Methicillin resistance in Staphylococcus aureus strains isolated from food and wild animal carcasses in Italy.

Following the detection of methicillin-resistant Staphylococcus aureus (MRSA) ST398 in food-producing animals, both livestock and wildlife, and derived products, are considered potential sources of MRSA in humans. There is a paucity of data on MRSA in foods in Italy, and the data regarding wild animals are particularly scarce. A total of 2162 food samples collected during official monitoring activities in 2008 were analyzed for the detection of S. aureus. Also, samples from 1365 wild animals collected by the National Reference Center for Wild Animal Diseases in 2003-2009 were subjected to anatomopathological examination. S. aureus isolates were processed for phenotypic and molecular methicillin resistance determinations. S. aureus was found in 2.0% of wild animal carcasses and in 3.2% of wild boar lymph nodes: none showed methicillin resistance. The prevalence of S. aureus in food was 17.1%. Two MRSA strains, both from bulk tank milk (prevalence 0.77%) were isolated: the strains were resistant to tetracycline, had spa-type t899, and were negative for the Panton-Valentine leukocidin gene. The low prevalence of MRSA suggests that the risk of transmission to humans via food is limited. However, attention should be paid to the cattle food chain, which may be a potential route of transmission of LA-MRSA.

The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.

OBJECTIVE: To describe the impact of empiric appropriate treatment and the risk factors associated with mortality in patients with bacteremia by E. coli, K. pneumoniae and P. mirabilis producing ESBL. METHODS: Data were reviewed in an 8-year retrospective study, and 128 bacteremias were found: 80 caused by E. coli (62.5%), 28 by K. pneumoniae (21.9%) and 20 by P. mirabilis (18.6%). RESULTS: The initial antibiotic treatment, administered within 72 h after the first positive blood culture, was appropriate with carbapenems or other antimicrobial agents with documented in vitro sensitivity in 53.8 and 16% of patients, respectively. The overall mortality 21 days after diagnosis was 17.2%, and it was 14.9 and 35.2% for patients adequately and inadequately treated, respectively. At univariate analysis the p value for mortality with and without appropriate treatment was 0.05, and significant differences were found only for previous positive blood cultures (p = 0.004) and presence of septic shock at diagnosis (p = 0.006). CONCLUSION: In this case series there was a high rate of initial appropriate empiric treatment, and only a marginal impact on mortality was found with regard to appropriate and inappropriate treatment. This report shows that the knowledge of ESBL-producing characteristics varies widely among the different case series for reasons that still have to be clarified.

Selective autoantibody production by Yaa+ B cells in autoimmune Yaa(+)-Yaa- bone marrow chimeric mice.

The accelerated autoimmune syndrome observed in BXSB/MpJ male mice is associated with the presence on the Y chromosome of an as yet unidentified mutant gene, designated Y chromosome-linked autoimmune acceleration (Yaa). To study the mechanisms by which the Yaa gene accelerates and/or induces the production of autoantibodies, we have developed double-congenic bone marrow chimeras containing B cells from autoimmune males carrying the Yaa gene, and from nonautoimmune male or female mice lacking it and differing by the Igh allotype. The analysis of the allotype of total immunoglobulins and anti-DNA antibodies in Yaa+ male-normal female (Yaa-) chimeric mice revealed that the selective activation of B cells from autoimmune Yaa+ male mice was responsible for the hypergammaglobulinemia and autoantibody production. This phenomenon was not due to an anti-HY interaction between female T helper cells and male B cells, because first, Yaa+ B cells were selectively stimulated to produce autoantibodies in Yaa+ male-Yaa- male chimeric mice; and second, normal male and female chimeras failed to develop an autoimmune syndrome. In addition, the fact that both B cell populations in Yaa(+)-Yaa- chimeras similarly responded to a foreign antigen, human IgG, argues against the possibility that the selective activation of Yaa+ B cells may be due to their hyper-responsiveness to T helper signals. We propose that a cognate interaction of T helper cells with Yaa+ B cells, because of possible T cell recognition of a Yaa-related molecule expressed on Yaa+ B cells, may be responsible for the acceleration and/or induction of autoantibodies in BXSB/MpJ mice.

Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome.

Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

Prevention of systemic lupus erythematosus in autoimmune BXSB mice by a transgene encoding I-E alpha chain.

