OBJECTIVES To review the autoimmune and rheumatic manifestations of patients with malignancy. METHODS A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes. RESULTS Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of ( a ) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). ( b ) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. ( c ) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy. CONCLUSION Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.

https://ard.bmj.com/content/annrheumdis/60/5/433.full.pdf

Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies

The indirect immunofluorescence assay (IIFA) on HEp-2 cells is widely used for detection of antinuclear antibodies (ANA). The dichotomous outcome, negative or positive, is integrated in diagnostic and classification criteria for several systemic autoimmune diseases. However, the HEp-2 IIFA test has much more to offer: besides the titre or fluorescence intensity, it also provides fluorescence pattern(s). The latter include the nucleus and the cytoplasm of interphase cells as well as patterns associated with mitotic cells. The International Consensus on ANA Patterns (ICAP) initiative has previously reached consensus on the nomenclature and definitions of HEp-2 IIFA patterns. In the current paper, the ICAP consensus is presented on the clinical relevance of the 29 distinct HEp-2 IIFA patterns. This clinical relevance is primarily defined within the context of the suspected disease and includes recommendations for follow-up testing. The discussion includes how this information may benefit the clinicians in daily practice and how the knowledge can be used to further improve diagnostic and classification criteria.

https://ard.bmj.com/content/annrheumdis/78/7/879.full.pdf

Clinical relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns (ICAP) perspective

Autoantibodies are often detected in hepatocellular carcinoma (HCC), and these responses may represent recognition of tumor Ags that are associated with transformation events. The identities of these Ags, however, are less well known. Using serological analysis of recombinant cDNA expression libraries (SEREX) from four HCC patients, we identified 55 independent cDNA sequences potentially encoding HCC tumor Ags. Of these genes, 15 are novel. Two such proteins, HCA587 and HCA661, were predominantly detected in testis, but not in other normal tissues, except for a weak expression in normal pancreas. In addition to HCC, these two Ags can be found in cancers of other histological types. Therefore, they can be categorized as cancer-testis (CT) Ags. Two other Ags (HCA519 and HCA90) were highly overexpressed in HCC and also expressed in cancer cell lines of lung, prostate, and pancreas, but not in the respective normal tissues. Four other Ags were identified to be expressed in particular types of cancer cell lines (HCA520 in an ovarian cancer cell line, HCA59 and HCA67 in a colon cancer cell line, HCA58 in colon and ovarian cancer cell lines), but not in the normal tissue counterpart(s). In addition, abundant expression of complement inactivation factors was found in HCC. These results indicate a broad range expression of autoantigens in HCC patients. Our findings open an avenue for the study of autoantigens in the transformation, metastasis, and immune evasion in HCC.

Large Scale Identification of Human Hepatocellular Carcinoma-Associated Antigens by Autoantibodies

Autoantibodies present in the serum of patients with a variety of inflammatory diseases have proven useful as diagnostic markers and as probes with which to elucidate biochemical and signaling pathways. The mechanisms governing the generation of autoantibodies remain elusive, constituting a critical missing link in our understanding of rheumatologic illnesses. Several lines of experimentation in recent years have strongly implicated events surrounding cell death in this process. This review will address the potential role played by death-specific modifications of autoantigens in bypassing tolerance to highly conserved autoantigens, including nucleic acids, lipids, and proteins.

/pdf/death-autoantigen-modifications-and-tolerance-4x9aqhw642.pdf

Death, autoantigen modifications, and tolerance

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

Objectif : Etudier les caracteristiques cliniques de patients qui ont des auto-anticorps de la proteine CENP-F du centromere et la frequence des auto-anticorps CENP-F chez des patients qui ont diverses maladies. Conception : Etude clinique et serologique retrospective. Methodes : On a identifie 36 patients atteints d'anti-CENP-F au moyen d'un trace caracteristique d'immunofluorescence indirecte (IFI) sur les cellules HEp-2. On a etudie aussi 50 patients atteints d'un melanome, 50 d'un cancer du sein, 10, d'un cancer du poumon, 354 souffrait de sclerodermie generalisee, 120, de lupus erythemateux dissemine et 50, de polyarthrite rhumatoide. On a produit des proteines recombinantes a partir de clones de 5 CENP-F de l'ADNc representant les acides amines 2192-3317 (p-F1), 5561-7126 (p-F2), 5892-6883 (p-F3), 7538-10116 (p-F4) et 9242-10096 (p-F5). On a etudie la presence de l'antigene CENP-F dans une souche de cellules de cancer du sein, des cryosections de cancer du sein, des tissus normaux du sein et des amygdales. Resultats : Vingt-deux des 36 patients qui avaient des anticorps CENP-F avaient des neoplasmes; on a diagnostique surtout des cancers du sein (9/22) et du poumon (5/22). Trente-trois serums etaient disponibles pour une etude plus poussee. Lorsqu'on en a analyse la reactivite aux peptides recombinants, les serums de 21 patients sur 21 qui avaient des neoplasmes et de 5 patients sur 12 qui avaient d'autres maladies ont lie le peptide p-F4 C-terminal. Lorsqu'on a etudie le tiers terminal du peptide p-F4 (p-F5), on n'a pas detecte de difference significative dans la tendance a la reactivite. Comme comparaison, la frequence de la reactivite avec des peptides representant d'autres domaines du CNP-F a ete inferieure a celle de la reactivite avec le p-F4 (p-F2 > p-F3 > p-F1). On n'a pas trouve d'auto-anticorps CENP-F dans aucun des serums temoins provenant de patients atteints de lupus erythemateux dissemine, de polyarthrite rhumatoide ou de sclerodermie generalisee, ou dans des serums non selectionnes provenant de diverses tumeurs malignes. On a identifie des antigenes CENP-F dans des tissus de cancer du sein, mais rarement dans des tissus normaux. Conclusions: Une proportion elevee d'individus qui ont des anticorps CENP-F ont des neoplasmes et ces serums presentent un biais en faveur de la reactivite avec des determinants dans le domaine carboxyle terminal du CENP-F. Les antigenes CENP-F semblent tres frequents dans les tumeurs malignes.

Whitehead Cm

Papers

High frequency of neoplasia in patients with autoantibodies to centromere protein CENP-F.