Induction of Autoantibody Production Is Limited in Nonautoimmune Mice1

Singh, Ram Raj; Ebling, Fanny M.; Albuquerque, Deijanira; Saxena, Vijay Kumar; Kumar, Vipin; Giannini, Edward H.; Marion, Tony N.; Finkelman, Fred D.; Hahn, Bevra H.

doi:10.4049/jimmunol.169.3.1647

Cited by 15 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously noted that among the different strains of mice (A/J, B10.BR, BALB/c, BALB.K, C57BL/6J, and C57BL/10J) immunized with SmD, only A/J mice demonstrated intermolecular B cell epitope spreading to A-RNP (19). These data suggest that the T and B cell responses to SmD are strain dependent and some autoantibodies might not be induced in normal mice (20). The lack of epitope spreading in BALB/c mice immunized with SmD in our model system is supported by recent findings of Langnickel et al (21).…”

Section: Discussionsupporting

confidence: 81%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 81%

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

View full text Add to dashboard Cite

show abstract

“…Even apparently healthy subjects and family members of lupus patients, who might be at risk of developing lupus (as predicted by genetic and biomarkers), might benefit from the peptide therapy, because it repairs a defect in Treg cell deficiency in lupus (51)(52)(53). Importantly, these peptides appear to be effective even when the autoimmune disease is already established and restores normal lifespan in lupus mice (2,3).…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Kang

Liu

Datta

2007

The Journal of Immunology

186

206

View full text Add to dashboard Cite

Subnanomolar doses of an unaltered, naturally occurring nucleosomal histone peptide epitope, H471–94, when injected s.c. into lupus-prone mice, markedly prolong lifespan by generating CD4+25+ and CD8+ regulatory T cells (Treg) producing TGF-β. The induced Treg cells suppress nuclear autoantigen-specific Th and B cells and block renal inflammation. Splenic dendritic cells (DC) captured the s.c.-injected H471–94 peptide rapidly and expressed a tolerogenic phenotype. The DC of the tolerized animal, especially plasmacytoid DC, produced increased amounts of TGF-β, but diminished IL-6 on stimulation via the TLR-9 pathway by nucleosome autoantigen and other ligands; and those plasmacytoid DC blocked lupus autoimmune disease by simultaneously inducing autoantigen-specific Treg and suppressing inflammatory Th17 cells that infiltrated the kidneys of untreated lupus mice. Low-dose tolerance with H471–94 was effective even though the lupus immune system is spontaneously preprimed to react to the autoepitope. Thus, H471–94 peptide tolerance therapy that preferentially targets pathogenic autoimmune cells could spare lupus patients from chronically receiving toxic agents or global immunosuppressants and maintain remission by restoring autoantigen-specific Treg cells.

show abstract

“…It could be that generation of regulatory T cells, which are important in controlling lupus (21,31,32), was impaired by continuous inhibition of COX-2 (33). Thus, for this or additional reasons, intermittent, but not continuous, therapy with low doses of celecoxib alone is better in prolonging survival in these lupus-prone mice.…”

Section: Discussionmentioning

confidence: 99%

Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus

Zhang

Bertucci

Smith

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To investigate the role of cyclooxygenase 2 (COX-2) in the functioning of different cell types involved in the lupus autoimmune response, and to examine the therapeutic effect of COX-2 inhibitors in mice prone to spontaneously develop systemic lupus erythematosus (SLE).Methods. Lupus-prone (SWR ؋ NZB)F 1 mice were fed with a diet containing different doses of the COX-2-specific inhibitor celecoxib or the nonspecific inhibitor aspirin, or a combination of both, and the effects of the therapy on autoantibody production, development of lupus nephritis, and mortality were determined. Expression of COX-2 by different cells of the lupus immune system and the effect of COX-2 inhibitors on the function of these cells in vitro and in vivo were assessed.Results. The immune cells of mice with SLE spontaneously hyperexpressed COX-2, and COX-2 inhibitors could cause cell apoptosis. Treatment with COX-2 inhibitors resulted in decreased autoantibody production and inhibition of the T cell response to the major lupus autoantigen, nucleosome, and its presentation by antigen-presenting cells. Surprisingly, a significant increase in survival occurred only in mice receiving intermittent therapy with the lowest dose of celecoxib (500 parts per million), approximating <100 mg of celecoxib/day in humans. A continuous diet, but not intermittent feeding, with the combination of celecoxib and aspirin delayed development of nephritis temporarily, but failed to prolong survival. Indeed, treatment with aspirin alone increased mortality.Conclusion. The contributions of the major players in the pathogenic autoimmune response, namely, T cells, B cells, dendritic cells, and macrophages that are abnormally hyperactive in lupus, depend on the increased expression and activity of COX-2, similar to inflammatory cells in target organs. Intermittent pulse therapy with low doses of select COX-2 inhibitors would be of value in the treatment of lupus.In systemic lupus erythematosus (SLE), hyperactivity of the immune system leads to activation of certain autoimmune T helper cells, which drive autoimmune B cells to produce somatically mutated IgG autoantibodies against apoptotic nuclear antigens (1-6). IgG immune complexes containing autoantigenic DNA and RNA bind Fc␥ receptors and Toll-like receptors (TLRs), which results in stimulation of type I interferon (IFN) production by hyperactive dendritic cells (DCs); moreover, autoimmune B cells bearing the T helper celldriven, high-affinity, somatically mutated B cell receptors are dually stimulated by TLRs (7-9). These events further amplify the ability of antigen-presenting cells (APCs) to present autoantigens to pathogenic T helper cells, which is an essential element of disease development (10-13).Normally, autoreactive T and B cells are eliminated by functional inactivation (anergy) and by activation-induced cell death (AICD; apoptosis), via Fas signaling (14). However, autoimmune T helper cells in human lupus resist AICD by up-regulating the expression of cyclooxygenase 2 (COX-2) and the anti...

show abstract

Induction of Autoantibody Production Is Limited in Nonautoimmune Mice1

Abstract: The author affiliations and grant information in the footnote section is incorrect. The corrected information is shown below.

Cited by 15 publications

References 0 publications

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

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus

Contact Info

Product

Resources

About