Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease
Introduction
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum IgG, IgA, and/or IgM, deficient antigen-specific antibody responses, and recurrent infections [1], [2], [3], [4]. Approximately 25% of subjects with CVID suffer from autoimmune disease [5], [6] which could be the result of immune dysregulation resulting in autoantibody formation to a variety of antigens. The autoimmune diseases vary from autoimmune hemolytic anemia, immune thrombocytopenia purpura, pernicious anemia, vitiligo, psoriasis, vasculitis, rheumatoid arthritis, kerato-conjunctivitis sicca, thyroiditis, to chronic autoimmune neutropenia [6], [7], [8]. Much research on B cell immunophenotyping has led to our understanding that CVID w/ AI is associated with decreased numbers of switched memory B cells (CD27+, IgM-, IgD-phenotype) and elevated serum levels of B-cell activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL); CVID subjects with transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) mutations also have a higher frequency of autoimmunity [8], [9], [10], [11], [12], [13], [14], [15], [16]. Recently, the CVID registry, established in 1996, divided 334 patients with CVID into 5 clinical phenotypes and reported that lower levels of CD8+ cells correlated with autoimmunity [17]. However, since CVID is a polygenic disease and since T cells are important to B cell development and function, we focused on T cell phenotyping. In addition, other laboratories have found that multiple T cell abnormalities ranging from loss of CD4+ naïve cells, disrupted T cell receptor B variable repertoires, to altered cytokine production existing in CVID subjects [3], [18], [19], [20]. Therefore, we designed our studies to test whether a specific subtype of T cells, the regulatory T cell, was impaired in CVID patients with autoimmune disease.
T regulatory cells (Treg) have been shown to be involved in a number of autoimmune diseases, but little research has studied their role in autoimmune disease in CVID. We have focused on Treg since their repertoire may be established very early on in life, and has implications for the proper suppression of immune dysfunction in childhood and adulthood [21]. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is due to a genetic defect in FoxP3 (forkhead box) leading to Treg deficiency, is associated with severe autoimmune disease [22], [23], [24]. Subjects with active systemic lupus erythematosus (SLE) have significantly lower numbers of Treg than subjects with either inactive disease or without autoimmunity [25]. In subjects with multiple sclerosis, Treg function is decreased [26], while Treg numbers are decreased in subjects with active Crohn's disease compared to those with inactive disease [27].
Recent published work has showed that CVID subjects have lower number of Treg compared to healthy controls [20]. A correlation between splenomegaly and Treg numbers was also shown, but a comparison between Treg and autoimmune disease was not performed in these CVID subjects. Furthermore, the functional characteristics of Treg were not analyzed in these subjects.
Published work with Treg cells has revealed a number of proteins that are necessary for the development and/or function of these cells. FoxP3 is a transcription factor that is associated with Treg development and function [28] and Granzyme A is involved in the granzyme/perforin pathway by which Treg cells kill target cells [29], [30]. XCL1 (lymphotactin) is a chemokine that has been previously shown to be directly correlated with Treg function in suppression and cytotoxicity [31] and pSTAT5 (phosphorylated signal transducers and activator of transcription 5) is an intracellular protein critical for in vivo accumulation of functional Treg [32]. GITR (glucocorticoid-induced TNF receptor) and CTLA-4 have been shown to be important for modulating Treg cell function [33], [34], [35].
In this study, CVID subjects with and without a diagnosis of autoimmune disease followed at Stanford Hospital and Clinics and Lucille Packard Children's Hospital were evaluated for Treg function and phenotype. Healthy control subjects were recruited for comparison analysis. Disease controls with X-linked agammaglobulinema (XLA) without autoimmunity were also analyzed.
Section snippets
Human subjects
The study was approved by the Stanford Administrative Panel on Human Subjects in Medical Research. All subjects signed informed consent forms before participating in the study. Fourteen subjects with CVID were recruited from Stanford Hospital and Clinics and Lucile Packard Children's Hospital, as well as 5 healthy adult controls. Two subjects with X-linked agammaglobulinemia (XLA) as identified by Bruton's tyrosine kinase deficiency were enrolled as controls. The study was carried out under the
Description of subjects
From 2005 to 2008, 14 CVID subjects were enrolled in our study. All these subjects were under longitudinal medical care by a Clinical Immunologist at Stanford Medical Center. Healthy controls (n = 5) and XLA subjects (n = 2) were assessed, determined not to have autoimmune disease by history and chart review and every attempt to sex-match and age-match was done (Table 1). The CVID subjects ranged from 6 years to 67 years of age with a mean age of 32 years of age. 53% were male and 47% were female.
Discussion
We have shown that CD4 + CD25hiCD127lo Treg in CVID subjects with autoimmune disease are lower in number in the peripheral blood and have a significantly reduced ability to suppress proliferation of autologous CD4+ effector cells and allogenic CD4+ effector cells compared to subjects with CVID without autoimmune disease, healthy controls and XLA. This inability to suppress potentially autoreactive T cells suggests that dysfunctional Treg may play a role in autoimmune disease in CVID. The main
Acknowledgments
We would like to thank Dr. David Lewis for the critical review of the manuscript. We appreciate the subjects and their families for their time and their blood samples. This study was funded by the Stanford Children's Health Research Program and the Immunity, Transplantation and Infectious Disease Institute at Stanford University School of Medicine.
References (54)
- et al.
Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)
Clin. Immunol.
(1999) - et al.
Common variable immunodeficiency: clinical and immunological features of 248 patients
Clin. Immunol.
(1999) - et al.
Inflammatory and autoimmune complications of common variable immune deficiency
Autoimmun. Rev.
(2006) - et al.
Common variable immunodeficiency: a new look at an old disease
Lancet
(2008) - et al.
The EUROclass trial: defining subgroups in common variable immunodeficiency
Blood
(2008) - et al.
Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes
J. Allergy Clin. Immunol.
(2007) - et al.
Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor
Immunity
(2003) - et al.
High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency
Clin. Immunol.
(2007) - et al.
Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease
Blood
(2002) - et al.
Memory B cells in common variable immunodeficiency: clinical associations and sex differences
Clin. Immunol.
(2008)
Common variable immunodeficiency disorders: division into distinct clinical phenotypes
Blood
T-cell homeostasis: the dark(ened) side of common variable immunodeficiency
Blood
Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency
Clin. Immunol.
Regulatory T cells and immune tolerance
Cell
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells
J. Allergy Clin. Immunol.
Quantification of regulatory T cells in patients with systemic lupus erythematosus
J. Autoimmun.
Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease
Clin. Immunol.
Human T regulatory cells can use the perforin pathway to cause autologous target cell death
Immunity
The C-class chemokine lymphotactin costimulates the apoptosis of human CD4(+) T cells
Blood
CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor
Immunity
Immune competence and switched memory B cells in common variable immunodeficiency
Clin. Immunol.
Common variable immunodeficiency: the immune system in chaos
Trends Mol. Med.
Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients
Clin. Immunol.
Uncoupling of T-cell antigen receptor and downstream protein tyrosine kinases in common variable immunodeficiency
Clin. Immunol. Immunopathol.
Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency
Blood
Primary immunodeficiency diseases: an update
Clin. Exp. Immunol.
Common variable immunodeficiency
Curr. Allergy Asthma Rep.
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Both authors contributed equally to receive first authorship.