Immune responses to the cleavage-associated neoantigens of fibrinogen in man. Identification and characterization of humoral antibodies specific for cleavage fragments.

Abstract

A B S T R A C T Cleavage of human fibrinogen and fibrin by plasmin is associated with modification of native antigenic expression and the exposure of cleavage-associated neoantigenic sites on the derivative molecular fragments.In this study, the presence of humoral antibodies in man to cleavage-associated neoantigens has been demonstrated by primary antigen binding radioimmunochemical assays. Specific binding of radioiodinated human fibrinogen D fragment by serum immunoglobulins was demonstrated in 52 of 59 random normal human sera and was independent of immunoglobulin concentration. Binding was mediated by F(ab')2 fragments of IgG, and specificity for neoantigens was indicated by the capacity of the D fragment but not native fibrinogen to competitively inhibit the antibody. The population distribution of antibody to these cleavage-associated neoantigens indicated the presence of a major group of individuals (77%) with a mean antigen binding capacity of 11.8 pmol/ml serum. Two minor populations with: (a) low or undetectable binding capacities (<6.0 pmol/ml serum) and (b) exhibiting markedly elevated binding capacities (> 18.0 pmol/ml serum) were delineated. Independent of these features, sera could also be readily separated into two groups that differed with respect to relative antibody affinity. The antibodies in most sera exhibited marked heterogeneity of binding affinity, whereas a small group of sera contained antibodies exlhibiting relative homoThis is Scripps Clinic and Research Foundation publication EP-964.

Measurement of Autoantibodies Against Fibrinogen and Fibrin Degradation Products by Enzyme-Linked Immunoassay

“…A high prevalence of autoantibodies interacting with fibrin ogen derivatives has been reported (2). These autoantibodies may occur in healthy subjects, albeit in low titre, and only in a few instances have pathologic consequences been ascribed to them (3)(4)(5).…”

Acquired Inhibitors of Coagulation Factors: Part II

“…[37][38][39][40][41][42][43][44][45][46][47][48] These antibodies are often associated with clinical bleeding, 38,39 but reports of nonclinically relevant antibodies exist. 48 In addition, while low titers of such autoantibodies were found in normal subjects, 40 high inhibitor levels were detected in patients with various disorders and in women with complicated pregnancy. 41,42 Indeed, Kondera-Anasz found an increased rate of fibrinogen antibodies in pregnant and in peripartum women, especially Rh-immunized and with com-plicated pregnancy, compared with nonpregnant women.…”

Fibrinogen Derivatives in Plasma

“…A second distinct neoantigen is present on fibrinogen fragment D (Plow & Edgington, 1973) and this represents a static intramolecular site that is expressed in a uniform equimolar fashion by degradation products containing fragment D (X, Y and D). Sera from normal adults have been shown to contain antibodies specific for cleavage fragments of fibrinogen (Plow & Edgington, 1975). The cleavage associated neoantigenic determinant responsible for eliciting this autoimmune response is similar, but not identical, to the neoantigenic site on fragment D that is recognized by the heterologous immune response of rabbits.…”