Identification of epitopes and immunodominant regions on the MICA protein defined by alloantibodies from kidney transplant patients

Abstract

Background: Several reports showed a contribution of anti-MICA (major histocompatibility complex class I chain-related molecule A) antibodies (Abs) to the development of acute and chronic rejection. Identification of the epitopes to which the Abs bind may help to determine immunoreactive regions essential for the major histocompatibility complex compatibility between donor and recipients, leading to the best outcome of the transplant.

Methods: Sera from 284 kidney transplant patients were screened for anti-MICA Abs by Luminex assay. MICA allele typing of the recipients was determined. The epitopes of MICA were mapped by screening a synthesized library of overlapping peptides from the extracellular domains of the protein against the sera from kidney transplant patients with anti-MICA Abs.

Results: Antibodies against MICA were detected in 50 of 284 patients (17.6%) and correlated with the development of acute rejection. Nine antigenic regions were immunoreactive with anti-MICA Abs in the sera samples. Four of these continuous epitopes mapped to polymorphic amino acids (aa). Five antigenic regions were shared epitopes found in all the MICA alleles. The polymorphic residues, 173 (E/K), 175 (S/G), and 181 (R/T), had determined allele-specific epitopes (reactivity patterns 1 and 2). In contrast, the aa 208Y and 213T were implicated in the cross-reactivity among alleles.

Conclusions: The presence of anti-MICA Abs could be an important marker for diagnosis because of their contribution to the outcome of the graft, regardless of presence of anti-HLA Abs. Additionally, the identification of epitopes revealed the in vivo antigens of the transplant and is spurring the development of new matching strategies to reduce the incidence of acute and chronic rejection.