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 disease.
The erythrocyte sedimentation rate (ESR) can track disease severity in a number of conditions, including systemic lupus erythematosus and IBD [10
]. Interestingly, most members of this NEMO kindred had persistent elevation of the ESR, even in the absence of symptoms or signs of an inflammatory condition. Despite the absence of demonstrable infection during these processes, infectious agents may still play a critical role in precipitating organ-specific disease. For instance, the patients may have had repeated sub-clinical infections and/or sub-optimal responses to specific pathogens. Such processes may lead to organ-specific autoimmune disease, either from an inappropriate immune response or from low-level persistence of the pathogen [20
]. Though CRP levels did not show a similar persistent elevation, similar discordance between CRP and ESR levels in systemic lupus erythematosus has been observed [21
Our data contrast with previous reports of decreased signs and symptoms of inflammation in patients with NEMO mutations [6
]. The most likely explanation is the varied phenotypes amongst the many NEMO mutations [22
]. Interestingly, we care for an additional family with two boys possessing a novel F312L mutation. These patients have shown similar hyperinflammatory responses during acute infection, with one of two boys also showing periods of persistent elevation of ESR despite clinical well-being. Further genotype-phenotype correlations may help further identify predisposing mutations and perhaps lend biologic insights.
Two of the patients progressed to develop chronic, organ-specific (intestinal) symptomotology, and notably, an unrelated child with the NEMO syndrome has had a similar clinical picture [2
]. The clinical course of our patients suggests that, while an infectious component may have contributed to or precipitated events, we did not achieve clinical resolution with antibiotic treatment even when we identified and eradicated the organism. Instead, sustained resolution of disease required glucocorticoids. Such a disease course is more consistent with IBD than with a chronic infectious process, despite the absence of classic histopathologic findings of IBD. The reason for this incongruity is unclear. In animal models of IBD, neutrophils are recruited in abundance during the acute inflammatory phase, leading ultimately to the recruitment of effector lymphocytes [23
]. It is also known that diminished NF-κB activity interferes with normal antigen presentation and T cell effector function [25
]. Such alterations could impact effector T cell differentiation and function, which may in turn affect the ability of T cells to infiltrate the bowel wall and produce the classic histopathology seen in IBD.
The anti-inflammatory effects of glucocorticoids are in large part dependent on inhibition of NF-κB activity [27
]. Thus, the effectiveness of glucocorticoid therapy in treating the bowel disease of NEMO patients is somewhat counterintuitive. Although the immune deficiency in NEMO syndrome patients is often significant, NEMO syndrome patients have residual NF-κB activity as complete NEMO mutations are embryonic lethal [1
]. Molecular characterization of hypomorphic NEMO alleles would further define this residual activity and the implications for immune dysregulation as well as the role of glucocorticoids in treatment of disease [26
Thus far, we have not needed to consider medications beyond glucocorticoids as the mainstay of our therapeutic regimen. However, the atypical enterocolitis raises the question of whether NEMO patients might require medications not typically used in the treatment of chronic enterocolitis. In IBD, glucocorticoids are used primarily during acute presentation or flares, with other medications used to control chronic disease [28
]. These medications include 5-ASA derivatives, such as sulfasalazine, or nucleoside synthesis inhibitors, such as 6-mercaptopurine. More recently, biologic agents such as infliximab, which inhibits TNF-α activity, have been used with success. Given the pathologic findings in our NEMO patients and the preponderance of neutrophils associated with disease, such medications may be less effective. Targeting TNF-α activity represents an additional option, but the NEMO patients' underlying susceptibility to mycobacterial disease must be taken into account before such therapy is considered.
Numerous hypotheses might explain the ileitis and colitis observed in our two patients. First, the host response to bacteria likely plays a crucial role in the initiation of local inflammation, which can in turn lead to chronic ileocolitis despite clearance of the organism [24
]. Patient 3 had C. difficile
colitis at the onset of his symptoms. Antibiotic therapy was sufficient to eliminate fecal evidence of the organism, but the patient's symptoms continued to worsen. Thus, the pathogen may have initiated a host response which evolved into a chronic inflammatory state [20
]. In particular, the newly appreciated role of NF-κB signaling in modulating NADPH oxidase activity might lead to delayed pathogen clearance and an altered host response to infection (even if the pathogen is ultimately eliminated) [30
]. While pathogenic bacteria could certainly contribute to an aberrant intestinal inflammatory response, increasing evidence suggests that, in susceptible individuals, the host response may be driven primarily by commensal bacteria [31
]. Specifically, diminished integrity of the epithelial gut barrier increases the inflammatory potential of commensal organisms, and animal models suggest a critical role for NEMO in maintaining the integrity of the epithelial barrier [32
T regulatory cells (TR
) are also thought to play a role in maintaining immune homeostasis in the gastrointestinal tract. Selective loss of TR
leads to severe inflammatory bowel disease in patients with the immune dysregulation, polyendocrinopahty, enteropathy, and X-linked syndrome (IPEX) [33
]. While TR
function in NEMO patients has not yet been examined, mice with T cells lacking NEMO exhibit impaired formation of TR
]. Further investigation into TR
numbers and function in NEMO patients may illuminate the specific role of TR
cells in gastrointestinal disease.
Lastly, though NF-κB activity is traditionally associated with enhanced immune responses, recent studies suggest NF-κB may also contribute to downmodulation of the immune response. In particular, interleukin-1 beta processing and secretion appear to be negatively regulated by NF-κB signaling [34
], and interference with IKK activity via pharmacologic inhibition or genetic deletion of IKKβ leads to hypersusceptibility to endotoxin mediated shock. It is plausible that diminished IKK activity secondary to defective NEMO function could have a similar effect.
Given the large numbers and distinct phenotypes of immune cells affected in the NEMO syndrome, these mechanisms are not mutually exclusive and multiple processes may be involved. Further investigation into the function of immune cells in NEMO syndrome patients and the phenotypic variations amongst the myriad NEMO mutations will likely provide insight to the cause of the aberrant immune responses seen in these individuals.