TACI Mutations Research Articles

Immunological Characteristics and Two Novel Mutations in TACI in a Cohort of 28 Pediatric Patients with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. Mutations in the gene encoding TACI (TNFRSF13B) were previously found to be associated with CVID. Previous studies have identified a variety of sequence variants in TACI where A181E and C104R were the most common, with variable frequencies in different ethnic populations. So far, no mutations were identified in the recently reported "TACI highly conserved" (THC) cytoplasmic domain, important for the induction of class switch recombination. Our study evaluated immunological and clinical data on a cohort of 28 Argentinean pediatric CVID patients and allowed the identification of two novel mutations in TNFRSF13B, including one, S231R, affecting the highly conserved THC domain. In contrast, none of the patients presented with A181E and C104R mutations.

Advances in basic and clinical immunology in 2010

Reports in basic and clinical immunology in 2010 reflected the use of state-of-the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti-CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T-cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease.

The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency

TNFRSF13B, which encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), is mutated in 10% of patients with common variable immunodeficiency. One of the 2 most common TACI mutations in common variable immunodeficiency, C104R, abolishes ligand binding and is found predominantly in the heterozygous state. The murine TACI mutant C76R is the equivalent of the human TACI mutant C104R. We sought to define the consequence of the C76R mutation on TACI function in mice that express both wild-type TACI and the murine C76R mutant. Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI(+/-) B6/129 background (C76R/TACI(+/-) mice) were constructed. Serum immunoglobulins and antibody responses to the type II T-independent antigen trinitrophenylated (TNP)-Ficoll were determined by means of ELISA. B-cell proliferation in response to a proliferation-inducing ligand was determined based on tritiated thymidine incorporation into DNA. IgG1 secretion by B cells in response to a proliferation-inducing ligand plus IL-4 was determined by means of ELISA. C76R/TACI(+/-) mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI(+/+) B6/129 control animals, and their B cells were impaired in their capacity to proliferate and secrete IgG1 in response to TACI ligation. Unexpectedly, TACI(+/-) mice had similarly impaired B-cell function as C76R/TACI(+/-) littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI(+/-) mice on the C57BL/6 background. These results suggest that the human TACI mutant C104R might impair TACI function in heterozygotes through haploinsufficiency.

Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B−A181E mutations in common variable immunodeficiency

Mutations in the TNFRSF13B ( TACI) gene have been reported to be associated with Common Variable ImmunoDeficiency (CVID). Of 48 patients evaluated within the immunodeficiency clinic, 39 had CVID, 6 had symptomatic IgA deficiency (IgAD) with or without IgG2 and IgG4 subclass deficiency, while 3 had unclassified immune dysregulatory disorders. In all 48 patients TACI genetic testing was performed, and monoallelic mutations were observed in 4 of the 39 CVID patients (10.26%), an incidence comparable to other studies. Of the 6 IgAD patients, 1 had a heterozygous TACI mutation (16.67%), while of the 3 unclassified patients, 1 had a monoallelic TACI mutation (33.3%), but his sibling who also had the same mutation had CVID. The A181E mutation is one of the statistically significant, among the known TACI gene mutations. Here, 5 of the 6 patients were found to have the A181E mutation (10.42%), which is higher than previously observed. We also evaluated 114 controls and found the A181E mutation in only 1 individual (0.88%). We report in this study that the A181E mutation is associated with a very heterogeneous clinical presentation along with variability in B-cell numbers and amount of TACI protein on memory B cells.

Transmembrane Activator and Calcium-modulator and Cyclophilin Ligand Interactor (TACI) Expression is Essential for Human B-cell Tolerance

RATIONALE: Common variable immune deficiency (CVID) is a heterogeneous disorder frequently complicated by autoimmunity. To date mutations in several genes have been associated with CVID, the most prevalent of which are mutations in the gene encoding the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). Given this association we have investigated the impact of TACI mutations on human B cell tolerance.

Immunologic messenger molecules: Cytokines, interferons, and chemokines

Cytokines and chemokines are secreted proteins involved in numerous aspects of cell growth, differentiation, and activation. A prominent feature of these molecules is their effect on the immune system with regard to cell trafficking and development of immune tissue and organs. The nature of an immune response determines which cytokines are produced and ultimately whether the response is cytotoxic, humoral, cell mediated, or allergic. For this chapter, cytokines are grouped according to those that are predominantly antigen-presenting cell or T lymphocyte derived; that mediate cytotoxic, humoral, cell mediated, and allergic immunity; or that are immunosuppressive. A discussion of chemokine function and their role in cell trafficking and disease follows.

