Monocyte-derived macrophages do not explain susceptibility to pulmonary non-tuberculous mycobacterial disease

Area of Science:

• Immunology
• Infectious Diseases
• Pulmonology

Background:

• Pulmonary infections caused by non-tuberculous mycobacteria (NTM) primarily affect older women without apparent immune deficiencies.
• Understanding the host immune response, particularly involving T-helper 1 (Th1) cytokines and macrophage/monocyte function, is crucial for NTM disease pathogenesis.

Purpose of the Study:

• To investigate potential defects in Th1 cytokine production or host macrophage/monocyte responses in individuals with NTM lung disease.
• To determine if genetic factors contribute to impaired immune responses in NTM patients.

Main Methods:

• Assessed interferon gamma (IFNγ) production by CD4 T cells upon stimulation with mycobacterial antigens.
• Generated monocyte-derived macrophages (MDMs) from NTM patients, their offspring, and healthy donors.
• Stimulated MDMs with Toll-like receptor (TLR) agonists (lipomannan, lipopolysaccharide) and recombinant human IFNγ to assess cytokine production and IFNγ receptor 1 (IFNγR1) expression.

Main Results:

• Patients with NTM disease exhibited robust IFNγ production from CD4 T cells when stimulated with mycobacterial antigens.
• No evidence of a genetic defect in the IFNγ pathway was found, as MDMs from NTM patients and controls showed similar IFNγR1 expression and responses to IFNγ.
• MDMs from NTM patients produced significantly less interleukin-6 (IL-6) in response to lipopolysaccharide (LPS) compared to controls, while other cytokine responses remained normal.

Conclusions:

• The study found normal T-cell mediated IFNγ responses in NTM patients.
• A potential defect in macrophage interleukin-6 production in response to LPS was identified in NTM patients, warranting further investigation.
• The findings suggest that while T-cell immunity is intact, specific macrophage signaling pathways may be implicated in NTM susceptibility.