HTLV-1 modifies the clinical and immunological response to schistosomiasis

The immunological response in HTLV-1 infected individuals is characterized by a prominent Type-1 cytokine response with high production of IFN-gamma and TNF-alpha. In contrast, helminthic infections and in particular chronic schistosomiasis are associated with a predominant production of IL-4, IL-5, IL-10 and IL-13. Liver fibrosis is the main pathological finding in schistosomiasis that occurs after many years of infection. This pathology is T cell dependent but the immune response mechanisms are not completely understood. The North-east region of Brazil is endemic for both HTLV-1 and schistosomiasis. In the present study the immune response, clinical severity, and therapeutic response to praziquantel of patients with schistosomiasis coinfected with HTLV-1 were compared with patients infected only with S. mansoni. Patients with HTLV-1 and S. mansoni had lower levels of IL-5 (P < 0.05) and higher levels of IFN-gamma (P < 0.05) in cultures stimulated with S. mansoni antigen and decreased S. mansoni antigen specific IgE levels when compared with patients with schistosomiasis without HTLV-1 coinfection. Liver fibrosis was mild in all HTLV-1 coinfected patients and efficacy of praziquantel was lower in patients dually infected than in patients infected only with S. mansoni.     

Phenotype and Cytokine Profile ofSchistosoma mansoniSpecific T Cell Lines and Clones Derived from Schistosomiasis Patients with Distinct Clinical Forms

It is essential to distinguish the role of T lymphocytes on the physiopathology associated to more severe forms of schistosomiasis and on the immunomodulation that evolves in the majority of infected people. In this study, we generated Schistosoma mansoni-specific T cell lines and clones from patients with the acute and chronic (intestinal and hepatosplenic forms) phases of disease, from former ones, and from uninfected individuals sensitized to parasite soluble antigens. T cell lines derived from nontreated acute infected donors were capable of producing IL-4 and IL-5, while cells from treated patients secreted IFN-gamma. Lines from intestinal chronic and antigen-sensitized donors preferentially produced IFN-gamma, while those from hepatosplenic patients secreted all three cytokines. The cytokine analysis of CD4+ T cell clones revealed a Th2/Th0 pattern (clones producing IL-4 and IL-5 and clones producing all three cytokines) for those derived from infected patients, while cells from antigen-sensitized donors exhibited an opposite Th1/Th0 pattern (clones producing IFN-gamma and clones producing all three cytokines). The possible role of these T cell populations on human schistosomiasis mansoni is discussed.     

Lack of antigen-specific Th1 response alters granuloma formation and composition in Schistosoma mansoni-infected MyD88-/- mice

To evaluate the role of the innate immune system during schistosomiasis in vivo, we infected myeloid differentiation factor 88 (MyD88)-deficient mice with Schistosoma mansoni and analyzed their pathognomonic formation of hepatic granulomas and T cell responses. Even though the differences between knockout and wild-type mice in terms of mortality, liver damage, serum IgE and parasite burden were insignificant, the liver granulomas in the MyD88-deficient mice were significantly smaller, less cellular and contained a reduced percentage of eosinophils. Histologically, these granulomas revealed stronger fibrosis, confirmed also by increased levels of soluble collagen and IL-13, implying a Th2 bias. Spleen cells from infected MyD88-deficient mice also produced significantly less IFN-gamma than their wild-type controls upon restimulation with Schistosoma-egg-antigen (SEA). Furthermore, SEA-loaded APC from naive wild-type or MyD88-deficient mice induced equal amounts of proliferation and cytokine secretion by T cells from wild-type infected mice. In contrast, Ag-specific T cells from infected MyD88-deficient mice produced hardly any IFN-gamma but considerably more IL-10, again regardless of the APC type. These findings indicate that the loss of IFN-gamma production is not due to impaired antigen presentation but may perhaps is due to suppression by IL-10-producing T cells. Thus, MyD88 plays an important role in cellular infiltration, granuloma composition and T cell responses during schistosomiasis.     

