Granulomatous inflammation in inborn errors of immunity

Abstract

Granulomas have been defined as inflammatory infiltrates formed by recruitment of macrophages and T cells. The three-dimensional spherical structure typically consists of a central core of tissue resident macrophages which may merge into multinucleated giant cells surrounded by T cells at the periphery. Granulomas may be triggered by infectious and non-infectious antigens. Cutaneous and visceral granulomas are common in inborn errors of immunity (IEI), particularly among patients with chronic granulomatous disease (CGD), combined immunodeficiency (CID), and common variable immunodeficiency (CVID). The estimated prevalence of granulomas in IEI ranges from 1%–4%. Infectious agents causing granulomas such Mycobacteria and Coccidioides presenting atypically may be ‘sentinel’ presentations for possible underlying immunodeficiency. Deep sequencing of granulomas in IEI has revealed non-classical antigens such as wild-type and RA27/3 vaccine-strain Rubella virus. Granulomas in IEI are associated with significant morbidity and mortality. The heterogeneity of granuloma presentation in IEI presents challenges for mechanistic approaches to treatment. In this review, we discuss the main infectious triggers for granulomas in IEI and the major forms of IEI presenting with ‘idiopathic’ non-infectious granulomas. We also discuss models to study granulomatous inflammation and the impact of deep-sequencing technology while searching for infectious triggers of granulomatous inflammation. We summarize the overarching goals of management and highlight the therapeutic options reported for specific granuloma presentations in IEI.

Inflammatory Complications in Chronic Granulomatous Disease

“…Infection likely precipitates most inflammatory episodes, and failure of clearance of phagocytosed material is likely an important inflammatory stimulus [34]. Phagocytes from patients with CGD, that lack functional NADPH oxidase accumulate at sites of infection but fail to clear microbial material or cellular debris, which leads to persistent cell activation and an exaggerated inflammatory response [35].…”

“…Phagocytes from patients with CGD, that lack functional NADPH oxidase accumulate at sites of infection but fail to clear microbial material or cellular debris, which leads to persistent cell activation and an exaggerated inflammatory response [35]. E.g., CGD patients can develop localized or disseminated granulomatous inflammation following BCG vaccination (BCG-itis) [34]. A French study reported that 7.5% of CGD patients suffer from postinfectious granulomatous inflammation in various organs [21].…”

A LTB4/CD11b self-amplifying loop drives pyogranuloma formation in chronic granulomatous disease

“…By histopathology, CGD granulomas are categorized as pyogranulomas composed largely of organized collections of neutrophils and macrophages. 1 , 2 Though patients with CGD suffer from various bacterial and fungal infections, 3 pyogranulomas are often sterile 2 , 4 and can be induced in murine models of this disease following the instillation of killed aspergillus or zymosan particles made from yeast cell walls into the peritoneum, skin, or lungs. 5 , 6 , 7 As such, CGD pyogranulomas are characteristic of the hyperinflammatory state in this disorder that also frequently results in autoimmunity, inflammatory bowel disease, and poor wound healing.…”

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022

“…In patients with Inborn Errors of Immunity (IEI), high morbidity and mortality associated with non-infectious comorbidities, such as inflammatory diseases and cancers, has been widely described in several cohorts of adult patients (1)(2)(3)(4). In a previous study, we demonstrated that among malignancies, gastric adenocarcinoma (GC) was the leading cause of death in a cohort of Italian CVID patients with a 10.1-fold excess mortality and with a cancer onset fifteen years earlier than the normative population (5).…”