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Multiple overlapping homologies between two rheumatoid antigens and immunosuppressive viruses
1Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Summary
Viral sequence similarities to human nuclear antigens suggest a role in autoimmune diseases like lupus and scleroderma. Specific viruses show extensive homology, potentially triggering autoantibody production against self-proteins.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Amino acid sequence homologies between viral and human nuclear antigens suggest potential viral triggers for autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma.
- Investigating these homologies can elucidate mechanisms of autoimmunity and identify novel therapeutic targets.
Purpose of the Study:
- To analyze the frequency and distribution of exact amino acid sequence homologies between viral proteins and key nuclear antigens implicated in autoimmune diseases.
- To determine if specific viral infections are associated with increased risk of developing SLE and scleroderma through molecular mimicry.
Main Methods:
- Comparative sequence analysis of 61 viral proteomes against 8 nuclear antigens and 41 control proteins, focusing on homologies of 5 or more amino acids.
- Statistical evaluation of pentamer and hexamer homology frequencies between viral, nuclear, and control protein datasets.
- Identification and mapping of homologous regions within the nuclear antigens, particularly in C-terminal domains.
Main Results:
- While pentamer and hexamer homologies between viruses and control proteins are common, two nuclear antigens (SLE-associated 70-kDa and scleroderma-associated CENP-B) exhibit unusual multiple homologies with specific immunosuppressive viruses (HSV-1, HIV-1, EBV, CMV).
- Herpes simplex virus 1 (HSV-1) and human immunodeficiency virus 1 (HIV-1) sequences are extensively duplicated in the 70-kDa antigen and CENP-B protein.
- Homologous regions in nuclear antigens are often clustered in C-terminal domains, contain autoantibody epitopes, and display contiguous or overlapping distributions, suggesting high-density potential epitopes.
Conclusions:
- The findings suggest that co-expression of certain heterologous viruses with shared immunosuppressive functions may induce autoantibodies that cross-react with nuclear proteins.
- This molecular mimicry mechanism provides a plausible explanation for the viral etiology of autoimmune diseases like SLE and scleroderma.
- Further research into viral-host protein interactions is warranted to understand and potentially prevent autoimmune conditions.