Transmembrane Activator And Calcium-modulating Cyclophilin Ligand Interactor Research Articles

An uncommon presentation of primary sclerosing cholangitis leading to the diagnosis of B cell lymphoma and common variable immunodeficiency

Abstract Common Variable Immunodeficiency (CVID) is a disorder of B cells, with hypogammaglobulinemia and an impaired immune response leading to increased risk of infection, autoimmune complications, and risk of malignancy. A 17-year-old, previously healthy male presented with three months of pruritus, jaundice and transaminitis. Imaging and biopsy showed liver heterogeneity without evidence of cholestasis or ductal dilation. Over time, imaging was consistent with primary sclerosing cholangitis (PSC). The patient eventually required liver transplant after several complications, despite stent therapy. Explant liver pathology revealed diffuse large B cell and follicular lymphoma, grade 3A with mature monoclonal B cells follicular in origin, negative for MYC rearrangement and MUM1. PCR detected IgH and IgK B cell clonality. He received chemotherapy without complication, for primary hepatic non-Hodgkin's lymphoma. Continued flatulence and diarrhea prompted endoscopy, revealing eosinophilic esophagitis. Due to his variable pathology, he was evaluated for a primary immunodeficiency. His labs demonstrated globally diminished immunoglobulins, a low Hib titer and one pathogenic mutation in TNFRSF13B (c.542C>A; p.Ala181Glu), a transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). Thus, the patient was diagnosed with CVID. This case highlights a unique presentation of CVID from demonstration of PSC and primary hepatic diffuse large B cell lymphoma. Consideration of immunodeficiencies early on in challenging cases of autoimmune and unique oncologic diagnoses may lead to earlier treatment of underlying conditions and prevention of future complications.

A Randomized, Placebo-Controlled, Phase 1 Study in Healthy Adult Volunteers of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ALPN303, a Potent Dual BAFF/APRIL Antagonist for the Treatment of Autoimmune Cytopenias

