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B-Cell Activating Factor Receptor Deficiency Is Associated with an Adult-Onset Antibody Deficiency Syndrome in Humans

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B-Cell Activating Factor Receptor Deficiency Is Associated with an Adult-Onset Antibody Deficiency Syndrome in Humans B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans Klaus Warnatza,1, Ulrich Salzera,1, Marta Rizzib, Beate Fischerb, Sylvia Gutenbergera, Joachim Bo¨ hmc, Anne-Kathrin Kienzlerb, Qiang Pan-Hammarstro¨ md, Lennart Hammarstro¨ md, Mirzokhid Rakhmanova, Michael Schlesiera, Bodo Grimbachera,2, Hans-Hartmut Petera, and Hermann Eibelb,3 aDepartment of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiencies, University Medical Center Freiburg, 79106 Freiburg, Germany; bClinical Research Unit for Rheumatology, Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, 79106 Freiburg, Germany; cInstitute of Pathology, University of Freiburg, 79106 Freiburg, Germany; and dDivision of Clinical Immunology, Karolinska University Hospital, SE-141 86 Huddinge, Sweden Edited by Klaus Rajewsky, Harvard Medical School, Boston, MA, and approved July 7, 2009 (received for review March 31, 2009) B-cell survival depends on signals induced by B-cell activating defects, some of which may affect genes regulating early B-cell factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in development and/or B-cell survival (13). Searching for genetic BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. defects affecting B-cell homeostasis, we identified two related Analyzing BAFF-R expression and BAFF-binding to B cells in com- individuals carrying the same homozygous deletion within the mon variable immunodeficiency (CVID) patients, we identified two TNFRSF13C gene removing part of the BAFF-R transmem- siblings carrying a homozygous deletion in the BAFF-R gene. brane region. Human BAFF-R deficiency strongly impairs the Removing most of the BAFF-R transmembrane part, the deletion development and homeostasis of follicular, IgM memory/ precludes BAFF-R expression. Without BAFF-R, B-cell development marginal zone, and class-switched memory B cells. However, in is arrested at the stage of transitional B cells and the numbers of contrast to the murine BAFF and BAFF-R mutants, the human all subsequent B-cell stages are severely reduced. Both siblings deficiency shows a late onset and variable penetrance, as it does IMMUNOLOGY have lower IgG and IgM serum levels but, unlike most CVID not inevitably lead to a clinically overt immunodeficiency. patients, normal IgA concentrations. They also did not mount a T-independent immune response against pneumococcal cell wall Results polysaccharides but only one BAFF-R-deficient sibling developed Identification of Human BAFF-R Deficiency. Searching for genetic recurrent infections. Therefore, deletion of the BAFF-R gene in defects affecting B-cell homeostasis, we screened a cohort of 138 humans causes a characteristic immunological phenotype but it CVID patients for individuals with low numbers of peripheral B does not necessarily lead to a clinically manifest immunodeficiency. cells. We found 35 patients (25%) with less than 5% B cells and 10% (n ϭ 14) with less than 3% B cells. BAFF serum levels were B lymphopenia ͉ primary immunodeficiency ͉ recessive mutation analyzed in 14 patients with less than 3% B cells, BAFF-R surface expression in 40 additional patients and BAFF binding -lymphocyte survival is maintained by tonic signaling of to B cells in 18 additional patients, respectively. Similar to a Bthe B-cell antigen receptor complex (1) and by signals previous report (14), BAFF concentrations were significantly induced after binding of the cytokine BAFF/BLYS to the higher in sera of CVID patients than in controls (Fig. 1A). For BAFF-receptor (BAFF-R), a member of the TNF receptor BAFF-R expression we found weaker signals in eight patients superfamily (2). In humans, BAFF-R is encoded by three including P1, who showed the lowest BAFF-R signal (Fig. 1 B exons of the TNFRSF13C gene located on chromosome 22q13. and C). In whole-cell lysates of Epstein-Barr virus (EBV)– Its transcript is translated into a type III transmembrane immortalized B cells from P1 BAFF-R protein expression was protein of 184 aa residues expressed by all surface Igϩ B cells also undetectable by Western blot analysis (Fig. 1D), and but not by plasma cells (3). BAFF, the only ligand of BAFF-R, RT-PCR of total RNA from P1 PBL revealed a 20–30-bp shorter is secreted by cells of nonhematopoietic as well as of hema- TNFRSF13C-specific fragment than RNA isolated from healthy topoietic origin, including monocytes, macrophages, neutro- donor PBL (Fig. 1D). Because these results suggested that P1 phils, and activated B cells (2, 4). might carry a BAFF-R mutation, we sequenced the BAFF-R In BAFF-R–deficient mice, B cells develop normally up to the gene of P1 and of all the patient’s family members (Fig. 2A) and stage of IgMϩ immature/transitional B cells but cannot complete detected a homozygous 24-bp in-frame deletion (del89–96), maturation in the spleen, as BAFF/BAFF-R–dependent survival signals are missing (5–8). Therefore, the numbers of follicular and marginal zone but not of transitional B cells are reduced by Author contributions: K.W., B.G., H.