Mycobacterium avium Complex Infections: Detailed Phenotypic and Functional Immunological Work-Up Is Required despite Genetic Analyses

Introduction: Cervical scrofulous lymphadenitis due to Mycobacterium avium complex (MAC) in immunocompetent adults is a rare disease. The presence of MAC infections demands meticulous clinical evaluation of patients along with detailed phenotypic and functional evaluation of their immune system including next-generation sequencing (NGS) analyses of target genes. Methods: Exact clinical histories of the index patients both suffering from retromandibular/cervical scrofulous lymphadenitis were obtained along with phenotypic and functional immunological evaluations of leukocyte populations followed by targeted NGS-based sequencing of candidate genes. Results: Immunological investigations showed normal serum immunoglobulin and complement levels, but lymphopenia, which was caused by significantly reduced CD3(+)CD4(+)CD45RO(+) memory T-cell and CD19(+) B-cell numbers. Despite normal T-cell proliferation to a number of accessory cell-dependent and -independent stimuli, the PBMC of both patients elaborated clearly reduced levels of a number of cytokines, including IFN-gamma, IL-10, IL-12p70, IL-1 alpha, IL-1 beta, and TNF-alpha upon TCR-dependent T-cell stimulation with CD3-coated beads but also superantigens. The IFN-gamma production deficiency was confirmed for CD3(+)CD4(+) helper and CD4(+)CD8(+) cytotoxic T cells on the single-cell level by multiparametric flow cytometry irrespective of whether PMA/ionomycin-stimulated whole blood cells or gradient-purified PBMC was analyzed. In the female patient L1, targeted NGS-based sequencing revealed a homozygous c.110T>C mutation in the interferon-gamma receptor type 1 (IFNGR1) leading to significantly reduced receptor expression on both CD14(+) monocytes and CD3(+) T cells. Patient S2 presented with normal IFNGR1 expression on CD14(+) monocytes but significantly reduced IFNGR1 expression on CD3(+) T cells, despite the absence of detectable homozygous mutations in the IFNGR1 itself or disease-related target genes. Exogenous addition of increasing doses of IFN-gamma resulted in proper upregulation of high-affinity Fc gamma RI (CD64) on monocytes from patient S2, whereas monocytes from patient L1 showed only partial induction of CD64 expression after incubation with high doses of IFN-gamma. Conclusion: A detailed phenotypic and functional immunological examination is urgently required to determine the cause of a clinically relevant immunodeficiency, despite detailed genetic analyses.