Targets for Sjogren Syndrome

Understanding the molecular targets implicated in Sjogren Syndrome (SS) is essential for elucidating the disease's pathogenic mechanisms, identifying therapeutic opportunities, and advancing drug development. SS is an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, leading to glandular dysfunction and systemic manifestations. The targets listed here—after critical filtering—are directly involved in B cell activation, T cell co-stimulation, cytokine signaling, and innate immune activation, all of which are central to SS pathogenesis. By dissecting these targets, researchers gain insight into the aberrant immune activation, autoantibody production, and tissue damage seen in SS. These targets also represent actionable nodes for therapeutic intervention, as evidenced by the clinical development of inhibitors, monoclonal antibodies, and biologics aimed at modulating these pathways. Collectively, these targets help define the immunological landscape of SS, provide biomarkers for disease activity, and inform rational drug design strategies.

B Cell Activation And Survival Pathways

This category encompasses targets that directly regulate B cell receptor (BCR) signaling, co-stimulation, and survival—processes that are central to the pathogenesis of Sjogren Syndrome. Dysregulated B cell activity underlies autoantibody production, glandular infiltration, and systemic manifestations. The following targets are included: Bruton Tyrosine Kinase (BTK), Spleen Associated Tyrosine Kinase (SYK), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD), CD22 Molecule (CD22), TNF Receptor Superfamily Member 13C (TNFRSF13C/BAFF-R), TNF Superfamily Member 13B (TNFSF13B/BAFF), and TNF Superfamily Member 13 (TNFSF13/APRIL). These molecules integrate BCR signaling, survival cues, and co-stimulatory signals, promoting B cell hyperactivity and persistence. Their dysregulation is well-documented in SS and is a major driver of disease onset and progression.

Bruton Tyrosine Kinase (BTK)

BTK is a non-receptor tyrosine kinase with pleckstrin homology, SH3, and SH2 domains, critical for BCR signaling. It is regulated by phosphorylation and is essential for B cell development, activation, and survival. BTK (Entrez: 695, KEGG: 695, UniProt: Q06187) transduces BCR engagement, leading to NF-κB and MAPK pathway activation. In SS, BTK is upregulated in salivary gland infiltrates and peripheral B cells, promoting autoantibody production and lymphoid organization. BTK inhibitors (e.g., ibrutinib, acalabrutinib) are in clinical trials for B cell–mediated autoimmune diseases, with preclinical data supporting efficacy in SS models. BTK is a promising therapeutic target and a potential biomarker for B cell activation in SS.

Spleen Associated Tyrosine Kinase (SYK)

SYK is a cytoplasmic tyrosine kinase (SH2 domains) that acts downstream of the BCR and Fc receptors. It is regulated by phosphorylation and protein interactions. SYK (Entrez: 6850, KEGG: 6850, UniProt: P43405) mediates signal transduction leading to calcium mobilization, MAPK activation, and gene transcription. Overactivation of SYK is observed in SS B cells and glandular tissue, contributing to autoimmunity and tissue damage. SYK inhibitors (e.g., fostamatinib) reduce B cell activation and have shown benefit in other autoimmune diseases, with translational potential for SS.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD)

PIK3CD encodes the p110δ catalytic subunit of PI3Kδ, which is highly expressed in leukocytes and contains a kinase domain and regulatory subunit interaction sites. PIK3CD (Entrez: 5293, KEGG: 5293, UniProt: O00329) is activated downstream of BCR and cytokine receptors, generating PIP3 to activate AKT and mTOR pathways. Gain-of-function and hyperactivation of PI3Kδ are linked to B cell hyperactivity and autoimmunity, as seen in SS. PI3Kδ inhibitors (e.g., idelalisib) are in use for B cell malignancies and are being explored for autoimmune indications.

CD22 Molecule (CD22)

CD22 is a transmembrane sialic acid–binding immunoglobulin-like lectin (Siglec) with immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD22 (Entrez: 933, KEGG: 933, UniProt: P20273) negatively regulates BCR signaling by recruiting phosphatases. Reduced CD22 expression or function is reported in SS B cells, leading to enhanced activation. Therapeutic anti-CD22 antibodies (e.g., epratuzumab) have been tested in SLE and SS, aiming to dampen B cell hyperactivity.