Background B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are tumor necrosis factor superfamily (TNFSF) members that bind transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), B-cell maturation antigen, and/or BAFF receptor (BAFF-R) on B cells and together support B-cell development, survival, and differentiation into antibody-secreting cells (ASC). In preclinical studies, co-neutralization of BAFF and APRIL can directly suppress ASC and reduce circulating immunoglobulins. Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) are diseases characterized by autoantibodies directed against red blood cells and platelets, respectively. Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with AIHA and ITP compared to healthy subjects, and polymorphisms in BAFF and TACI have been associated with ITP [Abdel-Hamid, et al., Am J Med, 2011; Emmerich, et al., Br J Haematol, 2007; Peng, et al., J Thromb Haemost, 2017; Yu, et al., Blood Adv, 2021]. Currently, there are no B cell targeting agents approved to treat AIHA or ITP. Rituximab, an anti-CD20 therapeutic which depletes CD20+ B cells, and thereby only indirectly reduces autoantibody production, has demonstrated some efficacy in both ITP [Neunert, et al., Blood, 2019] and AIHA [Jäger, et al., Blood Rev, 2019], though it is not approved for use in either indication. Belimumab, an anti-BAFF neutralizing antibody (Ab), has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus (SLE) [De Marchi, et al., Clin Exp Rheumatol, 2017] and also in combination with rituximab in patients with ITP [Mahévas, et al., Haematologica, 2021], but only had a modest impact on hematological manifestations in SLE patients [Manzi, et al., Ann Rheum Dis, 2012]. To address the shortcomings of existing B-cell-targeting agents, we have developed ALPN-303, an Fc fusion of an engineered TACI variant TNFRSF domain, which substantially improves upon the ligand affinity liabilities of wild type (WT) TACI, resulting in highly potent dual BAFF/APRIL inhibition superior to WT TACI-Fc, or to BAFF- or APRIL-specific monoclonal Abs. In preclinical studies, ALPN-303 demonstrates enhanced pharmacokinetic (PK) and immunomodulatory properties vs. WT TACI-Fc, which may translate to lower and/or less frequent doses in humans. ALPN-303 also suppresses autoantibodies and nephritis in mouse models of lupus. Taken together, these observations suggest that a potent dual BAFF/APRIL antagonist such as ALPN-303, by lowering pathogenic autoantibody levels, may be particularly beneficial in the treatment of antibody-related hematologic diseases, such as autoimmune cytopenias. Methods In this first-in-human study (NCT05034484), healthy adult volunteers have been enrolled in single ascending dose cohorts of intravenously (IV) or subcutaneously (SC) administered ALPN-303. For each IV cohort, the first 2 sentinel subjects are randomized 1:1 to receive ALPN-303 or placebo, followed by the remaining 4 subjects randomized 3:1 to receive ALPN-303 or placebo. SC cohorts are randomized 4:2 to receive a single SC dose of ALPN-303 or placebo. All subjects are followed to assess safety, PK, and pharmacodynamic (PD) effects including impacts on circulating immunoglobulins (Ig), and peripheral B-cell populations. Results ALPN-303 has been well tolerated in all cohorts evaluated to date and exhibits dose-dependent PK and expected PD effects, including dose-dependent reductions in circulating CD38+ (CD19+CD27+IgD-) ASC (Figure 1) and in serum Ig (Figure 2). To date, there have been no serious adverse events, and no events of cytokine release syndrome. Dose escalation will be complete by the time of the meeting; the presentation will include all available safety, PK, and PD data. Conclusions In this phase 1 study, ALPN-303 demonstrates acceptable preliminary safety and tolerability and exhibits dose-dependent PK and expected PD effects on circulating Ig and B-cell populations. These findings support future clinical development of ALPN-303 in patients with antibody-related diseases, including autoimmune cytopenias. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TACI Mutasyonu Bulunan Yaygın Değişken İmmün Yetmezlik Hastalarında T Hücre Vβ Repertuvarının Akan Hücre Sistemi ile Analizi

Objective: TCR (T Cell Receptor) which is expressed on T cells is responsible for recognizing antigens presented by HLA molecules of the APCs (Antigen Presenting Cells) and initiation of the immune response. It has been reported that TACI (Transmembrane activator and calcium modulating cyclophilin ligand interactor) mediates the interaction of B cells and dendritic cells which are both responsible for the processing of T cells. Materials and Methods: In this study, 24 TCRVβ clones were analyzed by using multiparametric flow cytometry in seven patients with TACI mutation [two homozygous (c.310T> C) five heterozygous (c.310T> C, c.226G> C, c.260T> A)], four CVID (Common Variable Immunodeficiency) patients who had not TACI defect (non-TACI) and five healthy controls. In this study group, serum Ig levels and infection history, CD4+ and CD8+ cell percentages, and HLA profiles were investigated. Results: Increased TCRVβ13.2 clone was observed in patients with TACI defects unlike control individuals and non-TACI-CVID patients (p=0.02). We found that there was a statistically significant decrease in TCRVβ8 clone (p=0.012) in TACI deficient CVID patients and non-TACI-CVID patients compared to control individuals. TCRVβ20 clones in non-TACI-CVID patients were decreased compared to TACI-CVID patients and control individuals (p=0.009). Decreased TCRVβ8 was also associated with TACI deficient CVID patients. Conclusion: Further studies and large cohorts are needed to understand the relationship between TCRVβ8, TCRVβ13.2, and CVID with TACI mutations.

Characteristics of the patients followed with the diagnosis of common variable immunodeficiency and the complications.

