How are low mannin-binding lectin (MBL) significant in Crohn's?

"Low Mannan-binding lectin serum levels are associated with complicated Crohn's disease and reactivity to oligomannan (ASCA)." in American Journal of Gastroenterology (2009)
"CONCLUSIONS: Low or deficient MBL serum levels are significantly associated with complicated (stricturing and penetrating) CD phenotypes but are negatively associated with the non-stricturing, non-penetrating group. Furthermore, CD patients with low or deficient MBL are significantly more often ASCA positive, possibly reflecting delayed clearance of oligomannan-containing microorganisms by the innate immune system in the absence of MBL."

"Partial overlap of anti-mycobacterial, and anti-Saccharomyces cerevisiae mannan antibodies in Crohn’s disease" In World J Gastroenterology (2008)

"Abstract CONCLUSION: Similar to ASCA, seroreactivity against mycobacteria may define CD patients with complicated disease and a predisposition for immune responses against ubiquitous antigens. While in some patients anti-mycobacterial antibodies strongly cross-react with yeast mannan; these cross-reactive antibodies only represent a minor fraction of total ASCA. Thus, mycobacterial infection unlikely plays a role in ASCA induction."

"Full article:  In conclusion, we were able to demonstrate that ASCA-positive patients had significantly more immune reactivities to mycobacterial antigens. In a subgroup of ASCA-positive CD patients, anti-mycobacterial immunoglobulins at least partially represent cross-reactive ASCA, while in others there seem to be separate ASCA and anti-mycobacterial antibodies that do not cross-react. Furthermore, purified anti-M smegmatis IgG showed low or no binding to yeast mannan. Therefore, we postulate that our results reflect more the predisposition of CD patients to develop increased immune reactivities to various ubiquitous antigens in general and mannosylated antigens in particular, rather than a role of mycobacteria in the induction of ASCA."

"Mannan-binding lectin deficiency results in unusual antibody production and excessive experimental colitis in response to mannose-expressing mild gut pathogens"
"Conclusions: These results suggest that systemic MBL helps to prevent excessive inflammation upon access of normally mild pathogens across the damaged intestinal epithelium. Lack of this innate defence promotes antibody responses with cross-reactive potential against common mannan epitopes. These interpretations are compatible with the increased prevalence of ASCA and complicated disease phenotypes in MBL-deficient patients with CD."

"Deficiency for mannan-binding lectin is associated with antibodies to Saccharomyces cerevisiae in patients with Crohn’s disease and their relatives" in Gut (2007)
"Therefore, our paper provides further evidence that genetically altered MBL levels in patients with Crohn’s disease and their relatives could be, at least partly, responsible for the enhanced  immune reactivity to yeast antigens seen in a subgroup of these patients and their relatives.  However, other factors also contribute to the development of this unusual immune reaction, as there are MBL-deficient healthy people who are ASCA negative."

c.f. "Mannan binding lectin (MBL) gene polymorphisms are not associated with anti-Saccharomyces cerevisiae (ASCA) in patients with Crohn’s disease" in Gut (2006)
"We found no association between the presence of ASCA and polymorphisms/mutations in the MBL gene in a large cohort of CD patients and conclude that the occurrence of ASCA is not related to MBL polymorphisms/mutations. This is in contrast with a previous report in which such an association was suggested. Therefore, we consider the relationship between ASCA and MBL highly controversial."

What is the significance of positive ASCA?

What are Anti-saccharomyces cerevisiae antibodies?

Relationship to Celiac Disease

Antibodies anti-Saccharomyces cerevisiae (ASCA) do not differentiate Crohn's disease from celiac disease in Arquivos de Gastroenterologia (2010)
From the article:

"The protective function of the intestinal mucosa is called "permeability"(12). When the intestinal mucosal barrier is broken, with junctions-mediated barrier defects, an influx of luminal antigens may result in inflammation, even by chronically stimulating resident, with consequent recruitement of immunocompetent cells from the lamina propria(3, 7). In patients with autoimmune diseases, like CD, or in infectious disease, and in various other clinical conditions, ASCA can be positive. The presence of ASCA may reflect a shared permeability disorder, leading to the enhanced exposure to various antigens that, depending on the genetic background, may provoke various or multiple autoimmune disorders.(3, 4, 5, 7, 9, 14). The antibodies in the sera of the analysed ASCA positive cases proved a systemic immune response against Sacharomyces cerevisiae (generally accepted as not a pathogen) and suggested the end of the oral tolerance against the yeast's antigens(3).  ...
In conclusion, the results show that ASCA was found in patients with CeD and disappear after a GFD. So, it is presumed that ASCA positivity is not a specific marker for Crohn's disease but correlates with the (auto) immune inflammation of the small intestine."

Relationship to CD subtype

"Serologic Investigations in Children with Inflammatory Bowel Disease and Food Allergy" in Mediators of Inflammation (2009)
" The occurrence of ASCA antibodies (IgA and/or IgG) was observed in 73.7% of children with Crohn’s disease, 17.5% with ulcerative colitis and almost 30% with allergic colitis, statistically significantly more frequent in children with Crohn’s disease in comparison with the other examined groups and controls. Statistically, patients with Crohn’s disease and the presence of ASCA revealed a significantly more frequent localization of lesions within the small bowel and a tendency towards older age (mean age 15.5). Sensitivity ASCA (IgG or IgA) for diagnosing Crohn’s disease was determined as 73.7%, specificity (in relation to controls) was 91.3%.
... In our examination we found a relation between the examined mutations of gene NOD2/CARD15 and the presence of antibodies. Similary Annese in a large group of patients with Crohn’s disease proved a relation between mutation NOD2/CARD15 and the localization in the small bowel, the narrowing form of the disease and the early age of diagnosis, but she also showed a relation between the mutation and the presence of ASCA [31]. The presence of ASCA is important for patients with undetermined colitis, however, 50% of these patients do not produce ASCA and p-ANCA."

"Genetic variants of the mannan-binding lectin are associated with immune reactivity to mannans in Crohn’s disease" in Gastroenterology (2004)
"Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T-cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA."