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Human leukocyte antigen-DRB1*1502 (DR2Dw12) transgene reduces incidence and severity of arthritis in mice
M A Gonzalez-Gay1, E Zanelli, S D Khare
1Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB1*0401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, susceptibility to mouse CIA is influenced by the MHC class II loci. To analyze the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB1*1502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2Aq) mice. Transgene-positive DRB1*1502 mice showed a significant reduction in the incidence and severity of arthritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB1*1502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our results suggest that the DRB1*1502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodominant regions(s) of the arthritogenic type II collagen molecule. By analogy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.
Insights
Introducing a human DRB1*1502 gene into mice reduced rheumatoid arthritis (RA) severity. This suggests a mechanism where the DRB1 molecule interferes with T-cell responses, potentially explaining RA predisposition.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Human rheumatoid arthritis (RA) susceptibility is strongly linked to specific Human Leukocyte Antigen (HLA) - DRB1 alleles.
- Conversely, certain DRB1 specificities are associated with reduced RA incidence.
- Murine collagen-induced arthritis (CIA), a model for RA, is also influenced by MHC class II loci.
Purpose of the Study:
- To investigate the impact of a DRB1 molecule, associated with low RA incidence, on the development of mouse CIA.
- To analyze the potential mechanism of protection conferred by the DRB1*1502 transgene in CIA.
Main Methods:
- Introduction of a human DRB1*1502 (DR2Dw12) transgene into CIA-susceptible B10.RQB3 (H2Aq) mice.
- Assessment of arthritis incidence and severity in transgene-positive and negative mice.
- Evaluation of T-cell proliferative responses to a self-derived DRB1 peptide in B10.RQB3-DRB1*1502 mice.
Main Results:
- Transgene-positive DRB1*1502 mice exhibited a significant reduction in both the incidence and severity of arthritis.
- The observed clinical improvement in arthritis correlated with diminished T-cell proliferation.
- This T-cell response reduction was specific to a self-derived DRB1 peptide from the third hypervariable region.
Conclusions:
- The DRB1*1502-mediated protection against CIA is likely due to the DRB1 molecule acting as a source of self-antigenic peptide.
- This self-antigenic peptide interferes with T-cell recognition of immunodominant regions of arthritogenic type II collagen.
- A similar mechanism may be critical in understanding HLA class II-associated predisposition to human RA.