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Chapter 10 : Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus

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Abstract:

Systemic lupus erythematosus (SLE) is an autoimmune disorder that is complex in clinical manifestation and, most likely, in etiology. This chapter focuses on molecular mimicry of host structures by microbial pathogens, one of the possible mechanisms that contributes to autoreactivity in lupus. Studies of serum from patients with bacterial infections led to the realization that nonautoimmune hosts, during the time of infection, make antibodies with specificities similar to those of autoantibodies in sera from patients with SLE. Reciprocal inhibition assays with dsDNA and pneumococcal polysaccharide performed with three of the cross-reactive antibodies demonstrated that dsDNA and polysaccharide bind at the same or a proximal site on these antibodies. DNA-protein binding usually requires a more polar interface and a far greater number of hydrogen bonds, both direct and water mediated, than protein-protein interactions. The anti-DNA specificity is generated both by activation of cross-reactive antibodies and by the process of somatic mutation but is most likely downregulated by the normal host. The cross-reactivity may be germ line gene encoded or may be generated by somatic mutation of the antibody. Nonautoimmune hosts can generate B cells with potentially pathogenic autospecificities, and the antigenic relatedness of DNA to carbohydrate antigens is sufficient to activate cross-reactive B cells. In humans, it remains to be determined if this cross-reactivity is potentially pathogenic; in mice, it clearly is. Immunization with a peptide mimotope of DNA can also induce lupus-like autoreactivity in mice.

Citation: Kowal C, Diamond B. 2000. Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus, p 127-141. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch10

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Bacterial Proteins
0.65767545
Bacterial Cell Wall
0.57088614
Immune Systems
0.5280715
Amino Acids
0.51804054
Lymphocytic choriomeningitis virus
0.49129203
0.65767545
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Figures

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Figure 1

Binding of affinity-purified Fab fragments to bacterial and self-antigens. Panels show binding of Fab to pneumococcal polysaccharide (A), PC (B), and dsDNA (C). (Modified from reference ).

Citation: Kowal C, Diamond B. 2000. Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus, p 127-141. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch10
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Image of Figure 2
Figure 2

Competitive inhibition ELISA (modified from reference ). The Fab fragment concentration was 1.25 μg/ml. The concentrations of dsDNA as soluble inhibitor were as follows: 0.00165 μg/ml (bar set 1), 0.0165 μg/ml (bar set 2), and 0.165 μg/ml (bar set 3). The concentrations of the pneumococcal polysaccharide were as follows: 0.002 μg/ml (bar set 1), 0.02 μg/ml (0.2 μg/ml for clone 8.55) (bar set 2), and 0.2 μg/ml (20 μg/ml for clone 8.55) (bar set 3). Values represent the mean optical densities (O.D.) for duplicate samples in the absence or presence of inhibitor.

Citation: Kowal C, Diamond B. 2000. Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus, p 127-141. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch10
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Tables

Generic image for table
Table 1

VH gene family usage in cross-reactive antibodies >

Citation: Kowal C, Diamond B. 2000. Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus, p 127-141. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch10
Generic image for table
Table 2

Sequences of phage clones selected by anti-dsDNA antibodies

Citation: Kowal C, Diamond B. 2000. Mimicry between DNA, Carbohydrates, and Peptides: Implications in Systemic Lupus Erythematosus, p 127-141. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch10

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