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

Abstract Common variable immunodeficiency disorder (CVID) is the most prevalent form of primary idiopathic hypogammaglobulinemia. Identification of genetic defects in CVID is hampered by clinical and immunologic heterogeneity. By flow cytometric immunophenotyping and cell sorting of peripheral B-cell subsets of 37 CVID patients, we studied the B-cell compartment at the B-cell subset level using the κ-deleting recombination excision circle assay to determine the replication history and the Igκ-restriction enzyme hot-spot mutation assay to assess the somatic hypermutation status. Using this approach, 5 B-cell patterns were identified, which delineated groups with unique replication and somatic hypermutation characteristics. Each B-cell pattern reflected an immunologically homogenous patient group for which we proposed a different pathophysiology: (1) a B-cell production defect (n = 8, 18%), (2) an early peripheral B-cell maturation or survival defect (n = 4, 11%), (3) a B-cell activation and proliferation defect (n = 12, 32%), (4) a germinal center defect (n = 7, 19%), and (5) a postgerminal center defect (n = 6, 16%). The results of the present study provide for the first time insight into the underlying pathophysiologic background in 5 immunologically homogenous groups of CVID patients. Moreover, this study forms the basis for larger cohort studies with the defined homogenous patient groups and will facilitate the identification of underlying genetic defects in CVID.

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Carrier-directed anti-hapten responses by b-cell subsets

Journal of Experimental Medicine ◽

10.1084/jem.146.1.1 ◽

1977 ◽

Vol 146 (1) ◽

pp. 1-10 ◽

Cited By ~ 37

Author(s):

GK Lewis ◽

JW Goodman

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Burst Size ◽

Cell Subset ◽

B Cell Activation ◽

Cell Subpopulations ◽

Activation Pathways ◽

B Cell Subsets

The capacity of the trinitrophenyl (TNP) haptenic group, coupled to a series of chemically dissimilar carriers, to cross-stimulate putative T- dependent and T-independent murine B-cell subpepulations was determined by using an in vitro limiting dilution technique to generate primary IgM responses. It was found that TNP-Ficoll and TNP-dextran, two T- independent antigens with little or no polyclonal mitogenicity, stimulate the same population of anti-TNP precursors, which is distinct from the precursor population activated by TNP-bacterial lipopolysaccharide (LPS), a T-independent polyclonal mitogen, or TNP-horse erythrocytes (HRBC), a T-dependent antigen. On the other hand, TNP-LPS and TNP-HRBC activate the same precursor population, indicating that LPS can substitute for the T- cell signal in T-dependent B-cell responses, whereas nonmitogenic T- independent antigens cannot. However, the cumulative evidence from this and other laboratories strongly indicates that LPS and T-dependent antigens activate B cells by different mechanisms. Of particular interest, LPS is incapable of activating B cells responsive to weakly- or nonmitogenic T-independent antigens. Based on clonal burst size, T-dependent antigens are capable of inducing greater antigen-specific B-cell proliferation than T-independent antigens. However, TNP conjugates of Ficoll and dextran, which are relatively poor inducers of polyclonal B-cell activation, induced larger anti-TNP clones than did TNP-LPS, a strong polyclonal mitogen. The findings reinforce the evidence favoring existence of multiple B- cell subpopulations with distinctive activation pathways. They also strengthen the proposition that a given B-cell subset can be activated by more than one mechanism.

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PTIP chromatin regulator controls development and activation of B cell subsets to license humoral immunity in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707938114 ◽

2017 ◽

Vol 114 (44) ◽

pp. E9328-E9337 ◽

Cited By ~ 4

Author(s):

Dan Su ◽

Stijn Vanhee ◽

Rebeca Soria ◽

Elin Jaensson Gyllenbäck ◽

Linda M. Starnes ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Humoral Immunity ◽

