Lupus and autoreactive immune repertoires

Research Interests

While the detection of molecular mechanisms as well as of genetic disease risk factors rapidly evolves, the systemic diversification of specificity repertoires, which is of obvious relevance for the pathogenesis of human autoimmune diseases, is still badly understood. In this situation, it is increasingly relevant to combine different types of knowledge in order to model the pathogenetic process that leads to autoimmune diseases as a whole, since they are known to depend on complex interactions of a variety of molecular and cellular mechanisms acting on different levels.
Systemic Lupus Erythematosus (SLE) is a human autoimmune disorder where altered physiologies and self-reactive repertoires of both B- and T-cells are intimately connected. Autoreactive IgG antibodies are the diagnostic hallmark of SLE and diversify over long time periods before disease becomes manifest, however, this depends also on nonspecific factors, such as type I interferons. Our current approach is to model, in a stepwise fashion, the ways in which different genetic factors and molecular mechanisms are interconnected in SLE pathogenesis, by analysing their relatedness in reference to standardized and quantitative broad-spectrum immunoblot autoantibody profiles.
In this context, we are particularly interested in the role of T-cell regulation. Since we found particular relations between antibody reactivity and regulatory T-cells in unaffected relatives of SLE patients, who often share elevated titres of SLE-associated auto-antibodies, we follow the hypothesis that these auto-antibody-positive unaffected relatives bear a particular capacity to regulate autoreactive immune repertoires that breaks down in clinically manifest disease. Consequently, our principal approach to model SLE pathogenesis is actually focused on genetic factors and molecular mechanisms relevant for T-cell regulation, in combination with a systematic study of first-degree relatives of SLE patients.
In parallel, we study T-cell regulation in mouse models and the effect of therapy with intravenous immunoglobulin (ivIg).

Group Members

Research Project

Lupus and its compensation in unaffected relatives by T-cell regulation

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with recognized morbidity, mortality and economic burden in developed countries. In northern Portugal (HGSA, Porto), a mean prevalence of 51,8 cases per 100.000 habitants was found, with the incidence growing from 1,0 per 1000 admitted patients in 1982 to 6,8 in 2000, and a mortality rate of 10,8%. 46% of the patients had lupus nephritis and more than 20% of these evolved to chronic renal insufficiency, needing hemodialysis and renal transplant.
SLE is characterized by auto-antibodies of various specificities, accumulating over years before clinical manifestation. The clinical course is characterized by recurrent flares and remission periods. Treatment is principally immunosuppressive. Relatively few patients reach stabilized long-term remission.
Unaffected relatives of SLE patients frequently share sustained enhanced levels of SLE-type auto-antibodies, most of them without ever acquiring clinical disease, which suggests a capacity to compensate the pathogenic effects associated with constitutive auto-antibody production. A therapy capable of restoring such a compensatory capacity in patients appears highly desirable.
T-cells contain a subset of regulatory cells. For SLE patients, a negative correlation of their frequency with disease activity and with circulating IgG autoantibody levels was reported. Conversely, we found that in unaffected relatives, CD4+CD25bright cells were positively correlated with auto-antibodies measured in diverse ways. Furthermore, autoantibody profiles were influenced by genetic polymorphisms affecting effects mediated by IL2, the cytokine with the clearest impact on regulatory T-cell function, in a way that characteristically differed between SLE patients, unaffected relatives and blood donor controls. Thus, an IL2-dependent T-cell regulatory feedback mechanism, abrogated in manifest SLE, appears capable of controlling the pathogenicity of constitutively enhanced SLE-type antibody production.
In this project, we will characterize this compensation mechanism, with the goal of new therapies aimed at its restoration and stabilisation. We will longitudinally study unaffected relatives and patients in stable remission, compared with active disease patients and healthy controls. We will simultaneously assess a range of informative parameters for SLE-associated immune alterations and subphenotype differentiation.

Funding

Fundação apra a Ciênica e a Tecnologia (FCT) Project Grants, Portugal

Collaborators

Centro Hospitalar de Lisboa Ocidental
Joao Faro Viana
Francisca Moraes-Fontes

IGC
Jocelyne Demengeot
Carlos Penha-Goncalves

IPO (Lisboa)
Cristina Joao

Hospital Santa Maria (Lisboa)
Carlos Ferreira

Hospital dos Marmeleiros (Funchal)
Jorge Martins

ICBAS (Porto)
Berta Martins

Hospital Geral Santo Antonio (Porto)
Carlos Vasconcelos
Margarida Lima

Publications

Zelenay S, Moraes-Fontes MF, Fesel, C, Demengeot J, Coutinho A (2007). Physiopathology of natural auto-antibodies: the case of regulation. J Autoimmun 29 :229-35

Guiyedi V, Chanseaud Y, Fesel, C, Snounou G, Rousselle JC, Lim P, Koko J, Namane A, Cazenave PA, Kombila M, Pied S (2007). Self-reactivities to the non-erythroid alpha spectrin correlate with cerebral malaria in gabonese children. PLoS ONE 2(4) :e389

Deshpande P, Fesel, C, Rajendra J, Cazenave PA, Mishra GC and Pied S (2006). Clusters of cytokines determine malaria severity in Plasmodium falciparum-infected patients from endemic areas of central India. J Infect Dis 194 :198-207

Ferreira R, Barreto M, Santos E, Pereira C, Martins B, Andreia R, Crespo F, Viana JF, Vasconcelos C, Ferreira C, Vicente AM and Fesel, C (2005). Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production. J Autoimmun 25(2) :155-163

Fesel, C, Goulart LF, Silva-Neto A, Coelho A, Fontes CJF, Braga E and Vaz NM, (2005). Increased polyclonal immunoglobulin reactivity toward human and bacterial proteins is associated with clinical protection in human Plasmodium infection. Malar J . 4(1) :Article 5

Barreto M, Santos E, Ferreira R, Fesel, C, Fontes MF, Pereira C, Martins B, Andreia R, Viana JF, Crespo F, Vasconcelos C, Ferreira C and Vicente AM (2004). Evidence for CTLA4 as a susceptibility gene for Systemic Lupus Erythematosus Eur J Hum Genetics 12 :620-626

Santos-Lima EC, Vasconcellos R, Reina-San-Martin B, Fesel, C, Cordeiro-Da-Silva A, Berneman A, Cosson A, Coutinho A and Minoprio P (2001). Significant association between the skewed natural antibody repertoire of Xid mice and resistance to Trypanosoma cruzi infection. Eur J Immunol 31 :634-645.

Fesel, C and Coutinho A (2000). Serum IgM repertoire reactions to MBP/CFA immunization reflect the individual status of EAE susceptibility J Autoimmun 14 :319-324

Mirilas P, Fesel, C, Guilbert B, Beratis NG and Avrameas S (1999). Natural antibodies in childhood: development, individual stability, and injury effect indicate a contribution to immune memory. J Clin Immunol 19 :109-115

Fesel, C and Coutinho A (1998). Dynamics of serum IgM autoreactive repertoires following immunization: strain specificity, inheritance and association with autoimmune disease susceptibility. Eur J Immunol 28 :3616-3629.