Our research focuses on the connection between immunology and vascular disease. We work in a translational science workflow, with a strong interrelationship between basic science and clinical medicine.
Adaptive and innate immune responses, as well as inflammation, are frequent phenomena throughout life, and are cornerstones of the pathophysiology of autoimmune diseases. Their relationship to cardiovascular risk in promoting endothelial dysfunction, atherogenesis and cardiovascular disease is a central interest of our research.
In some of our work, we have characterized a new family of antibodies against components of lipoproteins, especially against high density lipoproteins (HDL), which can block or disrupt their normal function in maintaining a healthy endothelium. This mechanism could be partially responsible for the increased cardiovascular risk associated with several autoimmune diseases, as in systemic lupus erythematosus, rheumatoid arthritis or psoriasis, but also for atherogenesis sensu lato. Additionally, the interference of HDL particles in T lymphocyte biology is also approached in our group, especially in systemic lupus erythematosus patients, where we study the dynamics of immune synapses in response to HDL and anti-HDL antibodies. We have also been exploring the role of anti-HDL antibodies in Alzheimer’s disease. In the context of autoimmunity and vascular disease we also focus on the microvascular dysfunction and deranged angiogenesis associated with systemic sclerosis. Furthermore, the emergence of neutralizing antibodies against biologic therapies, which results in treatment failure in several diseases, is a research interest of our group.
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.
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.
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.
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.
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.
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).
Figure 6. Anti-TNF-alpha antibodies levels in patients with Ankylosing Spondylitis (A) and Rheumatoid Arthritis (B).
- 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.
- Batuca JR, Amaral MC, Favas C, Justino GC, Papoila AL, Ames PRJ, Alves JD. Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease. Thromb Haemost. 2018 Jun;118(6):1088-1100
- Caetano J, Paula FS, Amaral MC, Oliveira S, Delgado Alves J. Nailfold Videocapillaroscopy Changes Are Associated with the Presence and Severity of Systemic Sclerosis-Related Interstitial Lung Disease. J Clin Rheumatol. 2018 May 19. doi: 10.1097/RHU.0000000000000815
- Ciampa A, Salapete C, Vivolo S, Ames PRJ. Oral anticoagulation cost in primary antiphospholipid syndrome: comparison between warfarin and hypothetical rivaroxaban. Blood Coagul Fibrinolysis. 2018 Jan;29(1):135-138
- Ames PRJ, Merashli M, Bucci T, Norouz-Zadeh J. Isoprostane in systemic sclerosis: A systematic review and meta-analysis. Mod Rheumatol. 2018 May 17:1-6
- Ames P, Bucci T, Merashli M, Amaral M, Arcaro A, Gentile F, Nourooz-Zadeh J, Delgado Alves J. Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial? Free Radical Research. 2018. DOI:10.1080/10715762.2018.1525712
- Goncalves J, Santos M, Acurcio R, Iria I, Gouveia L, Matos Brito P, Catarina Cunha-Santos A, Barbas A, Galvão J, Barbosa I, Aires da Silva F, Alcobia A, Cavaco M, Cardoso M, Delgado Alves J, Carey JJ, Dörner T, Eurico Fonseca J, Palmela C, Torres J, Lima Vieira C, Trabuco D, Fiorino G, Strik A, Yavzori M, Rosa I, Correia L, Magro F, D'Haens G, Ben-Horin S, Lakatos PL, Danese S. Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition. Aliment Pharmacol Ther. 2018 Sep;48(5):507-522
- Merashli M, Alves JD, Gentile F, Ames PR. Relevance of antiphospholipid antibodies in multiple sclerosis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2017 Jun;46(6):810-818
Merashli M, Alves JD, Ames PR. Clinical relevance of antiphospholipid antibodies in systemic sclerosis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2017 Apr;46(5):615-624.
- Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Žigon P6, Ambrožič A, Tomšič M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T. . Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017 Mar;26(3):266-276
- Batuca JR, Amaral MC, Favas C, Paula FS, Ames PR, Papoila AL, Delgado Alves J. Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial. Br J Clin Pharmacol. 2017 May;83(5):1002-1010
- Ames PRJ, Alves JD, Gentile F. Coagulation and complement in antiphospholipid syndrome Thromb Res. 2017 Oct;158:149-151
- Paiva-Lopes MJ, Delgado Alves J. Psoriasis-associated vascular disease: the role of HDL. J Biomed Sci. 2017 Sep 14;24(1):73
- Peres J, Martins R, Delgado Alves J, Valverde A. Rituximab in generalized myasthenia gravis: Clinical, quality of life, and cost–utility analysis Porto Biomed. J. 2017.http://dx.doi.org/10.1016/j.pbj.2017.02.002
- Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Žigon P, Ambrožič A, Tomšič M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017 Mar;26(3):266-276. doi: 10.1177/0961203316660203
- Marques A, Rodrigues AM, Romeu JC, Ruano A, Barbosa AP, Simões E, Águas F, Canhão H, Alves JD, Lucas R, Branco JC, Laíns J, Mascarenhas M, Simões S, Tavares V, Lourenço O, da Silva JA. Multidisciplinary Portuguese recommendations on DXA request and indication to treat in the prevention of fragility fractures. Acta Reumatol Port 2016;41(4):305-321.
