Interleukin-2-Inducible T-Cell Kinase (ITK) Deficiency - Clinical and Molecular Aspects

Abstract

In patients with underlying immunodeficiency, Epstein-Barr virus (EBV) may lead to severe immune dysregulation manifesting as fatal mononucleosis, lymphoma, lymphoproliferative disease (LPD), lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis (HLH) and dysgammaglobulinemia. Several newly discovered primary immunodeficiencies (STK4, CD27, MAGT1, CORO1A) have been described in recent years; our group and collaborators were able to reveal the pathogenicity of mutations in the Interleukin-2-inducible T-cell Kinase (ITK) in a cohort of nine patients with most patients presenting with massive EBV B-cell lymphoproliferation. This review summarizes the clinical and immunological findings in these patients. Moreover, we describe the functional consequences of the mutations and draw comparisons with the extensively investigated function of ITK in vitro and in the murine model.

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

“…Two patients had CD27 deficiency and one had ITK deficiency, conditions that have previously been associated with poor control of EBV infection (Table 1). 45,46 The second main group consisted of …”

Severe Epstein–Barr virus infection in primary immunodeficiency and the normal host

“…ITK is a member of the TEC kinase family (which includes BTK) and is required for normal development and signalling in lymphoid cells. Some benefit has been shown for rituximab and aciclovir therapy, but steroids do not appear to ameliorate the clinical features (Ghosh et al, 2014;Cipe et al, 2015). Clinical features are primarily related to EBVassociated lymphoproliferation but opportunistic infections associated with T-cell deficiencies have also been reported.…”

“…Progressive reduction in CD4 + T-cells, na€ ıve CD4 + T-cells and NKT-cell numbers is a common feature along with hypogammaglobulinaemia. Two patients have received HSCT (one matched sibling donor, one haploidentical donor) with one patient surviving (Ghosh et al, 2014). Nine patients have been described to date, eight of whom presented with LPD between the ages of 3 and 13 years (Ghosh et al, 2014).…”

Inducible T Cell Kinase Regulates the Acquisition of Cytolytic Capacity and Degranulation in CD8+ CTLs

“…In addition, lymphomas, defective antibody responses, and a broader susceptibility to viral infection were also reported in these patients (reviewed in (23)), highlighting a potential requirement for ITK for proper CTL function. Intriguingly, this clinical phenotype resembles a number of other primary immunodeficiencies, including X-linked lymphoproliferative syndrome (XLP-1), a disease caused by mutations affecting the small adaptor molecule, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP).…”