TNF Receptor Superfamily Member 13C (TNFRSF13C/BAFF-R)

BAFF-R is a transmembrane receptor with a cysteine-rich extracellular domain, binding BAFF to mediate B cell survival. TNFRSF13C (Entrez: 115650, KEGG: 115650, UniProt: Q96RJ3) is upregulated in SS, promoting survival of autoreactive B cells. BAFF-R signaling activates NF-κB and PI3K pathways. BAFF-R blockade is a validated therapeutic strategy in SS and SLE.

TNF Superfamily Member 13B (TNFSF13B/BAFF)

BAFF is a TNF family cytokine with a trimeric structure, produced by myeloid cells and glandular epithelium. TNFSF13B (Entrez: 10673, KEGG: 10673, UniProt: Q9Y275) is elevated in SS serum and glands, correlating with B cell expansion and autoantibody titers. BAFF antagonists (e.g., belimumab) are approved for SLE and under investigation for SS.

TNF Superfamily Member 13 (TNFSF13/APRIL)

APRIL is a TNF ligand structurally related to BAFF, binding to TACI and BCMA receptors. TNFSF13 (Entrez: 8741, KEGG: 8741, UniProt: O75888) is overexpressed in SS and supports plasma cell survival and immunoglobulin production. APRIL blockade reduces autoantibody production in preclinical models.

T Cell Co-Stimulation And Costimulatory Ligands

T cell–B cell interactions are pivotal in SS, particularly through co-stimulatory molecules expressed on antigen-presenting cells and T cells. This category includes CD40 Ligand (CD40LG), CD40 Molecule (CD40), CD80 Molecule (CD80), CD86 Molecule (CD86), and Inducible T Cell Costimulator Ligand (ICOSLG). These molecules mediate T cell help, B cell activation, and germinal center formation in exocrine glands. Their dysregulation fosters autoimmunity, lymphoid neogenesis, and tissue damage in SS.

CD40 Ligand (CD40LG)

CD40LG is a type II transmembrane protein of the TNF superfamily, expressed on activated T cells. It contains a TNF homology domain for CD40 binding. CD40LG (Entrez: 959, KEGG: 959, UniProt: P29965) is upregulated in SS infiltrating T cells, promoting B cell activation, class switching, and germinal center–like structures. CD40LG–CD40 interactions are critical for SS pathogenesis, and blockade reduces disease severity in models. Anti-CD40LG therapies are in early-phase trials.

CD40 Molecule (CD40)

CD40 is a TNFR family member with a cysteine-rich extracellular domain, expressed on B cells and antigen-presenting cells. CD40 (Entrez: 958, KEGG: 958, UniProt: P25942) is upregulated in SS glands and mediates B cell survival and activation upon CD40LG binding. Disruption of CD40 signaling ameliorates SS in animal models.

CD80 Molecule (CD80)

CD80 is a co-stimulatory receptor of the immunoglobulin superfamily, expressed on B cells and dendritic cells. CD80 (Entrez: 941, KEGG: 941, UniProt: P33681) binds CD28 and CTLA-4, modulating T cell activation. Overexpression in SS glands enhances T cell activation and perpetuates inflammation. CTLA4-Ig (abatacept) targets CD80/CD86 and is under investigation in SS.

CD86 Molecule (CD86)

CD86 is a co-stimulatory molecule structurally related to CD80, with immunoglobulin-like domains. CD86 (Entrez: 942, KEGG: 942, UniProt: P42081) is upregulated in SS and provides critical signals for T cell activation and B cell help. Therapeutic blockade of CD86 is being explored in autoimmune diseases.

Inducible T Cell Costimulator Ligand (ICOSLG)

ICOSLG is a transmembrane protein with an immunoglobulin domain, expressed on B cells and dendritic cells. ICOSLG (Entrez: 23308, KEGG: 23308, UniProt: O75144) interacts with ICOS on T cells, promoting T follicular helper cell differentiation and germinal center formation. Dysregulated ICOS–ICOSLG signaling is observed in SS glands, contributing to autoimmunity.

