Successful Treatment with Infliximab for Inflammatory Colitis in a Patient with X-linked Anhidrotic Ectodermal Dysplasia with Immunodeficiency

Abstract

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.

Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

“…Because the dominance of the memory phenotype and the skewed TCR repertoire among CD8 ϩ T cells in NEMO normal cells were observed in both patients 1 and 2 ( Figure 1C and Mizukami et al 18 ), continuous infection of pyogenic bacteria in patient 1 and M szulgai in patient 2 could be a reason for the emergence of NEMO normal cells and the elimination of NEMO low cells. The decrease in NEMO normal cells and restoration of NEMO low cells after anti-mycobacterial therapy in patient 2 support this hypothesis.…”

“…The decrease in NEMO normal cells and restoration of NEMO low cells after anti-mycobacterial therapy in patient 2 support this hypothesis. In the case of patient 1, the predominance of NEMO normal T cells with an effector/memory phenotype at diagnosis (Table 4 and Mizukami et al 18 ) is likely to be the result of chronic infection, and it is possible that NEMO low cells were predominant during his early infancy. Because some reports have indicated that TNF-␣-induced programmed cell death of several cell types, including a human T-cell line, was enhanced by hypomorphic NEMO mutations, 12,35 and considering our finding that the levels of TNF-␣ expressed in revertant T cells were similar to levels in healthy control T cells in vitro ( Figure 1F), TNF-␣ produced from these cells in response to infection could be involved in mutant T-cell elimination.…”

“…38 Indeed, in patient 4, the percentage of reverted T cells was reduced after repeated administrations of anti-TNF␣ blocking Ab, and the symptoms of inflammatory bowel disease improved. 18 Considering this evidence, somatic mosaicism in T cells might be an important factor leading to inflammatory disease in XL-EDA-ID patients with defective NF-B activation. However, our study did not show a tight association between inflammatory bowel disease and somatic mosaicism, and further investigation is needed to determine whether the NEMO normal T cells play a role in inflammatory processes in XL-EDA-ID.…”

“…Clinical details of patients 3, 4, and 10 have been reported previously. [18][19][20] These patients had clinical phenotypes characteristic of XL-EDA-ID such as ectodermal dysplasia, innate and/or acquired immunity defects, and susceptibility to pyogenic bacteria and Mycobacterium infection. Every patient had a mutation in the NEMO gene that caused reduced NF-B activation in a NEMO reconstitution assay, as described in "Proliferation of NEMO normal and NEMO low T cells."…”

“…Intracellular staining of human IFN-␥, TNF-␣, and NEMO was performed as previously described. 18 The stained cells were collected using a FACSCalibur flow cytometer (BD Biosciences) and analyzed using the FlowJo software (TreeStar).…”