Understanding chronic immunodeficiency disorders through assessment of cytotoxic lymphocyte function

Abstract

Representing an evolving and diverse group of syndromes, immunodeficiencies can currently be viewed as a spectrum of disorders where a dysfunction of the immune system plays a significant etiologic role. Cytotoxic lymphocytes are immune cells that are pivotal for the eradication of infected and malignant cells. They also contribute to immune-regulation. Congruently, patients with defects in cytotoxic lymphocyte function show increased susceptibility to infections, malignancies and inflammation.

This work focuses on the role of cytotoxic lymphocytes in syndromes where their pathophysiological involvement is suspected, but not established. The first study investigates the variability in cytotoxic effector functions introduced by commonly used pharmacological substances, knowledge that is important for the interpretation of patient data. The second study establishes a robust and sensitive addition to the arsenal of diagnostic assays for cytotoxic lymphocyte dysfunctions. The third study shows that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linked to viral infections and hypothesized to be caused by immune dysregulation, is not a syndrome where a substantial fraction of the patients has any obvious primary defect in lymphocyte cytotoxicity. The fourth and the fifth studies identify and functionally dissect the impact of autoantibodies directed against an inhibitory cytotoxic lymphocyte receptor, NKG2A, in patients with systemic lupus erythematosus (SLE), an autoimmune disorder.

In summary, the studies expand our knowledge and toolbox for assessing lymphocyte cytotoxicity and highlight the complexity of interpreting experiments investigating cytotoxic lymphocyte function in the context of chronic immunodeficiency disorders. Furthermore, they provide clinically relevant insights about the role of cytotoxic lymphocytes in both ME/CFS and SLE.