Intracellular protein complexes containing nucleic acids are common targets of autoantibodies in many autoimmune diseases. Central tolerance to these antigens is incomplete, yet nucleosomal DNA is expressed on the surface of cells dying by apoptosis. It is commonly believed that autoimmunity is prevented by the rapid uptake of apoptotic cells (ACs) by neighbors or professional phagocytes to which they deliver anti-inflammatory signals. Self-reactive, innate-like B cells contact and are selected by intracellular antigens expressed on ACs; however, how self-tolerance is maintained is not well understood. Here we report that IL-10 production by B cells, stimulated by contact with ACs, results from the engagement of Toll-like receptor 9 (TLR9) within the B cell after recognition of DNA-containing complexes on the surface of ACs. Until now, TLR9 ligation has been considered an inflammatory signal, but we have confirmed a hitherto unexpected immunoregulatory role by demonstrating the absence of the protective effect of ACs during experimental autoimmune encephalitis (EAE) in TLR9-deficient mice. Human circulating CD27 + B cells also respond to DNA-bearing ACs, but not to DNase-treated cells, by secreting IL-10. Chronic autoimmune disease may arise if this tolerance mechanism is not reimposed after episodes of inflammation, or if the regulatory B-cell response is subverted.

Immune suppression associated with morbillivirus infections may influence the mortality rate by allowing secondary bacterial infections that are lethal to the host to flourish. Using an in vitro proliferation assay, we have shown that all members of the genus Morbillivirus inhibit the proliferation of a human B-lymphoblast cell line (BJAB). Proliferation of freshly isolated, stimulated bovine and caprine peripheral blood lymphocytes is also inhibited by UV-inactivated rinderpest (RPV) and peste-des-petits ruminants viruses. As for measles virus, coexpression of both the fusion and the hemagglutinin proteins of RPV is necessary and sufficient to induce immune suppression in vitro.Morbillivirus infections induce severe disease in their natural hosts, causing high morbidity and mortality. (3,4). These morbilliviruses infect mammalian hosts, and disease is generally confined to one order of mammals; e.g., MV infects solely primates, while RPV and PPRV naturally infect only Artiodactyla (cloven-hoofed animals), and CDV naturally infects Carnivora (2).Despite widespread use of an effective live attenuated vaccine, MV remains a major killer disease of infants in developing countries, accounting for over 1 million deaths per annum. The main cause of death is secondary bacterial infections that flourish due to MV-induced immunosuppression. Although MV is rapidly cleared from the host, lymphoproliferative responses to mitogens and recall antigens are suppressed for up to several months postinfection. Both B and T subsets of leukocytes are affected, but not the CD4 ϩ /CD8 ϩ ratio (1). MV infection interferes with the differentiation and specialization of lymphocyte functions but does not alter those already established (11). In the case of RPV, lymphodepletion in the thymus, Peyer's patches, spleen, and pulmonary lymph nodes indicates that these infections also induce immunosuppression in infected hosts (27). Recently, we showed that cattle infected with a virulent strain of RPV also show reduced responses of leukocytes to mitogens ex vivo (15). As for MV, lung infections with bacterial secondary infection are common features of PPRV (12,19), and morbillivirus infections in marine mammals result in a severe pulmonary distress with increased levels of opportunistic bacteria, evidence of immunosuppression in these animals (5, 6).Many theories have been proposed to account for MVinduced nonresponsiveness of the immune system, although there is little agreement about the mechanisms involved (7,14,22,23,26). It is likely that there are many factors that contribute to immunosuppression in vivo. During the course of acute MV infection, only a small proportion of peripheral blood leukocytes are infected, indicating that indirect mechanisms, rather than the direct infection and destruction of lymphoid cells, are involved in the widespread immune unresponsiveness. Using a two-cell system, Schlender and colleagues showed that small numbers of MV-infected, UV-irradiated, lymphocyte presenter cells (PC) could inhibit the proliferation...

Rinderpest, or cattle plague, is caused by Rinderpest virus (RPV), which is related most closely to human Measles virus (MV), both being members of the genus Morbillivirus, a group of viruses known to have strong immunosuppressive effects in vitro and in vivo. Here, it was shown that peripheral blood mononuclear cells (PBMCs) isolated from cattle experimentally infected with either wild-type or vaccine strains of RPV impaired the proliferation of PBMCs derived from uninfected animals; however, in contrast to either mild or virulent strains of wild-type virus, the inhibition induced by the vaccine was both weak and transient. Flow-cytometric analysis of PBMCs obtained from cattle infected with different strains of RPV showed that the proportion of infected cells was virus dose-dependent and correlated with lymphoproliferative suppression.