Autoimmune Antigenic Epitope Peptides for Systemic Lupus Erythematosus

Autoimmune Antigenic Epitope Peptides for Systemic Lupus Erythematosus

Definition
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness characterized by circulating antibodies to self. These Sm autoantigen B/B'-derived peptides are early targets of the autoimmune response in patients with SLE, that induce spliceosome autoimmunity.

Discovery
Harley JB and Gaither KK in 1988 explained about autoantibodies. James A et al., (1995) explained Sm autoantigen B/B'-derived peptides are early targets of the autoimmune response 1. The disease is clinically diverse, as epitomized by the classification criteria as well as by the wide array of autoantibody specificities found in the sera of patients. Over the past several decades, the individual self proteins targeted by antinuclear antibodies (ANA) have been elucidated and characterized 2,3.

Structural Characteristics
Human B cell hybridomas were established to define new autoantigens of importance for autoimmune diseases. One lgG1, λ monoclonal antibody (FKN-E12), was derived from synovial B lymphocytes of a patient with sero-negative RA. The purified lg was used to select specifically binding peptides from a random peptide phage display library. Only one epitope with the heptamer sequence HLTFGPG was detected and named RASFp1. Very similar and partly identical sequences are found in the variable region of lg κ light chains in position 96–101, at the junction of framework 2 and the J-region. The antibody FKN-E12 was shown to detect the epitope RASFp1 also on human lgG κ chains, but only in a specific conformation. A 15-mer-peptide was synthesized containing RASFp1 within Vk-derived flanking regions, and an ELISA assay established. Sera of 142 individuals were studied. Only <5%>

Mode of Action
Autoimmunity begins with immune responses against a few small portions (‘epitopes’) of one or a few self-antigens in lupus and related autoimmune diseases. With time, these autoimmune responses shift, drift and diversify not only to other epitopes in the original antigen but also to other related and sometimes to unrelated antigens. Anti-Sm is a common and specific autoantibody found in systemic lupus erythematosus. After immunization with PPPGMRPP peptide from Sm B/B' on a MAP backbone, rabbits develop anti-Sm autoantibodies with B cell epitope spreading of the autoimmune response as well as other features of lupus autoimmunity. All peptide-immunized mouse strains eventually develop high titers of specific anti-peptide of immunization Abs. Mice immunized with Freund’s adjuvant alone have no measurable Ab binding to the PPPGMRPP peptide. With time, nearly half the mouse strains tested develop Abs that reacts with additional regions of Sm B/B' and Sm D. All the regions bound by mouse serum are major epitopes of the human systemic lupus erythematosus anti-Sm response. These same strains also develop significant anti-Sm and anti-nuclear ribonucleoprotein titers. In addition, some of these strains demonstrate positive anti-nuclear Abs and anti-dsDNA Abs. Experiments with congenic H-2 mice demonstrate that the H-2 region does not play a role in spreading the immune response from the peptide of immunization to other epitopes of the spliceosome. These results present a new murine model of B cell epitope spreading and lupus autoimmunity induced by peptide immunization that is strain specific and not apparently dependent upon the loci at H-2 5, 6.

Functions
Novel therapeutics, exploiting regulatory potential of the normal immune response to inhibit autoimmunity in lupus and understanding the pathways of autoimmune diversification in lupus and how normal subjects can ward-off such pathologic spreading of autoimmunity in SLE may pave the way for novel therapeutics for lupus and other autoimmune diseases 7.

Lupus and autoimmune diseases, massive expansion of T and B cell cohorts develops spontaneously in lupus. When such T–B cell diversification is triggered by exogenous immunization in normal subjects, they readily develop regulatory T cells that can effectively curtail the pathologic autoimmunity.

Systemic lupus erythematosus (SLE) epitopes, SLE is characterized by the developmentof T cell and antibody responses against a variety of self-antigens. Initial autoimmune response in SLE is restricted to few epitopes and dominant antigenic epitopes in apoptotic blebs are processed and presented to activate T cells, which then stimulate the first wave of autoreactive B cells 8.

References
1.Harley JB, Gaither KK (1988). Autoantibodies. Rheum Dis Clin North Am.,14:43–56.
2.Fujisaku A, Frank MB, Neas B, Reichlin M, Harley JB (1994). HLA-DQ gene complement and other histocompatibility relationships in man with the anti-Ro/SSA autoantibody response in systemic lupus erythematosus. J Clin Invest., 93:718–724.
3. Frank MB, McArthur R, Harley JB, Fujisaku A (1990). Anti-Ro (SSA) autoantibodies are associated with T cell receptor b genes insystemic lupus erythematosus patients. J Clin Invest., 85:33–39.
4.von Landenberg P, von Landenberg C, Grundl M, Schmitz G, Schölmerich J, Melchers I (1999). A new antigenic epitope localized within human κlight chains specific for rheumatoid arthritis and systemic lupus erythematosus. Journal of Autoimmunity, 13(1):83-87.
5.James JA, Harley JB (1998). A model of peptide-induced lupus autoimmune B cell epitope spreading is strain specific and is not h-2 restricted in mice. The Journal of Immunology, 160:502-508.
6.Harley JB, Scofield RH (1991). Systemic lupus erythematosus: RNA protein autoantigens, models of disease heterogeneity, and theories of etiology. J Clin Immunol., 11:297–307.
7.Mills JA (1994). Systemic lupus erythematosus. N. Engl. J. Med., 330:1871-1879.
8.Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al., (1982). The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum., 25:1271–1277.

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