Immune response and vascular disease

Jose-Delgado-Alves

José Alves

Principal Investigator

CV

Location:

CEDOC
Campus Sant'Ana
Pólo de Investigação, NMS, UNL
Rua Câmara Pestana, nº 6
1150-082 Lisboa, Portugal

Phone: (+351) 218 803 038 (ext 22492)
Fax: (+351) 351 218 803 028
E-mail: jose.alves(at)nms.unl.pt

Main interests

Vascular Medicine: atherogenesis, thrombogenesis and oxidative stress
Autoimmune diseases (e.g. Sistemic Lupus-SLE, antiphospholipid syndrome, rheumatoid arthritis, Miastenia Gravis)
Relationship between humoral respose and atherogenesis, with particular emphasis on HDL and oxidative stress

Research Areas

Our group has been studying the importance of the humoral response towards different key molecules that have been recognized as key elements in the pathogenesis of different diseases:
At the moment the areas of research that consider pairs of molecule/disease are:
1. HDL and atherosclerosis
2. Apo AI and Alzheimer´s Disease
3. Interferon Gamma and Systemic Lupus (SLE)
4. Ach receptor and Miastenia Gravis
5. TNF-alpha and autoimmune diseases

1. Humoral response towards HDL: a new mechanism for atherogenesis

Untitled1Our group has been studying the importance of HDL in atherogenesis for the last few years and showed that the presence of antibodies against different structures in the HDL complex may account for its quantitative and/or qualitative fault as a protective factor.
We showed the presence of anti-HDL antibodies and more particularly anti-Apo A-I antibodies (the main apolipoprotein contained in HDL) and anti-paraoxonase 1 (the main antioxidant enzyme in HDL) in patients with autoimmune diseases but also in patients with atherosclerosis-associated clinical events outside the context of autoimmune diseases. Furthermore we established an association between the titres of these antibodies and some markers of endothelial dysfunction.
Despite these reports, the interaction of the immune system and HDL has never been thoroughly addressed nor has the pathogenicity of these antibodies been determined.
The pathogenic potential of these antibodies may lead to the identification of a new biomarker for vascular disease, whilst presenting itself as a novel target for a different treatment approach which may redefine the treatment strategies and clinical trials design for HDL interventions in the future.

2. Anti-ApoA-I antibodies in pathogenesis of Alzheimer disease

The possibility of an interference of anti-Apo AI antibodies in the clearance properties of Apo-AI in relation to Beta-amyloid, the protein responsible for neurologic degeneration in Alzheimer´s Disease. We have started a FCT funded project, in which a clinical cohort of patients has been identified and will be followed for one year. The presence of anti-Apo AI antibodies in plasma and CSF will be assessed and its association with disease progression and clinical characteristics will be analyzed. Control populations will include other dementias and healthy subjects.

3. Anti-IFN-γ a new family of autoantibodies in SLE

Our group has identified the presence of anti-interferon gamma antibodies in patients with SLE. We have identified a clinical cohort where possible associations between the presence of these antibodies and other clinical variables will be addressed. In parallel we are testing isolated antibodies from patients in in vitro settings in order to determine whether these antibodies have biologic activity.

Untitled

4. Antibodies against the acetylcholine receptor as an indicator for diagnosis and therapy of Myasthenia Gravis

Patients with Miastenia Gravis have antibodies towards the Ach receptor. We have identified a specific peptide that may be the specific target for these antibodies. If confirmed, we will develop a fusion protein with this peptide and an Fc fraction of an immunoglobulin in order to identify in a patient whether CD20+ B lymphocytes are involved in the production of the pathogenic antibodies. That would provide clinicians with an easy tool to identify patients that might respond to specific anti-CD20 (rituximab or ocralizumab) drugs.

5. Neutralizing antibodies in anti-TNF therapy

Untitled3This study aims the development of a method for detection of anti-biological antibodies and determination their prevalence in study population. With the conjugation of the clinical information with laboratory results we will be able to identify predisposing factors and protective effects as well (eg, treatment failure or side effects).
This study aims the development of a method for detection of anti-biological antibodies and determination their prevalence in study population. With the conjugation of the clinical information with laboratory results we will be able to identify predisposing factors and protective effects as well (eg, treatment failure or side effects).

Projects

"Effect of Probiotics in intestinal permeability mediated by zonulin in Crohn's Disease"; Merck Serono SA /BMS

"Neutralizing antibodies in anti-TNF therapy"; Merck Sharp & Dohme

"HDL in regulation of T cell activation"; Fundação Amadeu Dias

"Capillaroscopy in diabetic retinopathy: evaluation of the micro-vasculature as a factor in evaluating inflammation"; Actelion International

"Angiogenesis and clinical remission in juvenile idiopathic arthritis"; Prémio de Investigação da Sociedade Portuguesa de Pediatria

“Clinical trial EXPLORE: Exploratory, double blind placebo controlled, randomized, single cross-over study to evaluate the potential anti-oxidant action of Niaspan”; Merck Serono S.A.

