Lilit Garibyan - Academia.edu (original) (raw)

Papers by Lilit Garibyan

Research paper thumbnail of Metalloproteinases: promising tumor markers for breast cancer management

Current Surgery, 2004

2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. ... more 2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol. 2001; 28:389-399. 3. Aapro MS. Neoadjuvant therapy in breast cancer: can we define its role? Oncologist. 2001;6(Suppl 3):36-39. 4. Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metasases: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol. 2001;19:628-633. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk post menopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Center Cooperative Group DBCG 82c Randomised Trial. Lancet. 1999;353:1641-1648. 6. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962. 7. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337:949-955.

Research paper thumbnail of The role of tumor markers in breast cancer management

Current Surgery, 2004

Physiologic nipple discharge will likely resolve without treatment and should be followed until r... more Physiologic nipple discharge will likely resolve without treatment and should be followed until resolution occurs. The decision of which diagnostic modality to use depends on the surgeon's familiarity with and availability of the tests. Although the role of cytology remains controversial, most authors agree that diagnostic imaging studies (ductography, ductoscopy, etc.) can be an appropriate adjunct to physical examination and mammography. In the end, excision of the duct after preoperative image localization may have the best results if the discharge is of a pathologic nature. Fuhrman GM. A simple approach to nipple discharge. Am Surg. 2000;66:960-966. 3. Dawes LG, Bowen C, Venta L, Morrow M. Ductography for nipple discharge: no replacement for ductal excision. Surgery. 1998;124:685-691. 4. Hunerbein M, Schwaz LE, Schneider U, Schlag PM. Evaluation of pathologic nipple discharge with ductoscopy. Letter to the editor. J Am Coll Surg. 2003;197:724-725. 5. Khan SA, Baird C, Staradub VL, Morrow M. Ductal lavage and ductoscopy: the opportunities and limitations.

Research paper thumbnail of Metalloproteinases: promising tumor markers for breast cancer management

Current Surgery, 2004

2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. ... more 2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol. 2001; 28:389-399. 3. Aapro MS. Neoadjuvant therapy in breast cancer: can we define its role? Oncologist. 2001;6(Suppl 3):36-39. 4. Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metasases: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol. 2001;19:628-633. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk post menopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Center Cooperative Group DBCG 82c Randomised Trial. Lancet. 1999;353:1641-1648. 6. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962. 7. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337:949-955.

Research paper thumbnail of DNA Binding by Kaposi's Sarcoma-Associated Herpesvirus Lytic Switch Protein Is Necessary for Transcriptional Activation of Two Viral Delayed Early Promoters

Journal of Virology, 2001

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus-8) establishes lat... more Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus-8) establishes latent and lytic infections in both lymphoid and endothelial cells and has been associated with diseases of both cell types. The KSHV open reading frame 50 (ORF50) protein is a transcriptional activator that plays a central role in the reactivation of lytic viral replication from latency. Here we identify and characterize a DNA binding site for the ORF50 protein that is shared by the promoters of two delayed early genes (ORF57 and K-bZIP). Transfer of this element to heterologous promoters confers on them high-level responsiveness to ORF50, indicating that the element is both necessary and sufficient for activation. The element consists of a conserved 12-bp palindromic sequence and less conserved sequences immediately 3 to it. Mutational analysis reveals that sequences within the palindrome are critical for binding and activation by ORF50, but the presence of a palindrome itself is not absolutely required. The 3 flanking sequences also play a critical role in DNA binding and transactivation. The strong concordance of DNA binding in vitro with transcriptional activation in vivo strongly implies that sequence-specific DNA binding is necessary for ORF50-mediated activation through this element. Expression of truncated versions of the ORF50 protein reveals that DNA binding is mediated by the amino-terminal 272 amino acids of the polypeptide.

Research paper thumbnail of The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function

Blood, 2009

TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin liga... more TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NFB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI ؊/؊ background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.

Research paper thumbnail of Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation

Journal of Allergy and Clinical Immunology, 2007

Background-Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor... more Background-Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) is a receptor used by B-cell activating factor of the TNF family (BAFF) and a proliferation inducing ligand (APRIL) to induce isotype switching independently of CD40 and is mutated in patients with common variable immunodeficiency (CVID).

