Anti-IFN-γ Autoantibody Syndrome Presenting with Disseminated Nontuberculous Mycobacteria Infections: A Case Series of Therapeutic Implications and Review of Literature

Abstract

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option.

Keywords: case series; immune deficiency; interferon gamma; mycobacterium avium complex; nontuberculous mycobacteria; rituximab.

Figure 1

Host defense mechanisms against non-tuberculous mycobacteria (NTM). Defects leading to disseminated NTM infection are shown in red. ISG15, interferon-stimulated gene 15; IFNGR, interferon-gamma receptor; TYK, tyrosine kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; GATA, transcription factor implicated in early haemopoietic, lymphatic, and vascular development; NEMO, nuclear factor kappa-light-chain-enhancer of activated B cells essential modulator; IL, interleukin; TFN, tumor necrosis factor; TLR, toll-like receptors. Reprinted with permission from Wu et al. [15]. Copyright 2015, Elsevier Ltd.

Figure 4

Rituximab mechanism of action. Rituximab targets and binds to MS4A1 expressed on the surface of B cells. Once bound to its target, rituximab induces apoptosis of CD20+ cells, resulting in depletion of B-cells. Rituximab is an IgG1-kappa antibody able to mediate complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) against CD20+ B cells to completely deplete this population. Mechanism of action: Blocking. Effect: Immunosuppressant, Fc-effector function. (mAbID). Reprinted with permission from Golfinopoulou et al. [31]. Copyright 2023 by the authors.

Figure 2

Evolution of chest CT imaging in Case 1: (a) before treatment—December 2021, (b) after treatment—December 2023. Interval improvement of dense consolidation in the right upper lobe.

Figure 3

Evolution of chest CT imaging in Case 2: (a) before treatment—December 2023, (b) after treatment—April 2024. Improvement in left lower lobe consolidation with moderate left pleural effusion. A, anterior; P, posterior.