P selectin and T cell profiles provide verification to understand the pathogenesis of liver cirrhosis in HCV and Schistosoma mansoni infections

Hepatitis C virus (HCV) and Schistosoma mansoni are two major causes of chronic liver disease (CLD). Both immune alteration and thrombocytopenia are common complications in the majority of cirrhotic patients. The current study aimed to monitor the effect of T cell profile and platelets activation on the pathogenesis of liver cirrhosis in patients suffered from single or concomitant schistosomiasis and HCV infections. The subjects were divided into 4 groups: Group I, patients infected with schistosomiasis; Group II, patients infected with HCV; Group III, patients with combined liver diseases and Group IV: healthy individuals. All groups were subjected to full clinical evaluation as well as laboratory examination including ELISA anti-HCV antibodies screening, parasitological examination, and complete blood picture as well as flow cytometry for CD41, CD42, CD62P (P selectin), CD63, CD4 and CD8. The platelets count was significantly decreased in HCV and/or schistosoma infected patients compared to controls. The percentage of the total T-lymphocytes and T-helper was significantly reduced in all infected groups, while the percentage of T-cytotoxic was increased. The patients possessed a significantly higher percentage of the platelets activation markers than control group. There were considerable correlations between the platelets counts and P selectin and MFI. Thrombocytopenia was a common finding in patients with CLD. Patients with CLD showed increased platelets activation which may contribute to the occurrence of thrombocytopenia and play a role in the pathogenesis of CLD. Infected patient showed reduction in the cell-mediated-immunity as evidenced by low T –helper cells.     

Profound effect of the absence of IL-4 on T cell responses during infection with Schistosoma mansoni.

T cell responses of interleukin (IL)-4(-/-) and wild-type (WT) mice infected with the helper T cell 2 (Th2) response-inducing pathogen Schistosoma mansoni were compared. As expected, given the important role of IL-4 in Th2 response induction, the absence of IL-4 resulted in diminished Th2 responses, apparent as reduced production of IL-4, -5, and -10 by CD4(+) cells isolated from the spleens of infected IL-4(-/-) mice. Surprisingly, these cells produced significantly less interferon (IFN)-gamma and proliferated less than did those from infected WT mice after T cell receptor ligation. CD8(+) cells isolated from infected IL-4(-/-) mice also produced less IFN-gamma than WT CD8 cells, although there was no difference in the proliferative responses of these cell populations. After infection, spleens of infected IL-4(-/-) mice did not enlarge to the same extent as those of WT mice, and attrition of the CD8(+) cell population within this lymphoid organ was noted. Taken together, the data indicate that in addition to inhibiting Th2 response development, the lack of IL-4 during schistosomiasis significantly affects additional aspects of T cell responses.     

Interleukin-12 promotes pathologic liver changes and death in mice coinfected with Schistosoma mansoni and Toxoplasma gondii

We previously demonstrated that mice concurrently infected with Schistosoma mansoni and Toxoplasma gondii undergo accelerated mortality which is preceded by severe liver damage. Abnormally high levels of serum tumor necrosis factor alpha (TNF-alpha) in the dually infected mice suggested a role for this and related proinflammatory mediators in the pathologic alterations. In order to evaluate the factors involved in increased inflammatory-mediator production and mortality, interleukin-12(-/-) (IL-12(-/-)) mice were coinfected with S. mansoni and T. gondii, and survival and immune responses were monitored. These IL-12(-/-) mice displayed decreased liver damage and prolonged time to death relative to wild-type animals also coinfected with these parasites. Relative to the response of cells from the coinfected wild-type animals, levels of TNF-alpha, gamma interferon, and NO produced by splenocytes from coinfected IL-12(-/-) mice were reduced, and levels of IL-5 and IL-10 were increased, with the net result that the immune response of the dually infected IL-12(-/-) mice was similar to that of the wild-type mice infected with S. mansoni alone. While dually infected wild-type animals succumb in the absence of overt parasitemia, the delayed death in the absence of IL-12 is associated with relatively uncontrolled T. gondii replication. These data support the view that S. mansoni-infected mice are acutely sensitive to infection with T. gondii as a result of their increased hepatic sensitivity to high levels of proinflammatory cytokines; IL-12 and TNF-alpha are implicated in this process.     

