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Category: Microbial Genetics and Molecular Biology
Peptide Induction of Systemic Lupus Autoimmunity, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555818074/9781555811945_Chap09-1.gif /docserver/preview/fulltext/10.1128/9781555818074/9781555811945_Chap09-2.gifAbstract:
Systemic lupus erythematosus often is cited as the classic representative of systemic autoimmunity, in contrast to organ-specific autoimmune disorders such as myasthenia gravis or Graves' disease. Autoantibodies are the unifying feature of lupus autoimmunity. Immunization with peptides is also capable of generating lupus autoimmunity and a clinical illness that closely resembles some forms of human lupus. The peptide immunization model of lupus grew from the immunochemical description of the fine specificity of the autoantigens. The Ro autoantigen is molecularly complicated. The specificity was originally defined as a precipitin line by Ouchterlony immunodiffusion and was appreciated to contain both RNA and protein. The spliceosome contains small nuclear RNPs (snRNPs) which are common antigenic targets for lupus autoantibodies, commonly called Sm and nRNP. Immunization with the major epitope of Sm D, which contains the glycine-arginine repeat, also produces a diversified response directed against Sm Dl, D2, and D3, as well as other spliceosomal autoantigens. Immunization with Ro peptides has also been carried out with mice. A myriad of additional predictions and molecular relationships must be defined and must be consistent with the possibility that Epstein-Barr virus is importantly involved in the pathogenesis of lupus before it will generally be accepted that Epstein-Barr virus is etiologically relevant to lupus. The animal model of lupus and of B-cell epitope spreading is also likely to teach fundamental lessons about the immune system and of the immunopathology of lupus autoimmunity.
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B-cell epitope spreading in the naturally arising anti-Sm B/B′ autoantibody response in human lupus. The cartoon shows the progression from binding of the initial structures, consisting of three repeated PPPGMRPP and PPPGMRGP, to a mature humoral response that involves at least nine other peptide-defined epitopes (none of the others of which have a similar primary sequence) ( 27 ). This figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
B-cell epitope spreading in the naturally arising anti-Sm B/B′ autoantibody response in human lupus. The cartoon shows the progression from binding of the initial structures, consisting of three repeated PPPGMRPP and PPPGMRGP, to a mature humoral response that involves at least nine other peptide-defined epitopes (none of the others of which have a similar primary sequence) ( 27 ). This figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
Development of the anti-Sm B/B′ response in one anti-Sm- and anti-nRNP precip itin-positive patient. This anti-Sm- and anti-nRNP precipitin-positive patient shows an increase in the number of antigenic determinants over time: 1 April 1986 (A), 7 July 1987 (B), 13 January 1988 (C), 8 June 1988 (D), 16 October 1988 (E), and 26 December 1988 (F). The data span a 2-year progression of system lupus erythematosus and exhibit an increase from binding of four groups of octapeptides to 15 separate groups ( 27 ). This figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
Development of the anti-Sm B/B′ response in one anti-Sm- and anti-nRNP precip itin-positive patient. This anti-Sm- and anti-nRNP precipitin-positive patient shows an increase in the number of antigenic determinants over time: 1 April 1986 (A), 7 July 1987 (B), 13 January 1988 (C), 8 June 1988 (D), 16 October 1988 (E), and 26 December 1988 (F). The data span a 2-year progression of system lupus erythematosus and exhibit an increase from binding of four groups of octapeptides to 15 separate groups ( 27 ). This figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
Model for peptide-induced lupus autoimmunity. Step 1, a normal animal is immunized with autoantigenic peptide (peptide #1) from a lupus autoantigen (AAg); step 2, this animal develops a normal antipeptide immune response; step 3, some of the B cells (B2) which make antipeptide antibody also bind to this peptide on the surface of the lupus autoantigen; alternatively, the component of the antipeptide (Peptide #1) antibody which is also capable of binding to autoantigen binds to the Fc receptors of antigen-presenting cells and monocytes and macrophages bind to the T-cell receptor on T cells (T2); step 4, these T cells are capable of providing help to other B cells (B3), which then produce autoantibodies which can bind to structures in addition to the immunization peptide on the surface of the autoantigen. This figure is taken from reference 19 . Copyright © 1998 Hogrefe & HuberPublishers. Reproduced with permission.
Model for peptide-induced lupus autoimmunity. Step 1, a normal animal is immunized with autoantigenic peptide (peptide #1) from a lupus autoantigen (AAg); step 2, this animal develops a normal antipeptide immune response; step 3, some of the B cells (B2) which make antipeptide antibody also bind to this peptide on the surface of the lupus autoantigen; alternatively, the component of the antipeptide (Peptide #1) antibody which is also capable of binding to autoantigen binds to the Fc receptors of antigen-presenting cells and monocytes and macrophages bind to the T-cell receptor on T cells (T2); step 4, these T cells are capable of providing help to other B cells (B3), which then produce autoantibodies which can bind to structures in addition to the immunization peptide on the surface of the autoantigen. This figure is taken from reference 19 . Copyright © 1998 Hogrefe & HuberPublishers. Reproduced with permission.
Binding of one PPPGIRGP-immunized rabbit serum sample with overlapping octapeptides of the Sm and nRNP proteins which do not contain the immunization peptide. After 20 weeks into the immunization protocol, serum from this one rabbit binds to many different regions of Sm D (A), nRNP 70K (B), nRNP A (C), and nRNP C (D). Preimmunization sera do not bind to any of these octapeptides at a level above the background binding. The background reactivity for these studies is equal to an optical density of <0.200 ( 27 ). A portion of this figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
Binding of one PPPGIRGP-immunized rabbit serum sample with overlapping octapeptides of the Sm and nRNP proteins which do not contain the immunization peptide. After 20 weeks into the immunization protocol, serum from this one rabbit binds to many different regions of Sm D (A), nRNP 70K (B), nRNP A (C), and nRNP C (D). Preimmunization sera do not bind to any of these octapeptides at a level above the background binding. The background reactivity for these studies is equal to an optical density of <0.200 ( 27 ). A portion of this figure is reproduced with the permission of Munksgaard International Publishing Ltd., Maiden, Mass.
Binding to select peptides of EBNA-1 and spliceosomal autoantigens. Binding is presented for an average of 10 anti-Sm precipitin-positive patient serum samples (black bars). Binding of sera from an average of 10 healthy controls is also presented (white bars). The proline-rich sequences are presented above, and the glycine-arginine repeat sequences are presented below. (Some data are taken from references 18 and 24 .)
Binding to select peptides of EBNA-1 and spliceosomal autoantigens. Binding is presented for an average of 10 anti-Sm precipitin-positive patient serum samples (black bars). Binding of sera from an average of 10 healthy controls is also presented (white bars). The proline-rich sequences are presented above, and the glycine-arginine repeat sequences are presented below. (Some data are taken from references 18 and 24 .)
The more-common autoantibodies in lupus
The more-common autoantibodies in lupus
Seroconversion against Epstein-Barr virus viral capsid antigen in sera from young lupus patients and controls a
Seroconversion against Epstein-Barr virus viral capsid antigen in sera from young lupus patients and controls a
Seroconversion frequencies in pediatric lupus and controls for IgG binding to cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus antigens a
Seroconversion frequencies in pediatric lupus and controls for IgG binding to cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus antigens a