Towards new guidelines for diagnosis and treatment of primary antibody deficiency: Using translational studies to uncover new diagnostic and therapeutic modalities

Abstract

Primary antibody deficiencies (PAD) are a group of disorders characterized by reduced antibody production, leading to a common form of primary immunodeficiency. This group includes specific polysaccharide antibody deficiency, immunoglobulin G subclass deficiency, common variable immunodeficiency (CVID), and agammaglobulinemia. B cell dysfunction is a key feature of PAD, resulting in recurrent respiratory and gastrointestinal infections due to compromised mucosal protection. Preventive measures such as vaccination, prophylactic antibiotics, and immunoglobulin replacement therapy (IRT) have been effective in reducing infections but complications like bronchiectasis, hearing loss, and malnutrition can still occur.

Non-infectious complications, including enteropathy, granulomatous lymphocytic interstitial lung disease (GLILD), and secondary hemophagocytic lymphohistiocytosis (HLH), contribute significantly to morbidity and mortality in CVID patients despite IRT. Enteropathy lacks effective treatment options, while GLILD and HLH require early intervention but have diagnostic challenges.

Genetic studies have identified over 40 genes linked to PAD, highlighting the complexity of the disorder. Monogenic causes are found in only a small percentage of cases, emphasizing the multifactorial nature of PAD.

T cell dysfunction has also been implicated in PAD, beyond the typical B cell abnormalities. CVID patients without a monogenic disease may experience T cell dysregulation, with elevated effector memory T cells and increased IFN-γ response genes. Dysregulated T cells contribute to the activation of monocytes, leading to the production of B cell activating factor (BAFF), which is linked to non-infectious complications, particularly in GLILD patients.

To address knowledge gaps in PAD, the thesis aims to improve understanding of the genetic landscape, optimize strategies for preventing infections, and develop treatments for non-infectious complications. Larger cohort studies and clinical trials are needed to establish evidence-based recommendations. Identifying predictive risk factors for specific complications is crucial for effective screening and treatment decisions. T cell functionality is a focus for normalizing non-infectious complications.

The thesis is divided into two parts: Diagnosis and pathophysiology of PAD, and Management of PAD. In the first part, various genetic variants associated with PAD are discussed, highlighting the complex interplay of B and T cells in the disease. In the second part, the effectiveness of prophylactic antibiotics and IRT in milder forms of PAD is compared, and treatment options for GLILD are explored, with a focus on corticosteroids as a first-line treatment.

Clinical recommendations include using next-generation sequencing for diagnosis, personalized treatment approaches, and intensive monitoring for patients at risk of complications. Standardized treatment approaches for GLILD are also advocated. Collaborative efforts and further research are needed to advance our understanding and management of PAD.

In conclusion, this thesis contributes to our understanding of PAD, providing insights into its genetic basis and treatment strategies. However, collaborative research and evidence-based approaches are essential to address remaining knowledge gaps and improve care for patients with this complex disease.