46,47 Natural antibodies of the IgM isotype are predominantly pre

46,47 Natural antibodies of the IgM isotype are predominantly present in healthy individuals. Natural IgM has multiple roles in the immune system. They are key to the homeostasis of the immune system, particularly relating to B lymphocytes and autoimmunity. All the tumor-specific antibodies belong nearly exclusively to the IgM class. It makes sense Rapamycin AY-22989 that anti-tumor immunity seems to be a part of natural immunity, and immune memory is not needed and therefore not induced. The detection of natural IgM antibodies against tumor-specific antigens of angiogenesis, such as ANG in osteosarcoma, has raised the possibility of an auto-immune aspect to this disease.43,48,49 Investigators in the European Organization for Research and Treatment of Cancer have been studying marker�CIgM immune complexes, which play a role in diagnosis and prognosis in cancer.

We have recently discovered the occurrence of cancer markers associated with IgM in liver and colorectal cancer, and we have demonstrated that marker�CIgM immune complexes are a novel class of tumor markers with a greater diagnostic potential compared to the corresponding free biomarker (Fig. 3). When detected as IgM complexes, both alpha-fetoprotein (AFP; the conventional serological marker for the detection of hepatocellular carcinoma (HCC)) and squamous cell carcinoma antigen (SCCA; a novel HCC biomarker),50 improved our diagnosis of liver cancer.50�C52 Further evidence of the diagnostic relevance of IgM immune complexes in cancer was also provided by carcinoembryonic antigen (CEA), which is the serological gold standard for the diagnosis of colorectal cancer (CRC).

53 The assessment of CEA�CIgM levels in CRC patients allowed the identification of a much higher number of patients compared to free CEA, and co-determination of both biomarkers increased sensitivity without compromising assay specificity.53 Figure 3. Schematic illustration of the immune response to cancer and development of IgM immune complexes in the bloodstream. To our knowledge, no investigations have been reported on the occurrence of ANG�CIgM immune complexes in the serum of patients with osteosarcoma. It has been established that natural IgM antibodies are useful serological markers in the diagnosis of systemic autoimmune diseases54,55,66 and that their diagnostic value is related to their immunologic specificity.

Since natural IgM antibodies are prevalent in human sera and are part of the normal immune response,26,56 one important problem that is inherent to IgM-based methods for identifying tumor-related antigens is demonstrating their tumor relevance.27 Natural IgM antibodies to angiogenic proteins encoded by oncogenes Brefeldin_A and tumor suppressor have been thought to represent prime candidates for biomarkers for early diagnosis of osteosarcoma.

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