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

Abstract

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...

Persistence of a Large Population of Exhausted Monoclonal B cells in Mixed Cryoglobuliemia After the Eradication of Hepatitis C Virus Infection

“…Clonal B cells of MC commonly secrete a natural antibody bearing an idiotype, encoded by the V H 1-69 variable gene, which has rheumatoid factor activity and cross-reacts with the E2 protein of HCV [1]. The V H 1-69-expressing B cells of MC patients can be subdivided into two major populations [2][3][4][5], one with the phenotype of normal human marginal zone (MZ) B cells (IgM + IgD + CD27 + CD21 + ), and one with the phenotype of the CD21 low innate-like B cells that are expanded in common variable immunodeficiency [6][7][8], in rheumatoid arthritis [7] and in human immunodeficiency virus infection [9].…”

“…The CD21 low B cells expanded in HIV infection and in common variable immunodeficiency are functionally exhausted, as they fail to proliferate in response to the stimulation of the B cell receptor (BCR) and of CD40 as well as of the innate Toll-like receptors (TLR) 9 and 7 [6][7][8][9]. Recently, the CD21 low V H 1-69-expressing B cells expanded in HCV-associated MC have been reported to be functionally anergic, and it was suggested that their counterparts could be normally functioning [3,4].…”

Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21low B cells

“…We found that, immediately after IVIG infusion, the number of circulating B cells decreases. Interestingly, after IVIG infusion, circulating B cells display a decrease in the expression of CD21, thus becoming similar to the functionally exhausted CD21 low B cells that spontaneously accumulate in some CVID patients [18][19][20] and in patients with HIV infection [21] or mixed cryoglobulinemia [22,23]. Our data suggest that IVIG therapy induces in vivo the B cells of CVID patients to differentiate into CD21 low B cells primed to undergo apoptosis.…”

“…CD21 low B cells were defined as CD20 ? cells with CD21 mean fluorescence intensity (MFI) below the threshold seen in mature B cells of CVID patients and of healthy donors [20]. The proportions of apoptotic cells were assessed by staining with annexin V and 7-aminoactinomycin D (7-AAD); annexin V-positive/7-AAD negative cells were classified as early apoptotic, and annexin V-positive/7-AAD positive cells as late apoptotic.…”

“…We also investigated whether down-regulation of CD21 was accompanied by a switch to the characteristic phenotype of CD21 low B cells, a peculiar population of functionally exhausted B cells that accumulate in a subgroup of CVID patients [29] and in patients with HIV infection [21] or with HCV-associated mixed cryoglobulinemia [22,23]. These CD21 low B cells are hallmarked by up-regulation of several inhibitory receptors including FCRL4, CD22, and CD95, and by altered regulation of homing receptors such as reduction of CD62L and expression of CD11c; furthermore, these cells are hyporesponsive to a variety of stimuli and are prone to apoptosis [18][19][20]. We found that the newly generated CD21 low B cells found in the circulation after IVIG infusion displayed the same peculiar pattern of receptors expressed by the spontaneous CD21 low B cells present before IVIG, namely increased FCRL4 and CD11c, and reduced CD62L expression (Fig.…”