The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus-host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-γ release, and faster co-stimulation of CD8+ T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8+ T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA-129Met variants appeared to reduce the severity of aGVHD.

https://www.embopress.org/doi/pdf/10.15252/emmm.201505246

The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation

Purpose of review Humoral responses beyond major histocompatibility antigens receive an increased attention of the transplantation community. We aimed to summarize the data on discovery of new antigenic targets, novel experimental findings, recent diagnostic developments, and introduction of new technologies in the field of non-HLA antigens in solid organ transplantation. Recent findings Non-HLA antibodies can be currently reliably detected by solid-phase assays (MICA, angiotensin type 1 receptor, collagen-V, vimentin), immunofluorescence (antibodies against antigens expressed on umbilical vein endothelial cells), or flow-crossmatch techniques (antibodies against donor endothelial progenitors). Influence of test positivity on transplant outcomes is variable and differs among non-HLA targets. Use of omics approach helped to identify a unique set of antigens in adult and pediatric patients with severe rejections and transplant glomerulopathy. Summary Paradigms for effective monitoring of non-HLA humoral responses need to be established in order to utilize advances provided by the rapid diagnostic developments. A systematic longitudinal assessment of pretransplant sensitization together with monitoring of posttransplant changes would represent an important step forward.

Role of non-HLA antibodies in organ transplantation.

Major histocompatibility complex class I-related chain A allele mismatching, antibodies, and rejection in renal transplantation

HLA and MICA polymorphism in Polynesians and New Zealand Maori: implications for ancestry and health.

Expression of MHC class I-related molecules MICA, HLA-E and EPCR shape endothelial cells with unique functions in innate and adaptive immunity.

Among the cell surface antigens that can elicit an immune response in transplant recipients MICA antigens occupy a special place They are similar to human leukocyte antigens (HLAs) while being very different from them They are not as polymorphic and their quantity is smaller In consequence, the impact of MICA antigens in transplantation is not as dramatic However, our early guess that these ligands of NKG2D could elicit antibodies and cell-mediated immunity has been definitely confirmed Careful analysis with MICA transfectant cells, for absorption and elution, established the specificity of the epitopes involved Typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure Acute graft-versus-host disease was observed in stem cell recipients who were mismatched for MICA

Y. Zou

Papers

Role of MICA in the immune response to transplants.