Functional analysis of TACI mutations in Common Variable Immunodeficency (CVID)

Functional analysis of TACI mutations in Common Variable Immunodeficency (CVID)

Transmembrane activator and calcium-modulator and cyclophilin ligand interactor mutations in common variable immunodeficiency

TNFRSF13B, the gene which encodes transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is mutated in nearly 10% of patients with common variable immune deficiency (CVID), an antibody deficiency syndrome characterized by loss of memory B cells and plasma cells. This review discusses the normal function of TACI and the role of TACI mutants in CVID. TACI activates isotype switching, mediates immunoglobulin production in response to type II T-independent antigens, and plays an inhibitory role in B cell homeostasis. Recent evidence indicates that TACI synergizes with CD40 and Toll-like receptors for immunoglobulin secretion and promotion of plasma cell differentiation. The two most common TACI mutants associated with CVID--C104R and A181E--are primarily found as heterozygous mutations suggesting that they either cause haploinsufficiency or exert a dominant negative effect. TACI mutations in CVID are associated with an increased susceptibility to autoimmunity and lymphoproliferation. TACI has a dual function in promoting B cell antibody responses and inhibiting B cell proliferation. The observation that TACI mutations are present in healthy participants suggests that modifier genes may play an important role in the development of CVID. The discovery of these genes will help understand the pathogenesis of this disease.

Novel Heterozygous Mutation 572insA in TACI Identified in a Patient with Selective IgA Deficiency.

Selective IgA deficiency (SIgAD) is relatively common disease in patients with primary immunodeficiency. Recently, mutations in TNFRSF13B, encoding transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), have been identified in 7~15% of patients with common variable immunodeficiency (CVID) and 10% of those with SIgAD. However, the role of TACI mutations in the molecular pathogenesis underlying SIgAD is still controversial and remains unsolved. We identified a novel heterozygous single adenine insertion, 572insA, in exon 4 of TNFRSF13B in a patient with SIgAD. Although the same mutation was detected in her mother and younger brother, their serum immunoglobulin levels were within normal range. This frameshift mutation produces a truncated form of TACI protein lacking majority of the intracellular domain. Peripheral blood B cells from the patient and her siblings with the TACI mutation were able to produce immunoglobulin without inferiority in the presence of dendritic cells, CD40L and IL-10. However, IgD+ or IgM+ B cells from the patient were impaired to produce Cα mature transcripts in response to APRIL, one of the ligands for TACI, reflecting impairment of class-switch recombination required for differentiation into IgA-producing cells. Thus, the T-cell independent B cell activation is impaired in the patient. We overexpressed cDNAs for wild-type (WT), C104R and 572insA mutant TACI in HEK 293 cells, and analyzed the effect on signal transduction through TACI. Immuno-precipitation analysis revealed that either 572insA or C104R mutant associated with WT TACI and formed an oligomeric complex. C104R TACI has been previously shown to exert a dominant-negative effect on ligand-induced TACI signaling, since it forms an oligomeric complex with WT TACI and disrupts ligand-induced receptor signaling. Similarly, since 572insA TACI lacks an intracellular domain that is important for signal transduction, it may exert a dominant-negative effect on ligand-induced TACI signaling. Although the heterozygous 572insA TACI mutation disrupts ligand-induced TACI signaling, not all individuals carrying the mutation display humoral immune deficiency. Thus, an additional genetic modifier and/or an environmental factor may be required for the development of immunological abnormalities due to TACI mutations.

Revisiting human primary immunodeficiencies

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations.