Males from the BXSB murine strain (H-2b) spontaneously develop an autoimmune syndrome with features of systemic lupus erythematosus (SLE), which results in part from the action of a mutant gene (Yaa) located on the Y chromosome. Like other H-2b mice, the BXSB strain does not express the class II major histocompatibility complex antigen, I-E. Here we report that the expression of I-E (E alpha dE beta b) in BXSB males bearing an E alpha d transgene prevents hypergammaglobulinemia, autoantibody production, and subsequent autoimmune glomerulonephritis. These transgenic mice bear on the majority of their B cells not only I-E molecules, but also an I-E alpha chain-derived peptide presented by a higher number of I-Ab molecules, as recognized by the Y-Ae monoclonal antibody. The I-E+ B cells appear less activated in vivo than the I-E- B cells, a minor population. This limited activation of the I-E+ B cells does not reflect a functional deficiency of this cell population, since it can be stimulated to IgM production in vitro by lipopolysaccharides at an even higher level than the I-E- B cell population. The development of the autoimmune syndrome in the transgenic and nontransgenic bone marrow chimeric mice argues against the possibility that the induction of regulatory T cells or clonal deletion of potential autoreactive T cells as a result of I-E expression is a mechanism of the protection conferred by the E alpha d transgene. We propose a novel mechanism by which the E alpha d transgene protects BXSB mice against SLE: overexpression of I-E alpha chains results in the generation of excessive amounts of a peptide displaying a high affinity to the I-Ab molecule, thereby competing with pathogenic autoantigen-derived peptides for presentation by B lymphocytes and preventing their excessive stimulation.

Tumor necrosis factor alpha is involved in mouse growth and lymphoid tissue development.

Tumor necrosis factor alpha (TNF-alpha), a major mediator of inflammation, also possesses a wide pleiotropism of actions, suggesting its involvement in physiological conditions. TNF-alpha mRNA is present in mouse embryonic tissues and also in fetal thymus and spleen. Repeated injections of a monospecific polyclonal rabbit anti-mouse TNF-alpha antibody in mice, starting either during pregnancy or at birth, led to a severe but transient growth retardation, already present at birth, reaching a 35% decrease in body weight at 3 wk, with complete recovery at 8 wk. The insulin growth factor I (IGF-I) blood levels were decreased to about 50%; growth hormone release and other endocrine functions were unaltered. A marked atrophy of the thymus, spleen, and lymph nodes was also observed, with lymphopenia and impaired development of T and B cell peripheral lymphoid structures. The pathways involving TNF-alpha in IGF-I release and early body growth are probably distinct from those by which TNF-alpha participates in early development of lymphoid tissues, where its low physiological release may contribute to enhance lymphoid cell expansion.

An excess of massive stars in the local 30 Doradus starburst.

The 30 Doradus star-forming region in the Large Magellanic Cloud is a nearby analog of large star-formation events in the distant universe. We determined the recent formation history and the initial mass function (IMF) of massive stars in 30 Doradus on the basis of spectroscopic observations of 247 stars more massive than 15 solar masses ([Formula: see text]). The main episode of massive star formation began about 8 million years (My) ago, and the star-formation rate seems to have declined in the last 1 My. The IMF is densely sampled up to 200 [Formula: see text] and contains 32 ± 12% more stars above 30 [Formula: see text] than predicted by a standard Salpeter IMF. In the mass range of 15 to 200 [Formula: see text], the IMF power-law exponent is [Formula: see text], shallower than the Salpeter value of 2.35.

Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice.

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.

A prospective study of prevalence of 60-days postoperative wound infections after cardiac surgery. An updated risk factor analysis.

AIM: Postoperative wound infections generally cause considerable extra morbidity, mortality and costs. The prevalence of total wound infections after cardiac surgery, including both sternal wound and donor site infections, ranges from 1.3 to 12.8%. The present study was conducted to identify the incidence of wound infections following cardiac surgery, to identify the risk factors and evaluate the efficacy of present modes of management. METHODS: From September 2004 to May 2005, 493 consecutive patients undergoing cardiac surgery were included in the study and were followed for the prevalence of surgical site infection (SSI) up to 60 days postoperatively. The wound infections were defined according to the Centers for Disease Control and Prevention (CDC) and U.S. National Nosocomial Infections Surveillance (NNIS) system criteria. RESULTS: The total incidence of SSI was 3.9%. Sternal wound infection (SWI) occurred in 17 patients (3.4%). Superficial wound infection was diagnosed in 10 patients (2%) and deep wound infection in 7 patients (1.4%). Donor site infection (DSI) occurred in 2 patients (0.4%). Early reoperation for bleeding, postoperative dialysis and the use of one internal mammary artery were independently associated with an increased risk of SWI. CONCLUSION: Preventing SSI in the operating room is the primary goal of the surgical team. Attention should be paid to antibiotic prophylaxis and Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage treatment. The identification of risk factors will help to further reduce the incidence of wound infection.

