TY - JOUR

T1 - IL-6 Autoantibodies Predict Lower Platelet Counts and Altered Plasma Cytokine Profiles in Healthy Blood Donors

T2 - Results From the Danish Blood Donor Study

AU - von Stemann, Jakob Hjorth

AU - Pedersen, Ole Birger Vesterager

AU - Hjalgrim, Henrik

AU - Erikstrup, Christian

AU - Ullum, Henrik

AU - Dowsett, Joseph

AU - Thørner, Lise Wegner

AU - Larsen, Margit Anita Hørup

AU - Sørensen, Erik

AU - Hansen, Morten Bagge

AU - Ostrowski, Sisse Rye

N1 - Publisher Copyright: Copyright © 2022 von Stemann, Pedersen, Hjalgrim, Erikstrup, Ullum, Dowsett, Thørner, Larsen, Sørensen, Hansen and Ostrowski.

PY - 2022

Y1 - 2022

N2 - Cytokine-specific autoantibodies (c-aAb) represent a novel type of immune dysfunction. Though they have been detected in both patient cohorts and healthy individuals, and have immunomodulatory properties, the full extent of their influence remains unknown. Based on the critical role of several cytokines in thrombopoiesis, we investigated if there is an association between c-aAb and platelet variables in healthy individuals, with a specific focus on c-aAb against a known thrombopoietic cytokine, IL-6. Using platelet count and mean platelet volume in 3,569 healthy participants of the Danish Blood Donor Study as dependent variables, we performed a series of multivariate regression analyses using five cytokine autoantibodies, including IL-6 c-aAb, as independent variables. In men, high titers of IL-6 c-aAb were negatively associated with platelet counts (β = −24 *109/l (95% confidence interval −43 to −6), p = 0.008) and positively associated with mean platelet volume (β = 0.4 fL (95% confidence interval 0.0–0.7) p = 0.043). These associations were exacerbated when adjusting for undetectable C-reactive protein levels, which we used as a proxy for c-aAb mediated IL-6 inhibition in vivo. Furthermore, in a smaller subgroup, individuals with high vs. low titer IL-6 c-aAb had different profiles of plasma IL-6, IL-10, TNFα and TPO, further suggesting a functional inhibition of IL-6 by high titers of circulating IL-6 c-aAb. We therefore speculate that in addition to their immunomodulatory potential IL-6 c-aAb may interfere with thrombopoiesis – directly or indirectly – under normal physiological conditions. This study is the first to suggest an influence of c-aAb on platelets in healthy individuals, beyond their apparent effects on immune competence.

AB - Cytokine-specific autoantibodies (c-aAb) represent a novel type of immune dysfunction. Though they have been detected in both patient cohorts and healthy individuals, and have immunomodulatory properties, the full extent of their influence remains unknown. Based on the critical role of several cytokines in thrombopoiesis, we investigated if there is an association between c-aAb and platelet variables in healthy individuals, with a specific focus on c-aAb against a known thrombopoietic cytokine, IL-6. Using platelet count and mean platelet volume in 3,569 healthy participants of the Danish Blood Donor Study as dependent variables, we performed a series of multivariate regression analyses using five cytokine autoantibodies, including IL-6 c-aAb, as independent variables. In men, high titers of IL-6 c-aAb were negatively associated with platelet counts (β = −24 *109/l (95% confidence interval −43 to −6), p = 0.008) and positively associated with mean platelet volume (β = 0.4 fL (95% confidence interval 0.0–0.7) p = 0.043). These associations were exacerbated when adjusting for undetectable C-reactive protein levels, which we used as a proxy for c-aAb mediated IL-6 inhibition in vivo. Furthermore, in a smaller subgroup, individuals with high vs. low titer IL-6 c-aAb had different profiles of plasma IL-6, IL-10, TNFα and TPO, further suggesting a functional inhibition of IL-6 by high titers of circulating IL-6 c-aAb. We therefore speculate that in addition to their immunomodulatory potential IL-6 c-aAb may interfere with thrombopoiesis – directly or indirectly – under normal physiological conditions. This study is the first to suggest an influence of c-aAb on platelets in healthy individuals, beyond their apparent effects on immune competence.

KW - autoimmunity

KW - blood donors

KW - cytokine autoantibodies

KW - cytokines

KW - epidemiology

KW - IL-6

KW - platelets

KW - thrombopoiesis

U2 - 10.3389/fmed.2022.914262

DO - 10.3389/fmed.2022.914262

M3 - Journal article

C2 - 35814772

AN - SCOPUS:85134042648

VL - 9

JO - Frontiers in Medicine

JF - Frontiers in Medicine

SN - 2296-858X

M1 - 914262

ER -