti del Marocco.

Responsabili di progetto
Daniela Piancatelli, Rajae El Aouad
MAROCCO - CNRST - Centre National pour la Recherche Scientifique et Technique
CNR/CNRST 2012-2013
Area tematica
Scienze biomediche
Stato del progetto

Proposta di ricerca

HLA genes encode highly polymorphic transmembrane glycoproteins which play an important role in recognition of foreign antigens; they are key elements in diseases and transplantation.
HLA allele frequency distribution in North Africans shows some differences from European and Mediterranean populations, while more important differences were found compared to sub-Saharans; some specific alleles and haplotypes could be of interest for clinical and research purposes (D. Piancatelli, et al. ASHI Quaterly 2007).
A different prevalence of some diseases is present in this area, as compared to other Countries, due to both genetic and environmental factors; the increasing immigration in many European Countries accounts for the necessity to know the original genetic substratum. Non classical HLA, class III genes and KIRs are among immune-related genes for which the extended study of polymorphisms could be important; high resolution HLA data could permit to reveal pathogenic mechanisms in diseases. HLA allele distribution is different among populations and HLA polymorphism could be a good marker to study disease susceptibility in HLA-associated autoimmune diseases. Celiac disease and spondyloarthropathies are taken in exame in this project.
Celiac disease
Celiac disease (CD) is an autoimmune disease caused by a disregulated  immune response to wheat gliadin in genetically predisposed individuals.
Caucasian populations from Europe and North America show a CD prevalence of 0.5-1% of the general population. Dietary introduction of wheat gluten in Africa caused a fast increase of CD prevalence in this region. A ten-fold higher frequency of celiac disease has been reported in a population of Arab and Berber origin from Algeria (5.6%) (Catassi C, et al Tissue Antigens 2001). This make of interest the study of the disease in populations from Morocco, well characterized by our group at classical and non classical HLA loci and TNF-a (class III) gene.
HLA genes are confirmed genetic risk factors for CD. However, it is still not known why only a small number of HLA-predisposed individuals develop CD and why, in a small percentage of patients, HLA association is not present. CD in the Maghreb area has a very high incidence, that could be associated both to diet habits and to the high frequency of DR3-DQ2 haplotypes (Moltalto G., World J Gastroenterology 2007).
The strong association (more than 90% of patients) of the HLA-DQ2 heterodimer, DQA1*0501/DQB1*0201, is well known, and in a smaller number of cases (8%) the DR4-DQA1*0301-DQB1*0302 haplotype is present (serological DQ8 association). HLA-DQ2 and DQ8 class II molecules expressed on APC are able to bind and present gliadin-derived peptides, deamidated by tissue transglutaminase in intestinal mucosa, to CD4+ T cells in the lamina propria and stimulate the adaptive response. However, the infiltration of CD8+T cells in the intestinal epithelium (intraepithelial lymphocytes, IEL) indicates the role of a cytolytic response in CD, that could be mediated by MIC-NKG2D interaction. MIC (MHC class I chain related) molecules are overexpressed on intestinal epithelium in CD, display a high level of polymorphism and have been suggested as additional susceptibility genes in CD (Bolognesi E, et al. Tissue Antigens 2003).
IELs also express alternative nonclassic class I molecules such as CD1d, which provide a mechanism for microbial nonpeptide or lipidic antigens presentation to NK T cells therefore being an important factor in normal mucosal immunity of the gastrointestinal tract.
In addition, TNFa-308 (A/G) polymorphism has been reported to be related to CD (Garrote JA, et al. Immunogenetics 2002). A high frequency of TNFa-308(A) allele was found by our group in Metalsa population from Morocco (Louie L. et al. 2006).
Spondyloarthropathies (SpA)
SpA represent in Morocco the second rheumatic disease (21.5%), after the common vertebral pathologies and they show particular characteristics as more severe disease, hip involvement and environmental characteristics.
The pathogenesis of these diseases is attributed to the interaction between genetic and environmental factors. In fact, frequently they show familial aggregation and are strongly associated with HLA-B27 antigen. It has been suggested that certain other HLA-B alleles may increase susceptibility to SpA in B27-negative patients.
However, the strength of this association varies markedly not only between the various SpA but also among racial and ethnic groups. The frequency of HLA-B27 is less than 1% among persons living from Africa. Recently, the epidemiology of SpA in sub-Saharan Africa has undergone changes due to the expanding epidemic of human immunodeficiency virus (HIV) and other bacterial infections (malaria etc) in Africans. 
Genome-wide scans have implicated regions on chromosome 2q, 6p, 6q, 10q, 11q, 16q, 17q and 19q in AS .
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a coinhibitory molecule which is expressed by activated T cells and interacts with the B7 molecule on the surface of APCs to induce down-regulation of T cell activation. Polymorphisms within CTLA-4 gene that lead to reduction of molecule expression might cause autoimmune T cell proliferation and contribute to the pathogenesis of autoimmune diseases.
Because a receptor-ligand relationship between particular combinations of KIR receptors, proteins involved in the activation and inhibition of NK and CD8+ T cells, and MHC class I molecules exists, it would be interesting to understand if there is a synergistic association between these polymorphic loci in SpA.
As the inflammatory causes of SpA are still unknown, we could investigate some genetic polymorphisms of surface Fc gamma receptors for IgG (V158F), that are important mediators of the antibody-dependent cell-dependent cytotoxicity (ADCC) process. Such  polymorphisms seem to confer conformational changes in the receptors resulting in a different affinity of the receptor for IgG.

Obiettivi della ricerca

During a previous CNR/CNCPRST project we analysed class I, II HLA, MICA and TNF-a polymorphisms in Moroccan populations, highlighting the presence of some uncommon allele/haplotype combinations. In the present study we are planning to assess the association of  some gene polymorphisms in CD and SpA.
Celiac disease
In consideration of the high prevalence of CD in North Africa, of HLA allele and haplotype frequencies in North Africa (intermediate between Sub-Sahara and Europe), of the increase of gluten dietary intake, of the lack of data on extracellular MICA and on CD1e polymorphisms, of the high frequency of the TNFa-308(A) allele found in Moroccans, the aims of the study will be:

to assess associations of HLA-DQ, MICA-HLA-B alleles and haplotypes in Moroccan CD patients and compare it with Caucasian European CD patients, to evaluate a possible functional effect of a different HLA genetic substraum;
to analyse the associations of SNPs of other potentially involved loci, TNF-a and CD1d, with CD.

Spondyloarthropathies (SpA)
We plan to analyze by SSP and sequence-based typing (SBT) the potential genetic involvement in SpA pathogenesis of :

The synergistic effect of KIR3DL1 and 3DS1 receptors, and their possible HLA-B ligands, since the low frequency of classical related-disease HLA-B27 antigen in Moroccan controls (Canossi A, 2010; Piancatelli D. 2004);
CTLA4 polymorphisms (promoter -318 C/T, exon 1+49A/G, exon 4 CT60 A/G) that may cause autoimmune T cell proliferation;
The two variants (V158F) of FCGR3A in SpA patients with different affinity for IgG antibodies, to examine the potential contribute of the isoforms on the level of macrophage activation in response to IgG-containing immune complexes.

Ultimo aggiornamento: 30/11/2023