Defined Blocks in Terminal Plasma Cell Differentiation of Common Variable Immunodeficiency Patients

Taubenheim, Nadine; Hornung, Marcus von; Durandy, Anne; Warnatz, Klaus; Corcoran, Lynn M.; Peter, Hans‐Hartmut; Eibel, Hermann

doi:10.4049/jimmunol.175.8.5498

Cited by 68 publications

(34 citation statements)

References 37 publications

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“…Such cells could alternatively arise through escape from the GC after initiation of proliferation at the centroblast state prior to the initiation of SHM. Although far from definitive evidence exists for this latter possibility, a small study of biopsied lymph nodes from three subjects with CVID found evidence of centroblasts but a lack of centrocytes, consistent with successful expansion of pre-mutated B cell populations in CVID (56). Increased B cell clonality is expected in patients who develop B cell lymphomas.…”

Section: Discussionmentioning

confidence: 97%

IgH sequences in common variable immune deficiency reveal altered B cell development and selection

et al. 2015

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Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ∼1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity determining region 3 (CDR3). We observed decreased selection against antibodies with long CDR3 regions in memory repertoires and decreased V gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive both from decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. CVID patients also exhibited abnormal clonal expansion of unmutated B cells relative to controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B cell stage and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.

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Section: Discussionmentioning

confidence: 97%

IgH sequences in common variable immune deficiency reveal altered B cell development and selection

et al. 2015

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“…The cellular studies of the immune system in CVID subjects to date have shown numerical and functional defects in B, T, natural killer cells, macrophages and monocytes [39–44]. T cell functional abnormalities are common (20% of CVID subjects) [4,45] with defects in cytokine production, T helper function, and T cell signaling [19,46–52].…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease

Chiang

Song

et al. 2009

Clinical Immunology

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Approximately 25% of subjects with common variable immunodeficiency (CVID) develop autoimmune disease. We analyzed Tcell subsets, specifically regulatory Tcells along with B cell subsets to determine whether there were changes in regulatory T cells which would correlate with the autoimmune disease clinical phenotype in CVID subjects. We hypothesized that regulatory T cell (CD4+CD25hiCD127lo) suppressive function would be impaired in CVID subjects with autoimmune disease. Using purified, sorted Treg from CVID subjects (n=14) and from healthy controls (HC, n=5) in standard suppression assays, we found the suppressive function of Treg from CVID subjects with autoimmune disease (CVID w/ AI, n=8) to be significantly attenuated compared to CVID subjects with no autoimmune disease (CVID w/o AI, n=6) and to HC (n=5). A number of proteins associated with Treg function were decreased in expression as detected through immunofluorescent antibody via flow cytometry (mean fluorescence intensity (MFI) of FoxP3, Granzyme A, XCL1, pSTAT5, and GITR in Treg was significantly lower (by up to 3 fold) in CVID w/ AI compared to CVID w/o AI and HC. Furthermore, a statistically significant correlation was found between intracellular MFI of FoxP3, Granzyme A, and pSTAT5 in Treg and the degree of Treg dysfunction. These results suggest that attenuation of Treg function is associated with autoimmune disease in CVID subjects and may contribute to autoimmune pathogenesis.

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“…Mice that are CD86 deficient fail to respond to antigen challenge, lacking antibody formation and isotype switching, congruent with defects seen in CVID [8,9]. CVID B cells exhibit increased apoptosis, presumably due to increased expression of CD95 (Fas) and reduced expression of CD38 [10–12]. With enhanced apoptosis, B cells could be unable to complete the maturation and differentiation process needed for B-cell development.…”

Section: Cvid B-cell Defects and Classification Schemesmentioning

confidence: 97%

Role of B cells in common variable immune deficiency

Ahn¹,

Cunningham‐Rundles²

2009

Expert Review of Clinical Immunology

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Common variable immune deficiency is a heterogeneous immune deficiency characterized by reduced serum immunoglobulins and a lack of antibodies. As the name implies, B-cell defects are variably defective. In particular, peripheral blood isotype-switched CD27 + memory B cells are reduced in number and have been the basis of several classification schemes. A lack of these B cells has been associated with selected clinical conditions, including immune cytopenias, splenomegaly, granulomatous disease and lymphadenopathy. Genetic defects in ICOS, CD19 and TACI have been described. In addition to defects in the production or survival of memory B cells, in most subjects, B cells have defects in Toll-like receptor signaling.

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Defined Blocks in Terminal Plasma Cell Differentiation of Common Variable Immunodeficiency Patients

Cited by 68 publications

References 37 publications

IgH sequences in common variable immune deficiency reveal altered B cell development and selection

IgH sequences in common variable immune deficiency reveal altered B cell development and selection

Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease

Role of B cells in common variable immune deficiency

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