Autoimmune Diseases

cal tumor manifestation or diagnostic detection. This has been shown in 7 of the 39 patients whose serum samples were available. In 4 patients only response A could be seen. In one patient response B and in two patients response C was detected 41,24 and 25 months before disease manifestation. Furthermore, we found a significantly higher frequency of p53 AAb in uranium miners compared with blood donors (p = 0.008). Taken together, there are important hints of a predictive value of p53 AAb regarding tumor development:

(1) these relatively cancer-specific AAb are detectable months to years before disease manifestation [31-34];

(2) the frequency of p53 AAb is significantly higher in risk groups for lung cancer compared to healthy blood


Hepatocellular carcinoma: anti-cyclin B1 in 15%, anticyclin A in 1%, anti-CDK2 in 1% [42]

Found in a patient with bladder and metastatic lung cancer [44]

Retrospective study of patients selected on the basis of a particular autoantibody specificity: association with cancer and other disorders involving increased cell proliferation [49]

Found in hepatocellular carcinoma [55]

Found in a patient with HCC [56]

Found in a patient with HCC [56]

Found in patients with HCC, lung cancer and dysgerminoma [56]

ANA specificity changed to HCC1 in a patient with liver cirrhosis who progressed to HCC [57]

donors as has been shown for uranium miners heavily exposed to alpha radiation [34], The higher frequency in older male blood donors compared to younger men or women (Table 3) may also be explained in part by a higher prevalence of "silent" tumors (prostate, lung) in older men. Unfortunately, we had no information about the smoking habits of these blood donors; (3) in the risk group of uranium miners without detectable tumor at time of serum analysis, the highest frequency of p53 AAb could be found in patients with a further increase of risk: scleroderma patients and miners with large silicotic opacities [35, 36]; and (4) in the follow-up of the autoimmune response in two miners, signs of epitope spreading could be observed.

Involved in cell cycle progression (Gl/S; G2/M); Increased expression in many cancers [39^12]

Member of the TLE (tranducin-like enhancer of split) protein family, many of which take part in regulating nuclear functions associated with the cell cycle [45]

Cell cycle-regulated centromere protein that appears to play an important role in mitosis [46, 47],

Nuclear enzyme that catalyzes the interconversion of topological forms of dsDNA (required for DNA replication, recombination and chromosome segregation); marker for proliferating cells [53]; target of antitumor drugs [54]; might be directly involved in oncogenesis [55]

Nucleolus organizer region proteins (89 and 93 kDa) involved in RNA polymerase I transcription

Protein of the nucleolar U3-RNP involved in pre-ribosomal RNA processing

Nucleolar protein involved in ribosome maturation and cell proliferation

64 kDa nuclear protein probably involved in splicing of pre-mRNA [57]

Therefore, p53 AAb should be determined in larger risk groups (e.g., smokers) for early diagnosis and therapy of cancer. On account of the low frequency, other possible autoimmune tumor markers, e.g., AAb against L-myc, pi85HKR~2/neL1 or some of those described below, should be further evaluated.

4. Autoantibodies to proliferation associated antigens other than oncoproteins

Proteins involved in cell-cycle regulation/progression and mitosis, but also other proteins involved in cellular processes that might be increased in unregulated cell growth, may drive autoimmune responses in tumor patients (Table 4). AAb against nuclear and cytoplasmic cell-cycle regulated or regulating proteins and proteins involved in splicing processes and ribosome biosynthesis could be detected in tumor patients. This supports previous observations that AAb responses against intracellular antigens are often directed at molecules involved in cellular biosynthetic or proliferative functions [37].

Cyclins and cyclin-dependent kinases (CDK) are a group of cell-cycle regulating proteins acting at different points of the cell-cycle progression. They are amplificated and overexpressed in many tumors [38— 41], Covini et al. [42] showed that AAb to cyclin Bl, cyclin A and CDK2 are present in sera of patients with hepatocellular carcinomas (HCC) in 15, 1 and 1%, respectively. Furthermore, anticyclin Bl antibodies could be found in patients with a higher risk of HCC development, e.g., in patients with chronic hepatitis (in 1 out of 70 cases) and cirrhosis (in 3 out of 70 cases), suggesting a predictive relevance of these AAb. To date, there are no reports about aberrant expression of cyclin B1 in HCC tissue. If an antigen-driven process caused by cyclin B1 overexpression results in AAb production, cyclin B1 antibodies should be also found in other tumors, such as leukemias, breast and colorectal cancers [39-41],

