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Preferential Reduction of Circulating Innate Lymphoid Cells Type 2 in Patients with Common Variable Immunodeficiency with Secondary Complications Is Part of a Broader Immune Dysregulation

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Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc).


We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype.


Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21low B cells, but we could not detect an association of the altered ILC phenotype with a TH1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients.


We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21low B cells, but not overtly with the relative expansion of TH1-like T cells. Given the relative abundance of TH1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.

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We thank Ed Pearce for mentoring and discussion during the studies. We would like to thank Monika Erler, Marion Klima, and Helene Kraus for the excellent organization of blood sampling. Furthermore, we would like to acknowledge Leif Hanitsch, Luis Muñoz, Oliver Hausmann, Fabian Kaiser, Florian Kollert, and Sigune Goldacker for providing us the access to secondary lymphoid tissues.


This study was supported by the Federal Ministry of Education and Research (BMBF 01EO1303) and by the DFG (SFB 1160, TP7). Y.T. is supported by grants from the DFG (SFB 1160, TP6, SPP1937, TA 436/3-1). The authors are responsible for the contents of this publication.

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Authors and Affiliations



D.F. performed the experiments, analyzed the data, and wrote the manuscript. B.K. and I.S. performed experiments and provided help. J.S. provided BAL samples. Y.T. critically read and contributed to the revision of the manuscript. S.U. and K.W. devised and supervised the study, designed the research, and edited the manuscript.

Corresponding author

Correspondence to Klaus Warnatz.

Ethics declarations

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants before inclusion into the study.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Table 1

(DOCX 18 kb)

Supplementary Fig.1

Longitudinal time study of the ILC compartment. Absolute counts of total ILCs (a) and ILC subsets (b-d) were analyzed twice within approximately six months. The first time point is marked by the left and the second time point by the right dot of each CVID patient or healthy donor (HD). (PPTX 110 kb)

Supplementary Fig.2

Cytokine production of ILCs. IFNγ, IL-4, IL-5 and IL-13 production by the whole ILC compartment (LinCD127+CD161+) was determined after 4 h PMA/Ionomycin stimulation. Gating strategy for unstimulated (a, top) and stimulated PBMCs (a, down) of a representative CVID patient. The percentage of IFNγ, IL-4, IL-5 and IL-13 producing ILCs is presented for HD and CVID patients (b). Red triangles represent CVIDio patients whereas black circles CVIDc patients. Mann-Whitney U test (PPTX 196 kb)

Supplementary Fig.3

ILC subset distribution in correlation to manifestations of liver involvement, granulomatous inflammation and autoimmune cytopenia. Absolute (left panels) and relative (right panels) counts of ILC subsets are presented for HD and CVID patients with and without complications of liver involvement, including nodular regenerative hyperplasia (NRH) (a), granulomatous inflammation (b) and autoimmune cytopenia (AIC), including immune thrombocytopenia or autoimmune hemolytic anemia (c), respectively. *P < .05, **P < .01 ***P < .001, ****P < .0001, Kruskal-Wallis test (PPTX 295 kb)

Supplementary Fig.4

Characterization of the ILC compartment in different tissues. (a) BALs from CVID patients were analyzed for total ILCs (left panel) and for their ILC subset distribution (right panel) and were compared to sarcoidosis patients as control cohort. (b) Total ILCs (left panel) and the different ILC subsets (right panel) of CVID lymph nodes were compared to control lymph nodes. Mann-Whitney U test (PPTX 109 kb)

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Friedmann, D., Keller, B., Harder, I. et al. Preferential Reduction of Circulating Innate Lymphoid Cells Type 2 in Patients with Common Variable Immunodeficiency with Secondary Complications Is Part of a Broader Immune Dysregulation. J Clin Immunol 37, 759–769 (2017).

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