Immune profiling of anti-SSA-positive at-risk individuals reveals increased type I IFN activity preceding lymphocyte abnormalities in Sjögren's disease.
Ritter J, Stefanski A, et al. • Frontiers in immunology • 2026
Increased type I IFN activity and IFN-associated signaling in T- and B-cell subsets are already present in anti-SSA-positive at-risk individuals, whereas altered B- and T-cell homeostasis was restricted to established Sjögren's disease, indicating progression from autoreactivity toward overt autoimmune disease.
Key Findings
Results
Anti-SSA-positive at-risk individuals showed significantly increased IFN activity reflected by Siglec-1 (CD169) expression on CD14+ monocytes compared with healthy donors, while levels tended to be lower than in patients with SjD.
Siglec-1 (CD169) expression on CD14+ monocytes was used as a surrogate marker for type I IFN activity.
At-risk individuals (n=7) showed significantly elevated Siglec-1 compared to healthy donors (n=21), but levels were intermediate between HDs and SjD patients (n=10).
Two of three women with a current or previous congenital heart block (CHB) pregnancy had the highest Siglec-1 levels within the at-risk group.
Age- and sex-matched HDs had a median age of 35.1 years and were 100% female.
Results
Cytokine profiling revealed a stage-associated IFN pattern, with IFN-α1 and IFN-ω already increased in at-risk individuals, whereas IFN-γ, IFN-β1, and type III IFNs showed a trend toward higher levels only in established SjD.
IFN subtypes were quantified in available plasma samples using the NULISA platform.
IFN-α1 and IFN-ω were elevated at the at-risk stage, preceding full disease establishment.
IFN-γ, IFN-β1, and type III IFNs trended higher in established SjD but not significantly in at-risk individuals.
This pattern suggests a sequential or stage-associated activation of different IFN subtypes during disease progression.
Results
Intracellular STAT1 expression was elevated across CD19+ B-cell subsets in at-risk individuals compared with healthy donors, but was generally less pronounced than in SjD patients.
STAT1 and IRF9 expression were analyzed by flow cytometry across lymphocyte subsets.
STAT1 elevation in B-cell subsets was present at the at-risk stage, indicating early IFN pathway activation before overt disease.
IRF9 was also increased in B-cell subsets from both at-risk individuals and SjD patients compared with HDs.
The magnitude of STAT1 elevation was intermediate in at-risk individuals, falling between HDs and established SjD.
Results
In CD3+ T-cell subsets, STAT1 and IRF9 expression were elevated in at-risk individuals compared with HDs and were largely comparable to levels observed in patients with SjD.
Unlike B-cell subset findings where at-risk levels were intermediate, T-cell STAT1 and IRF9 levels in at-risk individuals were largely comparable to SjD levels.
This suggests that T-cell IFN signaling may be activated earlier or more completely in the disease course than B-cell IFN signaling.
Phosphorylated STAT1 (pSTAT1), STAT2, IRF1, and IRF9 were all assessed as IFN signaling molecules by flow cytometry.
Results
B-cell subset distributions in at-risk individuals were similar to healthy donors, whereas patients with SjD showed a typical increase in naïve B cells and reduced pre-switched and switched memory B-cell frequencies.
At-risk individuals (n=7) did not show the B-cell homeostasis disturbances characteristic of established SjD.
SjD patients (n=10) exhibited increased CD8+ T-cell frequencies and a non-significant trend toward reduced double-negative T-cell frequencies.
Altered B- and T-cell homeostasis was restricted to established SjD, not present in the at-risk group.
This finding indicates that lymphocyte subset abnormalities are a later event in disease progression than IFN pathway activation.
Results
At-risk individuals had lower ANA and rheumatoid factor titers and lacked anti-SSB autoantibodies compared with patients with SjD.
Anti-SSB autoantibody positivity was absent in at-risk individuals but present in SjD patients.
Lower ANA and RF titers distinguished the at-risk group from established SjD.
The at-risk group included asymptomatic anti-SSA-positive women, including two with ongoing pregnancies with congenital heart block and one with a prior CHB pregnancy.
These autoantibody differences suggest the at-risk group represents an earlier, less fully developed autoimmune state.
Results
Women with current or previous congenital heart block pregnancies had the highest Siglec-1 levels within the at-risk group, suggesting particularly elevated type I IFN activity in this subgroup.
Two of three women with a current or previous CHB pregnancy had the highest Siglec-1 levels among all at-risk individuals.
The at-risk group included two ongoing pregnancies with CHB and one woman with a prior CHB pregnancy out of 7 total at-risk individuals.
Elevated IFN activity in CHB-associated pregnancies may be relevant to understanding neonatal cardiac injury in this condition.
What This Means
This research suggests that people who carry anti-SSA antibodies (a type of autoantibody associated with Sjögren's disease) but have not yet developed full-blown disease already show signs of an overactive immune signaling pathway called the type I interferon (IFN) pathway. The study compared seven asymptomatic anti-SSA-positive women—including some with pregnancies complicated by congenital heart block—against ten patients with established Sjögren's disease and 21 healthy women. The researchers measured several markers of immune activation in blood samples, including a protein called Siglec-1 on immune cells, various IFN subtypes in the blood, and IFN-related signaling molecules inside immune cells.
The key finding is that elevated IFN signaling appears to be an early event in the development of Sjögren's disease, preceding the disruption of normal immune cell populations (lymphocyte abnormalities). Specifically, certain IFN subtypes (IFN-α1 and IFN-ω) and IFN-related signaling proteins (STAT1 and IRF9) were already elevated in at-risk individuals, while the characteristic shifts in B-cell and T-cell populations seen in established Sjögren's disease were absent. This suggests a progression where IFN activation comes first, and then lymphocyte imbalances develop later as disease becomes established. Women who had pregnancies complicated by congenital heart block—a serious condition where maternal antibodies can affect the baby's heart—showed the highest IFN activity levels within the at-risk group.
This research matters because identifying early immune changes in people who carry disease-associated antibodies but haven't yet developed symptoms could help clinicians monitor disease progression and potentially identify windows for preventive intervention. The findings support a model in which type I IFN activity is an early driver of Sjögren's disease rather than simply a consequence of established disease, though the small sample size (particularly the 7 at-risk individuals) means these findings should be considered preliminary and in need of confirmation in larger studies.
Ritter J, Stefanski A, Aue A, Rincon-Arevalo H, Rapino L, Eren A, et al.. (2026). Immune profiling of anti-SSA-positive at-risk individuals reveals increased type I IFN activity preceding lymphocyte abnormalities in Sjögren's disease.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1723672