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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

Clinical and immunological phenotype. Initially, the index patient presented with a parapharyngeal abscess which was surgically drained (a). Immunological assessment revealed normal total number of B cells (b) but decreased numbers of non-switched (CD27+IgD+) and switched (CD27+IgD−) memory B cells in comparison to healthy donor. c At the age of 18 years, the patient showed EBV lymphoproliferative diseases including EBV reactivation, cervical lymphadenopathy (d), splenomegaly (e), and multiple splenic lesions (f), all of which normalized upon treatment with anti-CD20 (rituximab)
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Fig1: Clinical and immunological phenotype. Initially, the index patient presented with a parapharyngeal abscess which was surgically drained (a). Immunological assessment revealed normal total number of B cells (b) but decreased numbers of non-switched (CD27+IgD+) and switched (CD27+IgD−) memory B cells in comparison to healthy donor. c At the age of 18 years, the patient showed EBV lymphoproliferative diseases including EBV reactivation, cervical lymphadenopathy (d), splenomegaly (e), and multiple splenic lesions (f), all of which normalized upon treatment with anti-CD20 (rituximab)

Mentions: At the age of 15 years, she was referred to our hospital for the first time with fever and problems with swallowing and was found to have parapharyngeal abscess (Fig. 1a) and cervical lymphadenopathy. Blood results showed leukopenia (1.89 G/l), neutropenia (0.06 G/l), thrombocytopenia (minimum 119 G/l), and elevated C-reactive protein levels (CRP; 174 mg/l). No hepatosplenomegaly was apparent. The parapharyngeal abscess was surgically drained; histological evaluation revealed chronic abscess-forming inflammation, microbiologic culture infection with viridans group streptococci and actinomyces. Decreased leukocyte and thrombocyte counts prompted bone marrow aspiration, which revealed predominantly immature granulopoesis, compatible with bacterial infection, but no evidence of myelodysplasia or malignant disease. The patient improved with antibiotic therapy and absolute neutrophil counts normalized concomitantly. Immunological investigations following recovery revealed low absolute numbers of CD19+ B cells with reduced non-switched and switched memory cells (IgD+/CD27+; IgD−/CD27+) and low immunoglobulin levels (Fig. 1b, c and Table 1). Absolute numbers of T cells were normal; however, proliferation assays revealed impaired T-cell function in response to tetanus toxoid, CD3, and PMA with normal response to PHA (Table 1). The patient was started on intravenous and subsequently subcutaneous immunoglobulin substitution. Absolute neutrophil counts and thrombocytes were repeatedly decreased (thrombocytes with a minimum of 32 G/l) with spontaneous normalization; however, anti-granulocyte and anti-thrombocyte antibodies were negative. Few months later, she developed fever, neutropenia (0.1 G/l), elevated CRP (80 mg/l), esophagitis, cervical, axillary and supraclavicular lymphadenopathy, and mild hepatosplenomegaly. Axillary lymph node biopsy showed reactive changes and the patient improved with antibiotic therapy.Fig. 1


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)

Clinical and immunological phenotype. Initially, the index patient presented with a parapharyngeal abscess which was surgically drained (a). Immunological assessment revealed normal total number of B cells (b) but decreased numbers of non-switched (CD27+IgD+) and switched (CD27+IgD−) memory B cells in comparison to healthy donor. c At the age of 18 years, the patient showed EBV lymphoproliferative diseases including EBV reactivation, cervical lymphadenopathy (d), splenomegaly (e), and multiple splenic lesions (f), all of which normalized upon treatment with anti-CD20 (rituximab)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940442&req=5

Fig1: Clinical and immunological phenotype. Initially, the index patient presented with a parapharyngeal abscess which was surgically drained (a). Immunological assessment revealed normal total number of B cells (b) but decreased numbers of non-switched (CD27+IgD+) and switched (CD27+IgD−) memory B cells in comparison to healthy donor. c At the age of 18 years, the patient showed EBV lymphoproliferative diseases including EBV reactivation, cervical lymphadenopathy (d), splenomegaly (e), and multiple splenic lesions (f), all of which normalized upon treatment with anti-CD20 (rituximab)
Mentions: At the age of 15 years, she was referred to our hospital for the first time with fever and problems with swallowing and was found to have parapharyngeal abscess (Fig. 1a) and cervical lymphadenopathy. Blood results showed leukopenia (1.89 G/l), neutropenia (0.06 G/l), thrombocytopenia (minimum 119 G/l), and elevated C-reactive protein levels (CRP; 174 mg/l). No hepatosplenomegaly was apparent. The parapharyngeal abscess was surgically drained; histological evaluation revealed chronic abscess-forming inflammation, microbiologic culture infection with viridans group streptococci and actinomyces. Decreased leukocyte and thrombocyte counts prompted bone marrow aspiration, which revealed predominantly immature granulopoesis, compatible with bacterial infection, but no evidence of myelodysplasia or malignant disease. The patient improved with antibiotic therapy and absolute neutrophil counts normalized concomitantly. Immunological investigations following recovery revealed low absolute numbers of CD19+ B cells with reduced non-switched and switched memory cells (IgD+/CD27+; IgD−/CD27+) and low immunoglobulin levels (Fig. 1b, c and Table 1). Absolute numbers of T cells were normal; however, proliferation assays revealed impaired T-cell function in response to tetanus toxoid, CD3, and PMA with normal response to PHA (Table 1). The patient was started on intravenous and subsequently subcutaneous immunoglobulin substitution. Absolute neutrophil counts and thrombocytes were repeatedly decreased (thrombocytes with a minimum of 32 G/l) with spontaneous normalization; however, anti-granulocyte and anti-thrombocyte antibodies were negative. Few months later, she developed fever, neutropenia (0.1 G/l), elevated CRP (80 mg/l), esophagitis, cervical, axillary and supraclavicular lymphadenopathy, and mild hepatosplenomegaly. Axillary lymph node biopsy showed reactive changes and the patient improved with antibiotic therapy.Fig. 1

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