A comparison of epitope repertoires associated with myasthenia gravis in humans and nonhuman hosts

Abstract

Here we analyzed the molecular targets associated with myasthenia gravis (MG) immune responses, enabled by an immune epitope database (IEDB) inventory of approximately 600 MG-related epitopes derived from 175 references. The vast majority of epitopes were derived from the α-subunit of human AChR suggesting that other MG-associated autoantigens should be investigated further. Human α-AChR was mostly characterized in humans, whereas reactivity primarily to T. californica AChR was examined in animal models. While the fine specificity of T-cell response was similar in the two systems, substantial antibody reactivity to the C-terminus was detected in the nonhuman system, but not in humans. Further analysis showed that the reactivity of nonhuman hosts to the C-terminus was eliminated when data were restricted to hosts tested in the context of autoimmune disease (spontaneous or induced), demonstrating that the epitopes recognized in humans and animals were shared when disease was present. Finally, we provided data subsets relevant to particular applications, including those associated with HLA typing or restriction, sets of epitopes recognized by monoclonal antibodies, and epitopes associated with modulation of immunity or disease. In conclusion, this analysis highlights gaps, differences, and similarities in the epitope repertoires of humans and animal models.

Figure 1

(a) Relative abundance of references related to different disease categories. (b) Subcategorization of autoimmunity references.

Figure 2

Data were generated by querying for all (a) human AChR proteins or all (b) T. californica AChR proteins in the Molecule Finder and then exporting the positive assay data in Excel format. The percentage of epitopes derived from each subunit was then determined by sorting by “Source Molecule Name” field for each subunit designation.

Figure 3

Queries utilized the Source Antigen Molecule Finder to specify AChR, selecting B cell and T cell responses only (MHC binding and MHC ligand elution assays were excluded), and specifying Host Organism. The total number of positive epitopes was then tallied to generate relative percentages of reactivities.

Figure 4

Response frequency response.

Figure 5

Response frequency of Antibody response for clinical or induced disease.

Figure 6

Restricting MHC allele. Query included human AChR as antigen, T-cell responses only (B cell responses, MHC binding, and MHC ligand elution assays excluded) and MHC class II selected. Enumeration of each allele was done using Excel download of positive T-cell responses. Data include humans, as well as HLA-transgenic mice as host.