Development of Crohn’s Disease in a Patient with Multiple Sclerosis Treated with Copaxone

Charach, Gideon; Grosskopf, Itamar; Weintraub, Moshe

doi:10.1159/000143156

Cited by 12 publications

(7 citation statements)

References 16 publications

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“…The acute inflammatory response, dependent on the acute release of proinflammatory cytokines, is important for the clearance of bacteria and fecal material from the tissues, which takes place over a few hours. The lack of TNF after the administration of therapeutic antagonists for the treatment of other chronic inflammatory diseases has been reported to precipitate the development of CD (Charach et al, 2008; Yazisiz et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

Smith

Rahman

Hayee

et al. 2009

Journal of Experimental Medicine

364

306

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The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.

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Section: Discussionmentioning

confidence: 99%

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

Smith

Rahman

Hayee

et al. 2009

Journal of Experimental Medicine

364

306

View full text Add to dashboard Cite

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“…The concern of possible psoriasis exacerbation during interferon-beta use was raised (Fellner et al, 2014). Similarly, sporadic cases of Crohn's disease, myasthenia gravis and arthritis have been reported in patients on GA, which is a random polymer of glutamic acid, lysine, alanine and tyrosine therapy (Charach et al, 2008;Zheng et al, 2008;Frese et al, 2000;Heesen et al, 2001). Petrova et al (2010) studied changes in thyroid function in a sample of 158 people on GA therapy, and showed the relative safety of copaxone in respect to changes in thyroid gland.…”

Section: Discussionmentioning

confidence: 99%

Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients

Chouhfeh

Kavak

Teter

et al. 2015

Multiple Sclerosis and Related Disorders

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“…There is also some evidence to indicate that azathioprine metabolites, rather than merely suppressing adaptive inflammation, stimulate the release of proinflammatory cytokines by macrophages [38]. As a corollary, it is interesting to note case reports where the development of CD in patients with other inflammatory disorders has been precipitated by the use of treatments that downregulate TNF [47,48].…”

Section: If Macrophages Fail To Secrete Tnf-α In CD Why Do Anti-tnf 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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Development of Crohn’s Disease in a Patient with Multiple Sclerosis Treated with Copaxone

Cited by 12 publications

References 16 publications

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients

Crohn’s disease as an immunodeficiency

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