A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus.

Riemekasten, Gabriela; Marell, Jeannette; Trebeljahr, G; Klein, Roseli Pizzigatti; Hausdorf, Gert; Häupl, Thomas; Schneider‐Mergener, Jens; Burmester, G.-R.; Hiepe, Falk

doi:10.1172/jci2749

Cited by 92 publications

(120 citation statements)

References 36 publications

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“…An additional group has shown that this same region of Sm D1 is antigenic when the alternating arginines are dimethylated (35). Interestingly, this posttranslational modification may not be absolutely required for antigenicity of these sequences, as has been shown by this and other works (8,(33)(34). Additional experiments are underway to understand the overall importance of symmetrical dimethylation of these sequences with regard to lupus autoimmunity.…”

Section: Discussionmentioning

confidence: 77%

“…This carboxyl-terminal region of Sm D1 has been determined by several investigators to be the major target of the human and murine lupus anti-Sm D1 response (10 -14, 29 -30, 33). Immunization with this C-terminal D1 peptide causes lupus-like disease in rabbits as well as the production of anti-D1 and anti-D3 autoantibodies (33) and accelerates disease in lupus-prone animals (New Zealand Black/White mice) (34). The data from the (GR)-repeat portion of the D3 polypeptide, its similarity to D1, and the cross-reactivity of affinity-purified anti-D3 Abs with this region of D1 seem to support the theory of crossreactivity explaining the appearance of some autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Among the most important of these sequential epitopes is the glycine-arginine (GR)-rich carboxyl region of Sm D1, which is recognized by virtually all Sm-precipitin positive lupus patient sera (8, 10 -14). This region of Sm D1 also shows striking sequence homology to a portion of the Sm D3 protein, and immunization with this region of D1 results in the production of anti-D3 Abs (13). The (GR)-rich portions of the Sm D1 and D3 proteins thus appear to be significant targets of the anti-Sm response.…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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Autoantibodies directed against spliceosomal proteins are a common and specific feature of systemic lupus erythematosus. These autoantibodies target a collection of proteins, including Sm B, B′, D1, D2, and D3. We define the common antigenic targets of Sm D2 and D3 and examine their role in spliceosomal autoimmunity. Our results define nine major common epitopes, five on Sm D2 and four on Sm D3. These epitopes have significantly higher (more basic) isoelectric points than do nonantigenic regions. In fact, this association is of sufficient power to make isoelectric point an excellent predictor of spliceosomal antigenicity. The crystallographic structure of Sm D2 and D3 is now partially described. The anti-Sm D2 and D3 antigenic targets are located on the surface of the respective three-dimensional complexed proteins, thereby suggesting that these epitopes are accessible in the native configuration. All but one of these nine epitopes conspicuously avoid the specific regions involved in intermolecular interactions within the spliceosomal complex. One of the D3 epitopes (RGRGRGMGR) has significant sequence homology with a major antigenic region of Sm D1 (containing a carboxyl-terminal glycine-arginine repeat), and anti-D3 Abs cross-react with this epitope of Sm D1. These results demonstrate that spliceosomal targets of autoimmunity are accessible on native structure surfaces and that cross-reactive epitopes, as well as structural associations of various spliceosomal Ags, may be involved in the induction of autoimmunity in systemic lupus.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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“…Moreover, ELISA using components of Sm/RNP demonstrated that Vκ38C + antibodies strongly react to the glycine-arginine-rich C-terminal part (residues 83-119) of SmD1 (Fig. S2), the major epitope recognized by anti-Sm antibodies from SLE patients (24,25). Thus, Vκ38C + antibodies show antigen specificity similar to anti-Sm antibodies in SLE, although 56R/Vκ38C + are potentially reactive to other self-antigens (26).…”

Section: Cd40mentioning

confidence: 93%

Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells

Kishi

Higuchi

Phoon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/ 56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti-Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus.peripheral tolerance | lupus-related autoantibody | marginal zone B cells M aintenance of B-cell tolerance occurs at various checkpoints throughout B-cell development and maturation and involves multiple mechanisms. Self-reactive immature B cells are subjected to central tolerance mechanisms in the bone marrow, including deletion by apoptosis (clonal deletion), functional inactivation (clonal anergy), or Ig V gene replacement (receptor editing) (1-4). B-cell tolerance can also occur after B cells leave the bone marrow and home to peripheral lymphoid organs. This peripheral tolerance involves mechanisms such as anergy, ignorance, and maturation arrest (5-7). Moreover, how tolerance is maintained in self-reactive B cells, which are anergized in bone marrow and migrate to the peripheral lymphoid tissues, has been extensively studied. These B cells are excluded from the follicle or marginal zone (MZ) and show reduced longevity (2, 8-10) attributable to increased dependence on B cell-activating factor belonging to the tumor necrosis factor family (BAFF) for survival (11, 12). However, it is not fully understood how peripheral tolerance mechanisms are broken in autoimmunity.B-cell self-tolerance has been addressed using antibodytransgenic (Tg) mice in which most of the B cells are reactive to a particular self-antigen. The anti-DNA H-chain Tg mice 3H9 and 56R are well-characterized models for studying B-cell tolerance to nuclear antigens (1, 10, 13-16), to which autoantibodies are characteristically produced in various autoimmune diseases including systemic lupus erythematosus (SLE). The 56R H chain was generated by introducing an arginine residue to the 3H9 VH region to increase affinity of the transgene-encoded antibodies for DNA. When paired with almost any of the mouse endogenous Ig L chains, both the 3H9 and the 56R H chains form an...

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“…n systemic lupus erythematosus (SLE), 4 a typical systemic autoimmune disease, high affinity Abs to several autoantigens, such as dsDNA, nucleosomes, and Smith (Sm) proteins, specifically occur and lead to tissue damage (1)(2)(3). These autoantibodies, which belong to the normal repertoire of autoantibodies in healthy individuals, require T cell help for their production as IgG.…”

mentioning

confidence: 99%

Intravenous Injection of a D1 Protein of the Smith Proteins Postpones Murine Lupus and Induces Type 1 Regulatory T Cells

Riemekasten

Langnickel

Enghard

et al. 2004

The Journal of Immunology

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T cells that recognize nucleoproteins are required for the production of anti-dsDNA Abs involved in lupus development. SmD183–119 (a D1 protein of the Smith (Sm) proteins, part of small nuclear ribonucleoprotein) was recently shown to provide T cell help to anti-dsDNA Abs in the NZB/NZW model of lupus. Using this model in the present study, we showed that high dose tolerance to SmD1 (600–1000 μg i.v. of SmD183–119 peptide/mo) delays the production of autoantibodies, postpones the onset of lupus nephritis as confirmed by histology, and prolongs survival. Tolerance to SmD183–119 was adoptively transferred by CD90+ T cells, which also reduce T cell help for autoreactive B cells in vitro. One week after SmD183–119 tolerance induction in prenephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased IFN-γ and IL-4 expression and an increase in TGFβ. Increased frequencies of regulatory IFN-γ+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-γ+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-induced proliferation of naive T cells. In conclusion, these results indicate that SmD183–119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus.

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A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus.

Cited by 92 publications

References 36 publications

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells

Intravenous Injection of a D1 Protein of the Smith Proteins Postpones Murine Lupus and Induces Type 1 Regulatory T Cells

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