The role of the Yaa gene in lupus syndrome.

The BXSB/MpJ (BXSB) murine strain (H-2b) spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females. A mutant gene located on the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), is responsible for the acceleration of the disease observed in male BXSB mice. Studies on H-2 congenic and I-E transgenic mice have clearly demonstrated that the MHC class II genes play a crucial role in the development or protection of SLE. However, the MHC effect can be completely masked by the presence of the Yaa gene in mice with certain genetic backgrounds. It is intriguing that the Yaa gene effect is selective on autoimmune responses, varying in different lupus-prone mice. Studies on immune responses against foreign antigens have shown that the Yaa gene potentiates immune responses only against antigens to which mice are genetically (H-2-linked) low-responding, but not high-responding. Thus, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given antigens. Moreover, studies on Yaa(+)-Yaa- bone marrow cell chimeric mice have suggested that a specific cognate interaction of T helper cells with Yaa+ B cells is responsible for a selective enhancing effect of immune responses to foreign antigens as well as autoantigens. It is significant that unlike the lpr mutation, whose abnormality is associated with the capacity of the Fas antigen to mediate apoptosis, the Yaa gene by itself is unable to induce significant autoimmune responses in mice without apparent SLE background. This suggests that the molecular defect of the Yaa gene is likely to differ from that of the lpr gene, and that the Yaa gene effect requires the abnormal autosomal genome present in lupus-prone mice. Based on these findings, a possible molecular nature of the Yaa gene abnormality will be discussed.

Prevalence of HFE mutations in upper Northern Italy: study of 1132 unrelated blood donors.

BACKGROUND: In the Italian general population, prevalence of C282Y is lower than in Northern European countries. We hypothesised a higher prevalence of C282Y in Northern than in Central and Southern Italy. We previously identified a nonsense mutation (W169X) in haemochromatosis probands originating from a Northern Italian region (Brianza). AIM: To define the prevalence of HFE mutations in that region. Subjects and methods. A total of 1132 unrelated blood donors from the Blood Banks of Monza and Merate were investigated for C282Y, H63D, S65C and W169X mutations by PCR-restriction assays. A total of 300 were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. RESULTS: Two C282Y homozygotes, eight C282Y/H63D compound heterozygotes, 27 H63D homozygotes and one W169X heterozygote were found. The allele frequencies of C282Y, H63D, S65C, and W169X were 3.2, 13.4, 1.3, and 0.04%, respectively. CONCLUSIONS: Our results confirm the existence of a decreasing frequency of C282Y allele from upper to lower Northern Italy. This difference is probably related to the larger Celtic component of upper Northern Italian populations in which screening studies for haemochromatosis may even be cost effective. W169X, due to its severity, should be looked for in all haemochromatosis patients of Northern ancestry with an incomplete HFE genotype.

Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo.

Many clinical trials have shown the effectiveness of platelet-antiaggregant drugs in the treatment of obliterative peripheral arteriopathy, both locally and in the system, by improving the claudication symptoms and by preventing major cardiovascular events. In this study we evaluated the effectiveness of a 24-week treatment with triflusal, a comparatively new inhibitor of platelet aggregation, in patients affected by chronic peripheral arteriopathy, comparing twice-daily oral doses of 300 mg triflusal with twice-daily placebo doses. The percentages of successes (defined as a 40% increase of total walking distance over the basal control) were 63.6% in the triflusal group (35/55 patients) and 22.5% in the placebo group (14/62 patients). Patients treated with triflusal showed a more important increase in total walking distance and in pain-free walking distance over the basal values than those treated with placebo, together with an improvement of the symptomatology correlated with claudication. Moreover, in the triflusal group there was an increase in the peak-flow recorded through strain-gauge plethysmography. In conclusion, triflusal significantly increased both the distance which could be walked and the clinical symptoms, presumably by improving microperfusion.

Asteroseismology. Echography of young stars reveals their evolution.

We demonstrate that a seismic analysis of stars in their earliest evolutionary phases is a powerful method with which to identify young stars and distinguish their evolutionary states. The early star that is born from the gravitational collapse of a molecular cloud reaches at some point sufficient temperature, mass, and luminosity to be detected. Accretion stops, and the pre-main sequence star that emerges is nearly fully convective and chemically homogeneous. It will continue to contract gravitationally until the density and temperature in the core are high enough to start nuclear burning of hydrogen. We show that there is a relationship for a sample of young stars between detected pulsation properties and their evolutionary status, illustrating the potential of asteroseismology for the early evolutionary phases.

