Elsevier

Clinical Immunology

Volume 132, Issue 1, July 2009, Pages 124-131
Clinical Immunology

Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome

https://doi.org/10.1016/j.clim.2009.03.514Get rights and content

Abstract

The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.

Introduction

The nuclear factor kappa B (NF-κB) family of transcription factors is central to the induction of both innate and adaptive immune responses to a variety of pathogens [1], [2]. The activation of NF-κB proteins is regulated by a multimeric complex consisting of two catalytic subunits, the inhibitor of kappa kinase alpha and beta (IKKα and IKKβ), and a regulatory unit, IKK gamma (IKKγ), also known as the NF-κB essential modulator (NEMO).

The critical role of NF-κB activity in host defense has in part been demonstrated by a group of human disorders resulting from hypomorphic alleles of NEMO that are inherited in an X-linked pattern. These mutations can result in defects in both innate and adaptive immunity. Innate immune defects include impairment of IL-12 production and of Toll-like receptor (TLR) signaling [3], [4], while adaptive immune defects include deficits in B cell responses to specific immunization, and profound T cell lymphopenia [4], [5].

While the clinical aspects of the immune deficiency are increasingly well characterized, the clinical effects of altered NF-κB activity on the inflammatory response are less clear. Given the central role of NF-κB in upregulating pro-inflammatory cytokines, loss of NF-κB activity might predict a diminished inflammatory response despite pervasive infection, as observed in some patients [6]. However, NF-κB activity also plays a role in the generation of natural killer T cells, CD4+CD25+ regulatory T cells, and memory T cells [7], [8], [9]. Therefore, immune dysregulation and organ-specific inflammatory disease might also be anticipated. To date, few studies to elaborate on this issue have been reported [2].

To better understand the clinical manifestations of the immune dysregulation in NEMO deficiency, we studied seven members of a kindred affected by this syndrome. Despite the absence of overt clinical infection or inflammation, most of the patients exhibited sustained periods of elevation of inflammatory markers, reminiscent of those with systemic inflammatory disorders such as systemic lupus erythematosus and inflammatory bowel disease (IBD) [10], [11]. More strikingly, two of our eldest patients have developed an atypical enterocolitis (beginning at 8–10 years of age) that was only responsive to anti-inflammatory therapy. These findings suggest that some NEMO syndrome patients exhibit immune dysregulation inclusive of organ-specific inflammation.

Section snippets

Patient care and data collection

All seven patients in the cohort were seen monthly for intravenous immunoglobulin (IVIG) infusions (400 mg/kg every 4 weeks) at the University of California, San Francisco (UCSF) Pediatric Clinical Research Center (PCRC) of the UCSF Clinical and Translational Research Institute. Interval histories and physical examinations were obtained. The patients' antimicrobial prophylaxis regimen included penicillin (125 mg orally twice daily if < 5 years of age and 250 mg orally twice daily if > 5 years of

Patient demographics

Three of the patients (1–3) in the kindred have previously been described [12], and we have since diagnosed an additional four children (4–7) (Fig. 1). All patients, except Patient 7 who was diagnosed perinatally, presented with meningitis in the first 2 years of life (Table 1). Amongst those old enough to determine, all had the characteristic dentition of NEMO syndrome with variable dermatologic manifestations, including hypohidrotic ectodermal dysplasia, sparse hair, and hypopigmentation. At

Discussion

We show here that, in a kindred of 7 patients with NEMO syndrome, most manifest signs of persistent elevation of erythrocyte sedimentation rate in the absence of clinical symptoms. Two of the patients also developed organ-specific pathology (atypical enterocolitis), with durable resolution only after glucocorticoid treatment. These data suggest that specific NEMO mutations predispose to the development of serologic signs of systemic inflammation, with the potential to progress to autoimmune

Acknowledgments

We would like to thank Jeff Mold for assistance in preparation of histopathologic specimens, and Michael Pickens for gathering endoscopic images. We thank Ashish Jain and colleagues for genotype analysis. We would also like to thank Emily von Scheven for helpful discussions.

This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Laurence E. Cheng was

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    Current address: Departments of Medicine and Pediatrics, Case Western Reserve University and Allergy/Immunology Associates, Inc. 1611 South Green Road, #231, South Euclid, Ohio 44121.

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