An Antibody-Deficiency Syndrome Due to Mutations in the<i>CD19</i>Gene

Zelm, Menno C. van; Reisli, İsmail; Burg, Mirjam van der; Castaño, Diana; Noesel, Carel J. M. van; Tol, Maarten J.D. van; Woellner, Cristina; Grimbacher, Bodo; Patiño, Pablo Javier; Dongen, Jacques J. M. van; Franco, José Luis

doi:10.1056/nejmoa051568

Cited by 498 publications

(346 citation statements)

References 41 publications

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“…2,3 In about 90% of patients diagnosed with agammaglobulinemia and about 75% of cases with a Hyper-IgM syndrome, the underlying genetic defect has been identified. 2 Whereas mutations have been described in patients diagnosed with CVID, [4][5][6][7][8][9][10][11][12] in over 90% of these patients no associated genetic defect has been found. In fact, in most CVID patients a complex genetic trade rather than a single affected gene is likely to contribute to development of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 CD19 forms a complex with CD21, CD81 and CD225, and functions to lower the threshold for B-cell antigen receptor (BCR) signaling following antigen engagement. 13 Consequently, CD19-deficient and CD81-deficient patients were found to be defective in BCR stimulation and showed poor responses to vaccination.…”

Section: Introductionmentioning

confidence: 99%

“…13 Consequently, CD19-deficient and CD81-deficient patients were found to be defective in BCR stimulation and showed poor responses to vaccination. 5,12 We identified a Turkish immunodeficient boy who is a cousin of the first identified Turkish CD19-deficient patient, and was homozygous for the same CD19 gene mutation (c.972insA). Because the two patients were born in large families with consanguineous marriages, we assumed that many of the family members would be carriers of the CD19 mutation, and consequently have reduced protein expression.…”

Section: Introductionmentioning

confidence: 99%

“…Because the two patients were born in large families with consanguineous marriages, we assumed that many of the family members would be carriers of the CD19 mutation, and consequently have reduced protein expression. 5 We hypothesized that CD19 expression levels regulate BCR signaling and, therefore, we set out to study peripheral B-cell development and antibody responses in carriers of the CD19 mutation.…”

Section: Introductionmentioning

confidence: 99%

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B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

et al. 2010

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Homozygous CD19 mutations lead to an antibody deficiency due to disruption of the CD19 complex and consequent impaired signaling by the B-cell antigen receptor. We studied the effects of heterozygous CD19 mutations on peripheral B-cell development and antibody responses in a large family with multiple consanguineous marriages. Sequence analysis of 96 family members revealed 30 carriers of the CD19 mutation. Lymphocyte subset counts were not significantly different between carriers and noncarriers in three different age groups (0-10 years; 11-18 years; adults). B cells of carriers had reduced CD19 and CD21 median expression levels, and had reduced proportions of transitional (0-10 years) and CD5 þ B cells (adults). CD19 carriers did not show clinical signs of immunodeficiency; they were well capable to produce normal serum Ig levels and had normal responses to primary and booster vaccinations. The frequency of mutated Vk alleles was not affected. Heterozygous loss of CD19 causes some changes in the naive B-cell compartment, but overall in vivo B-cell maturation or humoral immunity is not affected. Many antibody deficiencies are not monogenetic, but likely caused by a combination of multiple genetic variations. Therefore, functional analyses of immune cell function should be carried out to show whether heterozygous mutations contribute to disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

et al. 2010

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“…In recent years CVID has been significantly linked in a minority of patients to defects in genes encoding for molecules as ICOS (inducible co-stimulator) [4], TACI (transmembrane activator and calcium-modulator and cytophillin ligand interactor) [5], CD19 (B-lymphocyte antigen CD19) and BAFF-R (tumor necrosis factor superfamily member 13C) [6,7], but in none of these patients SLE was observed [8]. In addition, a specific MBL allele, a component of the innate immune response, has been strongly associated with overall autoimmune disease in patients with CVID by contributing to both susceptibility to infections and increased frequency of autoimmune and inflammatory manifestations [9].…”

Section: Introductionmentioning

confidence: 99%

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms

et al. 2009

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The association of common variable immunodeficiency (CVID) and Systemic Lupus Erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients.In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed brochiectasis and had low levels of circulating MBL.These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.

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Molecular Genetics of Common Variable Immunodeficiency

Bogaert

Dullaers

Baere

et al. 2017

Encyclopedia of Life Sciences

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Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary immunodeficiencies (PIDs) characterised by antibody deficiency, poor responses to vaccination and an increased susceptibility to infections and complications due to immune dysregulation. The clinical diagnosis of CVID is an umbrella covering an immunologically and genetically heterogeneous group of diseases. To date, 22 disease‐causing genes have been associated with monogenic forms of CVID, encompassing 2–10% of reported cases. However, these genetic subtypes are now considered to account for distinct disease entities and have been removed from under the CVID umbrella. Furthermore, accumulating data suggest that the majority of CVID patients have a complex or multifactorial disorder, in which multiple genetic, epigenetic and/or environmental factors are involved. Genetic testing for monogenic causes should especially be performed in CVID patients with early onset of disease, noninfectious complications, a positive family history and/or consanguineous parents, since this could be important for genetic counselling, follow up and/or treatment decisions. Key Concepts CVID is a diagnosis of exclusion, encompassing a clinically, immunologically and genetically heterogeneous group of PID patients. Monogenic defects have so far been reported in 2–10% of CVID patients. The majority of CVID patients are believed to have a complex or multifactorial aetiology. Patients in whom a monogenic cause is identified are no longer classified under CVID, but under separate disease entities (IUIS classification). A monogenic cause of CVID is more probable in case of early onset of disease, complications of immune dysregulation, a positive family history and/or consanguinity. Especially in CVID patients with early onset of disease and/or noninfectious complications, genetic workup should be performed to identify or exclude an underlying monogenic cause since this could be important for patient management decisions.

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An Antibody-Deficiency Syndrome Due to Mutations in theCD19Gene

Abstract: Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective.

Cited by 498 publications

References 41 publications

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms

Molecular Genetics of Common Variable Immunodeficiency

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