The molecular functionalityof MICA and MICB in healthy individuals: polymorphisms and differential expression

Abstract

The MICA and MICB molecules are constitutively expressed in fibroblasts, monocytes, and epithelial cells. However, their expression may be stimulated in conditions such as cancer, infections, and autoimmune diseases, acting as cellular stress markers. MICA and MICB are encoded on chromosome 6 in the Major Histocompatibility Complex (MHC) region, the most variable region of the human genome. Polymorphisms seem to be associated with a differential expression profile of MICA and MICB on the cell surface and as soluble molecules, modulating the immune system by interacting with the NKG2D receptor, present in natural killer cells and T lymphocyte subpopulations. Here we propose to evaluate the molecular functionality of MICA and MICB in healthy individuals by identifying genetic markers that influence the transcriptional profile of these genes, splicing patterns, and the release of soluble molecules in mononuclear cells, both in physiological situations and after stimulation. For this purpose, we will select samples with specific genetic profiles after Sanger sequencing (e.g., samples carrying non-synonymous polymorphisms) with subsequent mononuclear cell culture. Then, we will quantify the expression of MICA and MICB at different levels (mRNA, membrane-bound, and soluble isoform) before and after stimulation with hydrogen peroxide or LPS. The expression data will be correlated with the genetic profile of the samples. Demonstrating the heterogeneity of expression of these molecules on the cell surface and/or released in a soluble manner in the supernatant will shed some light to understand the dynamics between MICA and MICB molecules in different pathological situations, including transplant, the association between MICA and MICB polymorphisms and some diseases. (AU)