Coinfection with Schistosoma mansoni reactivates viremia in rhesus macaques with chronic simian-human immunodeficiency virus clade C infection

We tested the hypothesis that helminth parasite coinfection would intensify viremia and accelerate disease progression in monkeys chronically infected with an R5 simian-human immunodeficiency virus (SHIV) encoding a human immunodeficiency virus type 1 (HIV-1) clade C envelope. Fifteen rhesus monkeys with stable SHIV-1157ip infection were enrolled into a prospective, randomized trial. These seropositive animals had undetectable viral RNA and no signs of immunodeficiency. Seven animals served as virus-only controls; eight animals were exposed to Schistosoma mansoni cercariae. From week 5 after parasite exposure onward, coinfected animals shed eggs in their feces, developed eosinophilia, and had significantly higher mRNA expression of the T-helper type 2 cytokine interleukin-4 (P = 0.001) than animals without schistosomiasis. Compared to virus-only controls, viral replication was significantly increased in coinfected monkeys (P = 0.012), and the percentage of their CD4(+) CD29(+) memory cells decreased over time (P = 0.05). Thus, S. mansoni coinfection significantly increased viral replication and induced T-cell subset alterations in monkeys with chronic SHIV clade C infection.     

Impaired Balance of Interleukin-4 and Interferon-y Production in Infections with Schistosoma mansoni and Intestinal Nematodes

In chronic infection with Schistosoma mansoni, IL-4 and IFN-gamma are co-modulated in opposite directions. This was shown when testing sera and cell culture supernatants from 31 Brazilian patients with schistosomiasis before, and three months after treatment with praziquantel. Thorough examinations were undertaken to account for polyparasitism with intestinal nematode infections involving tissue migrating larval stages that may induce analogous changes. Controls free of S. mansoni included a group (n = 17) matching the schistosomiasis patients' parasitation by intestinal nematodes and a group (n = 16) free of helminths other than T. trichiura. Serum IL-4 was greater than 20 pg/ml in 81% of schistosomiasis patients but in only 35 and 25%, respectively, of controls with and without intestinal nematodes. IL-4 data correlated inversely with the mitogen-induced IFN-gamma synthesis. Generation of IL-4 in response to phorbol esters was related to the intensity of infection by schistosomes and intestinal nematodes. The parasitological status three months after therapy with either praziquantel or mebendazole revealed a dichotomy: whereas the ratio of IFN-gamma to IL-4 generated in vitro was identical in uninfected controls and in patients who cleared the parasites, failure to eliminate the parasites was associated with lower IFN-gamma/IL-4 ratios generated in vitro.     

Dynamic analysis of splenic Th1 and Th2 lymphocyte functions in mice infected with Schistosoma japonicum.

Recent studies indicate that egg granuloma formation in murine Schistosoma mansoni infection is associated with Th2-mediated immune responses. The present study was designed to analyze dynamically the Th1 and Th2 responses in S. japonicum-infected animals and compare them with the results seen with S. mansoni. C3H mice were infected with 10 to 20 cercariae of S. japonicum and sacrificed 3 to 22 weeks later. Spleen cells were stimulated with parasite antigens (egg and adult worm) or the mitogen concanavalin A. Interleukin-2 (IL-2), IL-4, IL-5, and gamma interferon (IFN-gamma) levels were measured in the culture supernatants by enzyme-linked immunosorbent assay (ELISA) or bioassays. Additionally, cytokine-producing cells were enumerated by ELISPOT. The results show that Th2 cytokine production, characterized by IL-4 and IL-5, represents the major response in the first month after egg laying begins, while the Th1 functions of IFN-gamma and IL-2 production are greatly depressed. However, by 22 weeks Th2 responses have diminished and IFN-gamma production in response to concanavalin A is apparent. IL-2 responses are minimal at all times. In vitro depletion of T-cell subsets indicates that CD4+ cells are the major subset responsible for production of IL-5 at 7 weeks of infection. These findings suggest that, as in the case of S. mansoni infection, S. japonicum-induced immunopathology is temporally associated with the host Th2 response, although other experiments indicate that IFN-gamma is also involved.     

Interleukin-7 in the skin of Schistosoma mansoni-infected mice is associated with a decrease in interferon-gamma production and leads to an aggravation of the disease.