IntroductionIn this study, we aimed to retrospectively evaluate the clinical and laboratory findings and complications of 28 common variable immunodeficiency (CVID) patients.Material and methodsThe clinical features and laboratory data of 28 CVID patients were evaluated.ResultsNineteen patients were male. In 53.5% of the cases, complications included inflammatory bowel disease, cytopenia, bronchiectasis, granulomatous lymphocytic interstitial lung disease (ILD) and asthma. In their immunological evaluations, IgG, IgM, and IgA mean values were 474.8 ±214.1 mg/dl; 56.7 ±41.9 mg/dl; 35.3 ±58.2 mg/dl, respectively, and the vaccine response was positive in 64.2% of the cases. In all age groups, absolute lymphocyte counts, naive (CD19+IgD+27-), nonswitch (CD19+IgD-27+) memory B cells were numerically higher when compared to the data of healthy children; however, although switch memory (CD19+IgD+27+) B cells were proportionally low in the 4-8 and 12-18 age groups, they were low both numerically and proportionally in the 8-12 age group. No statistically significant difference was found between the cases with complications and without complications. But the cases with pulmonary complications were compared within the group, the CD8 ratio was high but the IgA level was low in patients with bronchiectasis and CD3 was numerically and proportionally low in the cases with ILD compared to others. According to the Paris classification, 11/27 (40.7%) of the cases, 3/27 (11.1%) of them and 13/27 (48.2%) of them were evaluated as MB0, MB1, and MB2, respectively.ConclusionsIn genetic studies, TACI (trans-membrane activator and calcium-modulating cyclophilin ligand interactor – TNFRSF13B) mutation was found positive in 25% of the cases.

Correlation of APRIL with production of inflammatory cytokines during acute malaria in the Brazilian Amazon.

IntroductionA proliferation‐inducing ligand (APRIL) and B cell activation factor (BAFF) are known to play a significant role in the pathogenesis of several diseases, including BAFF in malaria. The aim of this study was to investigate whether APRIL and BAFF plasma concentrations could be part of inflammatory responses associated with P. vivax and P. falciparum malaria in patients from the Brazilian Amazon.MethodsBlood samples were obtained from P. vivax and P. falciparum malaria patients (n = 52) resident in Porto Velho before and 15 days after the beginning of treatment and from uninfected individuals (n = 12). We investigated APRIL and BAFF circulating levels and their association with parasitaemia, WBC counts, and cytokine/chemokine plasma levels. The expression levels of transmembrane activator and calcium‐modulating cyclophilin ligand interactor (TACI) on PBMC from a subset of 5 P. vivax‐infected patients were analyzed by flow cytometry.ResultsAPRIL plasma levels were transiently increased during acute P. vivax and P. falciparum infections whereas BAFF levels were only increased during acute P. falciparum malaria. Although P. vivax and P. falciparum malaria patients have similar cytokine profiles during infection, in P. vivax acute phase malaria, APRIL but not BAFF levels correlated positively with IL‐1, IL‐2, IL‐4, IL‐6, and IL‐13 levels. We did not find any association between P. vivax parasitaemia and APRIL levels, while an inverse correlation was found between P. falciparum parasitaemia and APRIL levels. The percentage of TACI positive CD4+ and CD8+ T cells were increased in the acute phase P. vivax malaria.ConclusionThese findings suggest that the APRIL and BAFF inductions reflect different host strategies for controlling infection with each malaria species.

B cell activating factor (BAFF) and BAFF receptors: fakes and facts.

Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell subsets may represent useful biomarkers of biological and clinical responses. Among the BAFF receptors in a cohort of rheumatoid arthritis (RA) patients, the AA have shown, by fluorescence activated cell sorter (FACS) analysis of median fluorescence intensity (MFI), that transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) do not change, whereas the most important, BAFF receptor 3 (BR3), appears to be decreased before as well as after BCDT in all B cell subsets but not in plasmablasts, the most important subset, depleted by BCDT.

The Role of BAFF System Molecules in Host Response to Pathogens.