Cytokine And Jak/Stat Signaling

Cytokine signaling, particularly via the JAK/STAT pathway, is central to the chronic inflammatory milieu of SS. This category includes Interleukin 7 Receptor (IL7R), Janus Kinase 2 (JAK2), and Tyrosine Kinase 2 (TYK2). These molecules regulate lymphocyte survival, proliferation, and differentiation. Their dysregulation promotes lymphoproliferation, glandular infiltration, and systemic disease.

Interleukin 7 Receptor (IL7R)

IL7R is a heterodimeric receptor with an immunoglobulin-like domain, expressed on T and B lymphocytes. IL7R (Entrez: 3575, KEGG: 3575, UniProt: P16871) mediates IL-7–induced JAK/STAT signaling, promoting lymphocyte survival. IL7R is upregulated in SS and correlates with lymphoid infiltration and disease severity. Targeting IL7R signaling is a potential therapeutic approach.

Janus Kinase 2 (JAK2)

JAK2 is a cytoplasmic tyrosine kinase with a FERM domain and kinase domain, associating with cytokine receptors. JAK2 (Entrez: 3717, KEGG: 3717, UniProt: O60674) transduces signals from multiple cytokines, including IL-6 and IFN-γ. JAK2 is activated in SS salivary glands and lymphocytes, driving STAT phosphorylation and inflammatory gene expression. JAK inhibitors (e.g., baricitinib) are being evaluated in SS.

Tyrosine Kinase 2 (TYK2)

TYK2 is a JAK family kinase with similar domain structure to JAK2, mediating type I IFN and IL-12/23 signaling. TYK2 (Entrez: 7297, KEGG: 7297, UniProt: P29597) is implicated in SS through its role in interferon signature activation. TYK2 inhibition reduces glandular inflammation in preclinical models.

Innate Immune Activation And Pattern Recognition

Innate immunity and pattern recognition receptor (PRR) signaling are key contributors to SS pathogenesis, particularly through the activation of type I interferon pathways. This category includes Toll Like Receptor 7 (TLR7) and Toll Like Receptor 8 (TLR8), which recognize nucleic acids and activate downstream inflammatory cascades. Their upregulation in SS promotes interferon production, B cell activation, and tissue injury.

Toll Like Receptor 7 (TLR7)

TLR7 is a single-pass transmembrane protein with leucine-rich repeat (LRR) domains, expressed in endosomes of immune cells. TLR7 (Entrez: 51284, KEGG: 51284, UniProt: Q9NYK1) recognizes single-stranded RNA, leading to MyD88-dependent activation of IRF7 and NF-κB, resulting in type I IFN production. TLR7 is overexpressed in SS salivary glands and peripheral blood, correlating with disease activity. TLR7 antagonists are being developed for autoimmune diseases.

Toll Like Receptor 8 (TLR8)

TLR8 is structurally similar to TLR7, with LRR and TIR domains, and is expressed in monocytes and dendritic cells. TLR8 (Entrez: 51311, KEGG: 51311, UniProt: Q9NR97) detects single-stranded RNA, activating NF-κB and inducing proinflammatory cytokines. Increased TLR8 expression is reported in SS, contributing to chronic inflammation and autoimmunity.

Fc Receptor And Igg Transport

Fc Gamma Receptor and Transporter (FCGRT) is involved in the recycling and transcytosis of IgG. In SS, increased FCGRT expression may contribute to altered IgG handling, autoantibody persistence, and immune complex–mediated inflammation, though its role is less central than BCR or T cell costimulatory pathways.

Fc Gamma Receptor and Transporter (FCGRT)

FCGRT encodes the neonatal Fc receptor (FcRn), a transmembrane protein with an IgG-binding domain, expressed on endothelial and epithelial cells. FCGRT (Entrez: 2217, KEGG: 2217, UniProt: P55899) regulates IgG half-life and transport. In SS, increased FCGRT expression in salivary glands has been linked to enhanced IgG persistence and immune complex formation, contributing to local and systemic autoimmunity. Therapeutic modulation of FcRn is being explored in autoantibody-mediated diseases.