Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

Abstract

Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Faslpr (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4+ T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

“…As has been pointed out elsewhere, autoreactivity can also be protective, as is the case for many natural antibodies (NA) which may ameliorate autoimmunity (51, 52) and help maintain homeostasis (51). IgM NA are often positively charged to facilitate interaction with negatively charged targets (53), and may have high levels of poly-reactivity (54).…”

Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients

“…Recent reports describe a role of low-affinity self-reactive antibodies in the maintenance of immune homeostasis. 16,17 If this would be the case for FVIII-binding antibodies found in healthy individuals, these antibodies might be involved in the maintenance of peripheral immune tolerance against FVIII.…”

“…14,15 Furthermore, recent studies of self-reactive antibodies in healthy individuals indicated that these antibodies might be involved in the maintenance of immune homeostasis. 16,17 Gilles et al and others reported that the antibody response to FVIII in patients is not isotypically restricted and involves all IgG subclasses with a preponderance of IgG1 and IgG4. 18 Only limited information is available on the characteristics of antibodies against FVIII which are found in patients without FVIII inhibitors and in healthy individuals.…”

Antigen-Specific Suppression of Humoral Immunity by Anergic Ars/A1 B Cells

“…In view of recent studies indicating immunoregulatory properties of IgM (51–54) we determined whether transferred Ars/A1 B cells produced IgM a (Fig. 6C).…”