The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

P220 Severe hypogammaglobulinemia and poor antibody response in an asymptomatic patient with heterozygous taci mutation

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced serum immunoglobulin levels and increased risk of infections, autoimmunity, and cancer. Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations are found in 8-10% of CVID cases and sometimes in healthy non-hypogammaglobulinemic subjects. We present a 6 year-old boy with a heterozygous TACI mutation who had significant hypogammaglobulinemia and poor antibody responses but no infectious or autoimmune history.

Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults

BackgroundAdvanced age and human immunodeficiency virus (HIV) infection are associated with increased pneumococcal disease risk. The impact of these factors on cellular responses to vaccination is unknown. MethodsHIV-infected (HIV+) individuals 50–65 years old with CD4+ Tcells/μl (CD4) >200 on antiretroviral therapy (ART) ≥1 year received either the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine (PCV/PPV) or PPV only. HIV-uninfected (HIV−) controls received PCV/PPV. Phenotype distribution and surface expression of complement receptor CD21 and tumor necrosis factor superfamily receptors (TNFRs) were compared on serotype-specific B cells postvaccination. ResultsPostvaccination serotype-specific B cell percentages were significantly lower in HIV+ PCV/PPV compared to PPV groups, but similar between HIV+ or HIV− PCV/PPV groups. Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI)+ serotype-specific B cell percentages were significantly decreased in HIV+ PCV/PPV compared to PPV groups. CD21+ serotype-specific B cells were significantly higher in HIV− compared to HIV+ PCV/PPV groups. ConclusionsAn initial dose of PCV reduced the frequency, but not phenotype distribution, of serotype-specific B cells and also lowered TACI expression in aging HIV+ subjects postvaccination with PPV. These findings suggest that PCV does not enhance cellular responses to revaccination with PPV.

Effect of TACI signaling on humoral immunity and autoimmune diseases.

Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) is one of the receptors of B cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL). TACI is a regulator in the immune responses. TACI inhibits B cell expansion and promotes the differentiation and survival of plasma cells. The mechanisms underlying these effects probably involve changed expressions of some crucial molecules, such as B lymphocyte induced maturation protein-1 (Blimp-1) and inducible T-cell costimulator ligand (ICOSL) in B cells and/or plasma cells. However, abnormal TACI signaling may relate to autoimmune disorders. Common variable immune deficiency (CVID) patients with heterozygous mutations in TACI alleles increase susceptibility to autoimmune diseases. Taci −/− mice and BAFF transgenic mice both develop signs of human SLE. These findings that indicate inappropriate levels of TACI signaling may disrupt immune system balance, thereby promoting the development of autoimmune diseases. In this review, we summarize the basic characteristics of the TACI ligands BAFF and APRIL, and detail the research findings on the role of TACI in humoral immunity. We also discuss the possible mechanisms underlying the susceptibility of CVID patients with TACI mutations to autoimmune diseases and the role of TACI in the pathogenesis of SLE.

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen.

The transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI-deficient mice exhibit a CVID-like disease. However, 1%-2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies.

Synergy in B-Cell Activation between Toll-Like Receptor 9 and Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor (TACI) in A181E/C104R Compound Heterozygous Siblings

Purpose. Approximately 9% of common variable immunodeficiency (CVID) patients harbor variants in the transmembrane activator and CAML interactor gene, TACI, which contribute to CVID development. We found identical compound heterozygous TACI variants (C104R and A181E) in kindred of which one sibling had severe CVID with refractory auto immunity, and a second sibling remained asymptomatic. This study investigated possible differences in B-cell phenotype and function that could explain this divergent clinical expression. Methods. C104R and A181E TACI variants were identified through Sanger sequencing. Phenotypic evaluation of the lymphocyte compartment was performed by flow cytometry analyses. Lymphoblastoid cell lines (LCL) from the index patient, asymptomatic sibling, and controls were generated. Intracellular TACI expression was determined, and activation-associated calcium flux capacity was measured. In vitro stimulation assays and RT PCR were performed. Results. Both intracellular levels and surface expressed TACI protein were higher in the asymptomatic sibling than the CVID patient as were TACI-triggering-induced mRNA expression AID and production of Ig class-switched antibodies. In analogy, the asymptomatic sibling displayed enhanced Toll-like receptor 9 expression and signaling, suggesting a compensatory immune mechanism. Conclusions. Posttranscriptional regulation of TACI protein and cross-talk with TLR9 signaling may contribute to phenotypic diversity between individuals with TACI variants.

