Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.

T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies

“…While the CD40L is indispensable for the generation of the germinal center response after immunization, TNFα is required for the formation of primary follicles [ 22 ], being essential for the development and function of follicular dendritic cells [ 23 ]. Differently from HD, where the SARS-CoV-2 mRNA vaccine elicits a potent adaptive immune response in the absence of IFN-mediated inflammation [ 24 ], the CVID non-responders had a high frequency of CD8+IFNγ+ T-cells, indicating a T H 1-driven immune dysregulation [ 7 , 16 , 25 ] but also a defective IFNγ release by Spike peptide-stimulated cells. Thus, the functional dysregulation of T-cells might account for impaired T-B cells interaction and the lack of specific antibody responses, confirming the role of germinal center reaction on protective antibody generation [ 26 , 27 ].…”

The Immune Response to SARS-CoV-2 Vaccination: Insights Learned From Adult Patients With Common Variable Immune Deficiency

“…CVID-associated immune dysregulation is a Th1-mediated inflammatory process driven by the IFN-γ pathway ( 47 ) and by a persistent activation on innate immunity ( 48 ), possibly due to the activation of IFN-γ:STAT1:BAFF axis leading to a dysregulated B cell responses ( 49 ). The interferon signature in CVID has been also linked to the expansion of circulating IFN-γ-producing innate lymphoid cells ( 50 ). Differently from COVID-19, the highly augmented IFN signaling and cytotoxic signature has not been detected after vaccination with the SARS-CoV-2 mRNA vaccines ( 51 ).…”

Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency

“…CVID is a heterogeneous disorder where monogenic defects are found in ~ 10%, implying that several mechanisms of immune dysregulation can lead to these non-infectious complications [ 4 ]. It is unclear to which degree the individual clinical inflammatory complications have a shared pathogenesis, and various cells such as B cells, T cells, monocytes/macrophages, and type 3 innate lymphoid cells seem to be involved [ 5 – 9 ].…”