Common Variable Immunodeficiency patients with a phenotypic profile of immunosenescence present with thrombocytopenia

Abstract Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning “bins” yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27− CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes’ immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ CD4+ T-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.

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IMPAIRED CYTOKINE PRODUCTIONS BY CD4+ T CELLS IN COMMON VARIABLE IMMUNODEFICIENCY (CVID) ASSOCIATED WITH ABSENCE OF MEMORY B CELLS

10.26226/morressier.57bc1757d462b80290b4cefa ◽

2016 ◽

Author(s):

Laura Berron-ruiz

Keyword(s):

T Cells ◽

B Cells ◽

Common Variable Immunodeficiency ◽

Cd4 T Cells ◽

Memory B Cells ◽

Common Variable

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Impaired selective cytokine production by CD4+ T cells in Common Variable Immunodeficiency associated with the absence of memory B cells

Clinical Immunology ◽

10.1016/j.clim.2016.03.013 ◽

2016 ◽

Vol 166-167 ◽

pp. 19-26 ◽

Cited By ~ 5

Author(s):

Laura Berrón-Ruiz ◽

Gabriela López-Herrera ◽

Alexander Vargas-Hernández ◽

Leopoldo Santos-Argumedo ◽

Constantino López-Macías ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Common Variable Immunodeficiency ◽

Cd4 T Cells ◽

Cytokine Production ◽

Memory B Cells ◽

Common Variable

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CTLA-4 Expression in CD4+ T Cells From Patients With LRBA Deficiency and Common Variable Immunodeficiency With No Known Monogenic Disease

Journal of Investigational Allergology and Clinical Immunology ◽

10.18176/jiaci.0302 ◽

2018 ◽

Vol 28 (6) ◽

pp. 422-424 ◽

Cited By ~ 3

Author(s):

G Azizi ◽

M Jamee ◽

R Yazdani ◽

Y Bagheri ◽

F Fayyaz ◽

...

Keyword(s):

T Cells ◽

Common Variable Immunodeficiency ◽

Cd4 T Cells ◽

Monogenic Disease ◽

Lrba Deficiency ◽

Common Variable

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Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21low B cells

Allergologia et Immunopathologia ◽

10.1016/j.aller.2019.01.003 ◽

2019 ◽

Vol 47 (5) ◽

pp. 457-466 ◽

Cited By ~ 3

Author(s):

G. López-Herrera ◽

N.H. Segura-Méndez ◽

P. O’Farril-Romanillos ◽

M.E. Nuñez-Nuñez ◽

M.C. Zarate-Hernández ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Common Variable Immunodeficiency ◽

Common Variable

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A Detailed Phenotypic Analysis Using Six Color Flow Cytometry of Lymphocyte Subsets Mobilized with AMD3100 Compared to G-CSF.

Blood ◽

10.1182/blood.v104.11.408.408 ◽

2004 ◽

Vol 104 (11) ◽

pp. 408-408 ◽

Cited By ~ 1

Author(s):

Yoshiyuki Takahashi ◽

S. Chakrabarti ◽

R. Sriniivasan ◽

A. Lundqvist ◽

E.J. Read ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

B Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Phenotypic Analysis ◽

Color Flow ◽

Cd34 Cells

Abstract AMD3100 (AMD) is a bicyclam compound that rapidly mobilizes hematopoietic progenitor cells into circulation by inhibiting stromal cell derived factor-1 binding to its cognate receptor CXCR4 present on CD34+ cells. Preliminary data in healthy donors and cancer patients show large numbers of CD34+ cells are mobilized following a single injection of AMD3100. To determine whether AMD3100 mobilized cells would be suitable for allografting, we performed a detailed phenotypic analysis using 6 color flow cytometry (CYAN Cytometer MLE) of lymphocyte subsets mobilized following the administration of AMD3100, given as a single 240mcg/kg injection either alone (n=4) or in combination with G-CSF (n=2: G-CSF 10 mcg/kg/day x 5: AMD3100 given on day 4). Baseline peripheral blood (PB) was obtained immediately prior to mobilization; in recipients who received both agents, blood was analyzed 4 days following G-CSF administration as well as 12 hours following administration of AMD3100 and a 5th dose of G-CSF. AMD3100 alone significantly increased from baseline the PB WBC count (2.8 fold), Absolute lymphocyte count (ALC: 2.5 fold), absolute monocyte count (AMC: 3.4 fold), and absolute neutrophil count (ANC: 2.8 fold). Subset analysis showed AMD3100 preferentially increased from baseline PB CD34+ progenitor counts (5.8 fold), followed by CD19+ B-cells (3.7 fold), CD14+ monocytes (3.4 fold), CD8+ T-cells (2.5 fold), CD4+ T-cells (1.8 fold), with a smaller increase in CD3−/CD16+ or CD56+ NK cell counts (1.6 fold). There was no change from baseline in the % of CD4+ or CD8+ T-cell expressing CD45RA, CD45RO, or CD56, CD57, CD27, CD71 or HLA-DR. In contrast, there was a decline compared to baseline in the mean percentage of CD3+/CD4+ T-cells expressing CD25 (5.5% vs 14.8%), CD62L (12.1% vs 41.1%), CCR7 (2.1% vs 10.5%) and CXCR4 (0.5% vs 40.9%) after AMD3100 administration; similar declines in expression of the same 4 surface markers were also observed in CD3+/CD8+ T-cells. A synergistic effect on the mobilization of CD34+ progenitors, CD19+ B cells, CD3+ T-cells and CD14+ monocytes occurred when AMD3100 was combined with G-CSF (Figure). In those receiving both AMD3100 and G-CSF, a fall in the % of T-cells expressing CCR7 and CXCR4 occurred 12 hours after the administration of AMD3100 compared to PB collected after 4 days of G-CSF; no other differences in the expression of a variety activation and/or adhesion molecules on T-cell subsets were observed. Whether differences in lymphocyte subsets mobilized with AMD3100 alone or in combination with G-CSF will impact immune reconstitution or other either immune sequela (i.e. GVHD, graft-vs-tumor) associated with allogeneic HCT is currently being assessed in an animal model of allogeneic transplantation.