Research paper thumbnail of TSLP acts on infiltrating effector T cells to drive allergic skin inflammation

Proceedings of The National Academy of Sciences, 2008

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including kerati... more Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR ؊/؊ mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR ؊/؊ mice in response to OVA was normal. Skin dendritic cells from TSLPR ؊/؊ mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4 ؉ T cells from TSLPR ؊/؊ mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

Research paper thumbnail of Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells

Journal of Allergy and Clinical Immunology, 2009

Objective-To examine whether TACI synergizes with TLR4 in driving immunoglobulin (Ig) production ... more Objective-To examine whether TACI synergizes with TLR4 in driving immunoglobulin (Ig) production by B cells and to examine the mechanism of this synergy.

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

Journal of Allergy and Clinical Immunology, 2010

Background: TNFRSF13B, which encodes transmembrane activator and calcium modulator and cyclophili... more Background: 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. Objective: 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. Methods: Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI 1/2 B6/129 background (C76R/TACI 1/2 mice) were constructed. Serum immunoglobulins and antibody responses to the type II Tindependent 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. Results: C76R/TACI 1/2 mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI 1/1 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 1/2 mice had similarly impaired B-cell function as C76R/TACI 1/2 littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI 1/2 mice on the C57BL/6 background.

Research paper thumbnail of Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID

Journal of Clinical Investigation, 2007

B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for trans... more B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACI) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACI ligand. It is not known whether this is due to haploinsufficiency or dominant interference. Using in vitro transfection assays, here we demonstrate that C104R and the corresponding murine TACI mutant, C76R, which also does not bind ligand, dominantly interfere with TACI signaling. This effect was dependent on preassociation of the mutants with WT TACI in the absence of ligand. The mutants did not interfere with ligand binding by WT TACI, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACI preassembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how the heterozygous C104R TACI mutation can potentially lead to CVID.

Research paper thumbnail of TACI is mutant in common variable immunodeficiency and IgA deficiency

Nature Genetics, 2005

The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modula... more The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.

Research paper thumbnail of Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency

Research paper thumbnail of Metalloproteinases: promising tumor markers for breast cancer management

Current Surgery, 2004

2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. ... more 2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol. 2001; 28:389-399. 3. Aapro MS. Neoadjuvant therapy in breast cancer: can we define its role? Oncologist. 2001;6(Suppl 3):36-39. 4. Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metasases: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol. 2001;19:628-633. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk post menopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Center Cooperative Group DBCG 82c Randomised Trial. Lancet. 1999;353:1641-1648. 6. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962. 7. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337:949-955.

Research paper thumbnail of The role of tumor markers in breast cancer management

Current Surgery, 2004

Physiologic nipple discharge will likely resolve without treatment and should be followed until r... more Physiologic nipple discharge will likely resolve without treatment and should be followed until resolution occurs. The decision of which diagnostic modality to use depends on the surgeon's familiarity with and availability of the tests. Although the role of cytology remains controversial, most authors agree that diagnostic imaging studies (ductography, ductoscopy, etc.) can be an appropriate adjunct to physical examination and mammography. In the end, excision of the duct after preoperative image localization may have the best results if the discharge is of a pathologic nature. Fuhrman GM. A simple approach to nipple discharge. Am Surg. 2000;66:960-966. 3. Dawes LG, Bowen C, Venta L, Morrow M. Ductography for nipple discharge: no replacement for ductal excision. Surgery. 1998;124:685-691. 4. Hunerbein M, Schwaz LE, Schneider U, Schlag PM. Evaluation of pathologic nipple discharge with ductoscopy. Letter to the editor. J Am Coll Surg. 2003;197:724-725. 5. Khan SA, Baird C, Staradub VL, Morrow M. Ductal lavage and ductoscopy: the opportunities and limitations.

Research paper thumbnail of Metalloproteinases: promising tumor markers for breast cancer management

Current Surgery, 2004

2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. ... more 2. Mamounas E, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol. 2001; 28:389-399. 3. Aapro MS. Neoadjuvant therapy in breast cancer: can we define its role? Oncologist. 2001;6(Suppl 3):36-39. 4. Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metasases: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol. 2001;19:628-633. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk post menopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Center Cooperative Group DBCG 82c Randomised Trial. Lancet. 1999;353:1641-1648. 6. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962. 7. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337:949-955.

