IL-2-Inducible T-Cell Kinase Deficiency with Pulmonary Manifestations due to Disseminated Epstein-Barr Virus Infection

Abstract

IL-2-inducible T-cell kinase (ITK) deficiency is a rare inherited immunodeficiency disease characterized by homozygous mutations in the ITK gene and the inability to control Epstein-Barr virus (EBV) infection leading to EBV-associated lymphoproliferative disorders of B cell origin. Many aspects of its clinical presentation and immunologic phenotype are still unclear to clinicians. We report on a 14-year-old female patient with complaints of an 8-month history of cough and fever. Imaging studies revealed diffuse pulmonary nodules and mediastinal lymphadenopathy. Transbronchial lung biopsy showed nonmalignant polyclonal B cell proliferation. High titers of EBV DNA were detected by PCR analysis in bronchoalveolar lavage fluid, bone marrow, and blood. Genomic analysis revealed a homozygous single base pair deletion in exon 5 of the ITK gene (c.468delT) in this patient. Treatment with rituximab (anti-CD20 mab) resulted in complete clinical remission with resolution of pulmonary lesions and a negative EBV titer in serum. All patients with EBV-associated lymphoproliferative disorders should be analyzed for mutations in ITK.

Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia

“…As all previously reported ITK-deficient patients were analyzed when they showed EBV-induced lymphoproliferation, we here had the unique opportunity to dissect EBV-dependent and EBV-independent ITK deficiency phenotypes. Consistent with previous findings in mouse 7 and human, [8][9][10][11] flow cytometry indicated an absence of iNKT-cells ( Figure 1D), illustrating that the absence of iNKT-cells is a primary phenotype of ITK deficiency. Although CD4 lymphopenia has already been described in other ITK-deficient patients suffering from lymphoproliferative disease, 9,11 we here show that combined immunodeficiency with CD4 deficiency can be the predominant disease manifestation.…”

“…Consistent with previous findings in mouse 7 and human, [8][9][10][11] flow cytometry indicated an absence of iNKT-cells ( Figure 1D), illustrating that the absence of iNKT-cells is a primary phenotype of ITK deficiency. Although CD4 lymphopenia has already been described in other ITK-deficient patients suffering from lymphoproliferative disease, 9,11 we here show that combined immunodeficiency with CD4 deficiency can be the predominant disease manifestation. Furthermore, defective T-cell proliferation has not been described in ITK-deficient patients, although it is concordant with the findings in Itk 2/2 mice.…”

“…ITK is a tyrosine kinase comprising 2 Src homology and a pleckstrin homology domain, respectively, acting downstream of the T-cell receptor complex and playing a critical role during thymic CD4 All ITK-deficient patients reported to date developed EBVassociated B-cell lymphoproliferation accompanied by hepato-and splenomegaly or Hodgkin lymphoma. [8][9][10] Decreased numbers of iNKT-cells are a hallmark feature of the disease. [8][9][10][11] Surprisingly, this patient remained at sero-negative EBV status until the age of 17, although PCR-based copy-number analysis indicated borderline detectable EBV virus load (1000-2000 copies/mL).…”

“…[8][9][10] Decreased numbers of iNKT-cells are a hallmark feature of the disease. [8][9][10][11] Surprisingly, this patient remained at sero-negative EBV status until the age of 17, although PCR-based copy-number analysis indicated borderline detectable EBV virus load (1000-2000 copies/mL). As all previously reported ITK-deficient patients were analyzed when they showed EBV-induced lymphoproliferation, we here had the unique opportunity to dissect EBV-dependent and EBV-independent ITK deficiency phenotypes.…”

Targets for Ibrutinib Beyond B Cell Malignancies

“…Moreover, CD44 high CD62L − CD4 + T cells are slightly increased in TEC KO mice, and they produce more IL‐17 upon activation when compared to WT mice 43. ITK mutations in humans have been reported in several cases of a fatal Epstein–Barr virus (EBV)‐associated lymphoproliferative disorder 44, 45. ITK KO mice show altered T cell development and mature T cell effector function, affecting in particular conventional T cells, thus leading to increased numbers of CD4 + T cells with a CD44 high CD62L − memory phenotype and CD8 + T cells, with a CD44 high CD62L + innate‐like phenotype, that upon stimulation rapidly secrete high levels of effector cytokines such as IFN‐ γ 46.…”