CD4+ T cells play a major role for IgM and IgG anti-DNA production in mice infected with Plasmodium yoelii.

The infection by a non-lethal strain of Plasmodium yoelii induces the formation of autoantibodies such as anti-DNA and anti-Sm antibodies in mice. The extent of the relative increase in serum levels of IgM and IgG anti-DNA and anti-Sm antibodies and their kinetics were found to be similar to those of anti-hapten antibodies and of total IgM and IgG levels. This strongly suggested that anti-DNA and anti-Sm autoantibody responses observed in malaria-infected mice are a result of polyclonal activation of B cells. The analysis of the IgG subclasses reacting with DNA antigen showed significant levels of the T cell-dependent isotypes, IgG1 and IgG2. The role of T cells in the activation of autoreactive B cells was confirmed by using athymic nude mice. Indeed, BALB/c-nu/nu and C57BL/6-nu/nu mice failed to produce IgG anti-DNA antibodies after infection with P. yoelii. Moreover, the reconstitution of BALB/c nude mice with lymph node cells from congenic euthymic BALB-Igb mice showed the activation of autoreactive B cells in nude mice by T cells from euthymic mice. Studies in mice depleted of CD4+ T cells strongly suggested that malaria-induced anti-DNA antibodies were almost entirely dependent on the presence of CD4+ T cells, as this depletion significantly decreased IgM anti-DNA antibodies and completely abolished the IgG anti-DNA production, including the IgG3 subclass in infected mice. In contrast, depletion of the CD8+ T cell subset had no effect on the production of autoantibody in malaria-infected mice. Our results indicate that CD4+ T cells play a major role for both IgM and IgG anti-DNA production during the course of malaria infection.

Selective enhancing effect of the Yaa gene on immune responses against self and foreign antigens.

The BXSB Y chromosome-linked mutant gene, Yaa, accelerates the progression of a lupus-like autoimmune syndrome only in mice that are predisposed to autoimmune diseases. Unlike the lpr gene, which causes the defects in the Fas antigen-mediating apoptosis, the autoimmune enhancing activity of the Yaa gene is selective, depending on autoantigens, and varies among lupus-prone mice. To obtain a better definition of the role of the Yaa gene in the acceleration of autoimmune disease, we have investigated immune responses to several foreign antigens to determine whether the Yaa gene is able to potentiate immune responses to foreign antigens in a selective manner. We report here that the Yaa gene potentiated immune responses against foreign antigens only in mice which are genetically (H-2-linked) low responding, but not high or non-responding. Moreover, studies on Yaa(+)-Yaa- double bone marrow chimeric mice revealed that B cells from Yaa+ mice were selectively stimulated to produce antibodies to low-responding antigen, human IgG, while both B cell populations similarly responded to high-responding antigen, ovalbumin. Our results suggest that first, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given self or foreign antigens; and second, a specific cognate interaction of T helper cells with Yaa+ B cells is apparently responsible for the selective enhancement of immune responses to antigens, to which mice are genetically low responding.

Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice.

The polyclonal B cell activation is the earliest and most common immunologic abnormality in lupus-prone mice. However, its cellular mechanism(s) has not been well defined. To determine the contribution of CD4+ T cells in this immunologic abnormality, we have depleted CD4+ T cells in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice by treating them with anti-CD4 mAb from birth and determined the development of IgM and IgG polyclonal antibody formation. Our results indicate that first, different mechanisms control the development of IgM polyclonal B cell activation in these two autoimmune mice; in (NZB x NZW)F1 mice, IgM polyclonal B cell activation is likely to be a result of an intrinsic B cell defect, whereas CD4+ T cells seem to be responsible for this immunologic abnormality in MRL/MpJ-lpr/lpr mice. Second, the increased production of IgG antibodies, including the IgG3 subclass, was totally regulated by CD4+ T cells in both autoimmune mice. Because IgG3 antibodies can be highly nephritogenic, independent of their immunologic specificities, which is the result of the antibodies' cryoglobulin activity, the active role of CD4+ T cells in the production of IgG3 antibodies in lupus-prone autoimmune mice further strengthens the implication of CD4+ T cells in murine systemic lupus erythematosus.

Molecular and cellular basis for pathogenicity of autoantibodies.