Cell Activation ◽

Cell Receptor ◽

B Cell Receptor ◽

Transactivation Domain ◽

B Cell Activation ◽

Chromatin Regulator ◽

B Cell Subsets

B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo. By examining the effects of PTIP deficiency in mice at various ages during ontogeny, we demonstrate that PTIP promotes bone marrow B cell development as well as the neonatal establishment and subsequent long-term maintenance of self-reactive B-1 B cells. Furthermore, we find that PTIP is required for B cell receptor- and T:B interaction-induced proliferation, differentiation of follicular B cells during germinal center formation, and normal signaling through the classical NF-κB pathway. Together with the previously identified role for PTIP in promoting sterile transcription at the Igh locus, the present results establish PTIP as a licensing factor for humoral immunity that acts at several junctures of B lineage maturation and effector cell differentiation by controlling B cell activation.

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Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency

Blood ◽

10.1182/blood-2003-12-4359 ◽

2005 ◽

Vol 105 (2) ◽

pp. 511-517 ◽

Cited By ~ 58

Author(s):

Pernille Andersen ◽

Henrik Permin ◽

Vagn Andersen ◽

Lone Schejbel ◽

Peter Garred ◽

...

Keyword(s):

Tract Infection ◽

Respiratory Tract ◽

Respiratory Tract Infection ◽

Light Chain ◽

Common Variable Immunodeficiency ◽

Somatic Hypermutation ◽

Hot Spot ◽

Reference Interval ◽

Immunoglobulin Genes ◽

Common Variable

AbstractReduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in κ light-chain transcripts using a VκA27-specific restriction enzyme-based hot-spot mutation assay (IgκREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P = .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P = .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n = 18, P = .006). A slight decline of mutated fractions over years was noted (P = .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients.

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Association of clinical manifestations and B cell subsets with Freiburg and Paris classifications in patients with Common Variable Immunodeficiency (CVID).

Frontiers in Immunology ◽

10.3389/conf.fimmu.2015.05.00128 ◽

2015 ◽

Vol 6 ◽

Author(s):

Berrón-Ruiz Laura ◽

Vargas-Hernández Alexander ◽

Segura-Méndez Nora ◽

López-Herrera Gabriela ◽

Mogica-Martínez Dolores ◽

...

Keyword(s):

B Cell ◽

Common Variable Immunodeficiency ◽

Clinical Manifestations ◽

B Cell Subsets ◽

Common Variable

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B cell activation and human immunodeficiency virus infection. V. Phenotypic and functional alterations in CD5+ and CD5? B cell subsets

Journal of Clinical Immunology ◽

10.1007/bf00920013 ◽

1993 ◽

Vol 13 (6) ◽

pp. 381-388 ◽

Cited By ~ 13

Author(s):

Stefano Indraccolo ◽

Marta Mion ◽

Rita Zamarchi ◽

Arianna Veronesi ◽

Maria Luisa Veronese ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Infection ◽

Human Immunodeficiency Virus Infection ◽

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Immunodeficiency Virus ◽

B Cell Subsets

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Intrathecal B-cell activation in LGI1 antibody encephalitis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000669 ◽

2020 ◽

Vol 7 (2) ◽

pp. e669 ◽

Cited By ~ 2

Author(s):

Klaus Lehmann-Horn ◽

Sarosh R. Irani ◽

Shengzhi Wang ◽

Arumugam Palanichamy ◽

Sarah Jahn ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Mononuclear Cells ◽

Cell Activity ◽

Oligoclonal Bands ◽

B Cell Activation ◽

Cell Repertoire ◽

Antibody Titers ◽

B Cell Subsets

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

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Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma

Cancers ◽

10.3390/cancers14010128 ◽

2021 ◽

Vol 14 (1) ◽

pp. 128

Author(s):

Raphael Lievin ◽

Houria Hendel-Chavez ◽

Aliou Baldé ◽

Rémi Lancar ◽

Michèle Algarte-Génin ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Hodgkin Lymphoma ◽

Cell Activation ◽

Cell Subset ◽

Serum Levels ◽

Classical Hodgkin Lymphoma ◽

Cell Counts ◽

Cytokine Levels ◽

B Cell Subsets

Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

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