Naturally occurring mutation affecting the MyD88‐binding site of TNFRSF13B impairs triggering of class switch recombination

Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment of MyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize with MyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.

TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes

Mutations in the gene coding for the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) are found in 8% to 10% of subjects with common variable immunodeficiency (CVID). Although heterozygous mutations may coincide with immunodeficiency in a few families, most mutation-bearing relatives are not hypogammaglobulinemic. Thus, the role of TACI mutations in producing the immune defect remains unclear. This study examined the expression and function of TACI mutations in healthy heterozygous relatives. We examined the surface and intracellular expression of TACI protein in EBV-transformed B cells of patients and relatives with mutations in 7 families, binding of a proliferation-inducing ligand, and secretion of IgG and IgA by ligand-activated B cells. We tested whether Toll-like receptor 9 agonists increased TACI expression and whether an agonistic anti-TACI antibody could induce activation-induced cytidine deaminase mRNA in those with mutations. Intracellular and extracellular TACI expression was defective for B cells of all subjects with mutations, including subjects with CVID and relatives. Although Toll-like receptor 9 triggering normally up-regulates B-cell TACI expression, this was defective for all subjects with mutations. Triggering TACI by an agonistic antibody showed loss of activation-induced cytidine deaminase mRNA induction in all mutation-bearing B cells. However, ligand-induced IgG and IgA production was normal for healthy relatives but not for subjects with CVID. Thus, B cells of relatives of subjects with CVID who have mutations in TACI but normal immune globulin levels still have detectable in vitro B-cell defects.

Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency

Some, but not all, TACI mutations found in CVID impair TACI function and may potentially contribute to B cell dysfunction in heterozygotes via haploinsufficiency.

Autoimmune Manifestations in Common Variable Immunodeficiency

About 20% of subjects with common variable immune deficiency (CVID) develop an autoimmune complication, most often immune thrombocytopenia or hemolytic anemia. While the pathogenesis of autoreactivity is unknown for CVID subjects in general, and to a greater extent in those with autoimmunity, there is a loss of switched memory B cells. About 7-8% of CVID subjects have mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), a significant association with this immune defect, although the same mutations may be found in normal relatives and rarely in healthy blood donors. In addition to generalized B cell dysfunction, defective elimination of autoimmune B cells has been demonstrated.

Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes

Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance. Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear. TACI was sequenced from the genomic DNA of 176 subjects with CVID and family members. B cells of subjects with or without mutations were examined for binding to the ligand, a proliferation inducing ligand (APRIL), and for proliferation and immunoglobulin production after ligand stimulation. Data analysis was performed to assess the clinical relevance of TACI mutations. Heterozygous TACI mutations were found in 13 subjects (7.3%). Six with mutations (46%) had episodes of autoimmune thrombocytopenia, in contrast with 12% of 163 subjects without mutations; splenomegaly and splenectomy were significantly increased (P = .012; P = .001.) B cells of some had impaired binding of APRIL and on culture with this ligand were defective in proliferation and immunoglobulin production; however, this was not different from B cells of subjects without mutations. Eight first-degree relatives from 5 families had the same mutations but were not immune-deficient, and their B cells produced normal amounts of IgG and IgA after APRIL stimulation. Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID, but additional genetic or environmental factors are required to induce immune deficiency. Additional causes of this common immune deficiency syndrome remain to be determined.