HLA, Immune Response and Disease ― Classical and New Concept ―

Speaker

Takehiko Sasazuki　M.D., Ph.D, University Professor, Institute for Advanced Study Kyushu University

Title

HLA, Immune Response and Disease ―　Classical and New Concept　―

Abstract

HLA is composed of multigene family including HLA class I (HLA-A, B and C) and class II genes (DR, DQ, DP) which is most polymorphic in the human genomes located on the short arm of chromosome 6 in the stretch of 3.8 Mb. Peptide binding groove of HLA molecule　accommadates a specific peptide to evoke immune response through T cell activation to protect infectious diseases.

In my talk I will quickly summarize the human immune response and present our recent analysis of autoimmune thyroiditis, Graves disease (GD: hyperthyroidism) and Hashimoto thyroiditis (HT: hypothyroidism). Through detailed analysis of HLA genome of GD and HT we uncovered that HLA-DP5 is responsible for GD specifically.

Agonistic autoantibody, found in GD patients, against thyroid stimulating hormone receptor (TSHR) is causative to the disease.

This antibody has been reported to activate the CHMP / PKA / CREB / AKI cascade for cell survival decision. Furthermore it prevents and rescues cells from apoptosis by suppressing ROS. By analyzing the serum level of agonistic antibody to TSHR in GD patients together with HLA alleles, we proposed a model for development of GD and HT including conversion from HT to GD.

During these studied, Dr. Arase’s group reported that HLA class II molecule can bind misfolded protein itself and this misfolded protein・ HLA complex is the target of autoantibody in rheumatoid arthritis patients. In collaboration with Dr. Arase, we revealed that the autoantibody to TSHR in GD patients are reactive to the TSHR protein bound by HLA-DP5.

Furthermore it has been well known that HLA class II molecules bind longer peptides composed of 13~25 amino acids than HLA class I molecules do, because both ends of the peptide binding groove of HLA-class II molecules are open. Through collaboration with us, Dr. Yokoyama’s group found that 13mer peptide from allergen Cry j 1 is bound by HLA-DP5 and showed unique tertial structure comparing with those of 9mer Cry j 1 peptide bound by the same HLA-DP5.

All these new observations seem to test our critical discernment and insight into the autoimmune response and disease.