Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice.

Murine leukaemia virus has been suggested to contribute to both autoimmune disease and leukaemia in the NZB mouse and in the (NZB × NZW) F1 (abbreviated B/W) mouse. However, with apparently only xenotropic but no ecotropic virus constitutively expressed in these mice, few mechanisms could explain the aetiology of either disease in either mouse strain. Because pseudotyped and/or inducible ecotropic virus may play a role, we surveyed the ability of murine leukaemia virus in NZB, NZW and B/W mice to infect and form a provirus.

Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses.

Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic erythematosus lupus, in which DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways. Nevertheless, TLR9-deficient autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the functional properties of autoantigen-activated wild-type, TLR9-deficient, and TLR7-deficient B cells in an experimental system in which proliferation depends on BCR/TLR coengagement.

APOBEC3 enzymes restrict marginal zone B cells.

In general, a long-lasting immune response to viruses is achieved when they are infectious and replication competent. In the mouse, the neutralizing antibody response to Friend murine leukemia virus is contributed by an allelic form of the enzyme Apobec3 (abbreviated A3). This is counterintuitive because A3 directly controls viremia before the onset of adaptive antiviral immune responses.

Introduction: mechanisms of tissue injury in autoimmune diseases.

This issue of Seminars in Immunopathology is devoted to the most recent developments in our understanding of the mechanisms leading to tissue injury in autoimmune diseases. These include rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, autoimmune liver diseases, inflammatory bowel diseases, autoimmune skin diseases, autoimmune uveitis, and autoinflammatory diseases. This impressive account of basic and clinical research in a wide spectrum of immunological disorders provides the reader with a comprehensive view of the common and unique features of these diverse conditions.

Insertional hypermutation in mineral oil-induced plasmacytomas.

Unless stimulated by a chronic inflammatory agent, such as mineral oil, plasma cell tumors are rare in young BALB/c mice. This raises the questions: What do inflammatory tissues provide to promote mutagenesis? And what is the nature of mutagenesis? We determined that mineral oil-induced plasmacytomas produce large amounts of endogenous retroelements--ecotropic and polytropic murine leukemia virus and intracisternal A particles. Therefore, plasmacytoma formation might occur, in part, by de novo insertion of these retroelements, induced or helped by the inflammation.

Crystal structure determination of anti-DNA Fab A52.

A52 is a murine monoclonal antibody isolated from autoimmune New Zealand Black/New Zealand White F1 mice that recognizes single and double stranded DNA. This mouse strain spontaneously develops systemic lupus erythematosus-like symptoms and has served as a model for that disease for many years. The 1.

L chain allelic inclusion does not increase autoreactivity in lupus-prone New Zealand Black/New Zealand White mice.

L chain allelic inclusion has been proposed as a B cell tolerance mechanism in addition to clonal deletion, clonal anergy, and receptor editing. It is said to rescue autoreactive B cells from elimination by diluting out the self-reactive BCR through the expression of a second innocuous L chain. In autoimmune animals, such as lupus-prone mice, allelically included B cells could be activated and produce pathogenic autoantibodies.

B cell tolerance and positive selection in lupus.

Systemic lupus erythematosus is considered a prototype of systemic autoimmune diseases; however, despite considerable advances in recent years in the understanding of basic mechanisms in immunology, little progress has been made in elucidating the etiology and pathogenesis of this disease. This even holds for inbred mice, such as the lupus-prone New Zealand Black/New Zealand White F(1) mice, which are all genetically programmed to develop lupus at a predetermined age. This frustrating state of affairs calls for a fundamental change in our scientific thinking and the opening of new directions in lupus research.

BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus.

BAFF inhibition is a new B cell-directed therapeutic strategy for autoimmune disease. Our purpose was to analyze the effect of BAFF/APRIL availability on the naive and Ag-activated B cell repertoires in systemic lupus erythematosus, using the autoreactive germline D42 H chain (glD42H) site-directed transgenic NZB/W mouse. In this article, we show that the naive Vκ repertoire in both young and diseased glD42H NZB/W mice is dominated by five L chains that confer no or low-affinity polyreactivity.

