Are Martin Holm | PubMed Health

PubMed2004

Abnormal interleukin-7 function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins, leading to frequent infections, particularly of the respiratory tract. Frequently, T-cell abnormalities are observed. Interleukin-7 (IL-7) is involved in the homeostasis of lymphocytes, and may be elevated in lymphopenia. Mutations of genes related to IL-7 may lead to severe immunodeficiency disorders. We report elevated plasma levels of circulating IL-7 in a subgroup of CVID. These patients have increased numbers of circulating CD8+ T cells with decreased apoptosis and a predominance of CC chemokine receptor 7- (CCR7-) effector-memory T cells. Moreover, in some of these patients there is impaired response to IL-7 as assessed by in vitro proliferation and secretion of interferon gamma and transforming growth factor beta. These findings suggest novel pathogenic mechanisms and specific targets for further research in CVID.

Adult↗

PubMed2003

Impaired secretion of IL-10 by T cells from patients with common variable immunodeficiency--involvement of protein kinase A type I.

Common variable immunodeficiency (CVID) is a heterogeneous group of B cell deficiency syndromes. T cell abnormalities are present in a high proportion of patients with CVID, suggesting impaired T cell-mediated stimulation of B cells. Based on the importance of IL-10 for B cell function and the involvement of the cAMP/protein kinase A type I (PKAI) system in IL-10 synthesis, we examined IL-10 secretion in T cells from CVID patients and controls, particularly focusing on possible modulatory effects of the cAMP/PKAI system. Our main findings were: 1) anti-CD3 and anti-CD3/anti-CD28 activated T cells from CVID patients secreted less IL-10 than healthy controls. This defect was not related to varying proportions of T cell subsets (e.g., CD4(+)/CD8(+), CD45RA(+)/RO(+), or CD28(-) T cells); 2) PKAI activation through the cAMP agonist 8-CPT-cAMP markedly inhibited IL-10 secretion from T cells through CD3 and CD28 activation in both patients and controls, but the sensitivity for cAMP-dependent inhibition was increased in CVID; 3) selective PKAI inhibition by Rp-8-Br-cAMPS markedly increased IL-10 secretion in anti-CD3 and anti-CD3/anti-CD28-stimulated T cells in both patients and controls. Even at the lowest concentrations of Rp-8-Br-cAMPS, IL-10 secretion in CVID patients reached levels comparable to those in controls. Our findings suggest impaired secretion of IL-10 by T cells from CVID patients, suggesting a possible link between T cell deficiency and impaired B cell function in CVID. The involvement of the cAMP/PKAI system in this defect suggests a novel target for therapeutic immunomodulation in CVID.

8-Bromo Cyclic Adenosine Monophosphate↗