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Editorials |
Department of Medical Microbiology, Lund University, Malmö, Sweden
aAddress for correspondence: Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö SE-20502, Sweden.
The report by Waterboer et al. (1) in this issue represents one of the most thorough attempts to develop a high-throughput system for simultaneous analysis of antibodies against a large number of antigens. High-throughput assays, notably through various types of arrays, are increasingly important research tools in modern molecular medicine, but almost all the technologic development has been directed toward the analysis of DNA, RNA, and proteins (2), with more limited technologic progress in the field of serology. Will we see multiplexed antibody analysis, "serolomics", arising as a new research field alongside genomics, RNomics, and proteomics?
Measurements of groups of antibodies can have application in multiple areas of medicine. Analysis of a broad spectrum of autoantibodies is increasingly used in predictive diagnostics of autoimmune diseases (3), and autoantibodies against oncogene products are being studied in predictive oncology (4). The most interesting medical application, however, would be to rapidly assay the spectrum of microbiological agents to which a person has been exposed because past infections can be highly predictive of the risk of future diseases. Important examples include cardiovascular diseases, allergies, and cancer. Exposure to infections accounts for 
17% of human cancers, with human papillomavirus (HPV) being one of the most important oncogenic infections (5). HPV infection causes almost all cervical cancers as well as a significant proportion of cancers of the vulva, vagina, penis, anus, and oropharynx; together these HPV-related cancers account for >5% of all human cancers (5).
The HPV group of viruses today consists of >100 completely characterized types. Partial sequences of additional isolates indicate that at least another 100 HPVs exist. Of these, 15 genital HPVs are established as oncogenic in humans. HPV type 16 is by far the most important virus, accounting for more than 50% of all cervical cancers. HPV16 is even more dominating as an etiology of the noncervical HPV-associated cancers. HPV18 is another virus of particular interest because it is the dominant factor in adenocarcinomas of the cervix (5). Several prophylactic HPV vaccines have shown high efficacy against HPV infection and HPV-induced cervical precancers (6)(7), and it is highly likely that programs attempting HPV eradication by vaccination will be launched in the near future.
The antibody response to HPV is, in general, type-specific, and HPV serology is an important technology for determining the spread of type-specific HPV infections in populations and monitoring of the effect of HPV vaccines in inducing protective antibodies (5). Today, HPV serology is performed mostly in a limited number of expert laboratories, but it is likely to become widely used in clinical laboratories in the post-HPV vaccination era. The high efficiency and low variability of the Luminex method reported in this issue of Clinical Chemistry (1) make it an attractive method for HPV serology in high-throughput laboratories. Major HPV vaccination trials already use a Luminex-based method of HPV serology to monitor the immunogenicity of the vaccines (8). The method described by Waterboer et al. (1) represents a further advance because it does not require an inhibition step and allows standardized scale-up to a large number of antigens (up to 100) by use of simple expression methods that are likely to be adopted by many laboratories involved in high-throughput serology.
Waterboer et al. (1) deal with two different classes of antibodies that will be of interest in serolomics. The antibodies against the viral transforming proteins E6 and E7 are rare among healthy HPV-exposed individuals, but are common among patients with cervical cancer, particularly in late-stage disease. E6 and E7 antibodies have been studied extensively as potential tumor markers in HPV-associated cancers; they are not in clinical use, however, because their diagnostic sensitivity has not been very high and because these antibodies appear too late in the course of disease to give clinical benefit from early diagnosis (9). Will the increased sensitivity and low imprecision of the Luminex-based method and the possibility for easy combination of different antibody assays lead to renewed interest in the use of these antibodies in predictive oncology? The study by Waterboer et al. (1) certainly appears to represent a major advance in the technology.
The antibodies against the major HPV capsid protein, L1, are induced after infection and usually stay detectable for many years after clearance of the infection, i.e., they belong to the class of antibodies that mark past exposure to an infection. The concentrations of these antibodies correlate well with protection (neutralizing ability), and it is for L1 antibodies that there is an urgent need for efficient, standardized HPV serologic methods for use in vaccination implementation/evaluation efforts and for epidemiologic monitoring of the type-specific spread of HPV infections (5). Although the method described (1) has not been compared directly against more established HPV serologic methods such as the virus-like particle–based ELISA, competitive RIA, and neutralizing assays, it certainly seems promising. One hopes that further epidemiologic evaluation of the technology will be pursued with a high priority.
From an epidemiologic point of view, high-throughput technologies have, to some extent, been problematic. They typically provide data on a very large number of variables, but at substantial cost per tested individual, and they can cause problems with multiple-hypothesis testing. The major exceptions are the high-throughput methods that allow testing of very large numbers of patients but usually for a more limited number of variables. Examples include tissue microarrays that assemble tissues from up to 1000 patients per slide and "DNA arrays", a term coined in the Swedish National Biobank Programme to denote the construction of arrays of purified DNA from large population cohorts (10). The multiple antibody testing approach described by Waterboer et al. (1) is a compromise in this regard. The main principle is to increase the number of variables tested per individual, but advantages such as speed and low consumption of serum and reagents are also likely to enable testing of sufficiently large numbers of individuals at low cost so that the method can become a popular tool in molecular epidemiologic studies. These studies could encompass a wide variety of research areas in which assaying of antibodies could be informative.
References
The following articles in journals at HighWire Press have cited this article:
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  D. A.M. Heideman, T. Waterboer, M. Pawlita, P. Delis-van Diemen, I. Nindl, J. A. Leijte, J. M.G. Bonfrer, S. Horenblas, C. J.L.M. Meijer, and P. J.F. Snijders Human Papillomavirus-16 Is the Predominant Type Etiologically Involved in Penile Squamous Cell Carcinoma J. Clin. Oncol., October 10, 2007; 25(29): 4550 - 4556. [Abstract] [Full Text] [PDF]
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