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.
VascularAutoimmune diseases (e.g. Systemic Lupus Erythematosus, Antiphospholipid Syndrome, Rheumatoid Arthritis, Myasthenia gravis).
• Relationship between Vascularhumoral response 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. Characterization of anti-HDL antibodies: identification of their biologic activity, pathogenic potential and clinical relevance
The main goal of this project is to characterize the main targets (main epitopes) as well as the mechanisms by which they become immunogenic and disrupt the normal HDL functions and further demonstrate the biologic activity and consequent pathogenic capacity of the aHDL antibodies. The possible association with different clinical cohorts with specific epitope(s) recognised by anti-ApoA-I antibodies may lead to the identification of a new risk factor for vascular disease. The data obtained may also provide background information for potential new drugs and/or vaccines for the primary or secondary prevention of this disease.
Jalves_figure1
Figure 1. Immunoreactivity against human ApoA-I and different constructs of ApoA-I in serum from patients with psoriasis, type 2 diabetes, Alzheimer disease and systemic lupus erythematosus.

 
 
 
 
 
2. Humoral response against HDL and cardiovascular risk in patients with Psoriasis
Our group studied the presence of anti-HDL and anti-Apo A-I antibodies in patients with Psoriasis. These antibodies were associated with increased disease severity and may contribute to the pathogenesis of atherosclerosis.
JAlves_figure2
Figure 2. Levels of IgG anti-ApoA-I antibodies (A) and relationship between the titres of IgG anti-HDL antibodies with Psoriasis Area and Severity Index (PASI) in patients with Psoriasis (PSO)

 
 
 
 
 
 
 
 
 

3. Importance of Nailfold Capillaroscopy in Raynaud’s Phenomenon and other Immune-Mediated Vascular Diseases
Nailfold capillaroscopy detects very early microvascular alterations in patients with Raynaud’s phenomenon as well as other diseases with vessel function impairment like Diabetes mellitus or Arterial hypertension. We aim at defining new capillaroscopic patterns and/or biomarkers in order to predict the risk of developing such diseases and its complications.
JAlves_figure3
Figure 3. “Late" capillaroscopic pattern in systemic sclerosis

 
 
 
 
 
 
 
 
 
 
4. Notch signaling in dysangiogenesis and endothelial dysfunction
The aim of this project is to describe the role of Notch pathway in the endothelial dysfunction associated with disease states characterized by deranged neoangiogenesis, as is the case of systemic sclerosis.
JAlves_figure4
Figure 4. Microvascular endothelial cells from systemic sclerosis patients (IF: red, vimentin; green, von Willebrand factor).
 
 
 
 
 
 
 
 
 
 
 
5. The role of HDL in the activation of T and B lymphocytes and regulation of the immune response
HDL has atheroprotective and anti-inflammatory actions that have been mainly studied in the innate immune system. Its influence in the mechanisms of adaptive immune system is still poorly understood. This project aims at studying the influence of HDL in cell lipid metabolism and its role in the regulation of T and B cells-associated response, with focus on healthy individuals and patients with autoimmune diseases and diabetes.
JAlves_figure5
Figure 5. Inhibition of B and T cells interaction (double positive are conjugates) in the presence of HDL – assessed by ImageStream® imaging flow cytometry (unpublished data).
 
 
 
 
 
 
 
 
 
6. Neutralizing antibodies in anti-TNF therapy
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).
JAlves_figure6
Figure 6. Anti-TNF-alpha antibodies levels in patients with Ankylosing Spondylitis (A) and Rheumatoid Arthritis (B).

Projects

- Characterization of anti-HDL (aHDL) antibodies: identification of their biologic activity and clinical relevance - iNOVA4Health

- Humoral response towards HDL and vascular risk in patients with Psoriasis – Pfizer

- Familial Risk in Raynaud´s Disease, Systemic Sclerosis and Diabetes Mellitus– the role of vascular memory - Actelion International

- HDL in regulation of T cell activation.- Fundação Amadeu Dias

- Role of Dll-4 on the endothelial dysfunction in systemic sclerosis- Bolsa de Estudo em Autoimunidade NEDAI da SPMI

- Importance of Nailfold Capillaroscopy in Raynaud’s Phenomenon and other Immune-Mediated Vascular Diseases, Actelion International

- Anti-apolipoprotein A-I antibodies in the pathogenesis of Alzheimer disease - EXPL/NEU-SCC/0186/2012 and Fundação Amadeu Dias

- Importance of antibodies anti-IFN-gamma as a new family of autoantibodies. -Several sponsorships

- Neutralizing antibodies in anti-TNF therapy. -Private sponsorships

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

- 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.

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

- Department of Medicine IV, Fernando da Fonseca Hospital, PT

- Centre for Molecular Pathogenesis – Retrovirus and Associated infections unit (CPM-URIA), Faculty of Pharmacy – University of Lisbon, PT

- Centre for Haemostasis and Thrombosis St George’s Healthcare, University of London, UK

- Centre for Rheumatology Research, University College London, UK

- Corgenix Inc, Colorado, USA

- Department of Biochemistry, University of Okayama, JP

- Dipartimento di Medicina e Scienze della Salute, Università del Molise, IT

- Tropical Diseases Unit and Centre of Malaria and Tropical Diseases , IHMT, PT

- Neo-vascularization Unit , IMM, PT

Team photos

Team Jose Alves