An autoimmune disease prevented by anti-retroviral drugs.

Background: Both Aicardi-Goutières syndrome, a Mendelian mimic of congenital infection, and the autoimmune disease systemic lupus erythematosus can result from mutations in the gene encoding the enzyme Trex1. In mice, the absence of Trex1 causes severe myocarditis. The enzyme is thought to degrade endogenous retroelements, thus linking them to autoimmune disease.

B-cell anergy is maintained in anti-DNA transgenic NZB/NZW mice.

Clonal anergy has been well recognized as an important mechanism of B cell immunologic tolerance. However, the properties of anergic B cells and especially their role in the development of autoimmune disease in susceptible animals have been controversial. Here we show that low-affinity anti-DNA anergic B cells populate the mature B-cell compartment in the mouse spleen in excessive numbers and display paradoxical behavior in response to a combined B-cell receptor/TLR9 activation.

Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir.

Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F(1) mice die of glomerulonephritis more than a month earlier than untreated mice.

Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop.

Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR(-/-) B cells proliferated significantly less well and did not up-regulate costimulatory molecules.

Autoreactive anti-DNA transgenic B cells in lupus-prone New Zealand black/New Zealand white mice show near perfect L chain allelic exclusion.

Recent work on B cell tolerance and autoimmunity has suggested the L chain allelic inclusion is a property of autoreactive B cells and is closely linked to receptor editing. Allelic inclusion could rescue autoreactive B cells from clonal deletion by reducing their effective BCR surface density. We have investigated this phenomenon in anti-DNA producing hybridomas, derived from different strains of Ig gene-targeted, lupus-prone NZB/NZW mice.

Peripheral B cell receptor editing may promote the production of high-affinity autoantibodies in CD22-deficient mice.

CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22-/- mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vkappa1-Jkappa1 or Vkappa8-Jkappa5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age- and sex-dependent.

Treatment with a laminin-derived peptide suppresses lupus nephritis.

The role of DNA as the target for pathogenic lupus autoantibodies in systemic lupus erythematosus is equivocal and renal damage may be due to cross-reactivity of lupus Abs with glomerular components. We have previously shown that lupus autoantibodies bind to the laminin component of the extracellular matrix. In the present work, we have analyzed the fine specificity of the interaction of pathogenic murine lupus autoantibodies with this molecule and the effect of inhibiting their binding to laminin during the course of the disease.

Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.

The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus.

Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high-affinity anti-dsDNA autoantibodies from low-affinity precursors.

We have previously constructed knock-in (C57BL/6xBALB/c) F1 mice, each expressing an anti-DNA heavy (H) chain (D42), combined with one of three different light (L) chains, namely Vkappa1-Jkappa1, Vkappa4-Jkappa4 or Vkappa8-Jkappa5. All of these H/L chain combinations bind DNA with similar affinity and fine specificity. However, while mice carrying Vkappa1-Jkappa1-transgenic L chain were tolerized almost exclusively by L chain receptor editing, the mice expressing Vkappa8-Jkappa5 L chains utilized clonal anergy as their principal mechanism of B cell tolerance.

The efficiency of B cell receptor (BCR) editing is dependent on BCR light chain rearrangement status.

Anti-DNA knock-in mice serve as models for studying B cell tolerance mechanisms to a ubiquitous antigen. We have constructed six strains of double transgenic (C57BL/6xBALB/c)F1 mice, each expressing an unmutated or somatically mutated anti-DNA heavy (H) chain, combined with one of three different light (L) chains, namely V(kappa)1-J(kappa)1, V(kappa)4-J(kappa)4 and V(kappa)8-J(kappa)5. In vitro analysis of the various Ig H/L chain combinations showed that all had a similar specificity for single-stranded DNA and double-stranded DNA, but that antibodies encoded by the mutated H chain had higher affinities for the autoantigen.