The effect of recombinant interleukin-7 (rIL-7) on the course of murine schistosomiasis and the development of the accompanying immune response were investigated. We demonstrated that IL-7 expression could be detected in the skin of infected mice from 1 to 21 days following infection. We here report that intradermal injection of exogenous human IL-7, prior to the penetration of the parasite into the skin, leads to a more severe liver pathology and an increased number of surviving adult parasites. In addition, injection of rIL-7 alters parasite migration (estimation of burdens of young larvae in lungs and liver). Administration of rIL-7 led to a decrease of IL-12 and interferon-gamma-(IFN-gamma) specific messengers RNA in skin and, more markedly, in skin-draining lymph nodes. The number of B220 expressing cells was increased, and T-cell number was reduced, in IL-7-treated infected mice. In addition, levels of IFN-gamma and IL-4 in sera were significantly reduced, whereas there was a shift from a Th1 to a Th2 type associated humoral response towards the egg antigens. Our experimental observation illustrate that the exogenous administration of rIL-7 affects both the development of the host's immune response and the behaviour of the parasite within the infected host. The early and specific production of IL-7 in the host skin, following infection with Schistosoma mansoni, raises fascinating questions concerning the relationships between the parasite and its host at the very beginning of their interaction.     

Severe schistosomiasis in the absence of interleukin-4 (IL-4) is IL-12 independent

An interleukin-4 (IL-4)-dependent Th2 response allows wild-type mice to survive infection with the parasite Schistosoma mansoni. In the absence of IL-4, infected mice mount a Th1-like proinflammatory response, develop severe disease, and succumb. Neither the Th1 response nor morbidity is IL-12 dependent in this system.     

Infection with Salmonella typhimurium modulates the immune response to Schistosoma mansoni glutathione-S-transferase.

Immune response polarization is controlled by several factors, including cytokines, antigen-presenting cells, antigen dose, and others. We have previously shown that adjuvants and live vectors play a critical role in polarization. Thus, immunization with the Schistosoma mansoni 28-kDa glutathione-S-transferase (Sm28-GST) in aluminum hydroxide induced a type 2 cytokine profile and the production of immunoglobulin G1 (IgG1)- and IgE-specific antibodies. In contrast, mice infected with recombinant Salmonella typhimurium expressing Sm28-GST developed a type 1 cytokine profile and produced IgG2a-specific antibodies against Sm28-GST and Salmonella antigens. In this study, to determine if S. typhimurium not expressing Sm28-GST would still influence the type of the response against this antigen, we compared the profiles of the immune responses generated against Sm28-GST administered in alum in mice infected and not infected with S. typhimurium. Infected mice generated both IgG1 and IgG2a antibodies against Sm28-GST, while noninfected mice produced only IgG1 anti-Sm28-GST antibodies. Moreover, interleukin-4 (IL-4) mRNA expression in infected mice was near background levels, while gamma interferon (IFN-gamma) mRNA expression in coinfected mice was significantly higher than in mice immunized with Sm28-GST in alum only. However, after antigen-specific stimulation in vitro with Sm28-GST, levels of IL-4 and IFN-gamma cytokine production were similar in the two groups of mice. These results suggest that (i) the immune milieu produced during an infection may modify the response against an irrelevant antigen and (ii) isotype switching may be influenced by the cytokine environment of a bystander immune response, even though the specific antigen-driven cytokine production is not modified. Thus, the isotypic profile is not always an absolute reflection of the cytokines produced by antigen-specific Th cells.     

Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection

Hepatitis C virus (HCV) infection can persist despite HCV-specific T-cell immunity and can have a more aggressive course in persons coinfected with human immunodeficiency virus type 1 (HIV-1). Defects in antigen-presenting, myeloid dendritic cells (DCs) could underlie this T-cell dysfunction. Here we show that monocyte-derived DCs from persons with chronic HCV infection, with or without HIV-1 coinfection, being treated with combination antiretroviral therapy produced lower levels of interleukin 12 (IL-12) p70 in response to CD40 ligand (CD40L), whereas the expression of DC surface activation and costimulatory molecules was unimpaired. The deficiency in IL-12 production could be overcome by addition of gamma interferon (IFN-gamma) with CD40L, resulting in very high, comparable levels of IL-12 production by DCs from HCV- and HIV-1-infected subjects. Smaller amounts of IL-12 p70 were produced by DCs treated with the immune modulators tumor necrosis factor alpha and IL-1beta, with or without IFN-gamma, and the amounts did not differ among the uninfected and infected subjects. Blocking of IL-10 with an anti-IL-10 monoclonal antibody in the CD40L-stimulated DC cultures from HCV-infected persons increased the level of IL-12 p70 production. The ability of DCs from HCV-infected persons to stimulate allogeneic CD4+ T cells or induce IL-2, IL-5, or IL-10 in a mixed lymphocyte reaction was not impaired. Thus, myeloid DCs derived from persons with chronic HCV infection or with both HCV and HIV-1 infections have defects in IL-12 p70 production related to IL-10 activity that can be overcome by treatment of the DCs with CD40L and IFN-gamma. DCs from these infected subjects have a normal capacity to stimulate CD4+ T cells. The functional effectiveness of DCs derived from HCV-infected individuals provides a rationale for the DC-based immunotherapy of chronic HCV infection.     

