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CXCL9 as a Reliable Biomarker for Discriminating Anti–IFN-γ-Autoantibody–Associated Lymphadenopathy that Mimics Lymphoma

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Abstract

The diagnosis of adult-onset immunodeficiency syndrome associated with neutralizing anti-interferon γ autoantibodies (AIGA) presents substantial challenges to clinicians and pathologists due to its nonspecific clinical presentation, absence of routine laboratory tests, and resemblance to certain lymphoma types, notably nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI). Some patients undergo lymphadenectomy for histopathological examination to rule out lymphoma, even in the absence of a preceding clinical suspicion of AIGA. This study aimed to identify reliable methods to prevent misdiagnosis of AIGA in this scenario through a retrospective case–control analysis of clinical and pathological data, along with immune gene transcriptomes using the NanoString nCounter platform, to compare AIGA and nTFHL-AI. The investigation revealed a downregulation of the C-X-C motif chemokine ligand 9 (CXCL9) gene in AIGA, prompting an exploration of its diagnostic utility. Immunohistochemistry (IHC) targeting CXCL9 was performed on lymph node specimens to assess its potential as a diagnostic biomarker. The findings exhibited a significantly lower density of CXCL9-positive cells in AIGA compared to nTFHL-AI, displaying a high diagnostic accuracy of 92.3% sensitivity and 100% specificity. Furthermore, CXCL9 IHC demonstrated its ability to differentiate AIGA from various lymphomas sharing similar characteristics. In conclusion, CXCL9 IHC emerges as a robust biomarker for differentiating AIGA from nTFHL-AI and other similar conditions. This reliable diagnostic approach holds the potential to avert misdiagnosis of AIGA as lymphoma, providing timely and accurate diagnosis.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful for the technical support provided by the Core Labs, Department of Medical Research, National Taiwan University Hospital.

Funding

This study was partially funded by the National Science and Technology Council (110–2314-B-002–247, 111–2320-B-002–023, 111–2314-B-002–145 and 112–2320-B-002–040) and National Taiwan University Cancer Center (NTUCCS-112–07).

Author information

Authors and Affiliations

  1. Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan

    Chang-Tsu Yuan

  2. Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan

    Chang-Tsu Yuan

  3. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Chang-Tsu Yuan

  4. Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Wan-Ting Huang

  5. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

    Chia-Lang Hsu

  6. Department of Pathology, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan

    Hsuan Wang

  7. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Yi-Hua Pan, Un-In Wu, Jann-Tay Wang, Wang-Huei Sheng, Yee-Chun Chen & Shan-Chwen Chang

  8. Department of Medicine, National Taiwan University Cancer Center, No.57, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist., Taipei, 10106, Taiwan

    Un-In Wu

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Contributions

CTY and UIW did conception and design; CTY, WTH, HW, YHP, UIW, JTW, and WHS performed experiment and analysis; CLH did transcriptome analysis; CTY, UIW wrote the paper; YCC, SCC, UIW critical revised the paper.

Corresponding author

Correspondence to Un-In Wu.

Ethics declarations

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of National Taiwan University Hospital (No. 201412163RIND, 202301141RIND).

Consent to participate

Informed consent was obtained from all individual participants in the prospective observational study (No. 201412163RIND). Informed consent was approved to be waived in the retrospective observational study (No. 202301141RIND).

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Not applicable (there is no personal identity information in the manuscript).

Competing Interests

The authors declare no competing interests.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work the authors used chatGPT in order to enhance the English quality of the manuscript. After using this tool, the authors carefully reviewed and edited the content as needed and take full responsibility for the content of the publication.

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Yuan, CT., Huang, WT., Hsu, CL. et al. CXCL9 as a Reliable Biomarker for Discriminating Anti–IFN-γ-Autoantibody–Associated Lymphadenopathy that Mimics Lymphoma. J Clin Immunol 44, 35 (2024). https://doi.org/10.1007/s10875-023-01643-z

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