T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency

106

108

Section: Discussionmentioning

confidence: 56%

B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency

Driessen

Zelm

Hagen

et al. 2011

106

108

“…Although defects in TACI would be expected to impair plasma-cell development in CVID, deficient plasma cells in bone marrow and mucosal tissues are common findings in CVID subjects in general, with or without mutations in TACI. 36 On the other hand, the loss of TACI signals in CVID subjects who have mutations might still be revealed by the prominent lymphoid hyperplasia, autoimmunity, and loss of in vitro tolerance checkpoints (all particular features of these subjects), 5,7,13 suggesting loss of other important control mechanisms normally supplied by TACI activation.…”

Section: Discussionmentioning

confidence: 99%

Differential induction of plasma cells by isoforms of human TACI

García-Carmona

Cols

Ting

et al. 2015

Key Points• Activation of TACI on B cells leads to proliferation, isotype switch, and B-cell survival.• Human TACI is produced in 2 isoforms; only the short form is a potent inducer of plasmacell differentiation.Subjects with common variable immune deficiency may have mutations in transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI). Unlike the murine gene, human TACI undergoes alternative messenger (m)RNA splicing to produce isoforms with 1 or 2 ligand-binding domains. Because both isoforms are found in human B cells, we compared their functions in transduced murine B and human pre-B cells.Although murine cells and pre-B cells transduced with the long TACI isoform retained surface CD19 and immunoglobulin G, cells transduced with the short TACI isoform completely lost these B-cell characteristics. Expression of the short TACI isoform produced intense nuclear factor kB activation, nuclear p65 translocation, and colocalization with myeloid differentiation factor 88 and calcium-modulating cyclophilin ligand. The short TACI-transduced cells became larger and CD138 positive, demonstrated upregulated BLIMP1 and XBP1 mRNA, and acquired the morphology of plasma cells. In contrast, cells bearing the long isoform had significantly less BLIMP1 and XBP1 mRNA and, for human pre-B cells, remained CD138 negative. Although human B cells express both isoforms, the short isoform predominates in CD27 1 B cells, toll-like receptor 9-activated peripheral B cells, and splenic marginal zone B cells. Although the transcriptional controls for alternative splicing of isoforms remain unknown, differential signals via isoforms may control plasma-cell generation in humans.

“…4,5,7 The majority of subjects have normal numbers of peripheral blood B cells, but there are depleted numbers of circulating isotype switched memory B cells (IgD Ϫ IgM Ϫ CD27 ϩ ), defective somatic hypermutation, and impaired formation of plasma cells in bone marrow and other tissues. [8][9][10] Although there have been many investigations into the nature of this immune defect since it was first recognized in 1953, 11 the fundamental genetic or other causes of CVID remain unclear for the majority of patients. In a few rare cases, CVID has been linked to autosomal recessive genetic mutations, including inducible costimulatory, 12 CD19, 13,14 B cell-activating factor receptor, 15 CD20, 16 and CD81.…”

Section: Introductionmentioning

confidence: 99%

Morbidity and mortality in common variable immune deficiency over 4 decades

Resnick

Moshier²,

Godbold³

et al. 2012

694

819

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)