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Crohn's disease: an immunodeficiency?

Folwaczny, Christiana; Glas, Jürgenb; Török, Helga-Paulab

European Journal of Gastroenterology & Hepatology: June 2003 - Volume 15 - Issue 6 - p 621-626
Review in depth

Autoimmunity appears to be a key factor in Crohn's disease as it develops in a genetically susceptible host if the immunological tolerance towards bacterial antigens within the gastrointestinal tract is abrogated. The resulting excessive immunological activity leads to a chronic sometimes transmural inflammatory process within the bowel wall. However, several lines of evidence are compatible with an immunodeficiency preceding these processes: humoral or cellular immune defects can predispose to inflammatory bowel disease. An increased bacterial adherence at the intestinal mucosa, which is possibly attributable to impaired expression of defensins was observed in Crohn's disease. Furthermore, the 3020insC mutation of the NOD2/CARD15 gene which is associated with Crohn's disease results in impaired cytokine transcription. Lastly, therapeutic approaches such as the use of antibiotic therapy or granulocyte macrophage colony stimulating factor are in line with the concept of an immunodeficiency being a crucial element in Crohn's disease.

bMedizinische Klinik und aPoliklinik der Universität, Standort Innenstadt, Ludwig-Maximilians Universität, Munich, Germany.

Correspondence to PD Dr Christian Folwaczny, Medizinische Klinik und Poliklinik, Klinikum Innenstadt, Ludwig-Maximilians Universität, Nußbaumstr. 20, 80336 Munich, Germany. Tel: +49 89 5160 2625; fax: +49 89 5160 4187; e-mail: christian.folwaczny@medinn.med.uni-muenchen.de

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Introduction

The current pathophysiological model for inflammatory bowel disease (IBD) comprises a genetically mediated abrogation of the immunological tolerance towards luminal (e.g. bacterial) antigens, resulting in an excessive, largely T-cell driven, immunological activity which leads to a chronic inflammatory process within the bowel wall [1]. On the other hand clinical observations, immunological and genetic studies, animal models and therapeutic approaches suggest that the initial event in the complex pathophysiological process might not be characterized by a loss of immunological tolerance but rather resembles an immunodeficiency. Thus, the hypothesis presented herein is compatible with a fundamental change in the understanding of the pathophysiology of Crohn's disease (CD) and might have pivotal consequences for the development of new therapeutic approaches.

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Clinical observations

A variety of congenital immune defects present chronic enterocolitis resembling IBD [2,3]. Patients with X-linked agammaglobulinaemia or septic granulomatosis are prone to develop a CD like enterocolitis [2,4–6], whereas in Wiskott–Aldrich syndrome and the common variable immune deficiency colitis mimicking ulcerative colitis have been described repeatedly [7–15]. Further examples comprise chronic granulomatous disease [16–24], glycogen storage disease Ib [25–32], leucocyte adhesion deficiency [33], Chediak Higashi syndrome [34], Turner's syndrome [35–37] and congenital [38,39], cyclic [40,41] or autoimmune [42] neutropenias which feature CD. Furthermore, myelodysplastic and myeloproliferative disorders have been associated with CD [43,44]. It remains to be clarified whether these forms of enterocolitis represent a separate disease entity or classic IBD. Therapeutic approaches using high dose immunoglobulin in patients with X-linked agammaglobulinaemia and a CD like enterocolitis [6,45] or granulocyte/macrophage colony stimulating factor in patients with various neutropenias [46] suggest that the crucial step in these forms of enterocolitis is not an excessive immunological activity but is compatible with an impaired ability to resolve the microbiological challenge at the mucosa.