“Humoral response towards HDL evaluation of their impact on the HDL anti-atherogenic functions”; Prémio NEDAI da SPMI/ Several private sponsorships

"Importance of nailfold capillaroscopy in the evaluation of Raynaud’s phenomenon"; Actelion International

Publications
  • Isabel Ferreira and José Delgado Alves (2012). Atherogenesis and Vascular Disease in SLE, Systemic Lupus Erythematosus, Dr Hani Almoallim (Ed.), ISBN: 978-953-51-0266-3, InTech, DOI: 10.5772/26028. Available from INTECH: See Here
  • Ames PR, Batuca JR, Muncy IJ, De La Torre IG, Pascoe-Gonzales S, Guyer K, Matsuura E, Lopez LR. (2012) Aspirin insensitive thromboxane generation is associated with oxidatve stress in type 2 diabetes mellitus. Thromb Res. 130:350-4.
  • Batuca JR, Marinho AT, Caixas U, Gouveia S, Delgado-Alves J, Monteiro EC , Pereira SA. (2012) HDL in HIV infection: the effect of the antiretroviral efavirenz on HDL-quality and quantity. Nova Science Publishers, Inc Advances in medicine and biology. 53: 111-136.
  • Alves JD, Marinho A, Serra MJ. (2011) Tocilizumab: is there life beyond anti-TNF blockade? Int J Clin Pract. 65(4):508-13.
  • Neves M, Alves JD. (2011) Factors implicated in the generation and persistence of long-lived plasma cell-mediated autoimmunity. Autoimmun Rev. 10(7):375-82.
  • Ferreira I, Neves M, Alves JD. (2011) Atherosclerosis risk in antiphospholipid syndrome. International Journal of Clinical Rheumatology Vol. 6, No. 5, Pages 583-593.
  • Amaral MC, Favas C, Alves JD, Riso N, Riscado MV. (2010) Stress-related mucosal disease: incidence of bleeding and the role of omeprazole in its prophylaxis. Eur J Intern Med. 21(5):386-8.
  • Ames PRJ, Ortiz-Cadenas A, Garcia-de la Torre I, Nava A, Oregon-Miranda A, Batuca JR, Kojima K, Lopez LR, Matsuura E (2010) Rosuvastatin treatment is associated with a decrease of serum oxidised low-density lipoprotein/beta2-glycoprotein I complex concentration in type 2 diabetes. Br J Diabetes Vasc Dis. 10: 292-299.
  • Ames PR, Batuca JR, Ciampa A, Iannaccone L, Delgado Alves J. (2010) Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome. J Rheumatol 37(12):2523-30.
  • Amaral M, Favas C, Delgado Alves J. (2010) Persistency of low levels of anticardiolipin and anti-beta2 glycoprotein1 in thrombosis. Eur J Intern Med. 21(2):101-3.
  • Ames PR, Matsuura E, Batuca JR, Ciampa A, Lopez LL, Ferrara F, Iannaccone L and Delgado Alves J. (2010) High-density lipoprotein inversely relates to its specific auntoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome. Lupus 19(6):711-6.
  • Ames PR, Margaglione M, Mackie S, Alves JD. (2010) Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost. 16(6):628-36.
  • Charakida M, Besler C, Batuca JR, Sangle S, Marques S, Sousa M, Wang G, Tousoulis D, Delgado Alves J, Mackworth-Young C, Hughes G, D’Cruz D, Luscher T, Landmesser U and Deanfield JE. (2009) Vascular dysfunction in primary antiphospholipid syndrome; role of dysfunctional high density lipoprotein. JAMA 302(11):1210-1217.
  • Ames PR, Margarita A, Alves JD (2009). Antiphospholipid antibodies and atherosclerosis: insights from systemic lupus erythematosus and primary antiphospholipid syndrome. Clin Rev Allergy Immunol. 7(1):29-35.
  • Batuca JR and Delgado Alves J. (2009) C-reactive protein in systemic lupus erythematosus. Autoimmunity. 42(4):282-5.
  • Batuca JR, Amaral MC and Delgado Alves J. (2009) Humoral Mechanismof Atherogenesis. Ann N Y Acad Sci 1173:401-408.
  • Batuca JR, Ames PR, Amaral MC, Favas C, Isenberg DA and Delgado Alves J. (2009) Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus. Rheumatology (Oxford). 48(1):26-31.
  • Amaral MC, Alves JD. (2009) Pathogenesis of multi-organic failure in autoimmune diseases.Autoimmun Rev. 8(6):525-8.
  • Pereira SA, Batuca JR, Caixas U, Branco T, Delgado-Alves J, Germano I, Lampreia F and Monteiro EC. (2009) Effect of efavirenz on high-density lipoprotein antioxidant properties in HIV-infected patients. Br J Clin Pharmacol 68(6):891-7.
  • Ames PR, Antinolfi I, Ciampa A, Batuca JR, Scenna G, Lopez LR, Delgado Alves J, Iannaccone L and Matsuura E. (2008) Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease? Rheumatology (Oxford). 47(12):1832-7.
  • Alves JD, Steinhagen-Thiessen E, Darioli R, Hostalek U, Vogt A. (2008) Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk. Curr Med Res Opin. 24(10):2815-20.
