The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II alpha beta heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.

Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1

Phenotypic variation among organisms is central to evolutionary adaptations underlying natural and artificial selection, and also determines individual susceptibility to common diseases. These types of complex traits pose special challenges for genetic analysis because of gene-gene and gene-environment interactions, genetic heterogeneity, low penetrance, and limited statistical power. Emerging genome resources and technologies are enabling systematic identification of genes underlying these complex traits. We propose standards for proof of gene discovery in complex traits and evaluate the nature of the genes identified to date. These proof-of-concept studies demonstrate the insights that can be expected from the accelerating pace of gene discovery in this field.

https://science.sciencemag.org/content/sci/298/5602/2345.full.pdf

Finding Genes That Underlie Complex Traits

Expression cloning of SR-BI, a CD36-related class B scavenger receptor.

https://www.jbc.org/content/274/27/19055.full.pdf

A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism.

Transcription factors, normal myeloid development, and leukemia.

http://www.jbc.org/content/268/3/2126.full.pdf

Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors

Insulin-dependent diabetes mellitus is characterized by the infiltration of lymphocytes into the islets of Langerhans of the pancreas (insulitis) followed by destruction of insulin-secreting beta-cells leading to overt diabetes. The best model for the disease is the non-obese diabetic (NOD) mouse. Two unusual features of the class II major histocompatibility complex (MHC) of the NOD mouse are the absence of I-E and the presence of unique I-A molecules (I-ANOD), in which aspartic acid at position 57 of the beta-chain is replaced by serine. This feature is also found in the HLA-DQ chain of many Caucasians with insulin-dependent diabetes mellitus. We have previously reported that the expression of I-E prevents the development of insulitis in NOD mouse. Here we report that the expression of I-Ak (A alpha kA beta k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A beta-chain has aspartic acid as residue 57, but also when this residue is serine. These results show that the single amino-acid substitution at position 57 of the I-A beta-chain from aspartic acid to serine is not sufficient for the development of the disease.

Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice

Bone marrow derived cells (dendritic cells, macrophages and B cells) are involved in antigen presentation and T cell tolerance. However, the precise functions of each cell type remain unclear. To determine the role of macrophages we produced transgenic mice expressing I-E molecules only on macrophages, by introducing the hybrid gene containing the colony stimulating factor-1 (CSF-1) receptor promoter region and the structural gene encoding E alpha d into C57BL/6 mice. In these mice I-E restricted antigen presentation and T cell priming were impaired. With respect to T cell tolerance, I-E reactive T cells were anergized but not clonally deleted. These results clearly demonstrate that macrophages by themselves are defective in efficient I-E restricted antigen presentation, so that T cells exposed to antigens expressed on macrophages are led to anergy.

The role of macrophages in antigen presentation and T cell tolerance

Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. NOD mice were shown to express major histocompatibility complex class I Kd and Db antigens. To examine the possible involvement of major histocompatibility complex class I molecules in the development of autoimmune insulitis, we attempted to express a different type of class I molecule in NOD mice by crossing C57BL/6 mice transgenic for the class I Ld gene with NOD mice. The backcross progeny expressed the Ld antigen on the peripheral blood lymphocytes at a level comparable with that of the BALB/c mice. The cell surface expression of endogenous class I and class II antigens on the peripheral blood lymphocytes was not affected. Analysis of these mice revealed that the expression of the class I Ld antigen significantly reduced the incidence of insulitis at 20 weeks of age. In situ hybridization of a biotinylated probe on mouse chromosomes showed that the Ld transgene was located in the E area of chromosome 6 with which no genetic linkage to insulin-dependent diabetes mellitus was demonstrated. These results suggest that the NOD-type class I molecules are involved in the development of insulitis in NOD mice.

Toru Miyazaki

Papers

Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors

Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice

The role of macrophages in antigen presentation and T cell tolerance

Prevention of autoimmune insulitis in nonobese diabetic mice by expression of major histocompatibility complex class I Ld molecules.

Complete prevention of diabetes in transgenic NOD mice expressing I-E molecules.