Native preparations of evolutionarily conserved intracellular macromolecules are generally nonimmunogenic when injected in soluble form. However, vigorous immune responses were observed when common autoantigens such as histones, DNA or Sm antigen, or homologous liver homogenate were noncovalently coupled to latex beads prior to injection into mice. Antibody response to histone beads displayed immunologic memory and required a functional thymus, suggesting that T-helper cells were involved. However, bead-elicited autoantibodies could be distinguished from true autoantibodies in that they reacted with denatured, minor, or foreign components of the preparations or to regions unexposed in the native form of the immunogen. This response contrasted with spontaneously arising autoantibodies accompanying graft-versus-host (GVH) disease in the same strain of mice which preferred native nucleoprotein conformations within nuclei, chromatin, or DNA-histone complexes. Histone beads elicited antihistone antibodies displaying a sustained IgM isotype in contrast to spontaneously arising autoantibodies in GVH disease which were predominantly IgG. These studies demonstrate that immunization with autoantigens does not usually elicit true autoantibodies and suggest that lymphocyte populations responsible for pseudoautoimmune responses are different from autoantibody-producing cells. We speculate that if autoimmunity is driven by particulate forms of in vivo self-materials, additional factors are required for breaking the natural tolerance to native conformations within the immunogen.