Cell Composition Analysis of Matched Salivary Organoid and Adherent Cultures: Choose Your Sjögren Disease Research Tool Carefully.

Sjögren disease (SjD) is widely recognized by the presence of B cell-dominated lymphocytic infiltration in the salivary glands (SGs). Contrary to what was originally presumed, however, SG hypofunction in SjD is not strongly correlated with the degree of SG lymphocytic infiltration in the SGs.

Immunisation with Coronavirus-2 vaccines induces potent antibody responses and does not aggravate the lymphocyte compartment of primary Sjögren's syndrome patients.

OBJECTIVES: The peripheral lymphocyte compartment of patients with primary Sjögren's syndrome (pSS) differs strongly from healthy individuals. Whether this altered lymphocyte composition also changes abnormally during immune reactions, especially by novel CoV-2-vaccines, is unknown. METHODS: Peripheral blood mononuclear cells (PBMC) from 26 pSS patients and 6 healthy controls were compared before Coronavirus-2 (CoV-2) vaccination (Pfizer/BNT162b2, Moderna/mRNA-1273, AstraZeneca/AZD122 ChAdOx1 nCoV-19) and 7 days after secondary vaccination. Spike 1 (S1)-receptor binding domain (RBD)-specific IgG antibodies were measured in serum samples. Among PBMCs, B and T cell subpopulations were phenotypically analysed and RBD-specific B and plasma cells were evaluated. RESULTS: Immunisation induced CoV-2 specific serum antibodies in all pSS patients and healthy participants. When analysing pSS patients and controls together, frequencies of circulating IgG+ RBD-specific antibody-secreting cells (ASC) and anti-RBD serum titres correlated (r=0.42, p=0.022). Previously described alterations of peripheral B cells in pSS patients (e.g. reduced memory B cells, increased naive and transitional B cells and higher maturity of ASCs) remained stable during vaccination. The subset distribution of CD4+ and CD8+ T cells also stayed largely unchanged. However, frequencies of CD4+CXCR5-PD-1+ circulating peripheral helper T (cTPH)-like cells increased in pSS patients comparing pre- and post-vaccination (p=0.020), while circulating CD4+CXCR5+PD-1+ follicular helper T (cTFH)-like cells declined (p=0.024). CONCLUSIONS: An immune reaction induced by vaccination with the novel CoV-2 vaccines yields adequate antibody production and vaccine specific lymphocytes in pSS patients and controls. Aberrant lymphocyte subset distribution in pSS patients persisted after vaccination and no major changes were induced despite small changes in cTPH and cTFH cells.

Immunogenicity and safety of COVID-19 vaccination in patients with primary Sjögren's syndrome.

OBJECTIVES: To evaluate humoral and cellular immune responses and adverse events (AEs) after COVID-19 vaccination in patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC), and disease activity following vaccination in patients with pSS. METHODS: 67 patients with pSS and 33 HC (ratio 2:1) received COVID-19 vaccinations following the Dutch vaccination programme. Patients with pSS did not use immunomodulatory drugs, except hydroxychloroquine. Anti-spike 1 receptor binding domain IgG serum antibody levels were measured 28 days after complete vaccination. AEs were collected 7 days after vaccination. In a subgroup, salivary anti-SARS-CoV-2 antibodies and T-cell response by interferon-γ enzyme-linked immune absorbent spot was measured. RESULTS: 47 patients with pSS (70%) and 14 HC (42%) received BNT162b2 (Pfizer-BioNtech), 13 (19%) and 5 (15%) received ChAdOx1 nCoV-19 (AstraZeneca), 6 (9%) and 8 (24%) received mRNA-1273 (Moderna), and 1 (1%) and 6 (18%) received Ad.26.COV2.S (Janssen). All participants had positive anti-SARS-CoV-2 antibody levels (>2500 AU/mL) postvaccination. No differences in anti-SARS-CoV-2 antibody levels were observed between patients with pSS and HC, for each vaccine type. Salivary anti-SARS-CoV-2 IgG antibodies also increased, and a T-cell response was observed in patients with pSS and HC. Frequencies of systemic AEs were comparable between patients with pSS and HC (first vaccination: 34/67 (51%) vs 16/33 (48%), p=0.83; second: 41/66 (62%) vs 14/25 (56%), p=0.59). No significant worsening was observed in patient-reported and systemic disease activity, including auto-antibodies. CONCLUSIONS: Patients with pSS had similar humoral and cellular immune responses as HC, suggesting COVID-19 vaccination is effective in patients with pSS. AEs were also comparable, and no increase in disease activity was seen in patients with pSS.

Salivary Gland Stem Cells Age Prematurely in Primary Sjögren's Syndrome.

OBJECTIVE: A major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS. METHODS: SGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis. RESULTS: SGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells. CONCLUSION: This study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.