Comparison of hepatitis C viral loads in patients with or without human immunodeficiency virus.

A better understanding of how human immunodeficiency virus (HIV) coinfection affects the course of hepatitis C virus (HCV) infection is required to select patients with HIV who would benefit from current HCV therapy. Between June 1996 and March 2000, HCV RNA levels were quantified for 1,279 patients at the Louisiana State University Health Sciences Center; 28 of these patients were coinfected with HIV. HCV loads were quantified by the Bayer branched-DNA assay with a lower limit of detection of 0.2 Meq/ml. We compared the median HCV RNA levels of for patients coinfected with HIV and HCV and patients infected only with HCV who were in the same age range (23 to 55 years). The median HCV load for the 28 patients coinfected with HCV and HIV (17.8 Meq/ml) was significantly greater (P < 0.05) than that for similarly aged patients infected only with HCV (6.1 Meq/ml). The HCV load did not correlate with age or sex for either group of patients. A significant (R = -0.4; P < 0.05) negative correlation was observed between HCV load and CD4 count in the coinfected group, for whom the CD4 counts at the time of HCV load analysis ranged from 6 to 1,773/mm(3). The increased HCV load in patients coinfected with HCV and HIV compared to that in patients infected only with HCV and the inverse relationship of the HCV load to the CD4 count indicate that immunosuppression results in decreased control of HCV replication. In addition, we report significantly higher HCV loads among coinfected African Americans than Caucasians.     

Endometriosis: an inflammatory disease with a Th2 immune response component

BACKGROUND: Efforts have been made to correctly characterize the role of the immune response in endometriosis. The objective of this study was to analyse the interaction between Th1 and Th2 immune response patterns and endometriosis by evaluating a panel of cytokines. METHODS: Between January 2004 and November 2005, 98 patients, classified into two groups according to the histologically confirmed presence (Group A) or absence of endometriosis (Group B), were evaluated. Interleukins (IL) 2, 4 and 10, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) were measured by flow cytometry in the peripheral blood and peritoneal fluid of all patients. RESULTS: IFN-gamma and IL-10 levels were significantly higher in the peritoneal fluid of patients with endometriosis compared to those without endometriosis (P < 0.05). There was a significant alteration in the IL-4/IFN-gamma (P < 0.001), IL-4/IL-2 (P = 0.006), IL-10/IFN-gamma (P < 0.001) and the IL-10/IL-2 ratios (P < 0.001) in the peritoneal fluid of patients with endometriosis, with a predominance of IL-4 and IL-10, reflecting a shift towards Th2 immune response despite the increase in IFN-gamma concentrations. CONCLUSIONS: Endometriosis is an inflammatory disease involving a possible shift towards Th2 immune response component, as demonstrated by the relative increase in cytokines characteristic of this pattern of immune response.     

Vasoactive intestinal peptide inhibits liver pathology in acute murine schistosomiasis mansoni and modulates IL-10, IL-12 and TNF-alpha production

Vasoactive intestinal peptide (VIP) exerts a broad range of biologic actions that may include modulation of hepatic granuloma formation. This study aimed to investigate the effect of VIP administration on the course of acute murine schistosomiasis mansoni. Mice were infected each with 40 Schistosoma (S.) mansoni cercariae and injected intraperitoneally with VIP at a total dose of 1mug/kg body weight. VIP treatment was very effective in diminishing worm fecundity, hepatic granuloma size and number by about 54%, 75% and 51%, respectively, and reducing liver collagen content. Serum level of interleukin (IL)-10 was increased, while level of IL-12 and tumor necrosis factor (TNF)-alpha were decreased as a result of VIP administration. Carbohydrate antigen 19.9 (CA 19.9) induced by S. mansoni infection was decreased with VIP treatment. Activities of hepatic gamma-glutamyl transferase (gamma-GT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in liver tissue homogenate of infected treated mice were increased. These results indicate that suitable administration of exogenous VIP can be effective in ameliorating immunopathologic damage associated with schistosomiasis.     

