Common variable immunodeficiency disorders: division into distinct clinical phenotypes

Chapel, Helen; Lucas, Mary; Lee, Martin; Björkander, Janne; Webster, David; Grimbacher, Bodo; Fieschi, Claire; Thon, Vojtěch; Abedi, Mohammad Reza; Hammarström, Lennart

doi:10.1182/blood-2007-11-124545

Cited by 687 publications

(903 citation statements)

References 37 publications

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“…In this regard, it is of interest that patients chronically stimulated by HCV or HIV have an expansion of CD21 low B cells [9,11,12]. However, this possibility is made unlikely by the fact that CVID 1a patients are characterized by idiopathic lymphoproliferation and autoimmunity, but not by a higher rate of infections than CVID non-1a patients [25]. Nevertheless, it is possible that still unrecognized defect(s) in the telomere maintenance machinery make CVID 1a patients more susceptible to the accelerated shortening of telomeres driven by chronic infection.…”

Section: Discussionmentioning

confidence: 99%

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

et al. 2011

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A subset of patients with common variable immunodeficiency (CVID), group 1a of the Freiburg classification, is characterized by increased B cells expressing low levels of CD21 (CD21 low ), lymphoproliferation and autoimmunity. The CD21 low B cells have been shown to be profoundly anergic, and defects of BCR-mediated calcium signaling and of T cells have been described in CVID 1a. We found that also the classical naïve B cells from CVID 1a patients, but not from CVID non-1a patients, proliferated poorly. The B cells of CVID 1a patients had a reduced capacity to divide reminiscent of the proliferative arrest associated with replicative senescence. Thus, we investigated whether lymphocyte dysfunction in CVID 1a was related to telomere-dependent replicative senescence, and found that both the B and the T cells from CVID 1a patients had significantly shorter telomeres compared with B and T cells from CVID non-1a patients. Telomere lengths in B and T cells were significantly correlated, indicating that the rate of telomere attrition in lymphocytes is an individual characteristic of CVID patients. Our findings suggest that telomere-dependent replicative senescence contributes to the immune dysfunction of CVID 1a patients, and may provide an important clue for a better understanding of the pathogenesis of CVID.Key words: Anergy . IntroductionCommon variable immunodeficiency (CVID) is a heterogeneous disorder characterized by reduced antibody levels with low to normal numbers of circulating B cells [1]. Only a small proportion of CVID patients can be classified by the underlying genetic defect [2], and current classifications are mainly based on the B-cell phenotype [3,4]. A subset of CVID is hallmarked by the expansion of an unusual population of B cells with reduced expression of CD21 (CD21 low ); these patients are classified as CVID group 1a according to the Freiburg study [3]. Clinically, CVID 1a is characterized by a late onset, autoimmunity and benign polyclonal lymphoproliferation [3,4]. In addition, several T-cell abnormalities have been described in CVID 1a patients [5]. 854The CD21 low B cells of CVID patients express an array of inhibitory receptor and fail to proliferate in response to BCRdependent and -independent stimuli [6,7]. However, anergy is not limited to CD21 low B cells, since all mature B cells from CVID 1a patients fail to flux calcium upon BCR triggering [8]. CD21 low B cells are also increased in patients with HIV infection [9], systemic lupus erythematosus [10], or mixed cryoglobulinemia secondary to HCV infection [11,12], all conditions characterized by B-cell hyperactivation. Although the CD21 low B cells of patients with HIV infection or HCV-associated mixed cryoglobulinemia have mutated immunoglobulin genes [10][11][12], the CD21 low B cells of CVID 1a patients are unmutated and mostly autoreactive [6,7]. Similarly to those of patients with CVID, the CD21 low B cells of patients with HIV infection are profoundly anergic to B-cell stimuli [9].In this study, we observed that the B cells fr...

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Section: Discussionmentioning

confidence: 99%

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

et al. 2011

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“…A highly increased incidence (20-35%) of autoimmune disorders has been found in patients currently diagnosed with CVID. 23,24 In fact, several CD19-deficient patients have high levels of autoantibodies either with or without an autoimmune disease. 5,6,25 Because only five CD19-deficient patients have been described so far, it cannot be concluded whether loss of CD19 is associated with increased autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

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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“…Chapel et al established the onset of symptoms at a mean age of 26.3 years (median age of 24 years) (4). CVID represents a clinical and immunological syndrome that merges various diseases with different genetic roots.…”

Section: Introductionmentioning

confidence: 99%

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

Baldovino

Montin

Martino

et al. 2013

Autoimmunity Reviews

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Common variable immunodeficiency disorders: division into distinct clinical phenotypes

Cited by 687 publications

References 37 publications

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

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

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

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