prolonged half-life of the protein. It was suggested that the Proteins expressed by plasmids encoding human latter feature of persistence or resistance to degradation gave cyclins and cyclin-dependent kinase 2 (CDK2) were used rise to the humoral antibody response. Another possibility as antigens in immunoblotting. Fifteen of 100 patients was the finding that the abnormally regulated protein was with hepatocellular carcinoma (HCC) were found to complexed to heat shock protein 70, possibly enhancing the have autoantibodies reactive with cyclin B1 and with a immunogenicity of p53. 17
40-kd degradation product of cyclin B1-glutathione-S-
The case for antigen-driven autoantibody responses in cantransferase (GST) fusion protein. Only one serum was cer patients is further supported by the increasing number found to react with cyclin A and another single serum of studies on paraneoplastic neurological degenerative (PND) with CDK2 but no antibodies were detected to cyclin D1 syndromes associated with lung, breast, and ovarian canand E. The basis for autoimmune responses to cyclin cer. [22][23] Such PND syndromes with symptoms related to dis-B1 in HCC are unknown at the present time but the orders of the nervous system are characterized by autoantipossibilities might include aberrations in cyclin B1 regubodies which appear to react preferentially with nuclear and lation leading to altered product or its expression which cytoplasmic proteins of neuronal cells although the malignanresulted in stimulation of immune reactions. (HEPATOLcies involve non-neuronal tissue. One of the antigens which OGY 1997;25:75-80.)
has been identified belongs to a family of proteins with three RNA-binding protein motifs. The prototype of this Autoantibodies directed against intracellular antigens that family is the Drosophila elav (embryonic lethal abnormal viare either nuclear or cytoplasmic in location have long been sion) gene product, which is a protein vital in the early develreported in cancer. [2][4][6] Autoantibodies against intracellular opment of the central nervous system. Another neuronantigens are also a prominent feature of several systemic specific autoantigen in PND disorders called Nova-1 has also autoimmune diseases including systemic lupus erythematobeen shown to be a RNA-binding protein. 23 Autoantibodies sus and scleroderma. In the latter diseases, extensive studies in PND disorders have been suggested to be associated with on the nature of autoantigens and on the molecular and geclinical syndromes, 22,23 but generally autoantibodies in rheunetic structure of autoantibodies have given rise to the hymatic diseases have not been thought to be related to clinical pothesis that many spontaneously occurring autoantibodies symptoms. 13 are selected by an antigen-driven immune response. [11][12][13][14][15] Our interest in autoantibodies in cancer was stimulated Many of these autoantigens are components of larger subcelby the observation that in hepatocellular carcinoma (HCC), lular particles involved in important cell functions including there was a significantly increased prevalence of antinuclear DNA replication, transcription, pre-messenger RNA splicing, antibodies compared with the precursor conditions cirrhosis and translation. 13 or chronic hepatitis (31% vs. 13%) indicating that with These observations concerning the possible mechanisms transformation to malignancy, there appeared to be novel underlying induction of autoantibodies may be relevant to immune responses to some cellular antigens. In some pacancer in view of recent studies on autoantibodies to the tutients, liver malignancy was preceded by or concomitant with mor suppressor gene product p53 in certain malignancies. seroconversion from antibody negative to antibody positive Antibodies to p53 were detected in 13% of patients with lung status 29 as though the novel immune responses might be cancer and 10% of patients with breast cancer. 16,17 All the driven by proteins involved in the transformation process. antibody-positive patients had p53 missense mutations that One such nuclear antigen that has been cloned is a nuclear resulted in loss of function and in increased stability and protein with structural motifs found in the serine, arginine family of alternative splicing factors. There has been increasing evidence that perturbation of cell cycle regulation is one of the factors leading to cancer, [34][35] Abbreviations: PND, paraneoplastic neurological degenerative; HCC, hepatocellular carand there are many studies showing amplification and overcinoma; CDK2, cyclin-dependent kinase 2; PCNA, proliferating cell nuclear antigen; PBS, expression of cyclin genes. [39][40][41][42] Working on the premise that phosphate-buffered saline; Ig, immunoglobulin; GST, glutathione-S-transferase; pGEX, plasmid Gex; IPTG, isopropyl-b-thiogalactopyranoside; WB, Western blotting; NHS, normal in some patients with cancer, dysregulation of cyclins may human serum. result in such proteins stimulating autoantibody responses, From the 1 W. M. Keck Autoimmune Disease Center, Department of Molecular & Experiwe have analyzed the sera of HCC patients for antibodies to mental Medicine;