Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation

Ramakrishnan, Kesava A.; Rae, William; Barcenas-Morales, Gabriela; Gao, Yifang; Pengelly, Reuben J.; Patel, Sanjay; Kumararatne, Dinakantha; Ennis, Sarah; Döffinger, Rainer; Faust, Saul N; Williams, Anthony P.

doi:10.1016/j.jaci.2017.11.014

Cited by 30 publications

(20 citation statements)

References 12 publications

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“…It is likely that both T cell and NK cell abnormalities contributed to an overwhelming CMV infection in this patient. Anti-cytokine antibodies were not measured in our patient but they have also been described in patients with mutations in NFKB2 , these may be directed to type 1 interferons and also contribute to an impaired antiviral immunity (32).…”

Section: Discussionmentioning

confidence: 78%

Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome

et al. 2019

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Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871 * ) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.

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Section: Discussionmentioning

confidence: 78%

Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome

et al. 2019

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“…Ramakrishnan et al [39 ▪▪ ] presented a patient with chronic variable immunodeficiency caused by a heterozygous NFKB2 mutation. The patient developed severe pyogenic bacterial infections but also recurrent viral infections despite Ig replacement therapy.…”

Section: Nf-κb2 Deficiency May Be Associated With High Titre Neutralimentioning

confidence: 99%

“…Rituximab treatment which resulted in a marked reduction of some anticytokine titres and clinical improvement with no further invasive infections was observed. It is unclear, if this improvement is secondary to the reductions in the observed anticytokine titres, given the broad range of so far observed ACAA and potentially many as yet unknown related targets [39 ▪▪ ]. In line with this are findings in hypomorphic recombination activation gene deficient patients and Thymoma patients where the incidence and complexity of the patients anticytokine patterns where positively correlated with increased susceptibilities to infections [40,41].…”

Section: Nf-κb2 Deficiency May Be Associated With High Titre Neutralimentioning

confidence: 99%

Anticytokine autoantibodies leading to infection: early recognition, diagnosis and treatment options

Barcenas-Morales

Cortes-Acevedo

Döffinger

2019

Current Opinion in Infectious Diseases

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Purpose of review The current review gives a concise and updated overview of the relative new field of anticytokine autoantibodies (ACAA) and associated infections with a focus on recent findings regarding clinical manifestions, diagnostic and treatments. Recent findings Several recent case reports of unusual presentations of patients with neutralizing autoantibodies to IFN-γ and granulocyt macrophage colony-stimulating factor and expand the spectrum of clinical manifestations and suggest that anticytokine-mediated acquired immunodeficiency causing susceptibility to infection may be underdiagnosed. There is an expanding geographical distribution of antigranulocyt macrophage colony-stimulating factor associated Cryptococcus gattii infection. The spectrum of identified infections in patients with neutralizing antibodies to IFN-γ has a strong endemic component. Rituximab or cyclophophamide in addition to antimycobacterials could be a treatment options in refractory cases. NF-κB2 deficiency may be associated with a complex pattern of high titre neutralizing ACAA similar to autoimmune polyglandular syndrome type I and Thymoma. New technique for the detection of anticytokine antibodies are presented. Quantiferon testing, which is widely available for TB-diagnostic, may be repurposed to detect anti-IFN-γ autoantibodies. We propose that this test could be as well used to show if they are neutralizing. Summary ACAA are an emerging cause of acquired immunodeficiency which is likely underdiagnosed. Recent case reports document expanding spectra of clinical manifestations. NF-κB2 deficiency may be associated with a complex anti cytokine autoantibody pattern.

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“…In the patient's family, all three CVID-affected family members had a history of recurrent HSV skin lesions. Not surprisingly, loss-of-function NFKB2 mutations, leading to defective NF-κB2 protein function in the non-canonical NF-κB pathway, have been associated with susceptibility to viral infections, including HSV, varicella, herpes zoster, and molluscum contagiosum (6, 19–21). A NFKB2 gain-of-function mutation resulting in a combined immunodeficiency phenotype has also been reported to have increased susceptibility to viral infections.…”

Section: Discussionmentioning

confidence: 99%

“…At least two mechanisms may contribute to the increased susceptibility to viral infections in patients with NFKB2 defects: (1) Defective NK cell cytotoxicity has been described in a patient with CVID-like disease due to NFKB2 mutation (24); NK cells are critical in the cytotoxicity of virus-infected cells including herpes viruses (25), and (2) neutralizing anticytokine autoantibodies to interleukins and interferons have also been reported in an unrelated case of a CVID patient with a loss-function mutation in NFKB2 who had severe recurrent bacterial and viral infections that improved after treatment with the anti-CD20 B-cell targeting monoclonal antibody, rituximab. Post-treatment, the patient had a significant reduction of autoantibody titers and no recurrence of invasive infections (21). In the current case report involving severe herpes vegetans and HSV viremia, abnormal NK cell function as well as neutralizing anti-IFN-ω and anti-IFN-α antibodies were identified, likely contributing to the recurrent and severe nature of the patient's HSV infection, and rituximab is being considered as a treatment option.…”

Section: Discussionmentioning

confidence: 99%

Severe Facial Herpes Vegetans and Viremia in NFKB2-Deficient Common Variable Immunodeficiency

et al. 2019

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With the accessibility of next-generation sequencing modalities, an increasing number of primary immunodeficiency disorders (PIDDs) such as common variable immunodeficiency (CVID) have gained improved understanding of molecular pathogenesis and disease phenotype with the identification of a genetic etiology. We report a patient with early-onset CVID due to an autosomal dominant loss-of-function mutation in NFKB2 who developed a severe herpes vegetans cutaneous infection as well as concurrent herpes simplex virus viremia. The case highlights features of CVID, unique aspects of NF-κB2 deficiency including susceptibility to herpesvirus infections, the detection of neutralizing anticytokine antibodies, and the complexity of medical management of patients with a PIDD that can be aided by a known genetic diagnosis.

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Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation

Cited by 30 publications

References 12 publications

Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome

Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome

Anticytokine autoantibodies leading to infection: early recognition, diagnosis and treatment options

Severe Facial Herpes Vegetans and Viremia in NFKB2-Deficient Common Variable Immunodeficiency

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