Immune mechanisms in atherosclerosis

Atherosclerosis is a multifactorial chronic inflammatory disorder. Humoral immune factors as anticardiolipin antibodies (aCL), anti-oxLDL antibodies, circulating immune complexes (CICs), and proinflammatory cytokines such as IFN-gamma, TNF-alpha and EL-1beta have been implicated in atherogenesis. We have investigated these humoral factors in disorders prone to atherosclerotic vascular damage such as type 1 diabetes mellitus, stroke, rheumatoid arthritis and in individuals with high LDL-cholesterol levels, using prospective and retrospective study designs.

We could demonstrate that both the levels and prevalence of IgG-aCL and IgA-aCL were increased in patients with diabetes and rheumatoid arthritis. The IgM-aCL levels were higher in diabetic patients with vascular complications, in persons who developed stroke and in rheumatoid arthritis. Antibodies against oxLDL were not increased in patients with diabetes and stroke, using both Cu++ oxidized and NMA modified LDL as antigens. In contrast, levels and prevalence of all three isotypes of anti-oxLDL were increased in patients with rheumatoid arthritis, particularly those who had MI.

CICs were higher in patients with diabetes, and especially increased in patients with vascular complications. The concentrations of aCL were relatively higher in CICs than in serum. The concentration and prevalence of CICs were higher in patients with null alleles of C4A (C4A*QO). Patients with vascular complications had more often C4A*QO than C4B*QO.

Genetic polymorphism of cytokines IL- beta, its antagonist IL-1Ra and TNF-alpha have been associated to autoimmune and inflammatory disorders. There was no general association of these cytokine gene variants to the development of stroke. However, hypertensive male individuals bearing the low secretory allele Al of TNF-alpha had a higher risk to develop stroke.

Individuals with high cholesterol levels (>5.5 mmol/L) had a increased number of IL-4 producing cells and decreased numbers of IEFN-gamma and IL-2 obs producing cells, implicating that hypercholesterolemia modulates the immune response towards a Th2 type.

The mechanism leading to the formation of aCL and the exact mechanism of action of this antibody is incompletely known. However, aCL both in free and in immune-complex form may initiate vascular damage by binding directly to the endothelial cells, phospholipids of platelets, activating the compliment cascade and interfering with the coagulating cascade, thereby promoting thrombosis. CICs are also likely to have an additive effect on atherogenesis. Hypercholesterolemia seems to modulate the immune response towards a Th2 type and may thereby modulate atherogenesis.

List of scientific papers

I. Ahmed E, Nityanand S, Mustafa A, Brismar K, Lefvert AK (1999). "Anti-cardiolipin antibodies and circulating immune complexes in type 1 diabetes mellitus: increased prevalence and relation to vascular complications" Clin Exp Immunol 115(2): 255-9
https://pubmed.ncbi.nlm.nih.gov/9933450

II. 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

III. 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 Västerbotten cohort project" Stroke 31(6): 1289-93
https://pubmed.ncbi.nlm.nih.gov/10835446

IV. Trifunovic Cvetkovic J, Wiklund PG, Ahmed E, Weinhall L, Hallmans G, Lefvert AK (2001). "Gene polymorphisms of IL-1beta, IL-1Ra and TNF alpha: a nested case-referent study of their associations to risk of stroke" (Submitted)

V. Trifunovic Cvetkovic J, Wållberh-Jonsson S, Ahmed E, Rantapää-Dahlqvist S, Lefvert AK (2001). "Increased levels of autoantibodies against oxLDL, MDA-LDL and cardiolipin in patients with rheumatoid arthritis" (Submitted)

VI. Ahmed E, Lefvert AK (2001). "Hypercholesterolemia is associated with a Th1 to Th2 switch of the human immune system" (Manuscript)