  • Ehrenstein MR, Alves JD. (2008) Antibodies and other biomarkers - pathological consequences (2). Lupus. 17(3):256-8.
  • Batuca JR, Ames PRJ, Isenberg DA, Delgado Alves J. (2007) Antibodies toward High-Density Lipoprotein Components Inhibit Paraoxonase Activity in Patients with Systemic Lupus Erythematosus. Ann N Y Acad Sci . 1108 (1), 137–146.
  • Margarita A, Batuca J, Scenna G, Delgado Alves J., Lopez L, Iannaccone L, Matsuura E, Ames PRJ. (2007) Subclinical Atherosclerosis in Primary Antiphospholipid Syndrome. Ann N Y Acad Sci. 1108 (1), 475–480.
  • Ames PR, Delgado Alves J, Lopez LR, Gentile F, Margarita A, Pizzella L, Batuca JR, Scenna G, Brancaccio V and Matsuura E. (2006) Antibodies against beta2-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome. Clin Dev Immunol. 13(1):1-9.
  • Alves JD, Clapp BR, Stidwill R, Chen PP, Hingorani AD, Singer M, Isenberg DA. (2006) Human monoclonal IgG anticardiolipin antibodies induce nitric oxide synthase expression. Atherosclerosis. 185(2):246-53.
  • Ames PR, Iannaccone L, Alves JD, Margarita A, Lopez LR, Brancaccio V. (2005) Factor XIII in primary antiphospholipid syndrome.J Rheumatol. 32(6):1058-62.
  • Delgado Alves J, Mason LJ, Ames PR, Chen PP, Rauch J, Levine JS, Subang R, Isenberg DA. (2005) Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model. Rheumatology (Oxford). 44(10):1238-44.
  • Delgado Alves J, Radway-Bright EL, Lee S, Grima B, Hothersall J, Ravirajan CT, Isenberg DA. (2005) Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women. Lupus. 14(5):373-80.
  • Delgado Alves J, Inanc M, Diz-Kucukkaya R, Grima B, Soromenho F, Isenberg DA. (2004) Thrombotic risk in patients submitted to splenectomy for systemic lupus erythematosus and antiphospholipid antibody syndrome-related thrombocytopenia. Eur J Intern Med. 15(3):162-167.
  • Shoenfeld Y, Lev S, Blatt I, Blank M, Font J, von Landenberg P, Lev N, Zaech J, Cervera R, Piette JC, Khamashta MA, Bertolaccini ML, Hughes GR, Youinou P, Meroni PL, Pengo V, Alves JD, Tincani A, Szegedi G, Lakos G, Sturfelt G, Jönsen A, Koike T, Sanmarco M, Ruffatti A, Ulcova-Gallova Z, Praprotnik S, Rozman B, Lorber M, Chapman J, van-Breda-Vriezman PJ, Damoiseaux J. (2004) Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol. 31(7):1344-8.
  • Shoenfeld Y, Krause I, Kvapil F, Sulkes J, Lev S, von Landenberg P, Font J, Zaech J, Cervera R, Piette JC, Boffa MC, Khamashta MA, Bertolaccini ML, Hughes GR, Youinou P, Meroni PL, Pengo V, Alves JD, Tincani A, Szegedi G, Lakos G, Sturfelt G, Jönsen A, Koike T, Sanmarco M, Ruffatti A, Ulcova-Gallova Z, Praprotnik S, Rozman B, Lorber M, Vriezman VB, Blank M. (2003) Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol. 23(5):377-83.
  • Alves JD, Grima B. (2003) Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep.;5(5):383-90.
  • Alves JD, Ames PR. (2003) Atherosclerosis, oxidative stress and auto-antibodies in systemic lupus erythematosus and primary antiphospholipid syndrome. Immunobiology. 207(1):23-8.
  • Delgado Alves J, Kumar S, Isenberg DA. (2003) Cross-reactivity between anti-cardiolipin, anti-high-density lipoprotein and anti-apolipoprotein A-I IgG antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology (Oxford). 42(7):893-9.
  • Delgado Alves J, Ames PR, Donohue S, Stanyer L, Nourooz-Zadeh J, Ravirajan C, Isenberg DA. (2002) Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arthritis Rheum. 46(10):2686-94.
  • Ames PR, Margarita A, Delgado Alves J, Tommasino C, Iannaccone L, Brancaccio V. (2002) Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies. Lupus. 11(4):208-14.

Collaborations

Paul RJ Ames - Sports, Exercise & Vascular Medicine, Queen Mary University London, UK

Luis Lopez- Corgenix Inc, Colorado; USA

Elizabeht C Jury - Centre for Rheumatology Research, University College London, UK

David Isenberg - Centre for Rheumatology Research, University College London, UK

Marietta Charakida - Department of Vascular Physiology, The Institute of Child Health, University College London; United Kingdom

João Gonçalves - Centre for Molecular Pathogenesis – Retrovirus and Associated infections unit (CPM-URIA), Faculdade de Farmácia Universidade de Lisboa, PT

Gonçalo Justino - Centro de Química Estrutural, Instituto Superior Técnico, PTl

Team photos

Team Jose Alves