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Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.1995.tb02281.x ◽

2008 ◽

Vol 101 (1) ◽

pp. 82-88 ◽

Cited By ~ 24

Author(s):

M. FUNAUCHI ◽

J. FARRANT ◽

C. MORENO ◽

A. D. B. WEBSTER

Keyword(s):

T Cells ◽

Common Variable Immunodeficiency ◽

Cd4 T Cells ◽

Lymphocyte Responses ◽

Common Variable

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Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency

Blood ◽

10.1182/blood.v82.1.192.bloodjournal821192 ◽

1993 ◽

Vol 82 (1) ◽

pp. 192-201 ◽

Cited By ~ 43

Author(s):

JS Jaffe ◽

W Strober ◽

MC Sneller

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cd8 T Cells ◽

Common Variable Immunodeficiency ◽

Cytokine Production ◽

Interleukin 2 ◽

T Cell Subsets ◽

Cell Phenotype ◽

Common Variable

A substantial subgroup of patients with common variable immunodeficiency (CVI) exhibit an abnormal T-cell phenotype characterized by a low CD4/CD8 ratio associated with a significant increase in the absolute number of CD8+ T cells (CVI4/8low patients). In the present study, we examined the phenotypic and functional properties of purified T-cell subsets in this group of CVI patients. CD8+ T cells from CVI4/8low patients manifested increased expression of HLA-DR and CD57 and decreased expression of CD45RA as compared with CD8+ T cells from normal controls. When stimulated with anti-CD3 and phorbol 12-myristate 13-acetate, purified patient CD8+ T cells exhibited significantly decreased proliferation, c-myc expression, and interleukin-2 (IL-2) production compared with that of normal CD8+ T cells. Nevertheless, mitogen-activated patient CD8+ T cells secreted elevated amounts of gamma-interferon and IL-5 and normal amounts of IL- 4. This abnormal pattern of proliferation and cytokine production was limited to the CD8+ T-cell subset as CD4+ T cells from these patients exhibited normal proliferation and cytokine production. In further functional studies, purified CD8+ T cells from CVI4/8low patients manifested increased cytotoxic T-lymphocyte activity and suppressor activity, as compared with normal CD8+ T cells, when they were tested in (1) an anti-CD3 “redirected” cytotoxicity assay and (2) a suppressor assay consisting of CD8+ T cells and Staphylococcus aureus Cowan I (SAC) plus IL-2-stimulated normal (allogeneic) B cells. In the latter case, patient CD8+ T cells suppressed IgG production, but not IgM production. Finally, in studies to evaluate the role of patient CD8+ T cells in the pathogenesis of hypogammaglobulinemia, we determined the capacity of SAC and IL-2 to induce Ig production in highly purified patient B cells, ie, in the absence of patient CD8+ T cells. We found that, whereas B cells from one patient produced normal amounts of IgG, B cells from three patients were unable to produce normal amounts of IgG under these conditions. These data establish the phenotypic and functional characteristics of CD8+ T cells in CVI4/8low and clearly distinguish CVI4/8low patients from other patients with this syndrome. The data do not support the contention that hypogammaglobulinemia in CVI4/8low patients is due to a direct effect of CD8+ T cells on terminal B-cell differentiation, except in the occasional patient. The abnormal CD8+ T cells may, nevertheless, have more subtle effects of lymphoid function that play a role in disease pathogenesis.

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