Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry

Abstract

The origins of autoimmunity in systemic lupus erythematosus (SLE) are thought to involve both genetic and environmental factors. To identify environmental agents that could potentially incite autoimmunity, we have traced the autoantibody response in human SLE back in time, prior to clinical disease onset, and identified the initial autoantigenic epitope for some lupus patients positive for antibodies to 60 kDa Ro. This initial epitope directly cross-reacts with a peptide from the latent viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1). Animals immunized with either the first epitope of 60 kDa Ro or the cross-reactive EBNA-1 epitope progressively develop autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens. They eventually acquire clinical symptoms of lupus such as leukopenia, thrombocytopenia and renal dysfunction. These data support the hypothesis that some humoral autoimmunity in human lupus arises through molecular mimicry between EBNA-1 and lupus autoantigens and provide further evidence to suspect an etiologic role for Epstein-Barr virus in SLE.

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

“…The promiscuity of TCR to recognize multiple peptides makes molecular mimicry an interesting proposition for initiating autoimmunity. Due to relative simplicity, most of the focus for identifying molecular mimics for lupus-associated Ags has been on B cell epitopes (13,32). Our study suggests that mimicry at T cell level should also be considered as an important mechanism to activate self-reactive T cells.…”

“…Recent studies have suggested that molecular mimicry at single B cell epitope level may play an important role in the initiation of autoantibody responses in SLE (13). However, the role of T cell epitope mimicry in initiating an epitope spreading cascade in SLE has not been described.…”

Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE

“…Recent data suggest that breaks in tolerance to viral proteins (eg, EBNA1 protein of EBV) may be associated with subsequent cross-reactive autoimmunity to RNA-binding proteins such as Ro and Sm. 50,51 One hypothesis that warrants consideration is that the relevant viral-or self-antigens in SLE may be restricted by the disease-associated DR2 and DR3 Class II alleles (and/or their respective DQ alleles) for presentation to CD4 þ T cells, thereby increasing the probability that autoimmune responses might be initiated and propagated. An alternate hypothesis is that CD4 þ and CD25 þ T regulatory cells, which are important for suppressing autoimmune diseases, 52 may undergo inefficient positive selection on the SLE risk Class II alleles.…”

The type I interferon system in systemic lupus erythematosus

“…Indeed, autoantibodies are common during viral infections (91), either due to loss of tolerance to ubiquitous cellular autoantigens or due to molecular mimicry. The latter possibility is supported by data that link Epstein-Barr virus to SLE, because the major autoantigens SmBЈ and SmD1 cross-react with sequences from Epstein-Barr nuclear antigen 1 (EBNA-1), and immunization of mice with cross-reactive EBNA-1 sequences precipitates lupus-like autoimmunity (92). Furthermore, a peptide from the EBNA-1 antigen induces production of antibodies against 60-kd Ro in mice, and autoantibodies to this EBNA-1-related Ro 60 epitope were detected in patients an average of 3.9 years before the development of SLE.…”