TACI, an enigmatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties

BAFF is a B cell survival factor that binds to three receptors BAFF-R, TACI and BCMA. BAFF-R is the receptor triggering naïve B cell survival and maturation while BCMA supports the survival of plasma cells in the bone marrow. Excessive BAFF production leads to autoimmunity, presumably as the consequence of inappropriate survival of self-reactive B cells. The function of TACI has been more elusive with TACI −/− mice revealing two sides of this receptor, a positive one driving T cell-independent immune responses and a negative one down-regulating B cell activation and expansion. Recent work has revealed that the regulation of TACI expression is intimately linked to the activation of innate receptors on B cells and that TACI signalling in response to multimeric BAFF and APRIL provides positive signals to plasmablasts. How TACI negatively regulates B cells remains elusive but may involve an indirect control of BAFF levels. The discovery of TACI mutations associated with common variable immunodeficiency (CVID) in humans not only reinforces its important role for humoral responses but also suggests a more complex role than first anticipated from knockout animals. TACI is emerging as an unusual TNF receptor-like molecule with a sophisticated mode of action.

Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency

In some patients with common variable immunodeficiency (CVID) and immunoglobulin (Ig) A deficiency (IgAD), tumor necrosis factor (TNF) family receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) gene mutations have been reported. B cells from individuals with TACI mutations do not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL) which probably suggests impaired isotype switching. To clarify the pathogenesis of CVID and IgAD of Japanese patients, we investigated the mutations of TNF family members TACI, APRIL, B-cell activating factor (BAFF), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) genes and the expression levels of BAFF and APRIL in patients with CVID, IgAD and X-linked agammaglobulinaemia (XLA). We also investigated the relationship between age and the blood plasma levels of BAFF and APRIL. The causative gene mutations of TNF family members in our patients were not detected. In healthy subjects, the BAFF and APRIL plasma levels correlated inversely with age. The BAFF and APRIL plasma levels of patients with CVID, IgAD and XLA were significantly higher than those of healthy children. Elevated BAFF and APRIL expression levels might partially reflect the common immunological feature of primary antibody deficiency.

A TACI Mutation in a Patient with Autoimmune Lymphoproliferative Syndrome.

The autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte apoptosis caused by defects in the Fas apoptotic pathway. It is characterized by the association of chronic lymphoid accumulation and autoimmune manifestations. In a subgroup of patients the disease progresses through antibody deficiency and its clinical and laboratory features overlap those of common variable immunodeficiency (CVID). Some CVID cases are associated with mutations in gene TNFRSF13B, encoding TACI. Aim of this study was to determine whether TNFRSF13B mutations are also associated with ALPS. Methods. Genomic DNA from 31 ALPS patients was extracted from PBMCs after informed consent. Exons and intron-exon boundaries of TNFRSF13B gene were amplified by PCR and sequenced on an ABI PRISM 310 Genetic Analyzer. Results. A T>A transition at nt 275, that determined the non-conservative substitution of Isoleucine with Asparagine (I92N), was found in exon 3 from one patient. The mutation involved the second extracellular cysteine rich domain, which is critical for BAFF binding. It was not found in 100 control chromosomes. The patient showed a classical ALPS phenotype with lymphadenopathy, massive splenomegaly that required splenectomy, hepatomegaly and immune cytopenias (neutropenia and immune thrombocytopenic purpura); he had alopecia and high ANA levels. Serum immunoglobulins were normal (IgG titers at the lower level of the range); lymphocytes showed defective Fas-induced apoptosis. Discussion. TACI mutations might contribute to the ALPS phenotype in some cases. Our data confirm the relationships between ALPS and CVID and provides a possible molecular explanation for overlapping phenotypes.

IgA and IgG Hypogammaglobulinemia Are Associated with Mutations in the APRIL/BLYS Receptor TACI in Waldenstrom's Macroglobulinemia (WM).