Hepatosplenomegaly is associated with low regulatory and Th2 responses to schistosome antigens in childhood schistosomiasis and malaria coinfection

Hepatosplenomegaly among Kenyan schoolchildren has been shown to be exacerbated where there is transmission of both Schistosoma mansoni and Plasmodium falciparum. This highly prevalent and chronic morbidity often occurs in the absence of ultrasound-detectable periportal fibrosis and may be due to immunological inflammation. For a cohort of school-age children, whole-blood cultures were stimulated with S. mansoni soluble egg antigen (SEA) or soluble worm antigen (SWA). Responses to SWA were found to be predominantly Th2 cytokines; however, they were not significantly associated with either hepatosplenomegaly or infection with S. mansoni or P. falciparum. In comparison, SEA-specific Th2 cytokine responses were low, and the levels were negatively correlated with S. mansoni infection intensities and were lower among children who were coinfected with P. falciparum. Tumor necrosis factor alpha levels in response to stimulation with SEA were high, and a negative association between presentation with hepatomegaly and the levels of the regulatory cytokines interleukin-6 and transforming growth factor beta(1) suggests that a possible mechanism for childhood hepatomegaly in areas where both malaria and schistosomiasis are endemic is poor regulation of an inflammatory response to schistosome eggs.     

Infection of Mice Lacking Interleukin-7 (IL-7) Reveals an Unexpected Role for IL-7 in the Development of the Parasite Schistosoma mansoni

A single intradermal administration of recombinant interleukin-7 (IL-7) has been shown to aggravate the course of murine schistosomiasis, to favor the development of Th2-associated antibodies specific for the parasite, and to alter migration kinetics and/or migratory route of the parasite within its vertebrate host. Here we show that after infection of IL-7-deficient mice with Schistosoma mansoni, the predominant parasite-specific humoral response follows a Th1 pattern, and the development of the parasite is greatly impaired. In IL-7-deficient mice, increased numbers of larvae reach the lungs and fewer larvae reach the liver, compared to control mice. In the absence of IL-7, female worms show an altered fecundity, leading to decreased numbers of eggs trapped in the tissues and to an amelioration of the pathology of the infected host. The most striking observation is the blockade of parasite growth in an IL-7-defective environment, leading to dwarf male and female worms. The results of this study have important implications for the role of IL-7 in the host-parasite relationship and show how parasites can disable or evade the host immune response.     

Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis

There is evidence that nephritis is dominated by a Th1 immune response in systemic lupus erythematosus. Since IL-18 promotes polarization of the immune response toward Th1, we investigated the role of this cytokine in lupus nephritis (LN). A total of 133 lupus patients and 44 healthy subjects were enrolled. Demographic and clinical characteristics with renal biopsy data were recorded. IL-18 along with IFN-gamma and IL-4, two prototypical of Th1 and Th2 cytokines, were measured in serum by ELISA. Peripheral blood lymphocytes were analysed by flow cytometry for IFN-gamma and IL-4. IL-18 expression was determined by immunohistochemistry in 13 renal biopsy specimens from patients with LN and 2 controls. Serum IL-18 was higher in lupus patients than in controls. Levels of IL-18 correlated with urinary microalbumin and were increased in patients with LN when compared to those without LN. IL-18 expression was also increased within the glomeruli of nephritic patients and was primarily detected within the mesangial matrix and in infiltrating mononuclear cells. Measurement of IFN-gamma and IL-4 in either sera or peripheral blood lymphocytes showed high IFN-gamma along with low IL-4 expression in LN patients compared to patients without nephritis. A positive correlation between serum IL-18 and IFN-gamma levels was found. IL-18 may play a prominent role in the pathogenesis of LN by promoting a cytokine imbalance towards a Th1 immune response. Measurement of IL-18 may be helpful for the early identification of lupus patients with LN and may help gauge the response to treatment in patients with active LN undergoing treatment.