Using two different kinds of monoclonal autoantibodies, anti-mouse RBC (MRBC) autoantibodies and IgG3 rheumatoid factor (RF) cryoglobulins, we have attempted to better define the molecular and cellular basis of the pathogenicity of autoantibodies. Among eight anti-MRBC monoclonal antibodies (mAbs) obtained from NZB mice, only five of them are able to cause anemia. The distinct differences in specificity between pathogenic and non-pathogenic anti-MRBC mAbs emphasize the importance of autoantibody specificity for the pathogenesis of autoimmune hemolytic anemia. Histological examination has revealed that Fc gamma receptor-mediated erythrophagocytosis and sequestration of agglutinated RBC in spleens and livers are the major pathogenic mechanisms of hemolytic anemia. This indicates that the affinity of autoantibodies for the Fc gamma receptors of phagocytes and/or the ability to cause hemagglutination, both of which vary among immunoglobulin isotypes, are additional factors determining the pathogenic activity of anti-MRBC autoantibodies. Studies on a panel of anti-IgG2a RF mAbs derived from MRL-lpr/lpr mice have demonstrated that only the IgG3 isotypes of RF mAb are able to generate cryoglobulins and to induce skin leukocytoclastic vasculitis and glomerulonephritis in normal mice. Although the cryoglobulin activity of RF mAb associated with the IgG3 isotype has been shown to be solely responsible for the generation of glomerular lesions (both RF and cryoglobulin activities are necessary for cutaneous vascular lesions), the absence of nephritogenic activity by some IgG3 monoclonal cryoglobulins supports the idea that qualitative features of cryoglobulins are critical to determine their pathogenic activities. Of interest, IgG3 autoantibodies lacking the cryoglobulin activity may not be harmful, but even protective against the development of IgG3 cryoglobulin-mediated tissue lesions, because they inhibit the cryoglobulin formation of pathogenic IgG3 autoantibodies as a result of their nonspecific IgG3 Fc-Fc interaction. Our results on monoclonal autoantibodies clearly indicate the importance of certain subpopulations of autoantibodies in the pathogenesis of autoantibody-mediated cellular and tissue injuries.

Lack of association of V beta 8+ T cells with lupus-like syndrome in MRL-lpr/lpr mice.

To evaluate the role of V beta 8+ T cells in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice, we treated them with the F23.1 anti-V beta 8 monoclonal antibody (mAb) from birth to 4 months of age. Here we report that almost complete depletion of V beta 8+ T cells by the F23.1 mAb treatment neither inhibited nor delayed the development of hypergammaglobulinemia, autoantibody production and autoimmune glomerulonephritis in MRL-lpr/lpr mice. In addition, the F23.1 mAb treatment did not prevent the development of lymphadenopathy and the generation of a CD4-CD8- double-negative T cell subset, characteristically accumulating in lpr lymph nodes. Our results strongly argue against the idea that the V beta 8+ T cells play a critical role in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice.

Role of the major histocompatibility complex class II Ea gene in lupus susceptibility in mice.

The gene(s) encoded within major histocompatibility complex (MHC) act as one of the major genetic elements contributing to the susceptibility of murine systemic lupus erythematosus (SLE). We have recently demonstrated that lupus susceptibility is more closely linked to the I-E- H-2(b) haplotype than to the I-E+ H-2(d) haplotype in lupus-prone BXSB and (NZB x BXSB)F1 hybrid mice. To investigate whether the reduced susceptibility to SLE in H-2(d) mice is related to the expression of the MHC class II Ea gene (absent in H-2(b) mice), we determined the possible role of the Ea gene as a lupus protective gene in mice. Our results showed that (i) the development of SLE was almost completely prevented in BXSB (H-2(b)) mice expressing two copies of the Ead transgene at the homozygous level as well as in BXSB H-2(k) (I-E+) congenic mice as for H-2(d) BXSB mice, and (ii) the expression of two functional Ea (transgenic and endogenous) genes in either H-2(d/b) (NZB x BXSB)F1 or H-2(k/b) (MRL x BXSB)F1 mice provided protection from SLE at levels comparable to those conferred by the H-2(d/d) or H-2(k/k) haplotype. In addition, the level of the Ea gene-mediated protection appeared to be dependent on the genetic susceptibility to SLE in individual lupus-prone mice. Our results indicate that the reduced susceptibility associated with the I-E+ H-2(d) and H-2(k) haplotypes (versus the I-E- H-2(b) haplotype) is largely, if not all, contributed by the apparent autoimmune suppressive effect of the Ea gene, independently of the expression of the I-A or other MHC-linked genes.