Human T cell responses to autoantibody variable region peptides

Systemic lupus erythematosus (SLE) is marked by a Th cell–dependent B cell hyperresponsiveness, with frequent germinal center reactions and hypergammaglobulinemia. The specificity of Th cells in lupus remains unclear, but B cell Ids have been suggested. A hallmark is the presence of anti-dsDNA, mutated IgG autoantibodies with a preponderance of arginines in CDR3 of the Ig variable H chain (IgVH). B cells can present V region–derived Id peptides on their MHC class II molecules to Id-specific Th cells. We show that Id-specific Th cells support the proliferation of anti-dsDNA Id+ B cells in mice suffering from systemic autoimmune disease with SLE-like features. Mice developed marked clonal expansions of B cells; half of the IgVH sequences were clonally related. Anti-dsDNA B cells made up 40% of B cells in end-stage disease. The B cells expressed mutated IgVH with multiple arginines in CDR3. Hence, Id-driven T cell–B cell collaboration supported the production of classical anti-dsDNA Abs, recapitulating the characteristics of such Abs in SLE. The results support the concept that Id-specific Th cells may trigger the development of SLE and suggest that manipulation of the Id-specific T cell repertoire could play a role in treatment.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus

Aas-Hanssen

Funderud

Thompson

et al. 2014

“…Several groups have reported evidence in support of receptor presentation in autoimmunity (27,30,31,(35)(36)(37)(38)(39)(40). In a preceding study, we conducted a genealogical analysis of somatic mutations within an autoreactive B cell lineage obtained from a spontaneously diseased SNF 1 mouse.…”

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Guo

Smith

Guth

et al. 2005

The BCR V region has been implicated as a potential avenue of T cell help for autoreactive B cells in systemic lupus erythematosus. In principle, either germline-encoded or somatically generated sequences could function as targets of such help. Preceding studies have indicated that class II MHC-restricted T cells in normal mice attain a state tolerance to germline-encoded Ab diversity. In this study, we tested whether this tolerance is intact in systemic lupus erythematosus-prone (New Zealand Black × SWR)F1 mice (SNF1). Using a hybridoma sampling approach, we found that SNF1 T cells were tolerant to germline-encoded Ab sequences. Specifically, they were tolerant to germline-encoded sequences derived from a lupus anti-chromatin Ab that arose spontaneously in this strain. This was true both for diseased and prediseased mice. Thus, there does not appear to be a global defect in T cell tolerance to Ab V regions in this autoimmune-prone strain either before or during autoimmune disease.

“…Autoreactive, anti-V H , Th cells that recognize peptides processed from the V H of anti-DNA Ig molecules (4,20,(22)(23)(24)(25)(26)(27) arise spontaneously in humans and mice with systemic lupus erythematosus (6,20,28) and modulate the development and progression of disease in lupus mice (4,6,20,29,30). These MHC class II-restricted, anti-V H Th cells increase anti-DNA Ab production by BWF 1 B cells (15).…”

Section: Plus B)mentioning

confidence: 99%

Induction of Autoantibody Production Is Limited in Nonautoimmune Mice

Singh

Ebling

Albuquerque

et al. 2002

Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the VH region of anti-DNA Abs (hereafter called anti-VH T cells). Immunization with anti-DNA mAb, its γ-chain or peptides derived from its VH region induced anti-VH Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFβ; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFβ Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.