We report what we believe is a novel primary immunodeficiency, which leads to an XLP-like phenotype in girls, caused by a homozygous mutation in ITK on chromosome 5q31–5q32. This is the first molecular cause of an autosomal recessively inherited lymphoproliferative disease.
Both ITK-deficient individuals suffered from uncontrolled EBV infection meeting several criteria for secondary hemophagocytic lymphohistiocytosis, but without evidence of hemophagocytosis in BM and lymph nodes. In contrast to SAP deficiency, in which the development of preferably Burkitt lymphoma is not restricted to EBV-positive individuals, and XIAP deficiency, in which no case of lymphoma occurred so far, the leading symptom was an atypical, generalized EBV-positive B cell proliferation with progression to Hodgkin lymphoma in patient 1 (5
). It is not clear whether the progressive decline of lymphocytes in patient 1, which led to Pneumocystis jirovecii and BK virus infection, was due to ITK deficiency itself, chronic EBV infection, or the long-lasting virostatic therapy.
The non-receptor tyrosine kinase ITK is a member of the Tec kinase family, which also includes Bruton’s tyrosine kinase (BTK), Tec protein tyrosine kinase (TEC), RLK, and BM kinase X-linked (BMX) (15
). Tec kinases contain a conserved SH3, SH2 and catalytic (kinase) domain. The SH2 domain of non-receptor tyrosine kinases is a non-catalytic protein interaction module, which by engaging with a phosphotyrosine-containing signaling partner regulates activity of the catalytic domain (16
). Our results suggest that R335W mutant ITK causes a profound instability of the ITK protein rather than an impairment of ITK activation. Interestingly, mutations at exactly analogous positions within the SH2 domain have been described in BTK (Y361C) (17
) and SAP (Q99P) (18
), both leading to protein instability and the clinical phenotype of atypical X-linked agammaglobulinemia (XLA) and XLP, respectively (Figure D).
Given the pivotal role of ITK in a number of T cell signaling pathways, absence of Itk has been studied in great detail in mice, but no human disease with ITK deficiency has been described yet. The previously published experimental data in Itk–/–
mouse cells greatly facilitated the choice of ITK among our candidate gene list of 78 genes after linkage analysis. Loss of Itk in mice leads to major immunological abnormalities, e.g., decreased responses to TCR stimulation, T cell proliferation, production of IL-2 and other effector cytokines, as well as altered thymic selection of CD4+
cells by modulation of TCR signal strength (19
). In a set of elegant experiments, different research groups demonstrated that Tec kinase–deficient mice develop a large population of abnormal CD8+
T cells exhibiting innate immune properties but with high expression of the memory markers CD44 and CD122 (24
We also found a clearly increased memory phenotype in our patients pointing to a profoundly altered differentiation of the conventional T cell lineage (Table ). Perhaps the most important paralleling feature between Itk-deficient mice and humans is the absence or reduced numbers of NKT cells. Itk–/–
mice show a block of NKT cell maturation and reduced peripheral survival of NKT cells (8
In mice, NKT cells have been shown to provide a protective innate-type immune response to several microbes (27
) including viruses, e.g., HSV1 and HSV2 (28
) and hepatitis B virus (30
). Strong evidence for a paramount biological relevance of NKT cells in humans comes from the observation that boys with XLP due to SAP or XIAP deficiency show a severely reduced number, or even a complete absence, of NKT cells (5
). Thus, a critical role for NKT cells in the immune response to EBV infection in humans has been postulated (5
). The absence of NKT cells in patient 2 and the concomitant inability to clear EBV infection in the 2 ITK-deficient sisters strengthens the hypothesis of a role for NKT cells in the control of EBV infection. The fact that both heterozygous parents have low but still detectable numbers of NKT cells also suggests that ITK is required for the selection and/or survival of NKT cells not only in mice, but also in humans. Rigaud et al. found normal numbers of NKT cells in 8 patients with acute infectious mononucleosis, showing that the absence of NKT cells is not an immediate consequence of acute EBV infection (5
), whereas to our knowledge there are no data on NKT cell numbers in patients with chronic active EBV infection. EBV affects more than 90% of the world’s population, but why the adequate immunological control of this successful member of the herpes family seems to be critically dependent on this numerically rather tiny cell population remains obscure.
However, as there are autoimmune conditions in which patients with a severely reduced number of NKT cells are not especially susceptible to EBV infection (31
), the lack of NKT cells is likely to contribute to the impaired immune response to EBV but may not be the single underlying factor. Other evidence for a protective role of invariant NKT cells in human infection is rather limited. In 2003 Levy et al. reported a girl with severe varicella infection after varicella vaccination, in whom an absolute deficiency of invariant NKT cells was the only detectable immunologic abnormality (32
The immunophenotypical as well as functional analyses in our cases were performed following several months of active EBV infection. Thus, it is not possible to clearly distinguish between the impact of EBV infection and ITK deficiency itself. In the future, the identification and examination of further patients with ITK deficiency will certainly contribute to elucidating the functional implications of ITK deficiency in different lymphocyte lineages on host defense. We recommend that in all children with EBV-associated lymphoproliferative disorders, ITK deficiency should be considered because it may show striking clinical and immunological similarities to SAP or XIAP deficiency in boys.