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Determinant spreading: lessons from animal models and human disease
J McCluskey1, A D Farris, C L Keech
1Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia. j.mccluskey@microbiology.unimelb.edu.au
Immunological Reviews
|October 31, 1998
Summary
Systemic autoimmunity may arise from determinant spreading initiated by a single event. HLA class II type influences autoantibody patterns, suggesting a role in initiating autoimmune responses.
Area of Science:
- Immunology
- Autoimmunity
- Molecular Biology
Background:
- Spreading of immune responses is characteristic of organ-specific and systemic autoimmune diseases.
- Mixed antinuclear antibody patterns in systemic autoimmunity may result from determinant spreading.
- La/Ro ribonucleoprotein (RNP) is targeted in systemic lupus erythematosus and primary Sjögren's syndrome.
Purpose of the Study:
- To investigate if determinant spreading from a single initiating event causes mixed antinuclear antibody patterns.
- To explore the role of molecular chaperones in the autoimmune response.
- To determine the influence of HLA class II phenotype on autoantibody responses.
Main Methods:
- Immunization of mice with individual protein components of La/Ro RNP.
- Induction of autoantibodies against Ro60 (SS-A), Ro52 (SS-A), La (SS-B), calreticulin, and Grp78.
- Analysis of autoantibody responses and the impact of HLA class II phenotype.
Main Results:
- Immunization induced autoantibodies recognizing Ro60, Ro52, La, calreticulin, and Grp78.
- Diversified anti-La/Ro antibody responses were initiated by a single subdominant T epitope of La.
- HLA class II phenotype strongly influenced autoantibody patterns in primary Sjögren's syndrome.
Conclusions:
- Determinant spreading from a single event can explain mixed antinuclear antibody patterns.
- Physiological apoptosis may provide endogenous antigens driving determinant spreading, involving chaperone proteins.
- HLA class II alleles are critical in initiating and spreading systemic autoimmune reactions, with potential for molecular mimicry by exogenous agents.