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Immunological and genetic studies

Since the first description of CD it has been hypothesized that the chronic inflammatory process might reflect an infection [1]. During the last few decades numerous studies have aimed to identify a specific pathogen which might cause IBD. However, the vast majority of positive findings was not confirmed in subsequent studies and, until now, a distinct infectious agent causing CD or ulcerative colitis has not been described unequivocally [1]. Subsequently, this has led to the proposal that not a single bacterial or viral strain causes IBD but rather a disturbed composition of the commensal bacterial population within the intestine might be a pivotal condition for the manifestation of CD [1,47,48]. Furthermore, the loss of mucosal integrity leading to translocation of bacteria in the bowel wall was regarded as a crucial step for the propagation of the inflammatory process [1,49,50].Figure 1

Fig. 1

Fig. 1

On the other hand, recent data are compatible with a disturbed mucosal clearing function in IBD, resulting in increased adherence of various bacterial strains at the intestinal mucosa [51]. Most remarkably, Swidsinski and co-workers demonstrated that only the bacterial load but not the type or the composition of the isolated bacterial strains differed significantly between patients and controls. In addition, the most abundant bacteria recovered were described in intact rather than inflamed mucosal sites, which suggests that the changes in the mucosal flora in IBD are not secondary to but rather precede inflammation. In line with this concept an impaired expression of peptides with antibacterial activity, defensins, which are upregulated following bacterial or other inflammatory stimuli under normal conditions [52–55], was described in CD [56].

Recently, a frameshift mutation (3020insC) of the NOD2 (CARD15) gene was described in about 20% of patients with CD [57–68] and subsequently associated with ileal involvement and the fistulizing or fibrostenotic phenotype [60–68] which are characterized by an increased expression of Th1 cytokines, such as TNFα [69–72]. NOD2 functions as an intracellular receptor for bacterial components and activates the nuclear factor κB (NFκB) pathway following inflammatory stimuli, which results in increased transcription of proinflammatory cytokines [73–75]. The 3020insC mutation encodes for a NOD2 protein with a truncation in its leucine rich region which recognizes bacterial stimuli and induces pathogen specific responses. As compared to wild type NOD2 the ability of the mutated protein to confer responsiveness to lipopolysaccharides is significantly diminished in vitro [58]. The contradiction between the in-vivo situation which is characterized by an excessive stimulation of the NFκB pathway in CD and reduced NFκB activity in cells transfected with the 3020insC mutation remains to be clarified. These observations are compatible with a sensing deficit for bacterial stimuli in patients with CD who are carriers of the 3020insC mutation. In line with this concept is the observation that, thus far, a correlation between this mutation and the efficacy of therapy with anti-TNFα antibodies has not been observed [76,77].

Furthermore, similar to periodontitis, abnormal neutrophil function which is characterized by complement dysfunction and impaired superoxide generation of neutrophils resulting in reduced phagocytic, bactericidal and candidacidal activity, has been described in CD [46]. The latter is probably caused by distinct bacterial strains or risk factors which are common in the 20th century, such as cigarette smoking or the use of non-steroidal anti-inflammatory drugs (NSAIDs) [78–86]. The progression from neutrophil dysfunction to generation of CD certainly remains speculative but resembles neutrophil disorders associated with CD.

If neutrophils and macrophages fail to effectively confront the microbial challenge at the mucosal level, T cells are more broadly activated and a compensatory T-cell driven process would be perpetuated. Tuberculosis, in which the intestinal manifestations bear a striking resemblance to those of CD [1], offers a parallel explanation with an inadequate clearance of Mycobacterium tuberculosis by neutrophils, impaired macrophage function which results in granuloma formation and a predominantly T-cell response. Similar to Hermansky Pudlak syndrome, which is also associated with CD [87], the impaired clearing of M. tuberculosis might, at least in part, be explained by its interference with phagosome–lysosome fusion [88].

