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• W2108793518 abstract "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. 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. Case presentationA man was given a diagnosis of common variable immunodeficiency (CVID) in 1981 at the age of 20 years after recurrent bronchitis, pneumonia, and skin infections in association with panhypogammaglobulinemia. There was no family history of immunodeficiency. He was treated initially with intravenous immunoglobulin (IVIG) for 8 years before deciding to discontinue it for personal reasons. His recurrent infections returned over the next 6 years, and radiologic changes of early bronchiectasis developed, such that in 1995, IVIG was recommenced. However, during the first infusion, he had an anaphylactic reaction associated with high-titer anti-IgA antibodies, and IVIG was subsequently withheld.In 2003, he presented with anorexia, weight loss, fevers, and night sweats. Examination revealed hepatosplenomegaly (liver span of 20 cm and spleen 13 cm below the costal margin), and thoracic and abdominal computed tomographic (CT) scans showed mediastinal, hilar, and para-aortic lymphadenopathy with early bronchiectasis. Investigations showed mild pancytopenia and markedly abnormal liver function test results, with a prominent increase of serum alkaline phosphatase level. The IgG level had decreased further to 0.33 g/L. Subsequent investigations, including a lymph node biopsy, showed a predominance of CD8+ T cells in blood, lymph nodes, and bone marrow but no evidence of lymphoma.An alternative preparation of IVIG was commenced without incident, and he initially improved clinically, but over the following 18 months, the hepatosplenomegaly progressed (liver span of 25 cm and spleen 20 cm below the costal margin), with the return of nocturnal fevers and malaise. In 2005, his liver function deteriorated further. He had progressive renal impairment, with the creatinine value peaking at 0.3 mmol/L, and he was admitted for investigation. An abdominal CT scan confirmed massive hepatosplenomegaly and showed bilaterally enlarged kidneys. Peripheral blood phenotyping demonstrated a marked αβ T-cell receptor (TCR)–positive CD8+ lymphocytosis, which was also present on bone marrow aspirate (Table I). Vβ TCR expression analysis of blood by means of flow cytometry, covering approximately 70% of known Vβ families, showed this T-cell population to be polyclonal (Table II).Table ICell-surface phenotype of lymphocytes from blood, spleen, bone marrow, and splenic hilar lymph node taken in 2005 and analyzed by means of flow cytometryMarkerBloodSpleenBone marrowSplenic hilar lymph nodeCD392% (3772/μL)90%90%93%CD2—96%78%—CD412% (492/μL)6%10%30%CD880% (3280/μL)83%80%62%CD5—89%75%—CD7—90%61%—CD10—1%1%—CD190%1%0%—CD20—1%0%3%HLA-DR—5687%—Kappa—0%0%1%Lambda—0%0%1%CD3−/CD16 or CD56+ (NK cells)6%CD3+/CD16 or 56+1%Values represent percentages of lymphocytes as defined by light-scatter characteristics. In blood absolute counts are shown in parentheses.NK, Natural killer. Open table in a new tab Table IIExpression of TCR Vβ families in the peripheral blood, with the RRVβ familyResult (% of CD3 cells)RR (%)Vβ18.21.89-11.7Vβ23.24.03-23.48Vβ31.80.52-15.71Vβ41.60.79-3.26Vβ5.12.93.19-14.93Vβ5.21.70.49-4.98Vβ5.30.90.37-2.98Vβ7.16.20.64-20.01Vβ7.22.20.05-5.45Vβ84.22.26-29.47Vβ921.1-9.3Vβ110.70.25-5.11Vβ120.91-4.76Vβ13.11.91.62-8.16Vβ13.230.8-5.28Vβ13.63.30.84-8.8Vβ145.11.33-8.03Vβ160.80.42-1.9Vβ1711.12.28-12.61Vβ180.50.58-5.23Vβ203.50-9.73Vβ21.33.41.08-5.97Vβ225.11.99-9.89Vβ234.10.28-4.76Total78.3Seventy percent of the expected Vβ T-cell repertoire is covered by these reagents (IOTest Beta Mark PN IM3497; Beckman Coulter, Fullerton, Calif). No underexpression or overexpression of a specific Vβ TCR family was detected, which is consistent with a polyclonal T-cell proliferation. Open table in a new tab Diagnostic splenectomy and liver, kidney, and splenic lymph node biopsies were performed (results