Somatic Mutation and Light Chain Rearrangement Generate Autoimmunity in Anti–Single-Stranded DNA Transgenic Mrl/<i>lpr</i> Mice

Brard, Fréderic; Shannon, Michele; Prak, Eline Luning; Litwin, Samuel; Weigert, Martin

doi:10.1084/jem.190.5.691

Cited by 117 publications

(132 citation statements)

References 48 publications

(62 reference statements)

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…A similar finding was seen in mice expressing the neo-self Ag HEL in the thymus, where HEL-specific B cells were not tolerized, yet partial tolerance to HEL existed in the T cell compartment (43). In contrast to the significant B cell tolerance that exists to the lupusassociated autoantigens DNA and Sm (6,44,45), this finding suggests that even though hLa-or HEL-specific autoreactive B cells are not directly tolerized, the development of humoral autoimmunity is constrained by a deficiency of functional autoreactive Th cells. Under these circumstances, self-reactive B cells are not strictly ignorant, in that they appear to take up endogenous autoantigen constitutively and are capable of Ag presentation to T cells.…”

Section: Anti-hla B Cells and Clonal Ignorancementioning

confidence: 79%

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Aplin

Keech

Kauwe

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5–15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.

show abstract

Section: Anti-hla B Cells and Clonal Ignorancementioning

confidence: 79%

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Aplin

Keech

Kauwe

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…This is not unlikely, especially when one considers that secondary D to J H rearrangement is mechanistically similar to a secondary Vk to Jk rearrangement (8,9). Secondary light chain rearrangements occur routinely during the process of receptor editing, and recent work suggests that both central and peripheral editing can occur more frequently in lupus patients (43)(44)(45). Further, D-J H replacements were observed in an Abelson murine leukemia virus-transformed B cell line providing evidence that an initial D-J H recombination does not prevent secondary recombinations (41).…”

Section: Discussionmentioning

confidence: 99%

Heavy Chain Revision in MRL Mice: A Potential Mechanism for the Development of Autoreactive B Cell Precursors

Klonowski

Monestier

2000

The Journal of Immunology

View full text Add to dashboard Cite

Abs reactive to DNA and DNA/histone complexes are distinguished by the presence of positively charged amino acids, such as arginine, in the heavy chain complementarity-determining region 3. The presence of these amino acids partly results from atypical VH-D-JH rearrangements such as D-D fusions and D inversions. Previous results in our laboratory demonstrated that newborn autoimmune MRL/MpJ-+/+ mice undergo these unusual recombinations more frequently when compared with normal C3H/HeJ controls. In addition, the heavy chain junctions in newborn MRL mice demonstrated a preferred usage of VH-proximal D genes and distal JH genes suggestive of secondary gene rearrangements. In this study we explore the possibility that adult MRL B220+IgM− pre B cells, which have not yet undergone Ag selection, exhibit similar rearrangement patterns. Indeed, MRL pre-B cells possessed more atypical rearrangements (D-D fusions) than those of C3H/HeJ mice. However, the biased use of upstream D genes and downstream JH genes observed in the newborn MRL mice was not present in the pre-B cell library. These results suggest that the heavy chain rearrangement process persists later during B cell life in lupus-prone mice and lead us to propose a model of heavy chain receptor revision in the periphery of autoimmune mice.

show abstract

“…Low-affinity autoreactive B cells normally are anergic but can be activated in an autoimmune background, which leads to the generation of pathological autoantibodies (11). Alternatively, autoreactive B cells with very low affinity to self that are not tolerized might be activated by dual engagement of the antigenreceptor and Toll-like receptors (12).…”

mentioning

confidence: 99%

The evolution of human anti-double-stranded DNA autoantibodies

Wellmann

Letz

Herrmann

et al. 2005

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

188

163

View full text Add to dashboard Cite

It has been proposed that the anti-double-stranded DNA (dsDNA) response in patients with systemic lupus erythematosus (SLE) is antigen driven and that DNA or nucleosomes select anti-DNA reactive, somatically mutated B cells. We have used site-directed mutagenesis to systematically revert the somatic mutations of two human anti-dsDNA antibodies from SLE patients to analyze the resulting changes in DNA binding as well as binding to other autoantigens. Our data demonstrate that high-affinity binding to dsDNA and nucleosomes is acquired by somatic replacement mutations in a stepwise manner. Reactivity to surface structures of apoptotic cells is acquired by the same somatic mutations that generate high-affinity dsDNA binding. Importantly, revertant antibodies with germ-line V regions did not show any measurable DNA reactivity. We propose that anti-DNA autoantibodies are generated from nonautoreactive B cells during a normal immune response. B cells may acquire autoreactivity de novo during the process of somatic hypermutation. Nucleosomes, if available in lupus patients because of defects in clearing of apoptotic debris, might subsequently positively select high affinity anti-DNA B cells.somatic hypermutation ͉ systemic lupus erythematosus

show abstract

Somatic Mutation and Light Chain Rearrangement Generate Autoimmunity in Anti–Single-Stranded DNA Transgenic Mrl/lpr Mice

Cited by 117 publications

References 48 publications

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Heavy Chain Revision in MRL Mice: A Potential Mechanism for the Development of Autoreactive B Cell Precursors

The evolution of human anti-double-stranded DNA autoantibodies

Contact Info

Product

Resources

About