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NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation.

Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, Pickl W, Förster-Waldl E, Boztug K - J. Clin. Immunol. (2016)

Bottom Line: We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50.The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment.Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.

View Article: PubMed Central - PubMed

Affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

ABSTRACT

Purpose: NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID).

Methods and results: We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.

Conclusions: Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.

No MeSH data available.


Related in: MedlinePlus

Identification of a disease-causing mutation in. Disease severity and complications increased over time with two severe episodes of EBV-associated lymphoproliferation within one year (a). The patient was assessed using a targeted, next-generation sequencing-based gene panel with high on-target coverage (b). A heterozygous mutation in the RHD domain of the NFKB1 gene was identified, leading to a frameshift and a subsequent stop codon (c.491delG; p.G165A*31). The patient’s father was found to be a carrier of the disease (c) and shows an aberrant B cell immunophenotype despite his mild clinical manifestation (Table 1). The mutation leads to reduced phosphorylation of p105 upon stimulation in both index patient (II-1) and father (I-2), resulting in decreased protein levels of p50 (d)
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Fig2: Identification of a disease-causing mutation in. Disease severity and complications increased over time with two severe episodes of EBV-associated lymphoproliferation within one year (a). The patient was assessed using a targeted, next-generation sequencing-based gene panel with high on-target coverage (b). A heterozygous mutation in the RHD domain of the NFKB1 gene was identified, leading to a frameshift and a subsequent stop codon (c.491delG; p.G165A*31). The patient’s father was found to be a carrier of the disease (c) and shows an aberrant B cell immunophenotype despite his mild clinical manifestation (Table 1). The mutation leads to reduced phosphorylation of p105 upon stimulation in both index patient (II-1) and father (I-2), resulting in decreased protein levels of p50 (d)

Mentions: In the following years, the patient had three to four uncomplicated infections per year (sinusitis, pharyngitis, urinary tract infection). She complained of intermittent arthralgia; autoantibodies were repeatedly negative (rheumatoid factor (RF), anti-neutrophil cytoplasmatic antibody (ANCA), anti-cardiolipin antibodies, anti-nuclear antibody (ANA)). At the age of 18 years, splenomegaly (21 cm) with multiple hypodense changes, hepatomegaly (20 cm), and generalized lymphadenopathy occurred (not shown). Blood results showed reactivation of Epstein-Barr-virus (EBV) with 1.2 × 10E3 copies/ml. Within a short time, the patient deteriorated with high fever, elevated CRP (50 mg/l), and increasing hepatosplenomegaly and lymphadenopathy (liver 22 cm, spleen 26 cm; Fig. 1d). Further investigations were not suspicious for macrophage-activating syndrome. With rising EBV load (maximum 3.1 × 10E3 copies/ml), EBV-associated lymphoproliferative disease (EBV-LPD) was suspected. The patient was started on corticosteroid treatment (1 mg/kg) and weekly rituximab (375 mg/m2) was administered four times. Prompt clinical improvement was noted, EBV load turned negative, and CD19+ B cells were not detectable for 8 months (Fig. 2a). However with reemergence of peripheral blood B cells, a similar clinical picture with fever, lymphadenopathy, and hepatoslenomegaly reoccured and reactivation of EBV (maximal load 1.2 × 10E2 copies/ml) was detected. The patient was started on cortisone and four courses rituximab, which has led to remission of the disease again. In view of the relatively severe disease course, HLA typing of the patient and family has been initiated to prepare for allogeneic hematopoietic stem cell transplantation. On inquiry of the patient’s family, the patient’s father declared he had been suffering from frequent non-severe respiratory tract infections but not requiring regular medical attention.Fig. 2


NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation.

Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, Pickl W, Förster-Waldl E, Boztug K - J. Clin. Immunol. (2016)

Identification of a disease-causing mutation in. Disease severity and complications increased over time with two severe episodes of EBV-associated lymphoproliferation within one year (a). The patient was assessed using a targeted, next-generation sequencing-based gene panel with high on-target coverage (b). A heterozygous mutation in the RHD domain of the NFKB1 gene was identified, leading to a frameshift and a subsequent stop codon (c.491delG; p.G165A*31). The patient’s father was found to be a carrier of the disease (c) and shows an aberrant B cell immunophenotype despite his mild clinical manifestation (Table 1). The mutation leads to reduced phosphorylation of p105 upon stimulation in both index patient (II-1) and father (I-2), resulting in decreased protein levels of p50 (d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4940442&req=5

Fig2: Identification of a disease-causing mutation in. Disease severity and complications increased over time with two severe episodes of EBV-associated lymphoproliferation within one year (a). The patient was assessed using a targeted, next-generation sequencing-based gene panel with high on-target coverage (b). A heterozygous mutation in the RHD domain of the NFKB1 gene was identified, leading to a frameshift and a subsequent stop codon (c.491delG; p.G165A*31). The patient’s father was found to be a carrier of the disease (c) and shows an aberrant B cell immunophenotype despite his mild clinical manifestation (Table 1). The mutation leads to reduced phosphorylation of p105 upon stimulation in both index patient (II-1) and father (I-2), resulting in decreased protein levels of p50 (d)
Mentions: In the following years, the patient had three to four uncomplicated infections per year (sinusitis, pharyngitis, urinary tract infection). She complained of intermittent arthralgia; autoantibodies were repeatedly negative (rheumatoid factor (RF), anti-neutrophil cytoplasmatic antibody (ANCA), anti-cardiolipin antibodies, anti-nuclear antibody (ANA)). At the age of 18 years, splenomegaly (21 cm) with multiple hypodense changes, hepatomegaly (20 cm), and generalized lymphadenopathy occurred (not shown). Blood results showed reactivation of Epstein-Barr-virus (EBV) with 1.2 × 10E3 copies/ml. Within a short time, the patient deteriorated with high fever, elevated CRP (50 mg/l), and increasing hepatosplenomegaly and lymphadenopathy (liver 22 cm, spleen 26 cm; Fig. 1d). Further investigations were not suspicious for macrophage-activating syndrome. With rising EBV load (maximum 3.1 × 10E3 copies/ml), EBV-associated lymphoproliferative disease (EBV-LPD) was suspected. The patient was started on corticosteroid treatment (1 mg/kg) and weekly rituximab (375 mg/m2) was administered four times. Prompt clinical improvement was noted, EBV load turned negative, and CD19+ B cells were not detectable for 8 months (Fig. 2a). However with reemergence of peripheral blood B cells, a similar clinical picture with fever, lymphadenopathy, and hepatoslenomegaly reoccured and reactivation of EBV (maximal load 1.2 × 10E2 copies/ml) was detected. The patient was started on cortisone and four courses rituximab, which has led to remission of the disease again. In view of the relatively severe disease course, HLA typing of the patient and family has been initiated to prepare for allogeneic hematopoietic stem cell transplantation. On inquiry of the patient’s family, the patient’s father declared he had been suffering from frequent non-severe respiratory tract infections but not requiring regular medical attention.Fig. 2

Bottom Line: We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50.The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment.Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.

View Article: PubMed Central - PubMed

Affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

ABSTRACT

Purpose: NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID).

Methods and results: We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.

Conclusions: Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.

No MeSH data available.


Related in: MedlinePlus