Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Boosting with mycobacterial heparin-binding haemagglutinin enhances protection of Mycobacterium bovis BCG-vaccinated newborn mice against M. tuberculosis.

Heterologous prime-boost regimens are a valuable strategy to improve the generation of effector-memory T cell responses against intracellular pathogens. In this study we show that newborn mice vaccinated with bacillus Calmette-Guérin (BCG) and boosted with heparin-binding haemagglutinin (HBHA) had enhanced protective immunity against intranasal or aerosol Mycobacterium tuberculosis challenge over non-boosted mice, as evidenced by a considerable reduction of mycobacterial load in spleen and lung. The route of HBHA delivery had a differential impact on cytokine and antibody production in BCG-primed mice. The prime-boost regimen induced not only HBHA-specific IFN-gamma, but also other cytokines, such as IL-12 and TGF-beta, which may be associated with the generation of lung Th1 effector-memory lymphocytes, responsible for the enhanced protection against M. tuberculosis challenge.

The coiled-coil N-terminal domain of the heparin-binding haemagglutinin is required for the humoral and cellular immune responses in mice.

Heparin-binding haemagglutinin (HBHA) is a 28-kDa mycobacterial adhesin, composed of three functional domains. Previous work has shown that the C-terminal methylated domain is important for adherence, and it is involved in protective T cell immunity in mouse models. However, the role of the coiled-coil N-terminal domain of HBHA in its overall immunogenic capacity remains elusive. Herein, a comparison of the antibody and cellular immune responses after subcutaneous and intranasal immunization of mice with HBHA (native and recombinant) revealed that the methylation pattern is important but not essential for this property. Subcutaneous immunization of mice with a truncated protein, rHBHADeltaC, which lacks the C-terminal methylated domain, was sufficient to trigger humoral and cellular immune responses to HBHA in mice. Altogether we provide evidence that the coiled-coil N-terminal domain is required for HBHA immunogenicity in vivo.