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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/126371
Primary and secondary immunodeficiencies of the IL-12/IFN-γ axis
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[eng] IL-12/IFN-γ axis is a principal pathway for intramacrophagic pathogens immunity such as leishmania or mycobacteria. Alterations in this axis, being both congenic (causing the primary immunodeficiency Mendelian Susceptibility to Mycobacterial Disease, MSMD) or acquired (treatment with anti-TNF-α drugs) cause susceptibility to this type of microbes. MSMD causes susceptibility mainly to non-pathogenic mycobacteria, salmonella and candida; besides, MSMD- causing mutations have been detected in Mycobacterium tuberculosis and Leishmania patients. On the other hand, the death of an anti-TNF-α in-utero exposed infant after BCG vaccination together with the effect of anti-TNF-α drugs in tuberculosis reactivation in adults and the known tole of TNF-α in B cell maturation reveal the need for an in-depth study of in-utero exposition to anti-TNF-α drugs. With that our hypothesis is that patients with extrapulmonary Mycobacterium tuberculosis infection or visceral leishmaniasis have a primary dysfunction of the IL-12/IFN-γ axis and that exposure to anti-TNF-α antibodies during whole pregnancy in children born to mothers with inflammatory bowel disease affects the normal development of the neonatal immune system, conferring a secondary immunodeficiency, which includes a dysfunction of the IL- 12/IFN-γ axis.
Both extrapulmonary tuberculosis (n=23) and visceral leishmaniasis (n=24) patients presented alterations in the IL-12/IFN-γ pathway; however, we did not detect any complete defect. Concretely, the patients with extrapulmonary tuberculosis had a diminished response to IFN-γ while visceral leishmaniasis patients had a diminished production of IFN-g. Genetic study of these patients to unravel mutations causing partial forms of susceptibility to intramacrophagic infections is then needed. Besides, we detected an IL-12Rβ1 defect in a Peruvian patient that was misdiagnosed as multi-resistant tuberculosis, being a disseminated infection by the vaccine strain BCG. After the detection of the genetic defect, the patient was transferred to the National Institute of Health in the USA, where she received the appropriate treatment and the microbiological diagnosis was corrected resulting in the resolution of the infection. This case remarks the fact that suspicion of this forms of immune deficiency and their detection changes the prognostics and outcome of the patient.
The study of the effect of anti-TNF-α on the exposed infant immune system (n=7) revealed a T and B cell maturation defect that was corrected at 12 months, normal cell proliferation after mitogen stimulation and normal immunoglobulin production and vaccine response without an increase of severe infections. On the other hand, Treg cell frequency was low in exposed infants, without reaching normalization at 12 months of age. Treg cell frequency in neonates inversely correlated with anti-TNF-α through level in the mother during third trimester of pregnancy and with T cell proliferation after a mild mitogen stimulation. These data with the increased atopia/allergy in the studied infants suggest the need of a long-term follow-up for Treg cells and the advent of immune dysregulation events. Antimycobacterial response was diminished in exposed infants and not totally recovered after washing the drug from the blood in the culture. On the other hand, coinciding with the decrease of the drug levels in blood, the production of IL-12, IFN-γ and TNF-α increased. We conclude that the effects of anti-TNF-α exposure during pregnancy are not permanent and that BCG vaccination in these population should be avoided until, at least, 12 months of age.
By last, the transition between the intra- and extra-uterine world is a special life-situation where the immune system plays a major role. We studied it in healthy cord blood donors, with special
attention to the IL-12/IFN-γ pathway and B cell compartment, including regulatory B cells (Breg). Breg cells, defined as CD24hiCD38hi B cells, were expanded in cord blood, with capacity to produce IL-10 and to inhibit IL-4 and IFN-γ production by T cells with a similar phenotype when compared with adult Bregs. Besides, response to mycobacterial challenge was diminished. Interestingly, the diminished production of IFN-γ was associated with Breg cell frequency, opening the door to new research studying the role of these cells in different neonatal conditions as well as in cord blood derived stem cell transplantation.
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ESTEVE-SOLÉ, Ana. Primary and secondary immunodeficiencies of the IL-12/IFN-γ axis. [consulta: 5 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/126371]