Common variable immunodeficiency: how many diseases?

doi:10.1016/S0167-5699(97)01086-4

Immunology Today

Volume 18, Issue 7, July 1997, Pages 325-328

Immunology Today

https://doi.org/10.1016/S0167-5699(97)01086-4 Get rights and content

Abstract

Common variable immunodeficiency (CVID) is a major antibody-deficiency syndrome, leading to a significantly increased risk of bacterial infection, as well as autoimmune and granulomatous diseases. The clinical and immunological features are heterogeneous. Four decades have passed since it was first described and, despite considerable research, the fundamental cause(s) remain unknown. This article explores some of the problems of investigating the disease.

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The immunologic features of patients with early-onset and polyautoimmunity
2020, Clinical Immunology
Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.
Common variable immunodeficiency is associated with a functional deficiency of invariant natural killer T cells
2014, Journal of Allergy and Clinical Immunology
Citation Excerpt :
In this study, we have identified another cellular impairment that is present in most of the patients with CVID. The reduction in both number and function of iNKT cells is distinctive to patients with CVID and not shared by other antibody-deficient patients who share similarities of clinical presentation and treatment.30 Around 40% of the patients in our cohort showed a complete absence of iNKT cells.
Common variable immunodeficiency (CVID) is the commonest symptomatic primary antibody disorder, with monogenic causes identified in less than 10% of all cases. X-linked proliferative disease is a monogenic disorder that is associated with hypogammaglobulinemia and characterized by a deficiency of invariant NKT (iNKT) cells. We sought to evaluate whether a defect in iNKT cell number or function was associated with CVID.
An evaluation of the function and number of iNKT cells in CVID.
Six-color flow cytometry enumerated iNKT cells in 36 patients with CVID and 50 healthy controls. Their proliferative capacity and cytokine production (IFN-γ, IL-13, IL-17) was then investigated following activation with CD1d ligand alpha-galactosylceramide.
A reduction in the number of iNKT cells (31 iNKT cells/10⁵ T cells) in patients with CVID compared with healthy controls (100 iNKT cells/10⁵ T cells) was observed (P < .0001). Two cohorts could be discerned within the CVID group: group 1 with an abnormal number of iNKT cells (n = 28) and group 2 with a normal number of iNKT cells (n = 8). This segregation coassociated with the proliferative capacity of iNKT cells between the 2 groups. However, differences in the function of iNKT cells were noted in group 2, in which an increase in IFN-γ (P = .0016) and a decrease in IL-17 (P = .0002) production was observed between patients with CVID and controls. Finally, a significant association was seen between the number of iNKT cells and the percentage of class-switched memory B cells and propensity to lymphoproliferation (P = .002) in patients with CVID.
iNKT cells are deficient and/or functionally impaired in most of the patients with CVID.
Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations
2011, Blood
Citation Excerpt :
Idiopathic CD4+ T lymphocytopenia (ICL) is defined by an unexplained persistent CD4+ T lymphocyte count of < 300 cells/μL or < 20% of the total T-cell count.1 Since the discovery of human retroviruses, sporadic ICL patients were recognized with a CD4+ lymphocytopenia not infected by HIV or HTLV-1.2-7 Smith et al reviewed 230179 cases from the CDC AIDS Reporting System and described 47 ICL patients.2,3
A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4⁺ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34⁺ hematopoietic stem cells could not repopulate RAG2^−/−IL2Rγc^−/− mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition.
Spleen
2010, Differential Diagnosis in Surgical Pathology
Spleen
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Reduced frequency of CD4+CD25HIGHFOXP3+ cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: A link to autoimmunity?
2009, Clinical Immunology
Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease characterized by defective immunoglobulin production and often associated with autoimmunity. We used flow cytometry to analyze CD4⁺CD25^HIGHFOXP3⁺ T regulatory (Treg) cells and ask whether perturbations in their frequency in peripheral blood could underlie the high incidence of autoimmune disorders in CVID patients. In this study, we report for the first time that CVID patients with autoimmune disease have a significantly reduced frequency of CD4⁺CD25^HIGHFOXP3⁺ cells in their peripheral blood accompanied by a decreased intensity of FOXP3 expression. Notably, although CVID patients in whom autoimmunity was not diagnosed had a reduced frequency of CD4⁺CD25^HIGHFOXP3⁺ cells, FOXP3 expression levels did not differ from those in healthy controls. In conclusion, these data suggest compromised homeostasis of CD4⁺CD25^HIGHFOXP3⁺ cells in a subset of CVID patients with autoimmunity, and may implicate Treg cells in pathological mechanisms of CVID.

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Immunology Today

Abstract

Reference (43)

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Cited by (145)

The immunologic features of patients with early-onset and polyautoimmunity

Common variable immunodeficiency is associated with a functional deficiency of invariant natural killer T cells

Idiopathic CD4<sup>+</sup> T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

Spleen

Spleen

Reduced frequency of CD4<sup>+</sup>CD25<sup>HIGH</sup>FOXP3<sup>+</sup> cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: A link to autoimmunity?