Sera of cancer patients have been shown to be useful reagents for identifying new cellular proteins possibly involved in tumor development. A new cell-cycle-specific DNA-binding nuclear protein has been identified using autoimmune serum of a patient with bladder and metastatic lung cancer [43, 44], This serum produced a previously undescribed cell-cycle-related staining pattern on HEp-2 cells. According to the cell-cycle distribution the detected antigen was provisionally named SG2NA (S/G2 nuclear antigen). The structural analyses reveal that SG2NA belongs to the TLE (tranducin-like enhancer of split) protein family, many of which take part in regulating nuclear functions associated with the cell cycle [44]. The centromere protein F is another novel proliferation associated and cell-cycle-dependent protein detected by autoimmune sera. Casiano et al. identified a centromere protein provisionally designated p330d (doublet polypeptide of 330 kDa), which accumulates in the nuclear matrix during S phase, reaching maximum levels during G2 phase and localized at the centromeres during prophase and metaphase and at the central spindle and midbody regions during anaphase and telophase [45]. The same protein, designated centromere protein F (CENP-F), was identified by Rattner et al. [46] using a serum from a lung cancer patient. Already in 1986, an AAb called MSA 3 with a staining pattern of p330d/CENP-F was described by Humbel [47]. A retrospective analysis of the clinical features of the 36 CENP-F autoantibody positive patients showed that 22 of these (=61%) had neoplasms of various types [48]. The predominant types were breast (9 cases) and lung cancer (5 cases). Other types of cancer included stomach (2 cases), tracheal, tonsi-lar, nasopharyngeal, ovarial, HCC, and Waldenstrom's macroglobulinemia (1 case each). The other diseases were also associated with abnormal cell proliferation: chronic inflammatory diseases of liver, intestinum, pancreas and joints (8 cases), chronic renal allograft rejection (2 cases), SLE (2 cases) and undifferentiated connective tissue disease (1 case). The findings of this retrospective study of patients selected on the basis of a particular AAb specificity point to the probability that anti-CENP-F autoimmunity could be related to increased or abnormal cell proliferation, but important conclusions regarding disease associations cannot be drawn. A screening of several hundred sera of unse-lected cancer patients by indirect immunofluorescence on HEp-2 cells showed that the prevalence of CENP-F antibodies detectable with this method is very low (<0.1%) [49, 50], By analyzing the sera of 1365 patients with various tumors we found one CENP-F antibody and two antibodies with a CENP-F like pattern in patients with breast cancer. Furthermore, other AAb to mitosis-associated or cell-cycle-dependent expressed antigens (e.g., staining of the midbody region, of the chromatin only in mitotic cells, NuMA-like staining, variable staining in interphase nuclei) were seen in another 27 patients, but not in blood donors

[50]. Of the 73 uranium miners with lung cancer one had NuMA/centrophilin antibodies. Overall, in our screening of sera of 1438 tumor patients by indirect immunofluorescence on HEp-2 cells we found middle to high titred AAb showing mitosis associated/cell-cycle-dependent patterns in 31 patients with cancer (2.2%). This may be a further hint that autoimmunity to proteins related to increased or abnormal cell proliferation may be induced in cancer patients. Indeed, the results of Rattner et al. [48] and Landberg et al.

[51] suggest that the CENP-F protein may drive the AAb response. DNA topoisomerase II, another protein which is selectively enriched in the centromere of metaphase chromosomes, has been shown to be a marker for proliferating cells and a target of antitumor drugs [52, 53] and might be directly involved in oncogenesis [54]. Autoantibodies have been described in patients with HCC [55].

The screening of sera from tumor patients by immunofluorescence on tumor cell monolayer led also to the identification of autoantigens not involved in cell-cycle regulation or mitosis, but in splicing processes and ribosome biosynthesis [56-58], Antinuclear antibodies (ANA) have been found in a higher frequency in HCC patients (31 %) than in patients with chronic hepatitis or liver cirrhosis (13%) or in healthy subjects (5%) [56]. Most prevalent in HCC are AAb showing nucleolar or speckled pattern. Three of the autoantigens detected by antinucleolar antibodies have been identified as NOR-90/hUBF (human upstream binding factor), the U3-RNP associated fibrillarin and protein B23 (nucleophosmin), proteins engaged in some aspect of ribosome biosynthesis, a process that might be increased in unregulated cell growth [56], A novel nuclear autoantigen with splicing factor motifs, provisionally designated HCC1, was identified with an AAb developed in a patient with liver cirrhosis who progressed to HCC [57], Covini et al. [59] found 3 AAb in 204 HCC patients and 2 AAb in 194 chronic virus hepatitis patients that co-localized with non-snRNP splicing factor SC35, but showed different responses to MOLT-4 proteins in immunoblot. This leads to the suggestion that different proteins probably involved in mRNA splicing might be antigenic targets in HCC and patients with a higher risk of HCC development.

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