Determinant spreading: lessons from animal models and human disease

McCluskey, James; Farris, A. Darise; Keech, Catherine L.; Purcell, Anthony W.; Rischmueller, Maureen; Kinoshita, G; Reynolds, Pakathip; Gordon, Thomas P.

doi:10.1111/j.1600-065x.1998.tb01222.x

Cited by 123 publications

(116 citation statements)

References 116 publications

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“…Based upon these data, the current hypothesis is that in systemic autoimmune responses many spliceosomal Abs preferentially target regions of an Ag that are localized to the autoantigen surface. The mechanism of determinant spreading in SLE has also been proposed to involve structures that are positioned near one another on the surface of the three-dimensional structure (20). Amazingly, very few autoantigens have defined crystalline structures, which would allow testing of this hypothesis.…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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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“…Initially few polypeptides are targeted by the Abs and a progressive recognition of additional polypeptides of the snRNP particle ensues. This phenomenon has been termed "intermolecular epitope spreading," wherein an immune response to initial target Ags leads the immune responses to Ags targeted later (8). Based on the serological analyses of patient sera and mouse models, different snRNP proteins have been proposed to be the Ags responsible for initiating the epitope spreading cascade (7,9).…”

mentioning

confidence: 99%

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

Deshmukh

Bagavant

Sim

et al. 2007

The Journal of Immunology

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Autoantibody response against the small nuclear ribonucleoprotein (snRNP) complex is a characteristic feature of systemic lupus erythematosus. The current investigation was undertaken to determine whether activation of SmD-reactive T cells by synthetic peptides harboring T cell epitopes can initiate a B cell epitope spreading cascade within the snRNP complex. T cell epitopes on SmD were mapped in A/J mice and were localized to three regions on SmD, within aa 26–55, 52–69, and 86–115. Immunization with synthetic peptides SmD31–45, SmD52–66, and SmD91–110 induced T and B cell responses to the peptides, with SmD31–45 inducing the strongest response. However, only SmD52–66 immunization induced T cells capable of reacting with SmD. Analysis of sera by immunoprecipitation assays showed that intermolecular B cell epitope spreading to U1RNA-associated A ribonucleoprotein and SmB was consistently observed only in the SmD52–66-immunized mice. Surprisingly, in these mice, Ab responses to SmD were at low levels and transient. In addition, the sera did not react with other regions on SmD, indicating a lack of intramolecular B cell epitope spreading within SmD. Our study demonstrates that T cell responses to dominant epitope on a protein within a multiantigenic complex are capable of inducing B cell responses to other proteins within the complex. This effect can happen without generating a good Ab response to the protein from which the T epitope was derived. Thus caution must be taken in the identification of Ags responsible for initiating autoimmune responses based solely on serological analysis of patients and animals with systemic autoimmune disorders.

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“…Autoimmunity to Ro 60 and La is thought to be initiated against the Ro 60 component of the RNP, which may be followed by intermolecular spreading to La (for review, see ref. 6). …”

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confidence: 99%

A B cell apotope of Ro 60 in systemic lupus erythematosus

Reed¹,

Jackson²,

Gordon³

2008

Arthritis & Rheumatism

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Objective. Previous studies have attempted to segregate anti-60-kd Ro/SSA (anti-Ro 60) responses in systemic lupus erythematosus (SLE) and primary Sjö-gren's syndrome (SS) but have shown limited disease preference. The aim of the present study was to determine whether the presence of autoantibodies against an Ro 60 apotope (an epitope expressed on apoptotic cells) distinguishes anti-Ro 60 responses in SLE and primary SS.Methods. Multiparameter flow cytometry was used to select early apoptotic cells and measure the simultaneous binding of annexin V, propidium iodide, and anti-Ro 60-positive IgG from SLE patients (n ‫؍‬ 21) and patients with primary SS (n ‫؍‬ 19). The specificity of the Ro 60 apotope was determined by inhibition experiments with recombinant and native Ro 60.Results. Autoantibodies against the Ro 60 apotope were prevalent in SLE patients (13 of 21, 62%) and were rarely observed in patients with primary SS (1 of 19, 5%) (P ‫؍‬ 0.0002). Further, within SLE patients, autoantibodies to the Ro 60 apotope strongly distinguished patients with anti-Ro 60 alone (12 of 13, 92%) from those with both anti-Ro 60 and anti-La (1 of 8, 13%) (P ‫؍‬ 0.0005). When we considered all patients with anti-Ro 60 alone, the presence of autoantibodies to the Ro 60 apotope had both high sensitivity (92.3%) and high specificity (85.7%) for SLE compared with primary SS (P ‫؍‬ 0.0012). The presence of autoantibodies to the Ro 60 apotope may therefore be of diagnostic value in patients with isolated anti-Ro 60 responses.Conclusion. The preferential targeting of an Ro 60 apotope exposed on early apoptotic cells in a subset of SLE patients implies disease-specific pathways for the induction of anti-Ro 60 autoimmunity.

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Determinant spreading: lessons from animal models and human disease

Cited by 123 publications

References 116 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

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

A B cell apotope of Ro 60 in systemic lupus erythematosus

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