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Activated phosphatidylinositol 3-kinase-δ (PI3K-δ) syndrome (APDS) is a rare primary combined immunodeficiency caused by either dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of PI3K-δ (referred to as type 1 APDS) or dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits (type 2 APDS). In types 1 and 2 APDS, the PI3K-δ hyperactivity resulting from the gene mutations leads to similar clinical presentations, characterized by increased susceptibility to bacterial and viral infections and (to a lesser extent) autoimmune manifestations. A hallmark of this disease is lymphoproliferation, which may even be life threatening and require repeated surgical treatment. A major complication of APDS is malignancy (especially B-cell lymphomas), which greatly worsens the prognosis. Here, we review the different neoplastic conditions observed in patients with APDS and discuss the uncontrolled PI3K-δ activity in B and T cells that leads to malignant transformation.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies in humans that affect both children and adults. The patients display a decrease in IgG and/or IgA serum levels associated with lower, normal or higher IgM levels, which cause an increased susceptibility to bacterial but also viral infections. Main other complications are auto-immunity, lymphoproliferation and increased susceptibility to various types of cancers. PADs can be caused by B intrinsic and/or extrinsic defects leading to impaired early B cell development, B cell migration, B cell survival, B cell activation or defects in Immunoglobulin class switch recombination (CSR). Among the latter (B cell activation- and CSR-deficiencies), some PADs are linked to unbalanced signaling pathways, in which both gain of function and loss of function variations lead to different immune defects, pinpointing the requirement of a tightly controlled activity for proper immune response. 1) Activated PI3K-d Syndromes (APDS) are due to dominant mutations in either the PIK3CD gene encoding the p110d protein, the catalytic subunit of phosphoinositide 3 kinase d (PI3Kd) or the PIK3R1 gene encoding the regulatory subunit of phosphoinositide 3 kinase p85a. Both gene defects lead to hyperactivation of PI3K through an increased p110δ function. A frequent hyper-IgM phenotype is observed, likely due to both a T and a B cell defect. Of note, impaired or loss of function of p110δ or p85α subunit of PI3K leads to a completely different phenotype characterized by an autosomal recessive agammaglobulinemia. The main life-threatening complication of APDS is B lymphoma occurrence. Targeted therapy aiming to decrease PI3K activation is currently on trial. 2) The importance of the canonical NF-kB signaling for B cell function was firstly highlighted by the description that missense hemizygous mutations in the IKBKG gene, encoding NEMO, the NF-kB essential modulator, cause an X-linked CSR-deficiency associated with hyphohydrotic ectodermal dysplasia. Recently, heterozygous mutations in either the NFKB1 or the NFKB2 genes (encoding respectively for p105 processed to p50 and p100 processed to p52), have been reported to be causative for common variable immunodeficiency (CVID) due to haploinsufficiency of NF-êkB1 (p52) or NF-kB2 (p50), with less nuclear NF-kB accumulation and less transcriptional regulation. Some carriers are asymptomatic, pinpointing to incomplete penetrance, that suggests the role of gene modifyers or environmental factors. Although NF-κB1-deficiency affects mostly B cells, NF-kB2- deficiency combines a T, B and NK cell defect and is frequently associated to pituitary hormone deficiency. CARD11 (caspase recruitment domain containing protein 11)-deficiency (caused by loss of function bi-allelic mutations) also indicated the importance of CARD11 mediated canonical NF-kB1 signaling for B and T cell function since CARD11-deficient patients have a CVID phenotype. Interestingly, heterozygous gain of function mutations in CARD 11 lead to a different phenotype, the so-called BENTA syndrome ("B cell expansion with NF-kB and T cell anergy") characterized by B cell lymphocytosis, lymphoproliferation and immunodeficiency. These examples of PADs show that gain of function, haploinsufficiencies and loss of function mutations can be deleterious by disturbing the delicate balance required for adequate signaling pathways during the immune response. Disclosures No relevant conflicts of interest to declare.

Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.

B-lymphoproliferative disorder (BLPD) is a rare but severe complication of organ and bone marrow transplantation (BMT). Profound cytotoxic T-cell deficiency is thought to allow the outgrowth of Epstein-Barr virus–transformed B cells. When possible, reduction of immunosuppressive treatment or surgery for localized disease may cure BLPD. Therapeutic approaches using chemotherapy or antiviral drugs have limited effects on survival. Adoptive immunotherapy with donor T-cell infusions has given promising results in BMT recipients. We previously reported that administration of two monoclonal anti–B-cell antibodies (anti-CD21 and anti-CD24) could contribute to the control of oligoclonal BLPD. Here we report the long-term results of treatment with these monoclonal anti–B-cell antibodies for cases of severe BLPD. In an open multicenter trial, 58 patients in whom aggressive B-cell lymphoproliferative disorder developed after BMT (n = 27) or organ (n = 31) transplantation received 0.2 mg/kg/d of specific anti-CD21 and anti-CD24 murine monoclonal antibodies (MoAbs) for 10 days. The treatment was well tolerated. Thirty-six of the 59 episodes of BLPD in the 58 patients presented complete remission (61%). The relapse rate was low (3 of 36, 8%). Multivariate analysis identified the following risk factors for partial or no response to anti–B-cell MoAb therapy: multivisceral disease (P ≤ .005), central nervous system involvement (P ≤ .05), and late onset of BLPD (P ≤ .005). The overall long-term survival was 46% (median follow-up, 61 months); it was lower among BMT patients (35%) than organ transplant patients (55%). None of the patients who had received BMT for hematological malignancy survived for 1 year. Eight of these 11 patients presented monoclonal BLPD. Tumor burden was the only other variable that contributed significantly to poor survival. Thus, as assessed from this long-term study, the use of anti–B-cell MoAbs therefore appears to be a safe and relatively effective therapy for severe posttransplant BLPD.© 1998 by The American Society of Hematology.

The homozygous deletion of the inducible costimulator (ICOS), an activation-induced member of the CD28 family on T cells, causes an antibody deficiency syndrome in affected humans. The identification of a total of 9 ICOS-deficient patients revealed that this monogenic disease comprises the full clinical phenotype described for common variable immunodeficiency (CVID), including recurrent bacterial infections, adult as well as childhood onset, splenomegaly, autoimmune phenomena (autoimmune neutropenia), intestinal lymphoid hyperplasia, and malignancy (carcinoma of the vulva). All patients exhibited a profound hypogammaglobulinemia and a disturbed B-cell homeostasis. The severe reduction of class-switched memory B cells resulted from poor germinal center formation in the absence of ICOS. The additional decrease of naive B cells was associated with a partial inhibition of the early B-cell development at the pre-B-I stage. T-cell homeostasis seemed not to be affected, but low IL-10 production by ICOS-deficient T cells may contribute to the disturbed germinal center reaction. Human ICOS deficiency is indistinguishable from CVID and thus serves as a monogenic model for this complex syndrome.