Autoantibodies as Diagnostic Markers

Some of the antibodies produced by patients with systemic (non-organ-specific) or organ-specific autoimmune diseases are clinically useful for diagnosis, since their appearance is restricted to certain diseases or disease subtypes. These include antibodies to double-stranded (ds)DNA, Sm antigen, and ribosomal P proteins in systemic lupus erythematosus (SLE); DNA-topoisomerase I in systemic sclerosis (SSc); citrullinated-modified proteins in rheumatoid arthritis (RA); tRNA synthetase in myositis; glutamic acid decarboxylase and the protein tyrosine phosphatase-like molecule (known as IA-2) in insulin-dependent diabetes mellitus (IDDM); thyroid peroxidase and thyroglobulin in autoimmune thyroiditis; and the E2 component of pyruvate dehydrogenase (PDC-E2) in primary biliary cirrhosis (PBC) [2-8]. While many antibodies are highly specific to a particular disease, the usefulness of some of them as diagnostic markers is relatively poor due to their low prevalence. For example, this is the case for anti-Sm antibodies, which are a good marker for SLE but are found in only 5% (in Europe) to 20% (in North America) of lupus patients. On the other hand, the levels of some antibodies remain relatively constant in the serum of patients during the course of a disease, while other antibodies have fluctuating levels, depending on the phase, active or quiescent, of the disease. In the latter case, monitoring particular serum antibody subsets may be useful for prognosis. It is worth noting that the presence of particular antibody subsets in the serum of healthy individuals seems to predict the subsequent development of autoimmune diseases [6, 7]. This observation obviously complicates the setup and interpretation of assays since the serum of any "healthy" individual used to determine the threshold for positivity for each test may happen to be unexpectedly positive.

Before we describe in more detail the methodologies used to characterize serum autoantibodies with peptides and give some results that are relevant for a better definition of autoantibody specificity, it is important to highlight some basic concepts that are fundamental for a proper interpretation of data. As pointed out by Kavanaugh in his editorial [9], "improper use of (laboratory) tests may result in misdiagnosis, needless additional testing, and inappropriate therapy." As is the case with other laboratory tests, it is important to be aware of pos sible pitfalls of each peptide-based assay, to include the appropriate positive and negative controls, and to know the limitations of interpretation (sensitivity, in-tra-test variability, specificity) of each test. At the peptide level, improper synthesis or the use of peptides of low quality can dramatically affect the data and lead to false conclusions. In addition to summarizing well-established results, the object of this chapter is also to lay emphasis on the weak links of peptide-based diagnostic assays and to propose some solutions for the standardization of such tests. We will first set out two domains of peptide chemistry that have been intensively developed and have resulted in expansion of peptide-based-immuno-chemistry —namely, multiple peptide synthesis and multiple peptide presentation.

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