A novel patient with inherited TNF deficiency and tuberculosis

Abstract

Two otherwise healthy patients from Colombia, now aged 30 and 38 years, developed pulmonary tuberculosis due to inherited, complete TNF deficiency at the ages of 19 and 18 years. We report here a previously healthy Iranian patient with inherited complete TNF deficiency who was diagnosed with both pulmonary and extrapulmonary TB between 10 and 15 years of age. The homozygous TNF variant (c.673C>T) introduces a premature stop codon (TNF p.Q225*) resulting in losses of expression and function. Despite normal myeloid and lymphoid subset development, the patient's primary leukocytes do not secrete detectable amounts of TNF. As in the TNF-deficient Colombian patients, the respiratory burst of GM-CSF-derived macrophages is impaired. Our findings expand the spectrum of TB phenotypes in patients with TNF deficiency and confirm that TNF is essential for immunity to M. tuberculosis in humans but apparently redundant against many other pathogens, including weakly virulent mycobacteria.