Immunopathology of desialylation: human plasma lipoprotein(a) and circulating anti-carbohydrate antibodies form immune complexes that recognize host cells

Abstract

Human plasma lipoprotein(a) [Lp(a)], the dominant lipoprotein in atherosclerotic plaques, contains an apo(a) subunit of variable size linked to the apoB subunit of a low-density lipoprotein (LDL) molecule. Circulating lipoprotein immune complexes (ICs) assayed by ELISA using microplate-coated anti-apo(a) or anti-apoB antibody for capture and peroxidase-labelled anti-human immunoglobulins as probe consisted mostly of Lp(a) despite several-fold excess of LDL over Lp(a) in plasma. Microplate coating of plasma lipoprotein IC and probing with antibodies to apo(a) and apoB also revealed negligible presence of LDL compared to Lp(a). Peanut agglutinin specific to desialylated O-glycans bound significantly more to Lp(a) recovered after urea dissociation of IC than to free Lp(a). Plasma lipoproteins separated by ultracentrifugation and desialylated by neuraminidase formed IC with naturally occurring antibodies in normal plasma. These de novo ICs agglutinated desialylated but not normal human RBC in proportion to the polyagglutinin antibody titre of plasma used, suggesting availability of multiple unoccupied binding sites on the participating antibodies even after IC formation. Agglutination was inhibitable by galactosides and decreased 4-8 fold if precursor lipoprotein was selectively depleted of Lp(a), showing agglutinating ICs were contributed mainly by desialylated Lp(a) and galactose-specific antibodies. IC was 2 fold more agglutinating if lipoproteins used contained smaller rather than larger Lp(a) molecules of the same number. Small size/high plasma concentration Lp(a) phenotype and neuraminidase-releasing diseases including diabetes are risk factors for vascular disorders. Results suggest a possible route of Lp(a) attachment to vascular cells that offer terminal galactose on surface glycans following desialylation.

The Association of Lipoprotein(a) and Circulating Monocyte Subsets with Severe Coronary Atherosclerosis

“…The physiological role of Lp(a) as well as the mechanisms that contribute to its high atherogenicity are ambiguous. It is assumed that the formation of Lp(a)-containing circulating immune complexes [24] and their interaction with macrophages [25] may be possible pathogenetic mechanisms leading to the development of inflammation in the vessel wall. The association of autoAbs to Lp(a) as well as the lymphocyte activation marker sCD25 with the presence and severity of coronary atherosclerosis that we previously showed [19] may indicate the contribution of Lp(a) to atherogenesis by the activation of humoral and cellular immunity.…”

Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment

“…Much effort has been put into defining the physiological role of apo(a), but its exact mechanism of action has not been determined. Experimental studies demonstrate regulatory action of apo(a) in inflammation and wound healing as well as a modulatory role in the cholesterol efflux capacity of cells [ 41 , 42 , 43 ].…”

The known unknowns of apolipoprotein glycosylation in health and disease

“…Desialylation exposes underlying galactose moieties in N- and O- glycans, making ApoA(a) a ligand for tissue lectin galectin-1 and circulating anti-glycan antibodies ( Chellan et al., 2007 ; Kalaivani and Appukuttan, 2014 ; Mandagini et al., 2013 ; Sabarinath et al., 2014 ). Interactions with tissue galectin lead to foam cell formation in macrophages and anti-glycan antibody bound-Lp(a) immune complex increases the propensity of Lp(a) to be deposited on the vessel wall and trigger antibody-dependent cytotoxicity and atheroma formation ( Sabarinath and Appukuttan, 2015 ). Similarly, glycans on Apo(a) are important for anti-angiogenic function of Lp(a).…”