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Animal models

The Wiskott–Aldrich syndrome protein (WASP) leads to complex disturbances of the immune system, such as altered humoral immune responses and impaired function of T cells [14,15]. Furthermore, the identification of WASP resulted in the development of animal models exhibiting this complex immune defect which are characterized by chronic colitis [14]. Mice displaying a deficiency of the WASP develop chronic colitis by 4 months of age. In addition, chronic colitis develops in numerous genetically manipulated mice where gene disruption affects T-cell function, e.g. TCR-α−/−, TCR-ß−/−, IL-2−/−, IL-2Ra−/−, IL-10−/−, G-αi2 −/−, MHC class II−/− and the CD45Rbhi transfer model [89]. Furthermore, two murine knock-out models with enterocolitis (CCAAT/enhancer binding protein (CEBP)-∊ [90] and cell type specific disruption of the Stat-3 gene in neutrophils and macrophages [91]) support the role of disturbed macrophage and neutrophil function for the development of CD. Most interestingly, the administration of immunostimulatory DNA ameliorates clinical, biochemical and histological scores of colonic inflammation in dextran sodium sulphate induced colitis and hapten induced colitis in BALB/c mice regardless of the underlying T-cell responses, as recently demonstrated by Rachmilewitz and co-workers [92]. Based on a variety of experimental data the authors suggested that this effect might be explained by enhanced survival of colonocytes via suppression of apoptosis. In addition, the immunostimulatory effect on innate immunity, mainly on macrophages and monocytes, might limit the mucosal invasion of commensal bacteria (or their inflammatory products) and reduce the subsequent mucosal inflammation.

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Therapeutic approaches

Similar to ulcerative colitis, CD (in particular colitis Crohn or perianal fistulas) is one of the very few examples of chronic inflammatory diseases which can be treated by either immunosuppression or antibiotic therapy [1]. This therapeutic enigma is compatible with CD being neither a classic autoimmune disease nor a chronic infection caused by a single bacterial strain as the sole causative agent. Rather, the reduced clearance of bacteria from the intestinal mucosa might be considered as the initial pathophysiological step (which can be reversed by antibiotic therapy) resulting in excessive and perpetuated immunological activity (which is treated by immunosuppression). Following earlier trials CD might respond to immunostimulants such as Bacillus Calmette Guerin [93] or levamisole [94,95]. Interferon-α-2a and -2b and interferon-β [96–102] are further examples of immunostimulating therapies which were successfully administered in CD and ulcerative colitis. In patients with active IBD peranal bleeding is frequently observed. Several authors described a paradoxical effect of heparin therapy which led to cessation of the bleeding [103]. The effectivity of heparin in IBD is probably not related to immunomodulating effects of this substance [104] but rather caused by an improved intestinal barrier function via enhanced binding of basic fibroblast growth factor (bFGF) to mucosal defects thus facilitating mucosal healing [105]. Moreover, several patients with glycogen storage disease paralleled by an enterocolitis mimicking CD were successfully treated with granulocyte (filgrastim) or granulocyte macrophage colony stimulating factor (sargramostin) [46]. Most remarkably this approach was also beneficial in closing perianal fistulas in sporadic CD [106]. Subsequently, two pilot studies of filgrastim and sargramostin have reported that these substances may be effective for treating chronically active and fistulizing CD [107,108]. In an open label dose escalation trial the use of granulocyte macrophage colony stimulating factor (4–8 μl/kg/day) in 15 patients with moderate to severe CD resulted in a clinical response (ΔCDAI >100 points) in 12 patients [109]. Clinical remission was achieved in eight patients.

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Conclusion

Various observations support the concept of a hitherto underestimated immunodeficiency as a pivotal initial step in the complex pathophysiology of CD. Comparable to patients with inborn immune defects this might result in the perpetuated immunological activity leading to progressive tissue destruction. Hence, the hypothesis outlined herein is not necessarily a contradiction to the current pathophysiological model but rather supplements it.

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Keywords:

Crohn's disease; immunodeficiency; NOD2; CARD15; granulocyte macrophage colony stimulating factor

© 2003 Lippincott Williams & Wilkins, Inc.