Bacille Calmette-Guérin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families.

Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The ß1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.

Mecanismos moleculares de la respuesta inmune en la tuberculosis pulmonar humana / Molecular mechanisms of the immune response in human pulmonary tuberculosis

La tuberculosis pulmonar humana es una enfermedad infecciosa causada por M. tuberculosis; el control de la infección requiere el desarrollo de una respuesta inmune protectora. Este tipo de respuesta inmunológica incluye la participación de los macró-fagos alveolares, linfocitos T (CD4+,CD8+, NK y yδ) y la producción de citocinas como: 1L-2, IFN-γ, IL-12, IL-18 y TNF-α. Asimismo, de quimiocinas como: RANTES, MCP-1, MlP-lα e 11-8 que tienen un papel muy importante en la migración de las diferentes subpoblaciones celulares al sitio de infección para la formación del granuloma. El objetivo de este trabajo es ofrecer un panorama de los mecanismos inmunológicos involucrados en la respuesta inmune celular en la tuberculosis pulmonar humana.

Human pulmonary tuberculosis is an infectious disease caused by M. tuberculosis; the protective immune response plays a central role in the control and progression of this disease. The immune response includes the participation of alveolar macrophages, lymphocytes (subsets CD4+, CD8+, NK and yδ) and cytokine production such as IL-2, IFN-γ, IL-12, IL-18 and TNF-α. Moreover, chemokines like RANTES, MCP-1, MIP-lα and IL-8 play an important role in the chemotaxis of different cell populations at the infection site for the formation of granulomas. This paper provides an overview of the immune mechanisms involved in the cellular immune response in human pulmonary tuberculosis.