-H.P., and H.E. designed research; U.S., M. Rizzi, B.F., more than 95% (6). About 20% of B cells passing the develop- S.G., J.B., A.-K.K., Q.P.-H., L.H., M. Rakhmanov, M.S., and H.E. performed research; K.W., U.S., M. Rizzi, A.-K.K., Q.P.-H., L.H., and H.E. analyzed data; and K.W., U.S., B.G., H.-H.P., and mental block mount only weak high-affinity antibody responses H.E. wrote the paper. against T-independent and T-dependent antigens (6, 7). Be- The authors declare no conflict of interest. cause, in the gut of BAFF-R–deficient mice, mucosal IgA- This article is a PNAS Direct Submission. secreting plasma cells develop normally, they seem not to require Freely available online through the PNAS open access option. BAFF-R signals (6) 1 Common variable immunodeficiency (CVID) includes many K.W. and U.S. contributed equally to this paper. heterogeneous syndromes of unknown origin characterized by 2Present address: Royal Free Hospital and University College London, Department of Clinical Immunology, London, UK. hypogammaglobulinemia and recurrent respiratory infections 3To whom correspondence should be addressed at: Clinical Research Unit for Rheumatol- (9). Most patients have normal numbers of T and B cells, but ogy, University Medical Center Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany. approximately 10% of CVID patients are B-lymphopenic (10, E-mail: [email protected] 11). Although this group may include a few cases of BTK This article contains supporting information online at www.pnas.org/cgi/content/full/ deficiency (12), most B-lymphopenic patients have unknown 0903543106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903543106 PNAS ͉ August 18, 2009 ͉ vol. 106 ͉ no. 33 ͉ 13945–13950 Downloaded by guest on October 1, 2021 were able to bind BAFF (Fig. 1 C and E). The deletion, which was not found in the genomic DNA from 100 healthy controls, removes a stretch of eight hydrophobic amino acids forming part of the BAFF-R transmembrane region (Fig. 2B). In addition to del89–96, P1 and P2 also had a homozygous exchange of two consecutive base pairs resulting in the amino acid exchange of G64V, a previously reported polymorphism (15). Sibling II.4 and all offspring of P1 were heterozygous carriers of del89–96. Subsequently we sequenced the coding regions and the exon- intron boundaries of the three TNFRSF13C gene exons in all other 137 CVID patients included in this study and revealed several known TNFRSF13C polymorphisms (15) but no other patients carrying obvious disease-causing mutations. Lymphocyte Phenotyping of Human BAFF-R Deficiency. Phenotypic analysis of blood B cells from P1 and P2 over a period of more than 4 years showed a severe and persistent B lymphopenia in both percentage and absolute numbers, ranging from 1–2% (P1) to 2.8–3.1% (P2) of lymphocytes (normal range, 6–19% in 50 healthy controls) and 10–28 cells/␮l (P1) (normal range, 100– 500 cells/␮l), respectively (Table S1 and Fig. 3A). In both patients, the percentage of CD10ϩ transitional cells was in- creased (P1, 45%; P2, 21%; Fig. 3 B and C and Fig. S1) compared with controls (2.5–4.5%), and the absolute numbers were high but still within the normal range. The population of IgMϩ CD27ϩ marginal zone B cells was much smaller (3%, P1; 7%, P2 Fig. 1. Identification of BAFF-R-deficiency. (A) BAFF serum levels (ng/ml) in vs. 23–26%) and class-switched memory B cells were present but CVID patients and controls. Filled square, P1. (B) Mean fluorescence intensity reduced to approximately 7% (P2) and 6% (P1) of B cells (HD of BAFF-R signals detected by flow cytometry of blood lymphocytes gated on ϩ CD19ϩ B cells. Filled square, P1. (C) BAFF-R expression by B cells from P1, P2, and 10–20%, Fig. 3D). TACI expression by CD27 B cells was much healthy donors (HD1 and HD2). (D) Immunoblot for BAFF-R in whole-cell weaker than in controls (Fig. S2A). To exclude TACI deficiency, lysates of EBV lines from P1 and a healthy control. Loading control ␤-actin. we tested TACI expression and ligand binding using the EBV RT-PCR for TNFRSF13C mRNA of P1 and a healthy control. (E) BAFF-binding to B-cell line of P1. Because the affinity of TACI is higher for B cells from P1 and P2 compared with those in age- and sex-matched controls APRIL than for BAFF, the EBV line showed normal APRIL HD1 and HD (shaded histogram). but weaker BAFF binding. In contrast, a TACI-deficient EBV line derived from a CVID patient carrying a homozygous truncating TACI mutation (16) showed normal BAFF but no which was located in exon 2 of the TNFRSF13C gene of P1 and APRIL binding, indicating that BAFF-R is the primary receptor of P2.
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