TY - JOUR
T1 - Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation
AU - Meyer, Benedikt J.
AU - Kunz, Natalia
AU - Seki, Sayuri
AU - Higgins, Rebecca
AU - Ghosh, Adhideb
AU - Hupfer, Robin
AU - Baldrich, Adrian
AU - Hirsiger, Julia R.
AU - Jauch, Annaïse J.
AU - Burgener, Anne Valérie
AU - Lötscher, Jonas
AU - Aschwanden, Markus
AU - Dickenmann, Michael
AU - Stegert, Mihaela
AU - Berger, Christoph T.
AU - Daikeler, Thomas
AU - Heijnen, Ingmar
AU - Navarini, Alexander A.
AU - Rudin, Christoph
AU - Yamamoto, Hiroyuki
AU - Kemper, Claudia
AU - Hess, Christoph
AU - Recher, Mike
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly—but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation.
AB - Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly—but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation.
UR - http://www.scopus.com/inward/record.url?scp=85165257776&partnerID=8YFLogxK
U2 - 10.1007/s10875-023-01547-y
DO - 10.1007/s10875-023-01547-y
M3 - Journal articles
C2 - 37477760
AN - SCOPUS:85165257776
SN - 0271-9142
VL - 43
SP - 1840
EP - 1856
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 8
ER -