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Antiviral State of CD1c+ cDC associates with increased Natural Killer maturation and activation in Sjögren´s Syndrome

ABSTRACT: Primary Sjögren´s syndrome (pSS) is a heterogeneous inflammatory autoimmune disorder characterized by the infiltration of different immune subsets in exocrine glands and potential development of extra-glandular manifestations. pSS pathology and glandular tissue destruction have been linked to increased IFN responses and the induction of autoreactive T and B cells. However, association of innate immune cells such as Natural Killer (NK) cells and conventional dendritic cells (cDC) with the tissular damage and IFN environment in pSS remains understudied. Here, we identified higher expression of NKG2D, CD107a and superior cytotoxic function on circulating NK cells from pSS which was associated with significant enrichment in a subpopulation of CD16+CD56Hi NK cells in the blood of these patients. In addition, Granzyme B+ NK cells and MICab+ CD1c+ cDC could be found in proximity in tissue sections of salivary glands from pSS patients. Importantly, murine populations of CD64Hi CD11b+CD11c+ cDC and transitional NKG2Dhi CD11b+CD27+ NK1.1 cells, infiltrated in vivo into the salivary gland in a stablished pSS mouse model. Interestingly, transcriptional IFN signatures present on CD1c+ cDC from pSS are characterized by the upregulation of RIG-I and DDX60 sensors and the ISGs IFIT1 and IFIT3. These transcriptional patterns on CD1c+ cDC associated with high basal expression of MICa/b and SLAMF7 ligands for NK receptors, the Fc receptor CD64 and increased ability to induce maturation and CD107a expression in NK cells. Finally, expression of SLAMF7 and MICa/b after Poly I:C exposure was regulated by RIG-I and DDX60 on CD1c+ cDC. Therefore, crosstalk between CD1c+ cDCs and NK cells could contribute to the pathogenesis of pSS, and represent new cellular therapeutic targets for treatment of pSS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194263 | GEO | 2023/09/20

REPOSITORIES: GEO

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Project description:Background: Studies recently support that non-HLA antigens could be additional targets of injury in organ transplant recipients, and MICA was associated with an increased risk of graft loss. Methods: A ProtoArray platform was used to study 37 serum samples from 22 unique patients (15 renal recipients and 7 healthy controls). Thirty paired pre- and post-transplant serum samples were analyzed for detection of de novo post-transplant antibody responses in the 15 patients (10 acute rejection (AR), 5 Stable). Probes on ProtoArray and cDNA platforms (GSE: 3931) were re-annotated and compartment specific gene lists were analyzed using the integrated genomics method. Normal and transplant kidney IHC were performed for MICA antigen localization. Results: Mean MICA-Ab (antibody) signal intensity was significantly higher in transplant patients compared with healthy controls and de novo MICA-Ab were detected in 73% transplant patients. The mean post-transplant signal intensity of MICA-Ab was the highest in C4d+AR. Detection of MICA-Ab responses did not correlate with time post-transplantation, but significantly correlated with decline in graft function over the subsequent year. Integrative genomics predicted localization of the MICA antigen to the glomerulus. IHC confirmed cytoplasmic MICA staining solely in glomerular podocytes in normal kidney. In the transplant kidney, infiltrating mononuclear lymphocytes (T, B and NK) in AR had additional MICA staining. Conclusions: MICA can be highly detected regardless of graft dysfunction or AR. The intensity signal of the MICA antibody correlates with subsequent decline in graft function. The MICA antigen localizes to the glomerulus and infiltrating mononuclear cells in AR. Pre- and post-transplant serum antibodies were profiled for each patient, using the Invitrogen ProtoArrayÂ® Human Protein Microarray v3.0 platform (Invitrogen, Carlsbad, CA). This platform contains 5,056 non-redundant human proteins expressed in a baculovirus system, purified from insect cells and printed in duplicate onto a nitrocellulose-coated glass slide. Each protein is spotted twice on each array, to measure the quality of the signal intensity. Details for experiment processing and analysis follow the previous publication from our group (13). Prospector software was used to retrieve the expression based on immune response profiling of the .gal files.

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Antiviral State of CD1c+ cDC associates with increased Natural Killer maturation and activation in Sjögren´s Syndrome

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