Chronic granulomatous disease as a risk factor for autoimmune disease

Abstract

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune (AI) disorders. In this report, we describe antiphospholipid syndrome (aPL), recurrent pericardial effusion, juvenile idiopathic arthritis (JIA), IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease has important treatment implications for patients with CGD. KeywordsChronic granulomatous disease; autoimmune; antiphospholipid syndrome; IgA nephropathy; lupus; juvenile idiopathic nephropathy Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID) resulting from a defect in the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which is responsible for production of bactericidal reactive oxygen species (ROS) in phagocytes. As a result, CGD patients are at increased susceptibility to certain catalasepositive bacteria and fungi, and Aspergillus species 1 . The primary clinical features of CGD are recurrent infections and granuloma formation. However, reports of sarcoidosis 2 , JIA 3 , IgA nephropathy 4 , pericardial effusion 5 , and severe Crohn's-like inflammatory bowel disease 6 suggest that the breadth of altered immune regulation extends beyond recurrent infections and granulomas. We propose, in addition, that CGD patients are at significant risk for development of autoimmune disease (AI), and provide a series of case reports and a review of the literature to support that hypothesis. Specifically we report here the following AI in our CGD patients; antiphospholipid syndrome (aPL), juvenile idiopathic arthritis (JIA), IgA nephropathy; steroidresponsive recurrent pericardial effusions, cutaneous lupus erythematosus, and lastly, a case with 'geographic pulmonary lesions', a finding we have observed in four other CGD patients. A 14.5 year-old Caucasian male was diagnosed with X-linked (gp91 phox -deficient) chronic granulomatous disease (CGD) following the development of Serratia marcescens abscesses of his neck and mesentery at 3 years of age. Long-term prophylaxis consisting of trimethoprimsulfamethoxazole, itraconazole and interferon-γ (IFN-γ) was commenced. Of interest, his mother (a CGD carrier) and maternal aunt (not a carrier) were both diagnosed with discoid lupus. At 10 years, he developed cellulitis of his arm following a minor skin abrasion. Treatment with intravenous antibiotics was complicated by venous thrombosis in his affected arm, which was treated with a 3-month course of warfarin. At age 14, he described acute swelling, pain and redness of the left thigh, with no other associated symptoms, fever, or history of trauma. His laboratory tests were unremarkable, other than an ESR of 50 mm/hr (NIH range 0-25mm/hr). Doppler ultrasound revealed a left femoral deep venous thromb...

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

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NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

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Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

“…Patients with chronic granulomatous disease who lack functional Phox are not only susceptible to certain infections but also, present with uncontrolled noninfectious inflammation, including sterile tissue granulomas, bowel inflammation, and autoimmune disorders. 26,29,30 The molecular basis for increased inflammation in chronic granulomatous disease is not fully understood. Gene expression profiling suggested increased proinflammatory transcriptional activity in Phox-deficient leukocytes.…”