Sjögren Syndrome Candidate Autoantigen AQP5 Triggers AQP4 CNS Autoimmunity Through Self-Antigen Mimicry

Aquaporin (AQP)-4 (AQP4)-seropositive neuromyelitis optica (NMO) frequently coexists with rheumatologic autoimmune conditions, including Sjögren syndrome and systemic lupus erythematosus, 2 conditions that share a common HLA-DRB1 (HLA-DRB1*03:01) association with NMO. AQP4 is a member of a family of ubiquitously expressed water channels. Its immunodominant pathogenic T-cell epitope, which binds MHC II with exceptionally high affinity, is homologous to sequences in other AQPs, including AQP5, a candidate target autoantigen in Sjögren syndrome. Thus, we hypothesized that self-antigen molecular mimicry exists between AQPs and contributes to autoimmunity.

Previously, we examined binding of AQP4 T-cell epitopes to MHC II (I-A^b) by biochemical assays; we now evaluate interaction of I-A^b and AQPs by molecular modeling. T cells from mice immunized with the immunodominant AQP4 epitope or its homologous AQP5 sequence were examined for proliferation and cross-recognition between AQPs. T-cell receptor (TCR) engagement of individual T cells with AQP-MHC II complexes was examined using AQP4 and AQP5 peptide/MHC II tetramers. The pathogenic potential of AQP4-primed and AQP5-primed T cells was examined by T-cell adoptive transfer into naïve mice.

The immunodominant AQP4 T-cell epitope was predicted to make optimal contacts within the pockets of the MHC II antigen-binding cleft. Like AQP4, the corresponding homologous AQP5 amino acid sequence was predicted to bind MHC II, albeit with modest affinity. In a reciprocal manner, T cells were detected that proliferated to both AQP4 and AQP5. Multi-tetramer analysis of individual T cells demonstrated that the same TCR could engage both AQP4 and AQP5. T cells from mice immunized with AQP4 or AQP5 caused paralysis and CNS inflammation in recipient mice, but not in AQP4-deficient mice, demonstrating that AQP4 expression is obligately required in this model of aquaporin CNS autoimmunity.

T cells can express TCRs that recognize multiple AQPs. Autoimmunity can be initiated through molecular mimicry between distinct self-antigens such as AQP4 and AQP5 that are expressed in separate organs. These findings suggest that T-cell self-antigen mimicry may contribute to coexistence of NMO with other autoimmune conditions, such as Sjögren syndrome.