Specific expression of PAD4 and citrullinated proteins in lung cancer is not associated with anti-CCP antibody production

Abstract

Anti-citrullinated protein antibodies (ACPAs), produced against citrullinated proteins, are diagnostic and prognostic markers of rheumatoid arthritis (RA). The underlying mechanism that explains the connection of smoking, citrullination [catalyzed by peptidyl arginine deiminases (PADs)] and ACPAs is still unclarified in RA. Thus, we searched for a non-arthritic model in which an increased cell death allows the formation of autoantibodies. Data supporting that lung cancer might be a good candidate are as follows: (i) smoking plays a role in its pathogenesis, (ii) the disease is frequently accompanied by paraneoplastic syndrome, (iii) smoking increases citrullination in the lung, (iv) various types of malignancies are associated with increased citrullination and (v) lung cancer tissue shows similarities with RA synovium. Serum PAD4, rheumatoid factor (RF) and ACPA levels were measured in 42 lung cancer patients; expression of cytokeratin 7 (CK7), PAD4 and citrullinated proteins was visualized in 113 lung cancer tissues. All parameters were analyzed in correlation with smoking history. None of the patients had polyarthritis or autoimmune disease. Significantly increased RF levels were associated with higher PAD4 levels in smoker lung cancer patients compared with non-smokers. Both PAD4 and citrullination immunostaining strongly correlated with that of CK7 in lung cancer, however, did not differ according to smoking history. Two of 30 smoker lung cancer patients had high anti-cyclic citrullinated peptide levels. In conclusion, PAD4 and citrullination may be helpful in distinguishing lung cancer from healthy tissue. Smoking, abnormal serum PAD4 and RF levels may not be sufficient for the production of ACPAs and development of autoimmunity.

Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease

“…All of the protein antigens to which, in their citrullinated forms, the patients in our study had high titre antibodies are present in the lung 25 26. Citrullinated proteins have been identified in lung tissue,11 a finding not exclusive to RA 27. In addition, PAD enzymes, necessary for the conversion of arginine to citrulline in substrate proteins, have also been shown to be present in lung tissue 10 27.…”

“…Citrullinated proteins have been identified in lung tissue,11 a finding not exclusive to RA 27. In addition, PAD enzymes, necessary for the conversion of arginine to citrulline in substrate proteins, have also been shown to be present in lung tissue 10 27. Whether these observations support the possibility of antibody mediated lung tissue damage resulting from a pathogenic interaction between autoantibodies and their cognate citrullinated peptides will require additional mechanistic studies.…”

The lung may play a role in the pathogenesis of rheumatoid arthritis

“…Since it is well known that any inflammation can result in the generation of citrullinated peptides [57,60], it may be that the development of citrullinated peptides alone is not enough to trigger an autoimmune response. Such a possibility was proposed in a study by Baka and colleagues who identified lung tissue elevations of citrullinated peptides and PAD-4 in lung tissue from subjects with lung cancer, although few had serum ACPA elevations [61]. These data suggest other factors may be necessary to generate an autoimmune response to citrullinated peptides present in the lung.…”

Investigating citrullinated proteins in tumour cell lines

“…In recent years, studies have found that PADI4 is markedly over-expressed in a majority of human cancers, suggesting that PADI4 is a putative target for cancer treatment [9-11]. We recently also reported that the PADI4 gene may be a valid susceptibility gene for oesophageal carcinoma [12].…”