Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus

Abstract

The importance of microbial infection as a trigger for the induction of systemic lupus erythematosus is frequently debated. Clinical observations indicate that anti-viral and antibacterial responses are often accompanied by self reactivity, and anti-pneumococcal antibodies elicited in non-autoimmune individuals by pneumococcal vaccine express lupusassociated anti-DNA idiotypes. To explore the relationship between protective and pathogenic antibodies in humans, we have used the phage display immunoglobulin expression system to generate a combinatorial library from spleen cells of a lupus patient immunized with a polyvalent pneumococcal polysaccharide vaccine prior to splenectomy. From this library, monovalent antigen-binding fragments expressing the 3I V O 1-associated idiotype were isolated. This idiotype is expressed on up to 90 % of anti-DNA antibodies in the serum of lupus patients and on anti-pneumococcal antibodies in the serum of non-autoimmune individuals. Eight 3I + monovalent antigen-binding fragments reacting with pneumococcal polysaccharide, DNA or both were analyzed. Four of these fragments were cross-reactive with both foreign and self antigen, demonstrating that a high percentage of anti-bacterial antibodies produced in a patient with lupus bind double-stranded DNA. These studies provide support at the molecular level for a potential role of molecular mimicry in the generation of anti-DNA antibodies. In addition, this is, to our knowledge, the first panel of fully sequenced human anti-pneumococcal antibodies.

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

“…Consistent with this model is our observation that 4 of the antibodies bound pneumococcal polysaccharide, including 1 that was cross-reactive with histone. Cross-reactivity to this microbial antigen was also found to occur in a high percentage of anti-DNA antibodies isolated from this library, which was derived from a patient who had just been immunized with pneumococcal polysaccharide (19). Those data, together with the data from this study, support a hypothesis that microbial antigens may be a trigger for both DNA-binding and non-DNA-binding antibodies that recognize kidney antigens.…”

“…We obtained a portion of a spleen from an SLE patient who had nephritis and idiopathic thrombocytopenia and had been immunized with pneumococcal polysaccharide (Pneumovax-23; Merck, West Point, PA) prior to therapeutic splenectomy. The preparation of total cellular RNA and the generation of the combinatorial library with IgM and IgG heavy-chain sequences and lightchain sequences have previously been described (19).…”

“…The most striking feature of the antibodies is that all possess IgG heavy chains. The selection of phages expressing IgG Fab fragments appears to be the result of panning on kidney, since panning of the same library for an idiotype specificity yielded clones dominated by IgM heavy chains (19).…”

Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?

“…This theory is supported by the study of Kowal et al [93] that proved crossreactivity, at the molecular level, between pneumococcal antibacterial antibodies and generation of antiDNA antibodies, in SLE patients.…”

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

“…Theories explaining the polyreactivity that is typical of the human disease include cross-reactivity of antiforeign and anti-self Abs (24), somatic mutation of the anti-foreign response to generate autoreactivity (25,26), and epitope spreading of the immune response to target self Ags (27)(28)(29)(30)(31)(32)(33). We have previously shown that cross-reactivity of the serum Abs accounts for much of the anti-self response in these mice (18).…”