- Ames, P.R., Guardascione, M., Batuca, J.R., Arcaro, A., Gentile, F.and Amitrano, L. Nitric oxide metabolites, nitrative stress, and paraoxonase activity in hepatopulmonary syndrome. Scand J Gastroenterol. 2016 Jan;51(1):73-7.
- Paula FS, Ferreira I, Amaral MC, Delgado Alves J. Systemic sclerosis-related changes on nailfold videocapillaroscopy in genetic and metabolic myopathies. Rheumatology (Oxford). 2016 Oct;55(10):1911-2
- Ames PR, Margaglione M. Incidental splanchnic vein thrombosis: preliminary registry data. Lancet Haematol 2016; 3(6):e256-7.
- Caetano J, Pereira F, Oliveira S, Delgado Alves J. IgA-dominant postinfectious glomerulonephritis induced by methicillin-sensitive Staphylococcus aureus. BMJ Case Reports 2015; doi:10.1136/bcr-2014-208513
- Caetano J, Delgado Alves J. Heart rate and cardiovascular protection Eur J Intern Med. 2015 May;26(4):217-22
- Fernandes das Neves M, Oliveira S, Amaral MC, Delgado Alves J. Treatment of systemic sclerosis with tocilizumab. Rheumatology (Oxford). 2015 Feb;54(2):371-2
- Sokoll KB, Batuca J, Lopez LR, Hensor E, Emery P, Delgado Alves J, Ames PRJ. Effects of Atorvastatin on Atherosclerosis and Atherogenesis in Systemic Lupus Erythematosus: A Pilot Study ISRN Immunology. 2014 Article ID 29523
- Fernandes das Neves M, Oliveira S, Amaral Marta C, Delgado Alves, J. Immune-mediated necrotizing myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide BMJ Case Rep. 2015. doi: 10.1136/bcr-2014-206250
- Cunha L, Marcelino G, Amaral MC, Delgado Alves J. Magnesium – association with inflammation and renal disease in systemic lupus erythematosus Port J Nephrol Hypert 2015; 29(4): 323-331
- Sokoll, K. B., Batuca, J., Lopez, L. R., Hensor, E., Emery, P., Delgado Alves, J., & Ames, P. R. J. Effects of Atorvastatin on Atherosclerosis and Atherogenesis in Systemic Lupus Erythematosus: A Pilot Study. ISRN Immunology 2014; Article ID 295239, 7 p. https://doi.org/10.1155/2014/295239.
- Paula FS, Alves JD.Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biologics 2014;8:1-12
- Ames PR, Batuca JR, Muncy IJ, De La Torre IG, Pascoe-Gonzales S, Guyer K, Matsuura E, Lopez LR. Aspirin insensitive thromboxane generation is associated with oxidatve stress in type 2 diabetes mellitus. Thromb Res 2012; 130:350-4.
- Alves JD, Marinho A, Serra MJ. Tocilizumab: is there life beyond anti-TNF blockade? Int J Clin Pract 2011; 65(4):508-13.
- Neves M, Alves JD. Factors implicated in the generation and persistence of long-lived plasma cell-mediated autoimmunity. Autoimmun Rev 2011; 10(7):375-82.
- Ferreira I, Neves M, Alves JD. Atherosclerosis risk in antiphospholipid syndrome. Int J Clin Rheum 2011; 6(5): 583-593.
- Ames PRJ, Ortiz-Cadenas A, Garcia-de la Torre I, Nava A, Oregon-Miranda A, Batuca JR, Kojima K, Lopez LR, Matsuura E. 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 2010; 10: 292-299.
- Ames PR, Batuca JR, Ciampa A, Iannaccone L, Delgado Alves J. Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome. J Rheumatol 2010; 37(12):2523-30.
- Amaral M, Favas C, Delgado Alves J. Persistency of low levels of anticardiolipin and anti-beta2 glycoprotein1 in thrombosis. Eur J Intern Med 2010; 21(2):101-3.
- Ames PR, Matsuura E, Batuca JR, Ciampa A, Lopez LL, Ferrara F, Iannaccone L and Delgado Alves J. High-density lipoprotein inversely relates to its specific auntoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome. Lupus 2010; 19(6):711-6.
- Ames PR, Margaglione M, Mackie S, Alves JD. Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost 2009; 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. Antiphospholipid antibodies and atherosclerosis: insights from systemic lupus erythematosus and primary antiphospholipid syndrome. Clin Rev Allergy Immunol 2009; 7(1):29-35.
