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- Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic studyPublication . Martins, M; Williams, A H; Comeau, M; Marion, M; Ziegler, J T; Freedman, B I; Merrill, J T; Glenn, S B; Kelly, J A; Sivils, K M; James, J A; Guthridge, J M; Alarcón-Riquelme, M E; Bae, S-C; Kim, J-H; Kim, D; Anaya, J-M; Boackle, S A; Criswell, L A; Kimberly, R P; Alarcón, G S; Brown, E E; Vilá, L M; Petri, M A; Ramsey-Goldman, R; Niewold, T B; Tsao, B P; Gilkeson, G S; Kamen, D L; Jacob, C O; Stevens, A M; Gaffney, P M; Harley, J B; Langefeld, C D; Fesel, CA classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.
- A3.6 Two components contributing to reduced treg surface CD25 in sle patients and their unaffected relativesPublication . Costa, N; Marques, O; Godinho, S; Carvalho, C; Leal, B; Vasconcelos, C; Marinho, A; Moraes-Fontes, M F; Gomes da Costa, A; Ponte, C; Marques, R; Coias, T; Martins, A R; Viana, J F; Martins, B; Fesel, CBackground FOXP3+ regulatory T-cells (Tregs) in Systemic Lupus Erythematosus (SLE) are in a functionally deficient state with a characteristic reduction or absence of surface CD25 (the IL-2 receptor alpha chain). Genetic variation in the CD25-encoding IL2RA locus is associated with other autoimmune disorders.
- Broadened T-cell Repertoire Diversity in ivIg-treated SLE Patients is Also Related to the Individual Status of Regulatory T-cellsPublication . Costa, Nuno; Pires, Ana E.; Gabriel, Ana M.; Goulart, Luiz F.; Pereira, Clara; Leal, Bárbara; Queiros, Ana C.; Chaara, Wahiba; Moraes-Fontes, Maria F.; Vasconcelos, Carlos; Ferreira, Carlos; Martins, Jorge; Bastos, Marina; Santos, Maria J.; Pereira, Maria A.; Martins, Berta; Lima, Margarida; João, Cristina; Six, Adrien; Demengeot, Jocelyne; Fesel, ConstantinIntravenous IgG (ivIg) is a therapeutic alternative for lupus erythematosus, the mechanism of which remains to be fully understood. Here we investigated whether ivIg affects two established sub-phenotypes of SLE, namely relative oligoclonality of circulating T-cells and reduced activity of CD4 + Foxp3+ regulatory T-cells (Tregs) reflected by lower CD25 surface density.
- Coreferentiality: A New Method for the Hypothesis-Based Analysis of Phenotypes Characterized by Multivariate DataPublication . Fesel, ConstantinMany multifactorial biologic effects, particularly in the context of complex human diseases, are still poorly understood. At the same time, the systematic acquisition of multivariate data has become increasingly easy. The use of such data to analyze and model complex phenotypes, however, remains a challenge. Here, a new analytic approach is described, termed coreferentiality, together with an appropriate statistical test. Coreferentiality is the indirect relation of two variables of functional interest in respect to whether they parallel each other in their respective relatedness to multivariate reference data, which can be informative for a complex effect or phenotype. It is shown that the power of coreferentiality testing is comparable to multiple regression analysis, sufficient even when reference data are informative only to a relatively small extent of 2.5%, and clearly exceeding the power of simple bivariate correlation testing. Thus, coreferentiality testing uses the increased power of multivariate analysis, however, in order to address a more straightforward interpretable bivariate relatedness. Systematic application of this approach could substantially improve the analysis and modeling of complex phenotypes, particularly in the context of human study where addressing functional hypotheses by direct experimentation is often difficult.
- Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in IndiaPublication . Dalko, Esther; Das, Bidyut; Herbert, Fabien; Fesel, Constantin; Pathak, Sulabha; Tripathy, Rina; Cazenave, Pierre-André; Ravindran, Balachandran; Sharma, Shobhona; Pied, SylvianeSeveral immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.
- Active regulatory T-cells contribute to broadened T-cell repertoire diversity in ivIg-treated SLE patientsPublication . Costa, Nuno; Pires, Ana E; Gabriel, Ana M; Goulart, Luiz F; Pereira, Clara; Leal, Barbara; Queiros, Ana C; Chaara, Wahiba; Moraes-Fontes, Maria F; Vasconcelos, Carlos; Ferreira, Carlos; Martins, Jorge; Bastos, Marina; Santos, Maria J; Pereira, Maria A; Martins, Berta; Lima, Margarida; João, Cristina; Six, Adrien; Demengeot, Jocelyne; Fesel, Constantin
- Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality ModelingPublication . Fesel, Constantin; Barreto, Marta; Ferreira, Ricardo C.; Costa, Nuno; Venda, Lara L.; Pereira, Clara; Carvalho, Claudia; Morães-Fontes, Maria Francisca; Ferreira, Carlos M.; Vasconcelos, Carlos; Viana, João F.; Santos, Eugenia; Martins, Berta; Demengeot, Jocelyne; Vicente, Astrid M.In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4(+)CD25(bright) T-cells that were regularly 70-90% Foxp3(+). We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.
- Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malariaPublication . Herbert, Fabien; Tchitchek, Nicolas; Bansal, Devendra; Jacques, Julien; Pathak, Sulabha; Bécavin, Christophe; Fesel, Constantin; Dalko, Esther; Cazenave, Pierre-André; Preda, Cristian; Ravindran, Balachandran; Sharma, Shobhona; Das, Bidyut; Pied, SylvianePlasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)-mainly associated with acute renal failure (ARF)-and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha.
- Asymptomatic Plasmodium falciparum infection in children is associated with increased auto-antibody production, high IL-10 plasma levels and antibodies to merozoite surface protein 3Publication . Guiyedi, Vincent; Bécavin, Christophe; Herbert, Fabien; Gray, Julian; Cazenave, Pierre-André; Kombila, Maryvonne; Crisanti, Andrea; Fesel, Constantin; Pied, SylvianeMechanisms of acquired protection to malaria in asymptomatic Plasmodium falciparum carriers are only partially understood. Among them, the role plays by the self-reactive antibodies has not been clarified yet. In this study, the relationship between repertoires of circulating self-reactive and parasite-specific immunoglobulin G (IgG), their correlation with cytokine levels, and their association with protection against malaria was investigated in asymptomatic Plasmodium falciparum-infected Gabonese children.
- Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in IndiaPublication . Dalko, Esther; Das, Bidyut; Herbert, Fabien; Fesel, Constantin; Pathak, Sulabha; Tripathy, Rina; Cazenave, Pierre-André; Ravindran, Balachandran; Sharma, Shobhona; Pied, SylvianeSeveral immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.