Coreferentiality: A New Method for the Hypothesis-Based Analysis of Phenotypes Characterized by Multivariate Data

Many 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

Anti-brain protein autoantibodies are detectable in extraparenchymal but not parenchymal neurocysticercosis

Neurocysticercosis (NC) presents a spectrum of clinical manifestations, with two broad clinical entities based on the central nervous system location of the parasite: extraparenchymal (EP-NC) and parenchymal (P-NC). In this work, using quantitative immunoblot methodology, we demonstrate the presence of autoantibodies to brain proteins in CSF from EP-NC, but not P-NC, patients. There was striking correlation between the level of autoantibodies and the levels of the secreted metacestode glycoprotein HP-10, suggesting that the level of stimulation of the autoantibody response may be a function of the number of viable parasites. Nine corresponding proteins autoantigens were provisionally identified by mass spectroscopy. © 2020 Elsevier B.V.Neurocysticercosis (NC) presents a spectrum of clinical manifestations, with two broad clinical entities based on the central nervous system location of the parasite: extraparenchymal (EP-NC) and parenchymal (P-NC). In this work, using quantitative immunoblot methodology, we demonstrate the presence of autoantibodies to brain proteins in CSF from EP-NC, but not P-NC, patients. There was striking correlation between the level of autoantibodies and the levels of the secreted metacestode glycoprotein HP-10, suggesting that the level of stimulation of the autoantibody response may be a function of the number of viable parasites. Nine corresponding proteins autoantigens were provisionally identified by mass spectroscopy. © 2020 Elsevier B.V

Increased polyclonal immunoglobulin reactivity toward human and bacterial proteins is associated with clinical protection in human Plasmodium infection

BACKGROUND: Polyclonal B-cell activation is well known to occur in Plasmodium infections, but its role in pathogenesis or protection remains unclear. However, protective properties of natural antibodies have previously been demonstrated in other contexts. METHODS: Sera from asymptomatic and symptomatic Plasmodium-infected subjects locally detected in a survey study in the Brazilian Amazon, and from unexposed and exposed but presently uninfected control subjects, were assayed by a standardized quantitative immunoblot method allowing simultaneous detection of IgG or IgM reactivity to a large number of parasite-unrelated proteins. RESULTS: In subjects free of coinfection with hepatitis B virus, IgG reactivity to human brain antigens and Escherichia coli proteins was strikingly enhanced in asymptomatic Plasmodium-infected individuals when compared to such with clinical malaria symptoms, or to uninfected control subjects. This difference was most characteristic for limited exposure times (less than ten years locally, or 20 years in endemic areas). It was more significant than a similar trend found for IgG to Plasmodium falciparum antigens, and unrelated to parasitaemia levels. Asymptomatic subjects with comparatively short exposure characteristically showed relatively elevated IgG versus IgM reactivity. Polyclonal IgG reactivity appears triggered by previous P. falciparum but not Plasmodium vivax malaria. CONCLUSION: The observed difference in polyclonal antibody production seems related to intrinsic activation states of infected individuals, rather than to parasite-antigen specific immune responses. However, it appears influenced by preceding stimuli. This supports the idea that acquired clinical immunity may not exclusively depend on antigen-specific responses, but also on the individual polyclonal reaction

Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

Several 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.Indo-French Centre for the Promotion of Advanced Research, Associated International Laboratory Systems (LIA; CNRS), Immunology and Genetics of Infectious Diseases (SIGID), Department of Biotechnology from the Ministry of Science and Technology of India (DBT), Tata Institute of Fundamental Research (TIFR) (intramural funds), Université Lille (doctoral contract), IFCPAR (Raman-Charpak award), College Doctoral Lille Nord de France (AAP n10 award), Fondation des Treille, Conseil Régional du Nord-Pas de Calais

Auto-antibodies targeting brain antigens in Plasmodium falciparum infected patients as biomarkers of Cerebral Malaria

International audiencen.

Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling

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+CD25bright 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

Active regulatory T-cells contribute to broadened T-cell repertoire diversity in ivIg-treated SLE patients

Octapharma

Broadened T-cell Repertoire Diversity in ivIg-treated SLE Patients is Also Related to the Individual Status of Regulatory T-cells

Intravenous 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.Octapharma research funding; Fundação para a Ciência e a Tecnologia postdoctoral fellowships: (SFRH/BPD/20806/2004, SFRH/BPD/34648/2007); FCT Programa Pessoa travel grant

Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

BACKGROUND: Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. METHODOLOGY: To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. RESULTS/CONCLUSION: The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM