BackgroundActivated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.ConclusionAPDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Background The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in host defense against infections. Disseminated infection caused by BCG vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected individuals, the etiology of disseminated BCG disease is unexplained. Methods We investigated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, requiring hematopoietic stem cell transplantation. We also studied two otherwise healthy adults with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic cells compartments in these three persons and sequenced candidate genes, mutation of which could plausibly confer susceptibility to BCG disease. Results We detected two distinct disease-causing mutations affecting the transcriptional regulator IRF8. Both K108A and T80A mutations impair IRF8 transcriptional activity by disrupting IRF8 interaction with DNA. Mutation K108E was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. Mutation T80A was associated with an autosomal dominant milder immunodeficiency and a selective depletion of CD11c+ CD1c+ circulating dendritic cells. Conclusions These findings define a new class of human primary immunodeficiency, affecting the differentiation of mononuclear phagocytes. They also demonstrate that human IRF8 is critically required for the development of monocytes and dendritic cells and for anti-mycobacterial immunity.

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.

Key Points Ten cases of an indolent T-cell lymphoproliferative disease of the gastrointestinal tract are reported. It is important to recognize this condition because it can be mistaken for aggressive T-cell lymphoma, which may lead to unnecessary therapy.

• Diverse patient groups with GATA2 mutation develop mononuclear cytopenia and elevated Flt3 ligand. • Progressive cytopenias, risingFlt3 ligand, and terminal differentiation of lymphoid cells accompany clinical progression.Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56 bright NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8 1 memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making. (Blood. 2014;123(6):863-874)

The cytokines interleukin 2 (IL-2) and IL-15 have similar biological effects on T cells and bind common hematopoietin receptor subunits. Pathways that involve Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to be important for hematopoietin receptor signaling. In this study we identify the STAT proteins activated by in human T cells. IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5, and DNA-binding complexes containing STAT3 and STAT5 were rapidly activated by these cytokines in T cells. IL-4 induced tyrosine phosphorylation and activation of STAT3 but not STAT5. JAK1 and JAK3 were tyrosinephosphorylated in response to IL-2 and IL-S15. Hence, the JAK and STAT molecules that are activated in response to IL-2 and IL-15 are similar but differ from those induced by IL-4. These observations identify the STAT proteins activated by IL-2 and IL-15 and therefore define signaling pathways by which these T-cell growth factors may regulate gene transcription.Interleukin 2 (IL-2) is a key growth factor that induces the proliferation and functional differentiation of T lymphocytes and natural killer cells. IL-15 shares many characteristics with IL-2, such as the generation of cytotoxic T cells and lymphokine-activated killer cells (1-3). Two IL-2 receptor subunits, the , chain (p75) and the common y chain (-yc), are used by IL-15, and Yc is also shared by other cytokine receptors, including the IL-4 receptor (4, 5). Studies also suggest the existence of an IL-15 receptor subunit distinct from the IL-2 receptor subunits (3). The finding that IL-15 and IL-2 share receptor subunits and exhibit overlapping biological effects implies that they may activate common intracellular substrates but, as yet, this has not been explored.Recently, a signal transduction pathway that involves Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) has been found to be utilized by a number of growth factors and cytokines that bind members of the hematopoietin receptor family (6, 7). We and others (8-11) have cloned a member of the Janus family (JAK3) and have shown that JAK3 and JAK1 are functionally coupled to the IL-2 receptor, as well as other receptors that use 'yc (receptors for IL-4, -7, and -9). The requisite role of yc in signaling is perhaps best illustrated by the discovery that mutations of this subunit result in X chromosome-linked severe combined immunodeficiency (12). Many of these mutations disrupt JAK3-,yc interactions, suggesting that this disruption might be important in the pathogenesis of this immunodeficiency (13). Given that IL-15 shares this common receptor subunit, it was important to examine whether IL-15 might also activate JAK3 and JAK1. Studies of the mechanism by which hematopoietin receptors activate gene transcription indicate that STAT proteins become rapidly tyrosine-phosphorylated in the receptor complex and directly translocate to the nucleus, where they bind DNA and activate transcription (14...

Interleukin 12 (IL-12) is an important immunoregulatory cytokine whose receptor is a member of the hematopoietin receptor superfamily. Interleukin 12 (IL-12) is a monocyte/macrophage-derived cytokine (1, 2), which, through its many effects on natural killer (NK) and T lymphocytes, plays a central role in the initiation and control of cell-mediated immune responses (3,4). The receptor for IL-12 (IL-12R) is incompletely characterized, although a low-affinity subunit has recently been cloned (5). This subunit is a member of the hematopoietin receptor family, closely related to gpl3O. Like other family members, binding of IL-12 to the IL-12R induces rapid tyrosine phosphorylation of a range of intracellular substrates (6, 7). However, hematopoietin receptors do not possess intrinsic tyrosine kinase activity but instead associate with and activate members of the Janus (JAK) family of cytoplasmic protein tyrosine kinases (8-12). We have recently demonstrated that IL-12 treatment of human T and NK cells leads to the rapid tyrosine phosphorylation of both JAK2 and Tyk2 kinases, implicating these kinases in the immediate biochemical response to IL-12 (6).The biological effects of IL-12 include the rapid activation of early-response genes such as interferon y (IFN-,y) and perforin (3, 4), but the molecular mechanisms by which IL-12 might stimulate transcription are not known. A number of recent studies have identified a family of transcription factors called STATs (signal transducers and activators of transcription), which are involved in the signal-transduction cascades of many cytokines known to activate JAK kinases (8, 13-15). Originally described as mediators of IFN-induced transcription, STATs are latent cytoplasmic transcription factors that, after tyrosine phosphorylation, translocate to the nucleus and bind specific, but related, DNA sequences to promote transcription of cytokine-responsive genes (13). IFN-a induces tyrosine phosphorylation of STAT1 and STAT2, which associate with a nuclear 48-kDa DNA-binding protein to form a multiprotein transcriptional activator known as interferonstimulated gene factor 3 (16, 17). In contrast, IFN-,y promotes tyrosine phosphorylation and homodimerization of STAT1, which translocates to the nucleus and directly binds to a conserved sequence motif termed the IFN-y-activation site (18). Ligand binding to many hematopoietin receptors has now been shown to induce tyrosine phosphorylation of STAT family proteins, thereby promoting their ability to bind IFNy-activation site-related DNA sequences: the IL-6 family of cytokines activate both STAT1 and STAT3 (19,20), prolactin activates STAT1 (21) and STAT5 (22), and IL-4 activates a STAT protein designated IL-4-STAT (STAT6) (23). STAT4 is another family member with restricted distribution, being expressed mainly by myeloid cells and developing spermatogonia and also in thymus and spleen (24,25). To date, no STAT4-activating ligand has been identified.In this study we sought to determine whether STAT proteins could be identified ...

Infectious agents play a critical role in MALT lymphoma development. Studies from Italy showed Chlamydia psittaci infection in 87% of ocular adnexal MALT lymphomas and complete or partial regression of the lymphoma after C. psittaci eradication in four of nine cases. However, C. psittaci was not demonstrated in ocular adnexal MALT lymphomas from the USA. This study was thus designed to investigate further the role of C. psittaci, and other infectious agents commonly associated with chronic eye disease, in the development of ocular adnexal MALT lymphoma. The presence of C. psittaci, C. trachomatis, C. pneumoniae, herpes simplex virus 1 and 2 (HSV1, HSV2), and adenovirus 8 and 19 (ADV8, ADV19) was assessed separately by polymerase chain reaction in 142 ocular adnexal MALT lymphomas, 53 non-marginal zone lymphomas, and 51 ocular adnexal biopsies without a lymphoproliferative disorder (LPD), from six geographical regions. C. psittaci was detected at similar low frequencies in non-LPD and non-marginal zone lymphoma groups from different geographical regions (0-14%). Overall, the prevalence of C. psittaci was significantly higher in MALT lymphomas (22%) than in non-LPD (10%, p=0.042) and non-marginal zone lymphoma cases (9%, p=0.033). However, the prevalence of C. psittaci infection in MALT lymphoma showed marked variation among the six geographical regions examined, being most frequent in Germany (47%), followed by the East Coast of the USA (35%) and the Netherlands (29%), but relatively low in Italy (13%), the UK (12%), and Southern China (11%). No significant differences in the detection of C. pneumoniae, C. trachomatis, HSV1, HSV2, ADV8, and ADV19 were found between lymphomas and controls from different geographical regions. In conclusion, our results show that C. psittaci, but not C. pneumoniae, C. trachomatis, HSV1, HSV2, ADV8 or ADV19, is associated with ocular adnexal MALT lymphoma and that this association is variable in different geographical areas.