Immune mechanisms in atherosclerotic vascular disease

Atherosclerosis has been categorized as an inflammatory disorder, with similar chronic inflammatory conditions found in rheumatoid arthritis. It entails an unregulated accumulation of lipids in the vessel wall, which leads to the development of cardiovascular diseases. The WHO report from 1999 showed that cardiovascular diseases are the major cause of mortality and morbidity in Westernized countries. Antigens found in atherosclerotic lesions, like oxidized LDL or cardiolipin, induce humoral immune factors, such as anticardiolipin antibodies (aCL), antibodies against oxidized forms of LDL, circulating immune complexes (CIC) and pro-inflammatory cytokines, IL-1 beta and TNF alpha.

Anticardiolipin antibodies have been considered as risk factors for arterial and venous thrombotic events and cerebral infarction. Autoantibodies against oxLDL were associated to coronary artery disease, myocardial infarction, peripheral vascular disease, hypertension, pre-eclampsia and diabetes. We have investigated these humoral factors in patients with rheumatoid arthritis (RA) and in individuals who developed stroke using both prospective and retrospective study designs. We showed that the level and prevalence of IgG, IgM and IgA aCL antibodies were increased in RA patients.

RA patients with extraarticular manifestations have increased levels of IgM and lgA compared to patients without these manifestations. In patients who developed stroke level of IgM aCL was slightly increased compared to referents, but aCL could not be considered as an independent predictive marker for stroke. The level and prevalence of all three isotypes of anti-oxLDL antibodies were increased in RA patients, particularly in those who had myocardial infarction, while there was no association to the development of stroke.

We have investigated the polymorphisms of genes of pro-inflammatory cytokines, such as IL-1 beta and TNF alpha and anti-inflammatory IL-1Ra that suppresses the effect of IL-1 Beta. We demonstrated an association of low-secretory allele A1 of TNF alpha to RA. The severity of RA was influenced by carriage of high-secretory allele A2 of TNF alpha. Allele AI of TNF alpha was associated to development of stroke in hypertensive male patients, indicating that males bearing this allele have a higher risk to develop stroke. The study of polymorphisms of IL-1 beta revealed an association of genotype A2A2 to seventy of RA and no association to development of stroke.

The investigation of IL-1Ra gene polymorphisms revealed that genotype A1A2 was decreased in RA patients compared to referents, while A2A3 was increased- In contrast, there was no association of IL-1Ra polymorphisms to the development of stroke. IL-1 beta and IL-1Ra alleles of different haplotypes were compared between RA patients with and without cardiovascular complications. We showed that haplotypes AI+ IL-1 beta/A2+ IL-1Ra and A2+ IL-1 beta/A2+ IL-1Ra were decreased in RA patients with cardiovascular complications, indicating that A2 of IL-1Ra has a protective role by blocking the action of Il-1 beta. Similarly, haplotype A2+ IL-1 beta/A2+ IL-1Ra was more prevalent in normotensive patients who developed stroke.

List of scientific papers

I. Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B, Rantapaa-Dahlqvist S, Lefvert AK (2002). Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. J Rheumatol. 29(2): 212-9.
https://pubmed.ncbi.nlm.nih.gov/11838837

II. Cvetkovic Trifunovic J, Wallberg_jonsson S, Ahmed E, Rantapaa-Dahlqvist S, Lefvert AK (2002). Increased levels of autoantibodies against oxLDL, MDA-LDL and cardiolipin in patients with rheumatoid arthritis. Rheumatology.

III. Wallberg-Jonsson S, Cvetkovic JT, Sundqvist KG, Lefvert AK, Rantapaa-Dahlqvist S (2002). Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis. J Rheumatol. 29(5): 875-82.
https://pubmed.ncbi.nlm.nih.gov/12022343

IV. Cvetkovic Trifunovic J, Wiklund PG, Ahmed E, Weinehall L, Hallmans G, Lefvert AK (2002). Polymorphisms of IL-1beta, IL-1Ra and TNF-alpha genes and risk factor for stroke. [Manuscript]

V. Ahmed E, Trifunovic J, Stegmayr B, Hallmans G, Lefvert AK (1999). Autoantibodies against oxidatively modified LDL do not constitute a risk factor for stroke: a nested case-control study. Stroke. 30(12): 2541-6.
https://pubmed.ncbi.nlm.nih.gov/10582975

VI. Ahmed E, Stegmayr B, Trifunovic J, Weinehall L, Hallmans G, Lefvert AK (2000). Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten cohort project. Stroke. 31(6): 1289-93.
https://pubmed.ncbi.nlm.nih.gov/10835446