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

Gertjan J. Driessen, Menno C. van Zelm, P. Martin van Hagen, Nico G. Hartwig, Margreet Trip, Adilia Warris, Esther de Vries, Barbara H. Barendregt, Ingrid Pico, Wim Hop, Jacques J. M. van Dongen, Mirjam van der Burg

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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.
Original languageEnglish
Pages (from-to)6814-6823
Number of pages10
JournalBlood
Volume118
Issue number26
Early online date31 Oct 2011
DOIs
Publication statusPublished - 22 Dec 2011

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Common Variable Immunodeficiency
B-Lymphocytes
History
Cells
Defects
B-Lymphocyte Subsets
Agammaglobulinemia
Immunophenotyping
Germinal Center
Assays
Genetic Recombination
Cohort Studies
Cell Proliferation
Sorting
Mutation
Survival
Enzymes
Chemical activation

Keywords

  • adolescent
  • adult
  • aged
  • B-lymphocyte subsets
  • B-lymphocytes
  • cell proliferation
  • child
  • common variable immunodeficiency
  • female
  • flow cytometry
  • germinal center
  • humans
  • immunologic memory
  • immunophenotyping
  • male
  • middle aged
  • somatic hypermutation
  • young adult
  • immunoglobulin

Cite this

B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. / Driessen, Gertjan J.; van Zelm, Menno C.; van Hagen, P. Martin; Hartwig, Nico G.; Trip, Margreet; Warris, Adilia; de Vries, Esther; Barendregt, Barbara H.; Pico, Ingrid; Hop, Wim; van Dongen, Jacques J. M.; van der Burg, Mirjam.

In: Blood, Vol. 118, No. 26, 22.12.2011, p. 6814-6823.

Research output: Contribution to journalArticle

Driessen, GJ, van Zelm, MC, van Hagen, PM, Hartwig, NG, Trip, M, Warris, A, de Vries, E, Barendregt, BH, Pico, I, Hop, W, van Dongen, JJM & van der Burg, M 2011, 'B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency' Blood, vol. 118, no. 26, pp. 6814-6823. https://doi.org/10.1182/blood-2011-06-361881
Driessen, Gertjan J. ; van Zelm, Menno C. ; van Hagen, P. Martin ; Hartwig, Nico G. ; Trip, Margreet ; Warris, Adilia ; de Vries, Esther ; Barendregt, Barbara H. ; Pico, Ingrid ; Hop, Wim ; van Dongen, Jacques J. M. ; van der Burg, Mirjam. / B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. In: Blood. 2011 ; Vol. 118, No. 26. pp. 6814-6823.
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AU - Trip, Margreet

AU - Warris, Adilia

AU - de Vries, Esther

AU - Barendregt, Barbara H.

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AU - van Dongen, Jacques J. M.

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N2 - 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.

AB - 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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KW - male

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