IgA and IgG hypogammaglobulinemia are a common finding in patients with WM which may contribute to recurrent infections seen in up to half of WM patients. The etiology for this finding remains unclear. As part of these studies, we investigated the prevalence and genetic basis for IgA and IgG hypogammaglobulinemia among 89 previously untreated patients with the clinicopathological diagnosis of WM. Their median IgM was 2,980 (180–12,400) mg/dl, median BM involvement was 35% (5%–95%) and median B2M was 2.7 (1.4–13.7 mg/dL). Fifty-six (63%) and 66 (74%) of these patients demonstrated IgG (<700 mg/dL) and IgA (<70 mg/dL) hypogammaglobulinemia, respectively. Importantly, no correlation was seen between serum IgG and IgA levels and BM disease involvement, suggesting no direct impact of disease involvement on the production of uninvolved immunoglobulins. Given these findings, we undertook extensive germline and somatic sequence studies to determine if mutations existed within the APRIL/BLYS receptor TACI, which commonly is mutated in patients with Common Variable Immunodeficiency Disorder (CVID). Six of 29 (21%) sequenced patients displayed variants within TACI, which were present in both tumor cells (n=6) and germline (n=5). Importantly, patients displaying variants in TACI demonstrated significantly lower serum IgG (280 vs. 676 mg/dL; p=0.0009) and IgA (20 vs. 41 mg/dL; p=0.0006) levels versus patients without TACI variants. Lastly, sequence analysis of APRIL, BLYS as well as the TACI downstream TRAF proteins have led to detection of numerous variants which may further account for hypogammaglobulinemia among patients with normal TACI expression. These data suggest that aberrations in TACI signaling may account for IgG and IgA hypogammaglobulinemia in WM, akin to patients with CVID. Moreover, mutations within TACI signaling may have pathological implications for WM since a 300 fold increased incidence of lymphoma has been observed among CVID patients. The impact of TACI mutations on pathogenesis of WM is currently under investigation in our laboratory.

Mutational Analysis of Human BLyS in Patients with Common Variable Immunodeficiency

BLyS, a TNF family member, is crucial for B cell proliferation and differentiation by acting through its three receptors, TACI, BCMA and BAFF-R. The knock out model for BLyS is characterized by an immunological phenotype reminiscent of the human phenotype of common variable immunodeficiency (CVID). CVID is characterized by a defective B cell compartment, evidencing the putative importance of BLyS in its pathogenesis. On the contrary, the transgenic model for BLys is characterized by autoimmune manifestations, underlying its role in B cell regulation. In fact, mutations in TACI, one of the three BLyS receptors, are associated with CVID. Based on these facts, we hypothesized that BLyS could be a candidate gene for CVID. We screened 78 patients with CVID using DHPLC and direct sequencing: No disease causing mutations were identified. A novel heterozygous single nucleotide polymorphism (SNP) was found in exon 1 of one individual, however this SNP (G189A) does not lead to an amino acid substitution.

TACI mutation with invasive polyclonal CD8+ T-cell lymphoproliferation in a patient with common variable immunodeficiency

Mutations of the gene encoding the TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), TNFSRF13B, have recently been described in patients with common variable immunodeficiency (CVID). We report the case of a man with CVID in association with a heterozygous TACI gene mutation (C104R) who had a highly unusual, invasive, polyclonal CD8+ T-cell lymphoproliferation resulting in massive hepatosplenomegaly and causing renal impairment because of infiltration. Although lymphoproliferation is well described in CVID, the key features in this patient included the T-cell origin of the lymphoproliferation, its polyclonal nature, its infiltration into multiple organs, and the presence of the TACI gene mutation.

TACItly changing tunes: farewell to a yin and yang of BAFF receptor and TACI in humoral immunity?

The complex system of the tumour necrosis factor ligands BAFF and APRIL and their three receptors BCMA, TACI and BAFF receptor and its role in B-cell development and function is the objective of extensive research. Whereas the importance of BAFF/BAFF receptor interactions for B-cell survival could be clearly demonstrated, TACI is believed to counteract BAFF activity as a negative regulator in the murine model. The primarily immunodeficient phenotype of human TACI deficiency, however, claims a distinct function of this receptor in human peripheral B-cell development, class switch recombination and terminal differentiation. Common variable immunodeficiency comprises a heterogeneous group of antibody deficiency syndromes characterized by impaired terminal B-cell differentiation. By means of molecular genetics common variable immunodeficiency is still ill-defined, but the description of the deficiency of the inducible costimulator in a small subgroup of common variable immunodeficiency patients set the starting point for the molecular dissection of this disease entity. The recent discovery of genetic defects in the tumour necrosis factor receptor superfamily members TACI and BAFF receptor in patients with common variable immunodeficiency denotes further advances in this field. In this review we will discuss recent progress made in the understanding of the BAFF/APRIL-TACI/BCMA/BAFF receptor system in relation to the recent discovery that mutations in human TACI cause a primary humoral immunodeficiency. This suggests a refined role for TACI in human B-cell biology.