Abstract
MICA and MICB are ligands of the NKG2D receptor and thereby influence NK and T cell activity. MICA/B gene polymorphisms, expression levels and the amount of soluble MICA/B in the serum have been linked to autoimmune diseases, infections, and cancer. In hematopoietic stem cell transplantation, MICA matching between donor and patient has been correlated with reduced acute and chronic graft-vs.-host disease and improved survival. Hence, we developed an extremely cost-efficient high-throughput workflow for genotyping MICA/B for newly registered potential stem cell donors. Since mid-2017, we have genotyped over two million samples using NGS amplicon sequencing for MICA/B exons 2–5. In donors of German origin, MICA*008 is the most common MICA allele with a frequency of 42.3%. It is followed by MICA*002 (11.7%) and MICA*009 (8.8%). The three most common MICB alleles are MICB*005 (43.9%), MICB*004 (21.7%), and MICB*002 (18.9%). In general, MICB is less diverse than MICA and only 6 alleles, instead of 15, account for a cumulative allele frequency of 99.5%. In 0.5% of the samples we observed at least one allele of MICA or MICB which has so far not been reported to the IPD/IMGT-HLA database. By providing MICA/B typed voluntary donors, clinicians become empowered to include MICA/B into their donor selection process to further improve unrelated hematopoietic stem cell transplantation.
Highlights
The MICA (MHC class I polypeptide-related sequence A) and MICB (MHC class I polypeptide-related sequence B) genes are located between the MHC class I and class III genes inside the human major histocompatibility complex (MHC) [1]
Even though MICA and MICB do not seem to be as diverse as the conventional human leukocyte antigen (HLA) genes, a large number of distinct alleles have been described: release 3.37.0 of the IPD-IMGT/HLA database contains 109 MICA and 47 MICB alleles [6]
We determined MICA and MICB allele frequencies based on 1,201,896 samples of donors from DKMS Germany who declared to be of German descent
Summary
The MICA (MHC class I polypeptide-related sequence A) and MICB (MHC class I polypeptide-related sequence B) genes are located between the MHC class I and class III genes inside the human major histocompatibility complex (MHC) [1]. Being highly similar to the classical human leukocyte antigen (HLA) genes, they do not present peptides and are not expressed at the surface of human leukocytes but on endothelial cells, fibroblasts, epithelial cells, and tumor cells [2]. There they act as ligands for the NKG2D receptor which plays an important role in immune surveillance. MICA∗008 has been reported to be the most common MICA allele with frequencies ranging from 25 to 55% depending on the population. There, the allele MICB∗005 is the most common allele with frequencies of over 50%. It is followed by MICB∗002 and MICB∗004 with frequencies over 10% and MICB∗008 and the null allele MICB∗009N with frequencies over 5% [10,11,12,13]
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