Disseminated <i>Mycobacterium avium</i> infection associated with adult‐onset immunodeficiency because of anti‐interferon‐gamma autoantibodies: a case report

We present a case of disseminated Mycobacterium avium infection associated with anti-interferon-gamma (IFN-γ) autoantibodies in a woman with comorbid autoimmune conditions suggesting IFN-γ deficiency and pathogenesis with other autoimmune conditions. This case report suggests potential mechanisms for adult-onset immunodeficiency because of anti-IFN-γ autoantibodies. A 59-year-old woman from Guangxi Province in China presented with nodules, plaques, vegetation, and ulcers on her limbs and back, which had developed over the previous year (Figure 1); multiple enlarged lymph nodes were palpable in the axillary and inguinal regions. She had vitiligo and right renal atrophy and tested positive for antinuclear antibodies (ANA) and anti-SSA antibodies. The patient presented with mild livedo racemosa made the diagnosis of undifferentiated connective disease. Subsequent computed tomography showed abnormalities in the bone marrow cavity and lungs, while metagenomic next-generation sequencing (NGS) and culture showed Mycobacterium avium infection of the skin. Furthermore, an enzyme-linked immunosorbent assay showed a high titer of anti-IFN-γ autoantibodies (1:500). Lastly, acid-fast bacilli were found in skin biopsies (Figure 2). Thus, the patient was diagnosed with disseminated nontuberculous mycobacteria (NTM) infection associated with adult-onset immunodeficiency because of anti-IFN-γ autoantibodies. She then underwent long-term antinontuberculous mycobacteria and corticosteroid maintenance treatment (ethambutol [0.75 g/d], rifabutin [0.3 g/d], prothionamide [250 mg tid], clarithromycin [0.5 g bid], and prednisone [30 mg/day]). Six months later, the ulcer was almost healed, leaving contracture scars and vasodilation; furthermore, lung nodules and lymph nodes were significantly absorbed and smaller. The patient remains under close follow-up. The Medical Ethics Committee of Foshan Hospital of Traditional Chinese Medicine approved this study. The informed consent of the patient was obtained. NTM are prevalent in the environment but have low virulence in humans. Most infections are localized but can disseminate under certain conditions,1 particularly in patients with malignancy or HIV infection. Furthermore, children with genetic defects in the interleukin 12 (IL-12)/INF-γ axis are susceptible to severe NTM infection, known as Mendelian susceptibility to mycobacterial disease (MSMD). Since 2004, several cases of MSMD-like disease, caused by neutralizing anti-IFN-γ autoantibodies (nAIGAs), have been reported in adults.2 These patients had adult-onset immunodeficiency because of anti-IFN-γ autoantibodies. Most of these cases have been from Thailand and Taiwan; in mainland China, most have been from Guangxi Province, as also was our patient. The HLA-II alleles DRB1*16:02-DQB1*05:02 and DRB1*15:02-DQB1*16:02 are strongly associated with this disease.3 IL-12 is a potent activator of natural killer and T cells, inducing the production of IFN-γ. Binding of IFN-γ homodimers to their receptors activates JAK-STAT1 signaling, enhancing IL-12 production and inducing the production of antimicrobial proteins. Thus, by disrupting the function of IFN-γ, anti-IFN-γ autoantibodies impede the IL-12/IFN-γ axis, causing failure of microbial clearance.4 In these patients, disseminated M. avium complex and Mycobacterium abscessus infections are the most frequently observed pathogens; frequently affected sites are the lymph nodes, lungs, bones, and joints.5 Cutaneous involvement is also a feature of the nAIGA-related disease. In our patient, severe infectious lesions resulted in limited mobility of the left elbow; furthermore, she had vitiligo and undifferentiated connective disease, suggesting a common pathogenesis of these diseases and IFN-γ axis deficiency disorders. Currently, there is no standard treatment for this disease. Chronic, intensive antibiotic therapy generally does not control or eradicate NTM infection. However, rituximab can significantly decrease the nAIGA titer and restore IFN-γ-STAT1 function.4 As our patient had vitiligo and an undifferentiated connective tissue disease, we used low-dose corticosteroids to regulate her immune response, improving symptoms. However, the risks and benefits of corticosteroid use should be balanced. Thus, we report a case of disseminated M. avium infection associated with anti-IFN-γ autoantibodies. Comorbid autoimmune conditions suggest they may share a pathogenetic pathway with IFN-γ axis deficiency.