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Mycobacterium avium Complex Infections: Detailed Phenotypic and Functional Immunological Work-Up Is Required despite
Bernhard Kratzer1, Katharina Grabmeier-Pfistershammer1, Doris Trapin1
1Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria.
Insights
Rare cervical scrofulous lymphadenitis in immunocompetent adults can stem from immune deficiencies. Detailed immunological evaluation is crucial for diagnosis, even with genetic testing, to uncover causes of immunodeficiency.
Area of Science:
- Immunology
- Infectious Diseases
- Genetics
Background:
- Cervical scrofulous lymphadenitis caused by Mycobacterium avium complex (MAC) is rare in immunocompetent adults.
- MAC infections necessitate thorough clinical and immunological assessment, including next-generation sequencing (NGS).
Purpose of the Study:
- To investigate the underlying immunological and genetic causes of cervical scrofulous lymphadenitis in two immunocompetent adult patients.
- To correlate clinical presentation with detailed immune function and genetic findings.
Main Methods:
- Phenotypic and functional immunological evaluation of leukocyte populations.
- Targeted NGS-based sequencing of candidate genes.
- Multiparametric flow cytometry for cytokine production analysis.
Main Results:
- Patients exhibited lymphopenia with reduced memory T-cell and B-cell numbers.
- Reduced production of key cytokines (IFN-γ, IL-10, IL-12p70, IL-1α, IL-1β, TNF-α) was observed.
- One patient had a homozygous IFNGR1 mutation; the other showed reduced IFNGR1 expression on T cells without detectable mutations, indicating complex immune dysfunction.
Conclusions:
- Phenotypic and functional immunological assessment is essential for diagnosing clinically relevant immunodeficiencies.
- Genetic analyses alone may not fully explain the immune defects in such rare cases.
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-γ, IL-10, IL-12p70, IL-1α, IL-1β, and TNF-α upon TCR-dependent T-cell stimulation with CD3-coated beads but also superantigens. The IFN-γ 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-γ 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-γ resulted in proper upregulation of high-affinity FcγRI (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-γ.
Conclusion:
A detailed phenotypic and functional immunological examination is urgently required to determine the cause of a clinically relevant immunodeficiency, despite detailed genetic analyses.
