HLA-mediated protection in Goodpasture disease

Credit: Caio Bracey/Macmillan Publishers Limited

A new study provides insights into the molecular mechanisms of HLA-mediated susceptibility and protection in Goodpasture disease (GPD). This rare renal disorder is characterized by autoimmune responses to the non-collagenous domain of the α3 chain of type IV collagen (α3(IV)NC1). Expression of HLA-DR15 is associated with an increased risk of GPD, but this risk is reduced to baseline in the presence of the protective HLA allele HLA-DR1.

“The basis of the loss of immunological tolerance in most autoimmune diseases lies in the inheritance of HLA alleles that modulate the risk of autoimmunity,” explains researcher Richard Kitching. “In this study we used GPD to address two long-standing questions — what is the basis of HLA-mediated protection in autoimmune disease and how does a protective allele mitigate the excess risk conferred by a susceptibility allele?”

The researchers focused their investigations on the immunodominant T-cell epitope of α3(IV)NC1, α3_135–145. Using HLA-DR15-α3_135–145 tetramers, they showed that α3_135–145-specific CD4⁺ T cells were 100-fold more frequent in the peripheral blood of HLA-DR15⁺ patients with GPD than in HLA-DR15⁺ healthy controls. In seven of the eight patients, these epitope-specific cells were mainly conventional FOXP3⁻ T cells. Consistent with a protective role of HLA-DR1 in GPD, immunization with α3_135–145 led to renal infiltration of α3_135–145-specific CD4⁺ T cells and the development of GPD in HLA-DR15⁺ transgenic mice, but did not induce proinflammatory autoreactivity to α3_135–145 in HLA-DR15⁺DR1⁺ transgenic mice.

To determine the molecular basis of the protective effect of HLA-DR1, the researchers characterized the self-peptide repertoires of HLA-DR1 and HLA-DR15 allomorphs from naive HLA-DR1⁺ and HLA-DR15⁺ mice and identified consensus peptide-binding motifs. They report that these HLA alleles have distinct self-peptide repertoires and α3_135–145-binding registers. These differences result in the presentation of distinct peptide-HLA landscapes to T cells, which in turn lead to differences in the responding T-cell repertoires.

HLA allelic polymorphisms result in structurally important differences in presentation of the critical T-cell epitope of the disease-causing autoantigen

Further investigations indicated that α3_135–145-specific CD4⁺ T cells from transgenic mice that express HLA-DR15, HLA-DR1 or both HLA alleles have functional phenotypic differences. In HLA-DR15⁺ mice, the majority of these cells were conventional Foxp3⁻ T cells that secreted proinflammatory cytokines, whereas in HLA-DR1⁺ mice the majority of the epitope-specific CD4⁺ T cells were Foxp3⁺ regulatory T (T_reg) cells that secreted tolerogenic cytokines. HLA-DR15⁺DR1⁺ mice expressed both conventional and regulatory α3_135–145-specific CD4⁺ T cells. Analysis of the phenotypes of α3_135–145-specific CD4⁺ T cells from healthy people who were either homozygous for HLA-DR1 or HLA-DR15, or were heterozygous for these HLA alleles, gave similar results.

Finally, the researchers showed that α3_135–145-specific CD4⁺ T_reg cells generated in the context of HLA-DR1 suppress autoreactive conventional α3_135–145-T cells generated in the context of HLA-DR15, so maintain self-tolerance to α3_135–145 and protect against the development of GPD.

“HLA allelic polymorphisms result in structurally important differences in presentation of the critical T-cell epitope of the disease-causing autoantigen,” concludes Kitching. “These differences result either in the generation of conventional autoantigen-specific CD4⁺ T cells (in the context of the risk allele, HLA-DR15) or of dominantly protective antigen-specific T_reg cells (when the epitope is presented by the protective HLA allele, HLA-DR1). These findings provide a structural and mechanistic basis for understanding HLA-mediated susceptibility and protection in autoimmune disease.”