MIC genes in health and disease
Project leaders: Raphael Carapito, Perrine Spinnhirny and Seiamak Bahram
Detailed project description:
The MIC gene family encodes a distinct family of MHC class I genes at the centromeric extremity of the MHC class I region. The family is characterized by two genes, MICA and MICB that encode highly glycosylated MHC class I-like proteins, which are expressed at the cell surface, independently of β2-microglobulin and cytosolic peptides. Unlike other non-conventional MHC class I genes, a high degree of diversity has been documented for these genes: 107 alleles for MICA and 47 for MICB thus far (https://www.ebi.ac.uk/ipd/, date last accessed February 8th, 2019). Although these numbers are far smaller than those for classical HLA class I molecules (close to 22 000 alleles), one has to bear in mind that our current knowledge of HLA diversity spans from genotyping of close to 30 million individuals (current estimate of the size of international bone marrow registries), whereas the corollary for MICA and MICB comes from sequencing of a few thousand individuals only. MICA polymorphism has been associated with a number of diseases such as autoimmune disorders and cancer, but also with allograft rejection and GVHD. Most published studies on disease association have however suffered from the well-known caveats of HLA-disease associations: strong linkage disequilibrium with neighboring loci (notably HLA-B here), small size of cohorts and/or the lack of replication in independent cohorts. Furthermore very few data are available for MICB.
In this 18th IHIWS project, we aim to:
- fully characterize the diversity of MICA and MICB in various (healthy) populations from diverse ethnic backgrounds,
- comprehensively analyze MICA/B-disease associations, notably (but not limited) to autoimmune conditions and cancer,
- further characterize the influence of MIC genes in solid (especially kidney, heart and lung) and hematopoietic cell transplants.
- study the impact of MICA/B matching on the outcome of haploidentical hematopoietic cell transplantation, a setting in which the impact of MIC genes has not yet been evaluated.
Milestones in years:
2019: Identification of diverse populations, patients, graft donors and recipients to be included in the study. Inclusion of key laboratories worldwide. Collection of HLA-typing and clinical data. Sample collection.
2020: MICA and MICB genotyping
2021: Continuation of MICA and MICB typing and analyses
Patient/sample description (if applicable, details, inclusion/exclusion criteria):
- Healthy subjects (can be donors of hematopoietic cell transplantation).
- Donor and recipients of unrelated-donor hematopoietic cell transplants.
- Donor and recipients of first haploidentical transplantations.
- Patients with any HLA-linked autoimmune (or otherwise) disease.
- Patients with solid cancers (lung, breast, ovary,…) and hematopoietic malignancies.
Data required (number, type of data, inclusion/exclusion criteria):
For all samples two-field resolution HLA typing for HLA-A, -B, -C, -DRB1, -DRB3-5, -DQB1, and -DPB1 is required.
For healthy subjects, the ethnic origin/population should be known precisely.
For disease samples, baseline demographics and disease characteristics is needed.
For transplantations, access to clinical data via the PROMISE or other database(s) should be granted.
All cohorts must have cleared ethics/regulatory setting of the country of origin.
Samples required (if applicable, number, type of samples, inclusion/exclusion criteria):
At least 2 µg of high molecular weight genomic DNA.
Reagents/additional assays required:
500µl of patient serum is requested to measure soluble MICA and MICB levels.
Data infrastructure required:
Excel file with requested information.