detailed below).Differential diagnosisThis man with established CVID had progressive hepatosplenomegaly characterized by a polyclonal CD8 lymphocytosis in blood. This progressed despite IVIG replacement until finally resulting in renal impairment. The main diagnostic possibilities for the hepatosplenomegaly included (1) lymphoma, (2) granulomatous disease, (3) amyloidosis, and (4) infiltrative lymphoproliferation, possibly related to chronic viral infection. For the renal failure, the main considerations were (1) infiltrative lymphoproliferative disease, possibly lymphoma; (2) amyloidosis; and (3) obstruction caused by retroperitoneal lymphadenopathy. Although most cases of CVID are idiopathic, the differential diagnoses for genetic causes of CVID are listed in Table III.1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google Scholar, 3Weston S.A. Prasad M.L. Mullighan C.G. Chapel H. Benson E.M. Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed?.Clin Exp Immunol. 2001; 124: 465-469Crossref PubMed Scopus (37) Google Scholar, 4Kanegane H. Tsukada S. Iwata T. Futatani T. Nomura K. Yamamoto J. et al.Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry.Clin Exp Immunol. 2000; 120: 512-517Crossref PubMed Scopus (69) Google Scholar, 5Eastwood D. Gilmour K.C. Nistala K. Meaney C. Chapel H. Sherrell Z. et al.Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency.Clin Exp Immunol. 2004; 137: 584-588Crossref PubMed Scopus (45) Google Scholar, 6Aghamohammadi A. Kanegane H. Moein M. Farhoudi A. Pourpak Z. Movahedi M. et al.Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency.Int J Hematol. 2003; 78: 45-47Crossref PubMed Scopus (28) Google Scholar, 7Soresina A. Lougaris V. Giliani S. Cardinale F. Armenio L. Cattalini M. et al.Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency.Eur J Pediatr. 2002; 161: 656-659Crossref PubMed Scopus (34) Google Scholar, 8Nistala K. Gilmour K.C. Cranston T. Davies E.G. Goldblatt D. Gaspar H.B. et al.X-linked lymphoproliferative disease: three atypical cases.Clin Exp Immunol. 2001; 126: 126-130Crossref PubMed Scopus (59) Google Scholar, 9Morra M. Silander O. Calpe S. Choi M. Oettgen H. Myers L. et al.Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome.Blood. 2001; 98: 1321-1325Crossref PubMed Scopus (105) Google Scholar, 10Gilmour K.C. Cranston T. Jones A. Davies E.G. Goldblatt D. Thrasher A. et al.Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression.Eur J Immunol. 2000; 30: 1691-1697Crossref PubMed Scopus (64) Google Scholar, 11Grimbacher B. Hutloff A. Schlesier M. Glocker E. Warnatz K. Drager R. et al.Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.Nat Immunol. 2003; 4: 261-268Crossref PubMed Scopus (599) Google Scholar, 12Warnatz K. Salzer U. Gutenberger S. Schlesier M. Grimbacher B. Peter H.H. et al.Finally found: Human BAFF-R deficiency causes hypogammaglobulinemia.Clin Immunol. 2005; 115: S20Google Scholar, 13Castano D. Patino P.J. Woellner C. Salzer U. Grimbacher B. Montoya C.J. et al.Novel humoral immunodeficiency in humans associated with deleterious homozygous mutation in CD19.Clin Immunol. 2005; 115: S29Google ScholarTable IIIProteins in which mutations have been described in association with CVIDProteinGeneBtkBruton's tyrosine kinase3Weston S.A. Prasad M.L. Mullighan C.G. Chapel H. Benson E.M. Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed?.Clin Exp Immunol. 2001; 124: 465-469Crossref PubMed Scopus (37) Google Scholar, 4Kanegane H. Tsukada S. Iwata T. Futatani T. Nomura K. Yamamoto J. et al.Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry.Clin Exp Immunol. 2000; 120: 512-517Crossref PubMed Scopus (69) Google ScholarSAPSH2D1A5Eastwood D. Gilmour K.C. Nistala K. Meaney C. Chapel H. Sherrell Z. et al.Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency.Clin Exp Immunol. 2004; 137: 584-588Crossref PubMed Scopus (45) Google Scholar, 6Aghamohammadi A. Kanegane H. Moein M. Farhoudi A. Pourpak Z. Movahedi M. et al.Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency.Int J Hematol. 