Research paper thumbnail of DNA Binding by Kaposi's Sarcoma-Associated Herpesvirus Lytic Switch Protein Is Necessary for Transcriptional Activation of Two Viral Delayed Early Promoters

Journal of Virology, 2001

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus-8) establishes lat... more Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus-8) establishes latent and lytic infections in both lymphoid and endothelial cells and has been associated with diseases of both cell types. The KSHV open reading frame 50 (ORF50) protein is a transcriptional activator that plays a central role in the reactivation of lytic viral replication from latency. Here we identify and characterize a DNA binding site for the ORF50 protein that is shared by the promoters of two delayed early genes (ORF57 and K-bZIP). Transfer of this element to heterologous promoters confers on them high-level responsiveness to ORF50, indicating that the element is both necessary and sufficient for activation. The element consists of a conserved 12-bp palindromic sequence and less conserved sequences immediately 3 to it. Mutational analysis reveals that sequences within the palindrome are critical for binding and activation by ORF50, but the presence of a palindrome itself is not absolutely required. The 3 flanking sequences also play a critical role in DNA binding and transactivation. The strong concordance of DNA binding in vitro with transcriptional activation in vivo strongly implies that sequence-specific DNA binding is necessary for ORF50-mediated activation through this element. Expression of truncated versions of the ORF50 protein reveals that DNA binding is mediated by the amino-terminal 272 amino acids of the polypeptide.

Research paper thumbnail of The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function

Blood, 2009

TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin liga... more TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NFB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI ؊/؊ background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.

Research paper thumbnail of Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation

Journal of Allergy and Clinical Immunology, 2007

Background-Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor... more Background-Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) is a receptor used by B-cell activating factor of the TNF family (BAFF) and a proliferation inducing ligand (APRIL) to induce isotype switching independently of CD40 and is mutated in patients with common variable immunodeficiency (CVID).

Research paper thumbnail of TSLP acts on infiltrating effector T cells to drive allergic skin inflammation

Proceedings of The National Academy of Sciences, 2008

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including kerati... more Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR ؊/؊ mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR ؊/؊ mice in response to OVA was normal. Skin dendritic cells from TSLPR ؊/؊ mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4 ؉ T cells from TSLPR ؊/؊ mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

Research paper thumbnail of Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells

Journal of Allergy and Clinical Immunology, 2009

Objective-To examine whether TACI synergizes with TLR4 in driving immunoglobulin (Ig) production ... more Objective-To examine whether TACI synergizes with TLR4 in driving immunoglobulin (Ig) production by B cells and to examine the mechanism of this synergy.

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

Journal of Allergy and Clinical Immunology, 2010

Background: TNFRSF13B, which encodes transmembrane activator and calcium modulator and cyclophili... more Background: 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. Objective: 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. Methods: Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI 1/2 B6/129 background (C76R/TACI 1/2 mice) were constructed. Serum immunoglobulins and antibody responses to the type II Tindependent 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. Results: C76R/TACI 1/2 mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI 1/1 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 1/2 mice had similarly impaired B-cell function as C76R/TACI 1/2 littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI 1/2 mice on the C57BL/6 background.

Research paper thumbnail of Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID

Journal of Clinical Investigation, 2007

B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for trans... more B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACI) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACI ligand. It is not known whether this is due to haploinsufficiency or dominant interference. Using in vitro transfection assays, here we demonstrate that C104R and the corresponding murine TACI mutant, C76R, which also does not bind ligand, dominantly interfere with TACI signaling. This effect was dependent on preassociation of the mutants with WT TACI in the absence of ligand. The mutants did not interfere with ligand binding by WT TACI, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACI preassembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how the heterozygous C104R TACI mutation can potentially lead to CVID.

Research paper thumbnail of TACI is mutant in common variable immunodeficiency and IgA deficiency

Nature Genetics, 2005

The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modula... more The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.

Research paper thumbnail of Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency