Low numbers of regulatory T cells in CVID: association with chronic inflammation

Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway.
Clinical & Experimental Immunology (Impact Factor: 3.04). 04/2007; 147(3):521-5. DOI: 10.1111/j.1365-2249.2006.03314.x
Source: PubMed


Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. Abnormalities of CD4+CD25high forkhead box P3 (FoxP3)+ regulatory T cells (Treg) have been associated with autoimmune and inflammatory disorders, and we hypothesized that CVID might be characterized by Treg abnormalities. CD3+ cells from patients and controls were analysed for the expression of FoxP3 mRNA by real time reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells from CVID patients and controls were stained for Treg markers, analysed by flow cytometry and compared to clinical characteristics. The main findings were: (i) CVID patients had significantly decreased expression of FoxP3 mRNA and decreased proportions of CD4+CD25highFoxP3+ cells compared to controls; (ii) CVID patients with splenomegaly had even lower proportions of Treg compared to other patients and controls; (iii) serum levels of the inflammatory marker neopterin were correlated negatively with the proportions of Treg within the CVID population, while there was no significant association with bronchiectasis. We have demonstrated decreased proportions of Treg in CVID patients, particularly in those with signs of chronic inflammation. Decreased proportions of TReg are suggested to be pathogenetically important in autoimmunity, and our results suggest that TReg may have a similar role in CVID.

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    • "This indicates that CVID subjects with inflammatory conditions are likely to suffer from a more significant defect of adaptive immunity than those CVID subjects without inflammatory conditions. These data are in line with previous observations that CVID subjects with fewer isotype switched memory B cells, more impaired thymic and B cell bone marrow output, or reduced numbers and function of regulatory T cells, have a significantly greater likelihood of inflammatory consequences [29,30,60,61,62]. Greater losses of adaptive immunity could lead to an expansion of innate immune responses and potentially the global IFN signature observed. "
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    ABSTRACT: About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "In a subset of patients with granulomatous form of CVID characterized with lymphopenia, autoimmune disorders, including rheumatoid-like arthritis, were even more common, occurring in more than one-half of patients [7]. In CVID, low proportions of CD4 + CD25+, Foxp3 T regulatory cell subset correlated with presence of autoimmunity and splenomegaly [16]. In patients with NBS regulatory T cells so far were not investigated. "
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    ABSTRACT: We report on pediatric patient with Nijmegen breakage syndrome (NBS), a rare DNA repair disorder characterized by microcephaly, immunodeficiency and predisposition to malignant lymphomas, who developed juvenile idiopathic arthritis (JIA)-like polyarthritis. In patients with primary immunodeficiencies (PID), septic arthritis due to pyogenic bacteria or mycoplasmal arthritis are the most common osteoarticular manifestations. In certain PID, chronic, non-infectious arthritis resembling rheumatoid arthritis may occur. In our patient microbiologic cultures of synovial fluid including Mycoplasma spp. were negative. At first, because of suspected mycoplasmal arthritis we used macrolides and doxycycline combined with hydroxychloroquine but without therapeutic response. However, the use of rituximab led to remission of her polyarthritis lasting for 9 months. Autoimmune features were rarely reported in NBS. An occurrence of JIA-like, chronic polyarthritis in NBS, a DNA repair disorder characterized by decreased tolerance of immunosuppressive drugs such as methotrexate and a high natural risk for lymphomas, makes therapeutic approach even more complex.
    Full-text · Article · Sep 2013 · Italian Journal of Pediatrics
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    • "As a result of this failure, recurrent infections particularly with encapsulated bacteria in respiratory tract are often seen in CVID patients [1] [8] [9]. The antibody response is affected at both early and late stages of B cell maturation including up-regulation of CD70 and CD86 in naïve B cells, somatic hypermutation and antibody affinity maturation [1] [10]. Numerous reports have shown the reduced amounts of class-switched memory B cells ( "
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    ABSTRACT: Common variable immunodeficiency (CVID) is one of the predominant antibody disorders where abnormalities in regulatory T cells (Tregs) may result in autoimmunity and chronic inflammation. To evaluate Tegs frequency and function, 13 CVID patients and 10 age- and sex-matched healthy volunteer were enrolled. The percentages of Tregs were calculated using flow cytomety method. For assessment of Treg function, Tregs were isolated and their suppressive functions were determined using Tregs suppression assay. The levels of immunoregulatory cytokines IL-10 and TGF-β produced by Tregs were also measured. Our results revealed that Tregs frequency (P<0.001) and their suppressive functions (P<0.001) were impaired in CVID patients. The level of TGF-β did not differ between CVID patients and controls (p=0.09); while the amount of IL-10 was remarkably decreased in CVID patients (P=0.007). Our findings suggest that disturbed Tregs frequency and their functional characteristics might account for aberrant immune responses observed in CVID patients.
    Full-text · Article · Mar 2013 · Cellular Immunology
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