2003; 78: 45-47Crossref PubMed Scopus (28) Google Scholar, 7Soresina A. Lougaris V. Giliani S. Cardinale F. Armenio L. Cattalini M. et al.Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency.Eur J Pediatr. 2002; 161: 656-659Crossref PubMed Scopus (34) Google Scholar, 8Nistala K. Gilmour K.C. Cranston T. Davies E.G. Goldblatt D. Gaspar H.B. et al.X-linked lymphoproliferative disease: three atypical cases.Clin Exp Immunol. 2001; 126: 126-130Crossref PubMed Scopus (59) Google Scholar, 9Morra M. Silander O. Calpe S. Choi M. Oettgen H. Myers L. et al.Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome.Blood. 2001; 98: 1321-1325Crossref PubMed Scopus (105) Google Scholar, 10Gilmour K.C. Cranston T. Jones A. Davies E.G. Goldblatt D. Thrasher A. et al.Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression.Eur J Immunol. 2000; 30: 1691-1697Crossref PubMed Scopus (64) Google ScholarICOSICOS11Grimbacher B. Hutloff A. Schlesier M. Glocker E. Warnatz K. Drager R. et al.Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.Nat Immunol. 2003; 4: 261-268Crossref PubMed Scopus (599) Google ScholarTACITNFRSF13B1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google ScholarBAFF-RTNFRSF13C12Warnatz K. Salzer U. Gutenberger S. Schlesier M. Grimbacher B. Peter H.H. et al.Finally found: Human BAFF-R deficiency causes hypogammaglobulinemia.Clin Immunol. 2005; 115: S20Google ScholarCD19CD1913Castano D. Patino P.J. Woellner C. Salzer U. Grimbacher B. Montoya C.J. et al.Novel humoral immunodeficiency in humans associated with deleterious homozygous mutation in CD19.Clin Immunol. 2005; 115: S29Google ScholarSAP, Signaling lymphocyte activation molecule (SLAM)–associated protein. Open table in a new tab Laboratory and other Testing-Procedures1981Immunoglobulin levels were as follows: IgG, 1.8 g/L (reference range [RR], 7-16 g/L); IgA, less than 0.1 g/L (RR, 0.7-4.5 g/L); and IgM, 0.30 g/L (RR, 0.8-2.5 g/L).2003The results of full blood count showed a hemoglobin level of 90 g/L, a white cell count of 3.1 × 109/L, and a platelet count of 112 × 109/L.Liver function tests showed a bilirubin level of 13 μmol/L (RR, 2-21 μmol/L), an albumin level of 40 g/L (RR, 35-53 g/L), an alkaline phosphatase level of 795 U/L (RR, 25-110 U/L), a gamma glutaryl transferase level of 138 U/L (RR, 10-49 U/L), an alanine transaminase level of 40 U/L (RR, 10-47 U/L), and an aspartate transaminase level of 53 U/L (RR, 5-40 U/L).Electrolytes, urea, and creatinine values were normal.Immunoglobulin levels were as follows: IgG, 0.33 g/L; IgA, 0.07 g/L; and IgM, 0.27 g/L.Flow cytometry on peripheral blood showed the following: CD8+ T cells, 75% of lymphocytes (1365/μL); CD4+ T cells, 16% (291/μL); CD19+ B cells, 1% (18/μL). B-cell phenotyping demonstrated the absence of CD27+ memory B cells and increased CD21− B cells, which is consistent with CVID category Ia.14Warnatz K. Denz A. Drager R. Braun M. Groth C. Wolff-Vorbeck G. et al.Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease.Blood. 2002; 99: 1544-1551Crossref PubMed Scopus (497) Google ScholarLymph node biopsy (right axilla) showed interfollicular and parafollicular histiocytic proliferation with admixed small lymphocytes, which is consistent with a reactive lymphadenitis. No granulomas were seen. No organisms, including acid fast bacilli, were identified or cultured. Results of PCR for Toxoplasma gondii was negative. Flow cytometry on the lymph node showed CD8+ T cells to constitute 60% of lymphocytes, with 17% CD4 cells and 14% CD19 cells. There was no B-cell monoclonality, with a normal kappa/lambda ratio.Bone marrow aspirate and trephine biopsy showed no morphologic abnormality. Seventy-five percent of lymphocytes were CD8+ T cells, with 13% CD4+ T cells and 6% CD19+ B cells. There was no B-cell monoclonality.2005The results of full blood count showed a hemoglobin level of 89 g/L, a white cell count of 6.9 × 109/L, a lymphocyte count of 4.1 × 109/L, and a platelet count of 129 × 109/L. Blood film