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ASCA: genetic marker, predictor of disease, or marker of a response to an environmental antigen?
  1. F Seibold
  1. Correspondence to:
    Professor F Seibold
    Department of Gastroenterology, Inselspital, Freiburgstrasse, 3010 Bern, Switzerland; frank.seiboldinsel.ch

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Anti-Saccharomyces cerevisiae antibodies (ASCA) may be a marker of an immune response to an environmental antigen that occurs in the context of early stage Crohn’s disease

The presence of antibodies against the yeast Saccharomyces cerevisiae (ASCA) and against neutrophils (pANCA) has been used as diagnostic serological markers for inflammatory bowel disease (IBD) for many years. The combination of a positive ASCA test with a negative pANCA test has a positive predictive value of 96% and a specificity of 97% for Crohn’s disease (CD).1 However, both antibodies have been found in other diseases, such as autoimmune liver disease, primary sclerosing cholangitis (pANCA), and in gluten sensitive enteropathy (ASCA). Therefore, their role as diagnostic serological markers for IBD seems to be limited.

Antibody determination is of interest in patients with indeterminate colitis. However, almost 50% of these patients do not develop ASCA or pANCA antibodies whereas in antibody positive patients, ASCA+/pANCA− predicts CD in 80% of patients with indeterminate colitis and ASCA−/pANCA+ predicts ulcerative colitis (UC) in 64%.2

Generation of both antibodies is poorly understood. Several studies have shown that titres of both antibodies do not correlate with disease activity, as known from classical autoimmune disease. Antibody titres seem to be stable over long periods of time. Surprisingly, pANCA in UC persist after colectomy,3 and we have observed patients who have had their last flare up of CD more than 20 years ago and currently display normal findings in gastroscopy, colonoscopy, and histology, but still have high titres of ASCA. Thus these antibodies seem to represent stable serological markers. The only clinical parameter confirmed by several groups is the correlation between ASCA positivity and ileal involvement of disease and penetration as well as structuring disease behaviour.4

The question has been raised whether pANCA and ASCA represent genetic markers for susceptibility to IBD. Several studies tried to elucidate this question. Family studies showed that 16–30% of healthy first degree relatives of patients with UC were pANCA positive.5,6 Although these studies could not be confirmed by others, probably due to methodological problems, they indicate that pANCA may be a genetic marker.7 Comparable with pANCA research, several studies showed that ASCA were detectable in 20–25% of first degree relatives of patients with CD.8,9 Healthy spouses however were generally antibody negative, indicating that genetic and not environmental factors play a decisive role. The prevalence of ASCA in families with more than two affected members suffering from CD was significantly higher than in families with only two affected members, which points towards the role of ASCA as a genetic marker.10 In the same study however, the prevalence of these serological markers did not differ in pure Crohn’s families overall from sporadic cases. Therefore, the question needs to be raised whether these antibodies develop as an epiphenomenon during the onset of disease. It is known that luminal antigens such as bacteria and yeast seem to play an essential role for the perpetuation of inflammatory processes. In patients with CD, loss of immune tolerance towards the resident bacterial flora is one of the major pathogenetic concepts for this disease. Possibly, pANCA are due to cross reactivity to bacterial antigens.11 Bacterial and yeast antigens are ubiquitous, permanently present in the gastrointestinal tract. Therefore, it would be of great interest to evaluate when these antibodies are generated.

The study of Israeli and colleagues12 in this issue of Gut is the first to provide an answer to this question (see page 1232). In this study, ASCA were detected in 31% of patients before the clinical diagnosis of CD. Furthermore, an increase in ASCA frequency was observed over time, with the highest frequency documented in the 36 months before the diagnosis of CD. These results indicate that ASCA development occurs before or during the early stages of disease. This thesis was confirmed by one patient who was ASCA negative 80 months before diagnosis but was ASCA positive 48 months before diagnosis. Hence ASCA do not seem to be generated as genetic markers in early childhood but in the context of early disease. ASCA may therefore be a marker of an immune response to an environmental antigen that occurs in the context of an early stage of disease. In some patients with other autoimmune diseases, such as lupus erythematosus and rheumatoid arthritis, antibodies were detected up to nine years before diagnosis.13,14 However, whether inflammatory bowel disease (IBD) autoantibodies are markers of future disease, as has been suggested for classical autoimmune disease, has yet to be determined. If this hypothesis is true, the high frequency of ASCA in family studies would indicate that the frequency of diseased family members is substantially higher than actually known.

In Israeli’s study,12 four of eight patients had an increase in ASCA titres whereas in two patients the titres decreased. The increase in titres was interpreted as crescendo autoimmunity by Israeli et al, although this finding must be interpreted carefully considering the small number of patients available.12 Furthermore, antibody titres in IBD are generally stable, in contrast with various other autoimmune diseases where there is a correlation between clinical activity and titre levels. Therefore, it is questionable whether IBD and other classical autoimmune diseases can be compared.

The initial event leading to IBD is still unclear but of major interest. ASCA positivity has been found to be associated with a deficiency in mannan binding lectin, a component of the innate immune system.15 The theory that the initial incident leading to IBD is an infection in patients with a defect in their innate immune system is still speculation. The data of Israeli et al can be interpreted in two ways: either the autoimmune reactions precede the disease or a latent subclinical disease is followed by generation of antibodies as an epiphenomenon. Which came first, the chicken or the egg?

Approximately seven decades after the first description of CD, our knowledge about this disease is still limited. Above all we do not know the number of undiagnosed cases, if there are asymptomatic patients, or whether a subclinical form of CD exists, as is in the case of individuals who are hepatitis C virus RNA positive but have normal transaminases. Ten to 20 year since the description of ASCA and pANCA, the paper of Israeli and colleagues12 shows that ASCA and pANCA precede the clinical diagnosis of IBD. This study should encourage the scientific world to perform large studies where antibody positive and negative healthy family members are followed over a long period of time. This will help determine whether CD develops more frequently in antibody positive persons compared with those who are antibody negative. Furthermore, regular precise clinical observation may detect subclinical disease in antibody positive and negative patients.

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Anti-Saccharomyces cerevisiae antibodies (ASCA) may be a marker of an immune response to an environmental antigen that occurs in the context of early stage Crohn’s disease

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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