- Batuca JR and Delgado Alves J. C-reactive protein in systemic lupus erythematosus. Autoimmunity 2009. 42(4):282-5.
- Batuca JR, Amaral MC and Delgado Alves J. Humoral Mechanismof Atherogenesis. Ann N Y Acad Sci 2009; 1173:401-408.
- Batuca JR, Ames PR, Amaral MC, Favas C, Isenberg DA and Delgado Alves J. Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus. Rheumatology (Oxford) 2009; 48(1):26-31.
- Amaral MC, Alves JD. Pathogenesis of multi-organic failure in autoimmune diseases.Autoimmun Rev 2009; 8(6):525-8.
- Pereira SA, Batuca JR, Caixas U, Branco T, Delgado-Alves J, Germano I, Lampreia F and Monteiro EC. Effect of efavirenz on high-density lipoprotein antioxidant properties in HIV-infected patients. Br J Clin Pharmacol 2009; 68(6):891-7.
- Ames PR, Antinolfi I, Ciampa A, Batuca JR, Scenna G, Lopez LR, Delgado Alves J, Iannaccone L and Matsuura E. Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease? Rheumatology (Oxford) 2008; 47(12):1832-7.
- Alves JD, Steinhagen-Thiessen E, Darioli R, Hostalek U, Vogt A. 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 2008; 24(10):2815-20.
- Ehrenstein MR, Alves JD. Antibodies and other biomarkers - pathological consequences (2). Lupus 2008; 17(3):256-8.
- Batuca JR, Ames PRJ, Isenberg DA, Delgado Alves J. Antibodies toward High-Density Lipoprotein Components Inhibit Paraoxonase Activity in Patients with Systemic Lupus Erythematosus. Ann N Y Acad Sci 2007; 1108 (1), 137–146.
- Margarita A, Batuca J, Scenna G, Delgado Alves J., Lopez L, Iannaccone L, Matsuura E, Ames PRJ. Subclinical Atherosclerosis in Primary Antiphospholipid Syndrome. Ann N Y Acad Sci 2007; 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. Antibodies against beta2-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome. Clin Dev Immunol 2006; 13(1):1-9.
- Alves JD, Clapp BR, Stidwill R, Chen PP, Hingorani AD, Singer M, Isenberg DA. Human monoclonal IgG anticardiolipin antibodies induce nitric oxide synthase expression. Atherosclerosis 2006; 185(2):246-53.
- Ames PR, Iannaccone L, Alves JD, Margarita A, Lopez LR, Brancaccio V. Factor XIII in primary antiphospholipid syndrome.J Rheumatol 2005; 32(6):1058-62.
- Delgado Alves J, Mason LJ, Ames PR, Chen PP, Rauch J, Levine JS, Subang R, Isenberg DA. Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model. Rheumatology (Oxford) 2005; 44(10):1238-44.
- Delgado Alves J, Radway-Bright EL, Lee S, Grima B, Hothersall J, Ravirajan CT, Isenberg DA. Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women. Lupus 2005; 14(5):373-80.
- Delgado Alves J, Inanc M, Diz-Kucukkaya R, Grima B, Soromenho F, Isenberg DA. Thrombotic risk in patients submitted to splenectomy for systemic lupus erythematosus and antiphospholipid antibody syndrome-related thrombocytopenia. Eur J Intern Med 2004; 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. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004; 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. Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol 2003; 23(5):377-83.
- Alves JD, Grima B. Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep 2003; 5(5):383-90.
- Alves JD, Ames PR. Atherosclerosis, oxidative stress and auto-antibodies in systemic lupus erythematosus and primary antiphospholipid syndrome. Immunobiology 2003; 207(1):23-8.
- Delgado Alves J, Kumar S, Isenberg DA. 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) 2003; 42(7):893-9.
- Delgado Alves J, Ames PR, Donohue S, Stanyer L, Nourooz-Zadeh J, Ravirajan C, Isenberg DA. 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 2002; 46(10):2686-94.
- Ames PR, Margarita A, Delgado Alves J, Tommasino C, Iannaccone L, Brancaccio V. Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies. Lupus 2002; 11(4):208-14.
- Internal Medicine Department 4 - Fernando Fonseca Hospital, Amadora, Portugal
- Systemic Immune-mediated Diseases Unit – Fernando Fonseca Hospital, Amadora, Portugal
- Centre for Molecular Pathogenesis – Retrovirus and Associated infections unit (CPM-URIA), Faculty of Pharmacy – University of Lisbon, Portugal
- Centre for Haemostasis and Thrombosis St George’s Healthcare, University of London, United Kingdom
- Centre for Rheumatology Research, University College London, United Kingdom
- Department of Biochemistry, University of Okayama, Japan
- Dipartimento di Medicina e Scienze della Salute, Università del Molise, Italy
- Tropical Diseases Unit and Centre of Malaria and Tropical Diseases , IHMT, Portugal
- Neo-vascularization Unit, Molecular Medicine Institute, Portugal