showed lymphocytosis and confirmed thrombocytopenia in the absence of platelet aggregates. No large granular lymphocytes were seen.Liver function tests showed a bilirubin level of 16 μmol/L, an albumin level of 32 g/L, an alkaline phosphatase level of 1186 U/L, a glutaryl transferase level of 136 U/L, an alanine transaminase level of 32 U/L, and an aspartate transaminase level of 46 U/L.CT of the abdomen-pelvis revealed massive hepatosplenomegaly, bilaterally enlarged kidneys (16 cm in length), no dilatation of the collecting system, and no renal calculi.Peripheral blood phenotyping by means of flow cytometry demonstrated CD8+ lymphocytosis (3280 cells/μL, Table I). All (100%) CD3 cells were αβ-TCR+. Vβ-TCR expression analysis demonstrated polyclonality (Table II).Bone marrow aspirate and trephine biopsy showed hypercellular marrow with trilineage maturation and mild lymphocytosis without evidence of lymphoma. Flow cytometry showed an increased population of CD8+ cells (80%) expressing the activation marker HLA-DR (Table I).Histopathology of liver, spleen, and kidney biopsy specimens revealed marked expansion of the white pulp of the spleen by a diffuse and nodular infiltrate of small lymphoid cells, with extensive spillover of these cells into the red pulp (Fig 1, A). A similar dense, nodular, and diffuse small cell lymphoid infiltrate was present in the liver, involving the portal tracts and lobules (Fig 1, C), and in the renal interstitium associated with architectural distortion of the parenchyma (Fig 1, E). These infiltrates all stained strongly for CD8 on immunoperoxidase (Fig 1, B, D, and F). There was no evidence of granulomatous inflammation or amyloidosis on Congo Red staining.Flow cytometry of spleen cells showed that CD8+ T cells comprised the majority of infiltrating cells and the expressed activation markers CD38 and HLA-DR, minimal CD71 and CD69, and no CD25 (Fig 2), which is consistent with a state of chronic activation.15Biselli R. Matricardi P.M. D'Amelio R. Fattorossi A. Multiparametric flow cytometric analysis of the kinetics of surface molecule expression after polyclonal activation of human peripheral blood T lymphocytes.Scand J Immunol. 1992; 35: 439-447Crossref PubMed Scopus (89) Google ScholarFig 2Flow cytometry of spleen cells showing expression of T-cell markers (left histograms, gated on lymphocytes by light scatter) and activation markers (right histograms, gated on T lymphocytes). Lymphocytes express all mature T-cell markers and are predominantly CD8+. T cells express the activation markers CD38 and HLA-DR but minimal expression of the other activation markers. Isotype controls are represented by dotted lines. PE, Phycoerythrin; FITC, fluorescein isothiocyanate; PC5, phycoerythrin-cyanin 5.View Large Image Figure ViewerDownload (PPT)Flow cytometric analysis for expression of proteins possibly deficient in CVID showed that surface expressions of CD19 and B cell–activating factor belonging to the TNF family (BAFF) receptor (BAFF-R/BR3) were normal in comparison with those seen in healthy control subjects (data not shown). Expression of inducible costimulator (ICOS) by T cells could not be determined because the patient's lymphocytes failed to activate in response to PHA, possibly because of the immunosuppressive medication that he was taking at the time of the attempted analysis (see below).For viral studies, PCR test results for EBV, cytomegalovirus, human herpes virus 6, hepatitis B virus, and hepatitis C virus in blood were negative. PCR test results for human herpes virus 8 in tissue sections of the spleen were also negative. Hepatitis B virus surface antigen was negative.In genetic testing X-linked lymphoproliferative disease was excluded by sequencing cDNA from peripheral blood, which showed a normal SH2D1A gene (S. Tangye, personal communication). Sequencing of the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) gene, however, revealed a heterozygous cysteine to arginine mutation at amino acid 104 (C104R) identical to the one described by both Geha and Grimbacher (Fig 3).1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google ScholarFig 3C104R heterozygous mutation in TACI gene exon 3. The T to C mutation in the sense strand is indicated, and the codon triplet is boxed. Exons were amplified by means of PCR, with primers described in Salzer et al2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google Scholar and sequenced with ABI Big Dye Version 3.1 (Applied Biosystems, Foster City, Calif) and an ABI Prism 3100 Genetic Analyser.View Large Image Figure ViewerDownload (PPT)Diagnosis with discussion of pathogenesis and management planThis patient has a polyclonal, invasive, CD8+ T-cell lymphoproliferative disease on a background of CVID associated with a mutation of the TACI gene. There were no compelling cytologic features of T-cell lymphoma, except for tissue infiltration, and the polyclonal nature of the CD8 T-cell lymphoproliferation did not support it. There was no evidence of granulomatous disease, which can often complicate this condition.16Sander C.A. Medeiros L.J. Weiss L.M. Yano T. Sneller M.C. Jaffe E.S. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome.Am J Surg Pathol. 1992; 16: 1170-1182Crossref PubMed Scopus (120) Google Scholar The disorder was not a proliferation of large granular lymphocytes because the morphology was that of typical lymphocytes, and natural killer cell markers were negative (Table I).The patient was subsequently started on oral prednisolone, 75 mg/d. His fevers and malaise immediately resolved, and his creatinine and alkaline phosphatase levels both decreased to 0.12 mmol/L and 454 U/L, respectively. He was started on azathioprine (3 mg/kg) to assist weaning of his steroid dose, and his renal and hepatic functions have stabilized. His CD8 count remains increased (1548 cells/μL) but is significantly lower than baseline. The long-term plan of management is to control the end-organ effects of his lymphoproliferative disease, particularly the renal impairment, with immunosuppressive medications. Should these fail, consideration will be given to the use of mycophenolate, reserving traditional antilymphoma regimens as third-line therapy.The key interest points in this case are the development of an infiltrative polyclonal CD8 T-cell lymphoproliferative disorder in association with CVID and the discovery of a mutation in the TACI gene in the same patient. Most cases of CVID are sporadic, whereas only a small proportion are familial.17Hammarstrom L. Vorechovsky I. Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID).Clin Exp Immunol. 2000; 120: 225-231Crossref PubMed Scopus (355) Google Scholar Of the familial cases, few have a clear-cut molecular explanation. It has been recognized that some cases of X-linked (Bruton's) agammaglobulinemia3Weston S.A. Prasad M.L. Mullighan C.G. Chapel H. Benson E.M. Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed?.Clin Exp Immunol. 2001; 124: 465-469Crossref PubMed Scopus (37) Google Scholar, 4Kanegane H. Tsukada S. Iwata T. Futatani T. Nomura K. Yamamoto J. et al.Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry.Clin Exp Immunol. 2000; 120: 512-517Crossref PubMed Scopus (69) Google Scholar or X-linked lymphoproliferative (Duncan's) disease5Eastwood D. Gilmour K.C. Nistala K. Meaney C. Chapel H. Sherrell Z. et al.Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency.Clin Exp Immunol. 2004; 137: 584-588Crossref PubMed Scopus (45) Google Scholar, 6Aghamohammadi A. Kanegane H. Moein M. Farhoudi A. Pourpak Z. Movahedi M. et al.Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency.Int J Hematol. 2003; 78: 45-47Crossref PubMed Scopus (28) Google Scholar, 7Soresina A. Lougaris V. Giliani S. Cardinale F. Armenio L. Cattalini M. et al.Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency.Eur J Pediatr. 2002; 161: 656-659Crossref PubMed Scopus (34) Google Scholar, 8Nistala K. Gilmour K.C. Cranston T. Davies E.G. Goldblatt D. Gaspar H.B. et al.X-linked lymphoproliferative disease: three atypical cases.Clin Exp Immunol. 