Dr. Diego Catalán
Young Investigator
Universidad de Chile
Research Lines
Identification of immunodominant epitopes in autoimmune diseases
This research line is aimed at identify and characterize immunodominant T cell epitopes that elicit immune responses associated to different autoimmune diseases, such as rheumatoid arthritis. This challenge will be accomplished through the isolation of a great number of peptides that are being presented to auto-reactive T cells by MHC molecules displayed in the surface of antigen presenting cells. These MHC/peptide complexes can be obtained directly from the inflamed synovial tissue or from antigen presenting cells pulsed in vitro with a suspected antigen or antigenic-mixture, such as synovial fluid. Peptides are then identified through a methodology involving HPLC separation and mass spectrometry sequencing. The immunogenicity of peptides is evaluated by testing their ability to activate T cells from patients suffering from the rheumatoid arthritis. The identification of immunodominant epitopes is very important to understand the properties that make a particular self-protein suitable to break tolerance in autoimmune diseases. More importantly, the knowledge of immunodominant epitopes allows us to design vaccines intended to restore tolerance in patients suffering from autoimmune diseases. This research line is being developed in collaboration with Dr. Dolores Jaraquemada and Dr. Iñaki Álvarez, from Universitat Autònoma de Barcelona, Spain.
Role of B cells in autoimmunity and tolerance induction
It is now becoming increasingly accepted that B cells are not just the precursors of antibody-secreting cells, but also participate in the immune homeostasis by performing several diverse functions that range from antigen presentation to immune tolerance. In this sense, an IL-10-producing regulatory B cell population (Breg) has been described, which confers protection against experimental autoimmunity. Bregs have been recently discovered in humans, sharing most of the functions reported for murine Bregs. Moreover, functional defects in this Breg population have been observed in patients with autoimmune diseases such as systemic lupus erythematous.
In addition, B cells express an array of molecules suitable for an adequate modulation of their functions, including FcgRIIb, Siglecs and complement receptors. FcgRIIb is a molecule expressed on B cells that plays an essential role in regulating humoral immune response, by delivering inhibitory signals upon binding to immune complexes. Several studies agree that the absence of FcgRIIb increases the susceptibility to experimental autoimmunity, while alterations in their expression have been detected in B cells from patients with autoimmune diseases, such as rheumatoid arthritis (Catalán et al, 2010).
We are currently studying the role of human B cells in tolerance induction, with special focus on Bregs and B cells inhibitory receptors. For this purpose, we are assessing if patients with autoimmune or inflammatory diseases, such as systemic sclerosis and inflammatory bowel diseases, exhibit defects on B cells’ regulatory functions.
Cytokine-blocking therapies for autoimmune diseases
This research line is aimed at elucidating the mechanisms involved in the clinical success demonstrated by biological therapies, such as cytokine-blocking antibodies or soluble receptors, in the treatment of rheumatoid arthritis and other autoimmune diseases. We have demonstrated that different lymphoid cell populations, including Th1, Th17, Tregs, and NK cells, among others, are affected by antibodies blocking TNF or the IL-6 receptor, in rheumatoid arthritis patients (Aravena et al., 2011; Pesce et al., 2013). Also, we evaluate whether changes in the balance between these cell subsets are related to clinical improvement in disease severity scores, searching for potential predictive or follow-up markers for these therapies. Finally, our group is interested in performing in vitro experiments, with the purpose to dissect the multiple effects of pro-inflammatory cytokines on isolated T-cell sub-populations, and to test if these effects can be reversed by cytokine-blocking drugs.
Laboratory members
Octavio Aravena
Ph.D. student at Universidad Andrés Bello.
His doctoral thesis is aimed at studying the involvement of the key molecule TIM-1 in human regulatory B cells induction and activation, and in the ability of these cells to generate a state of immunological tolerance by the interaction with TIM-4 expressed in antigen presenting cells. In addition, he is characterizing protocols for in vitro regulatory B cells induction, with a view to develop future cell therapies with regulatory B cells for autoimmune diseases or to prevent transplant rejection. Finally, he is studying the function of TIM-1+ regulatory B cells in patients with systemic sclerosis.
Phone: +56 2 978 6114
E-Mail: aravena.octavio@gmail.com
María Asunción Beltrán
M.Sc. student at Universidad de Chile.
Her thesis is oriented to identify peptides processed and presented by antigen-presenting cells in inflamed joints from rheumatoid arthritis patients. For this objective, she will isolate HLA-DR molecules from rheumatoid arthritis patients’ sinovial tissue and analyze the peptides bound to them through mass spectrometry. Finally, she will classify the most immunodominant peptides according to their ability to elicit T-cell responses in rheumatoid arthritis patients.
Phone: +56 2 978 6114
E-Mail: asuncionbeltranvi@gmail.com
Jorge Berendsen
M.Sc. student at Universidad de Chile.
His thesis is focused in defining the role of inhibitory sialic acid receptors Siglec 2 and Siglec10, on the regulation of IL-10 secretion by human regulatory B cells.
Phone: +56 2 978 6114
E-Mail: jberendsen@clinicalascondes.cl
Elianet Fonseca
M.Sc. student at Universidad de Chile.
Her thesis is intended to study the mechanisms involved in the regulation of B cell phenotype and cytokine secretion profile by the FcgammaRIIb inhibitory receptor, with special emphasis in the regulatory B cell population, and to evaluate the presence of alterations in this receptor on systemic sclerosis patients.
Phone: +56 2 978 6114
E-Mail: elianet.fonseca@ug.uchile.cl
Paulina Vega
M.Sc. student at Universidad de Chile.
Her thesis is aimed at the study of the expression of TIM-1 receptor in different B cell populations, and its role on the secretion of IL-10 by B cells obtained from healthy donors and systemic sclerosis patients.
Phone: +56 2 978 6114
E-Mail: pawli.vega@gmail.com
Ashley Ferrier
Molecular Biotechnology Engineer student at Universidad de Chile
His thesis is focused on the evaluation of the distribution and function of human B cells subpopulations in Systemic Sclerosis, with special emphasis in the transitional B cell sub-population, reported as containing most regulatory B cells (Bregs), with the final goal to understand the mechanisms involved in the loss of tolerance subjacent to this autoimmune disease.
Phone: +56 2 978 6114
E-Mail: afe.whasf@gmail.com
Verónica Ramos
Biochemist, Pontificia Universidad Católica de Valparaíso
Her research activities are focused on the genetic screening of healthy individuals and rheumatoid arthritis (RA) patients with the purpose to study the association of HLA-DRB1 alleles with the disease, in Chilean population. In addition, she performs the preparation of synovial tissues from RA patients for further microscopic and molecular analyses. Finally, she is cloning the enzyme human peptidyl arginine deiminase 4 (PAD4), responsible for protein citrullination, a posttranslational modification involved in RA pathogenesis.
Phone: +56 2 2978 9503
E-Mail: vramosv.bqa@gmail.com
Most relevant publications
Cuchacovich M, Bueno D, Carvajal R, Bravo N, Aguillón JC, Catalán D, Soto L. Clinical parameters and biomarkers for anti-TNF treatment prognosis in rheumatoid arthritis patients. Clin Rheumatol. 2014 Aug 2. (Epub ahead of print)
Pesce B, Soto L, Sabugo F, Wurmann P, Cuchacovich M, López MN, Sotelo PH, Molina MC, Aguillón JC, Catalán D. Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Immunol. 2013 Mar;171(3):237-42.
Catalán D, Aravena O, Zúñiga R, Silva N, Escobar A, Sabugo F, Wurmann P, Soto L, González R, Alfaro J, Larrondo M, Cuchacovich M, and Aguillón JC. Weak CD4+ T cell responses to citrullinated vimentin in rheumatoid arthritis patients carrying HLA-DR9 alleles. Rheumatol Int. 2012 Jun;32(6):1819-25.
Aravena O, Pesce B, 1, Soto L, Orrego N, Sabugo F, Wurmann P, Molina MC, Alfaro J, Cuchacovich M, Aguillón JC and Catalán D. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets. Immunobiology. Dec;216(12):1256-63.
Catalán D, Aravena O, Sabugo F, Wurmann P, Soto L, Kalergis AM, Cuchacovich M, Aguillón JC; Millenium Nucleus on Immunology and Immunotherapy P-07-088-F. B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcgammaRIIb, which are modulated by anti-tumor necrosis factor therapy. Arthritis Res Ther. 2010;12(2):R68.
Projects
- National Council for Scientific and Technological Research (CONICYT – Chile). Seeking for mechanisms involved in the IL-10 secretion by regulatory B cells: Implications for therapeutic interventions on autoimmune diseases. 2012 – 2015. Grant number: 11121497.
- National Council for Scientific and Technological Research (CONICYT – Chile). Fcgamma receptors and regulatory B cells: A novel network behind the immune response governing systemic sclerosis. 2012 – 2015. Grant number: 1121100.
- Vice-rectory of Investigation and Development, Universidad de Chile.Identification of T-cell epitopes in rheumatoid arthritis: Searching candidates for the design of an antigen-specific therapy. 2011 – 2013.Grant number: I 10/02-2.