Microbial Mannan Inhibits Bacterial Killing by Macrophages: A Possible Pathogenic Mechanism for Crohn’s Disease

Mpofu, Chiedzo; Campbell, Barry J.; Subramanian, Sreedhar; Marshall‐Clarke, S.; Hart, C. A.; Cross, Andy; Roberts, Carol L.; McGoldrick, Adrian; Edwards, Steven W.; Rhodes, Jonathan M.

doi:10.1053/j.gastro.2007.08.004

Cited by 64 publications

(47 citation statements)

References 61 publications

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“…In addition, we used purified lipoarabinomannans with or without a richly mannosylated arabinose moiety (LAM from M smegmatis and ManLAM from M tuberculosis, respectively) because of similar oligomannose side chains as found in mannan from S cerevisiae, the specific antigen for ASCA. In agreement with published data [19,20] , terminal α-1,3 linked mannose which is part of the dominant ASCA epitope was present at different extents in our mycobacterial preparations. In particular this epitope was strongly present in ManLAM from M tuberculosis while it was completely absent in LAM from M smegmatis.…”

Section: Discussionsupporting

confidence: 93%

“…The snowdrop lectin Galanthus nivalis agglutinin or lectin (GNL) has been shown to have high specificity for such terminal mannose sugar residues [16,17] and has been used to detect ASCA epitopes from microorganisms directly or in infected tissue [11,20] . After coating ELISA plates with mycobacterial lysates, purified LAM or ManLAM, or, as a positive control, yeast mannan, GNL differentially bound to these antigens.…”

Section: Resultsmentioning

confidence: 99%

“…Two other publications have demonstrated presence of the GNL-reactive motif in some mycobacterial species, including M bovis, M avium and Mycobacterium avium ssp. paratu-berculosis (MAP) [19,20] . Hence, we were interested whether ASCA-positive CD patients may also more frequently contain antibodies against distinct mycobacterial strains and specifically against LAM, and whether these antibodies would be of cross-reactive nature.…”

Section: Introductionmentioning

confidence: 99%

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Partial overlap of anti-mycobacterial, and anti- Saccharomyces cerevisiae mannan antibodies in Crohn's disease

Müller¹,

Schaffer²,

Schoepfer³

et al. 2008

WJG

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AIM:To test whether humoral immune reaction a g a i n s t myc o b a c t e r i a m ay p l ay a ro l e i n a n t i - S a c c h a r o my c e s c e r e v i s i a e a n t i b o d i e s ( A S C A )generation in Crohn's disease (CD) and/or whether it correlates with clinical subtypes. M E T H O D S :T h e d o m i n a n t A S C A e p i t o p e w a s ASCA and anti-mycobacterial antibodies were affinity purified to assess cross-reactivities. Anti-mycobacterial IgG were induced by BCG-infection of mice. RESULTS: G N L b o u n d t o d i f f e r e n t e x t e n t s t o mycobacterial lysates, abundantly to purified mannosecapped (Man) LAM from M tuberculosis , but not to uncapped LAM from M smegmatis . Fifteen to 45% of CD patients but only 0%-6% of controls were seropositive against different mycobacterial antigens. Anti-mycobacterial IgG correlated with ASCA (r = 0.37-0.64; P = 0.003-P < 0.001). ASCA-positivity and deficiency for mannan-binding lectin synergistically associated with anti-mycobacterial IgG. In some patients, anti-mycobacterial antibodies represent crossreactive ASCA. Vice-versa, the predominant fraction of ASCA did not cross-react with mycobacteria. Finally, fistulizing disease associated with antibodies against M avium , M smegmatis and MAP (P = 0.024, 0.004 and 0.045, respectively). 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.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Partial overlap of anti-mycobacterial, and anti- Saccharomyces cerevisiae mannan antibodies in Crohn's disease

Müller¹,

Schaffer²,

Schoepfer³

et al. 2008

WJG

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“…A few CD-associated microbial species have been described (notably AIEC and Mycobacterium species) that appear able to either bypass an intact intestinal barrier or evade or suppress macrophage function [24,[67][68][69]. These species might therefore be able to initiate a chronic inflammatory response even in 'innate immunocompetent' hosts.…”

Section: Intestinal Microbesmentioning

confidence: 99%

“…Although it is impossible to establish causality with this approach, focused metagenomic studies represent a powerful tool for further study of this aspect of the intestinal environment in health and disease and should be applied across populations. Bifidobacterium species and Faecalibacterium prausnitzii appear to have a clinically relevant association with CD, but it remains to be determined whether 'restoration' or alteration of the balance of microbial species in the bowel is of therapeutic benefit [65,66] (although again, this would not necessarily demonstrate causality).A few CD-associated microbial species have been described (notably AIEC and Mycobacterium species) that appear able to either bypass an intact intestinal barrier or evade or suppress macrophage function [24,[67][68][69]. These species might therefore be able to initiate a chronic inflammatory response even in 'innate immunocompetent' hosts.…”

mentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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The Role of Dysbiosis in Inflammatory Bowel Diseases

Dicksved

Willing

2011

Handbook of Molecular Microbial Ecology II

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Microbial Mannan Inhibits Bacterial Killing by Macrophages: A Possible Pathogenic Mechanism for Crohn’s Disease

Cited by 64 publications

References 61 publications

Partial overlap of anti-mycobacterial, and anti- Saccharomyces cerevisiae mannan antibodies in Crohn's disease

Partial overlap of anti-mycobacterial, and anti- Saccharomyces cerevisiae mannan antibodies in Crohn's disease

Crohn’s disease as an immunodeficiency

The Role of Dysbiosis in Inflammatory Bowel Diseases

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