2001; 126: 126-130Crossref PubMed Scopus (59) Google Scholar, 9Morra M. Silander O. Calpe S. Choi M. Oettgen H. Myers L. et al.Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome.Blood. 2001; 98: 1321-1325Crossref PubMed Scopus (105) Google Scholar, 10Gilmour K.C. Cranston T. Jones A. Davies E.G. Goldblatt D. Thrasher A. et al.Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression.Eur J Immunol. 2000; 30: 1691-1697Crossref PubMed Scopus (64) Google Scholar with mutations in the Btk and SH2D1A genes, respectively, can masquerade as CVID. These patients might present similarly to those with CVID, but they can be detected by means of direct sequencing of the relevant gene. Little was known of other genetic conditions that could be manifest as CVID until the last few years, during which several mutations in proteins associated with B-cell activation have been discovered (Table III).The first of these was a homozygous mutation of the ICOS gene,11Grimbacher B. Hutloff A. Schlesier M. Glocker E. Warnatz K. Drager R. et al.Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.Nat Immunol. 2003; 4: 261-268Crossref PubMed Scopus (599) Google Scholar an important costimulator for the activation of B cells by T cells.18Grimbacher B. Warnatz K. Peter H.H. The immunological synapse for B-cell memory: the role of the ICOS and its ligand for the longevity of humoral immunity.Curr Opin Allergy Clin Immunol. 2003; 3: 409-419Crossref PubMed Scopus (40) Google Scholar This mutation has only been described in 9 patients,19Salzer U. Maul-Pavicic A. Cunningham-Rundles C. Urschel S. Belohradsky B.H. Litzman J. et al.ICOS deficiency in patients with common variable immunodeficiency.Clin Immunol. 2004; 113: 234-240Crossref PubMed Scopus (157) Google Scholar and all possessed an identical mutation suggesting common ancestry. Recent reports have documented a further 2 apparently rare mutations associated with CVID, one involving BAFF-R and affecting a single patient12Warnatz K. Salzer U. Gutenberger S. Schlesier M. Grimbacher B. Peter H.H. et al.Finally found: Human BAFF-R deficiency causes hypogammaglobulinemia.Clin Immunol. 2005; 115: S20Google Scholar and the other involving the B cell–specific signaling protein CD19 in 3 siblings.13Castano D. Patino P.J. Woellner C. Salzer U. Grimbacher B. Montoya C.J. et al.Novel humoral immunodeficiency in humans associated with deleterious homozygous mutation in CD19.Clin Immunol. 2005; 115: S29Google Scholar In contrast, a third mutation, involving the TACI gene, has been demonstrated in a much greater proportion of patients with CVID,1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google Scholar with estimates of 5% to 10% prevalence.2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google Scholar TACI, a member of the TNF receptor family, is thought to be important in mediating isotype switching in B cells by binding its ligands BAFF and a proliferation-inducing ligand (APRIL; Fig 4).1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 20Castigli E. Wilson S.A. Scott S. Dedeoglu F. Xu S. Lam K.P. et al.TACI and BAFF-R mediate isotype switching in B cells.J Exp Med. 2005; 201: 35-39Crossref PubMed Scopus (427) Google Scholar Unlike the other genetic causes of CVID, TACI gene mutations are often heterozygous, and TACI surface expression seems preserved,1Castigli E. Wilson S.A. Gariby L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (561) Google Scholar, 2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google Scholar except in the few cases of homozygous deficiency.2Salzer U. Chapel H.M. Webster A.D.B. Pan-Hammarström Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (535) Google ScholarFig 4Speculative mechanism for the pathogenesis of CVID in the setting of the TACI mutation on the basis of experiments reported by Castigli et al.1Castigli E. Wilson S.A. Gariby L. Rachid" @default.
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