Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency

Alachkar, Hana; Taubenheim, Nadine; Haeney, M R; Durandy, Anne; Arkwright, Peter D.

doi:10.1016/j.clim.2006.05.003

Cited by 106 publications

(71 citation statements)

References 33 publications

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“…Subsequently, the lack of switched memory B cells (B cells of the CD27 + , IgM-IgDphenotype) were characteristic of a large proportion of subjects with CVID, and that there relative lack of these cells could be used to divide patients into two clinically and immunologically different groups [3,9,10]. The lack of switched memory B cells was also found related to a lack of antibody production to pneumococcal vaccine, and interestingly, in these and other studies, also to the presence of autoimmune disease [11,12]. These data imply that the general immaturity of B cells, as highlighted by the lack of capacity for isotype switching in this segment of the CVID population, is a key element behind the retention of autoimmune clones.…”

Section: Granulomatous Disease Autoimmunity and Memory B Cell Phenomentioning

confidence: 71%

Autoimmune Manifestations in Common Variable Immunodeficiency

Cunningham‐Rundles

2008

J Clin Immunol

128

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Section: Granulomatous Disease Autoimmunity and Memory B Cell Phenomentioning

confidence: 71%

Autoimmune Manifestations in Common Variable Immunodeficiency

Cunningham‐Rundles

2008

J Clin Immunol

128

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“…6 Although the phenotype of circulating B cells was available for only about half of this patient population, we found that lower numbers of isotype switched memory B cells were associated with both autoimmunity and chronic lung disease, in accordance with previous studies. 9,33,[45][46][47][48][49] Although the genetic causes of CVID are likely to be multiple and most remain to be elucidated, these data show that the overall survival of patients has improved over time. More than 50% of the surviving subjects in this cohort are either students, working, retired but healthy, or otherwise pursuing normal activities of daily living, which suggests that the majority of patients carry out normal lives on replacement Ig therapy.…”

Section: Discussionmentioning

confidence: 99%

Morbidity and mortality in common variable immune deficiency over 4 decades

Resnick

Moshier²,

Godbold³

et al. 2012

Blood

694

819

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The demographics, immunologic parameters, medical complications, and mortality statistics from 473 subjects with common variable immune deficiency followed over 4 decades in New York were analyzed. Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL. Males were diagnosed earlier (median age, 30 years) than females (median age, 33.5 years; P ‫؍‬ .004). Ninetyfour percent of patients had a history of infections; 68% also had noninfectious complications: hematologic or organspecific autoimmunity, 28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal inflammatory disease, 15.4%; malabsorption, 5.9%; granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%. Females had higher baseline serum IgM (P ‫؍‬ .009) and were more likely to develop lymphoma (P ‫؍‬ .04); 19.6% of patients died, a significantly shorter survival than age-and sexmatched population controls (P < .0001). Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications (hazard ratio ‫؍‬ 10.95; P < .0001). Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and gastrointestinal disease with or without malabsorption, but not with bronchiectasis, autoimmunity, other cancers, granulomatous disease, or previous splenectomy. (Blood. 2012;119(7):1650-1657)

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“…It is likely that more individuals with dysfunctional CD27 will be identified among patient cohorts with hypogammaglobulinemia (with or without EBV-LPD) and absent CD27-expressing memory B cells, potentially leading to the recognition of CD27 deficiency as a novel, albeit probably a rare, combined immunodeficiency. [31][32][33] Of note, Patients 1 and 3 also showed expansion of transitional and CD21 low B cells, which is reportedly associated with increased risks of lymphadenopathy, splenomegaly, and granuloma formation in CVID, similar to XLP patients. 34 …”

Section: Immunological Consequencesmentioning

confidence: 99%

Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27

et al. 2012

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CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B-and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NKcell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemophagocytosis, lymphoproliferation, and lymphoma development.

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Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency

Cited by 106 publications

References 33 publications

Autoimmune Manifestations in Common Variable Immunodeficiency

Autoimmune Manifestations in Common Variable Immunodeficiency

Morbidity and mortality in common variable immune deficiency over 4 decades

Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27

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