Broad Alterations of Self-Reactive Antibody-Repertoires of Plasma IgM and IgG in B-Cell Chronic Lymphocytic Leukemia (B-CLL) and B-CLL Related Target-Restricted Autoimmunity

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a malignant CD5⁺ B-cell clone. The leukemic clone commonly expresses IgM antibodies exhibiting reactivity toward a wide range of self-antigens. However, B-CLL associated autoimmunity is typically restricted to self-antigens expressed by blood cells, and mediated by IgG autoantibodies of polyclonal origin. In the present study, we addressed the question whether self-reactive antibody repertoires of plasma IgM and IgG are disturbed by monoclonal immunoglobulins of B-CLL patients, and whether antibody repertoires of patients exhibiting B-CLL associated target-restricted autoimmune disease (AID) differ from those of B-CLL patients without AID. We investigated antibody repertoires at a global level, using a technique of quantitative immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We demonstrate that self-reactive antibody repertoires of plasma IgM and IgG are broadly altered in patients with B-CLL, that alterations in self-reactive antibody repertoires are not restricted to B-CLL patients exhibiting AID, and that target-restricted autoimmunity in B-CLL patients is associated with altered antibody repertoires not restricted to the target organ. We conclude that monoclonal alterations of immunoglobulin production in B-CLL are associated with broad defects of self-reactive antibody repertoires. Our observations suggest that the application of therapeutic FVIg preparations might influence B-CLL by restoring normal self-reactive antibody repertoires in plasma.

Key Words:

• B-CLL
• autoimmunity
• antibody repertoires
• quantitative immunoblotting