Sjögren Syndrome

Genetics

A genetic contribution to the risk for primary Sjögren syndrome is supported by familial clustering of cases and aggregation of cases in families with other autoimmune diseases. First-degree relatives of patients with Sjögren syndrome have a higher prevalence of rheumatoid arthritis, systemic lupus erythematosus, inflammatory myopathy, type 1 diabetes mellitus, and multiple sclerosis. Nevertheless, most cases of primary Sjögren syndrome occur sporadically in the absence of a family history of autoimmune disease.

Most of the genetic susceptibility is conferred by polymorphisms in the human leukocyte antigen (HLA) loci, with the strongest effects from the HLA-DR and HLA-DQ class II HLA molecules. Primary Sjögren syndrome is associated with HLA class II alleles DRB1∗03:01, DQA1∗05:01, and DQB1∗02:01. Other genetic susceptibility loci identified in genome-wide association studies include those linked to type I interferon signaling ( IRF5 , IL12A , and STAT4 , OAS1 ), B-cell development and activation ( BLK , EBF1 ), nuclear factor kappa β (NF-κB) signaling ( TNIP1 , TNFAIP3 ), and lymphocyte trafficking ( CXCR5 ).

Immune Mechanisms of Disease

The immunologic mechanisms of primary Sjögren syndrome involve dysregulation of both adaptive and innate immune pathways that drive a chronic inflammatory response in the target tissues. In the salivary glands, foci of mononuclear cells infiltrate areas of preserved acinar gland architecture ( E-Fig. 247-1 ). Immunohistochemical analyses of these infiltrates show a predominance of CD4 ⁺ T lymphocytes and B lymphocytes, which together represent about 90% of the immune cells. The other immune cells comprising the infiltrate consist of CD8 ⁺ T lymphocytes, CD56 ⁺ natural killer cells, FoxP3 ⁺ T regulatory lymphocytes, macrophages, and myeloid and plasmacytoid dendritic cells. T and B lymphocytes tend to coalesce around ducts and blood vessels and, in more inflammatory lesions, form germinal center-like structures.

The salivary gland tissue is flooded with pro-inflammatory chemokines and cytokines. Activated epithelial cells secrete CXCL12 , CXCL13 , and CCL2 , as well as other mediators that cooperate to recruit, retain, and promote the survival of B lymphocytes. Macrophages and myeloid dendritic cells secrete tumor necrosis factor (TNF), IL-6, IL-12, and IL-18 in abundance. There is overexpression of type I interferon-inducible genes in both the salivary gland tissue and the peripheral blood.

B lymphocytes are the precursors of antibody-secreting cells, which produce the autoantibodies and lead to the hypergammaglobulinemia, cryoglobulinemia, and elevated levels of circulating immune complexes. Most B lymphocytes in salivary gland tissue express a memory phenotype and immunoglobulin (Ig) domains encoded by somatically hypermutated immunoglobulin V region genes, with structural characteristics typical of an antigen-driven response. The survival of B lymphocytes is enhanced by the upregulation of B-cell activating factor, which is produced mainly by plasmacytoid dendritic cells, as well as epithelial cells and macrophages, and is inducible by type I interferon.

Antibodies to SSA (Ro) and SSB (La) antigens, while diagnostic and prognostic biomarkers, are not known to be directly involved in causing the disease. In contrast, antibodies to the muscarinic receptor 3 (MR3) may suppress glandular function. Acetylcholine binds to the MR3 receptor expressed on the surface of lacrimal and salivary acinar glands, where it stimulates tear and salivary flow.

A prominent feature of primary Sjögren syndrome is the increased risk of lymphoma, usually a marginal zone lymphoma ( Chapter 171 ). The evolution of lymphoma in this setting is initiated by a polyclonal B lymphocyte response, with expansion of oligoclonal and monoclonal B lymphocyte populations followed by clonal transformation. The mechanisms underlying malignant transformation appear to depend on the activation of NF-κB. The A20 protein is a critical gatekeeper and inhibitor of the NF-κB pathway. The TNFAIP3 gene encoding the A20 protein is somatically deleted in some cases of marginal zone B-cell lymphoma without autoimmunity, whereas the risk for lymphoma in patients with primary Sjögren syndrome is associated with a single nucleotide polymorphism in the coding region of the TNFAIP3 gene. This polymorphism leads to a functional abnormality in the A20 protein, which in turn, promotes overactivation of the NF-κB pathway and loss of an important escape mechanism in lymphomagenesis.

Pathobiology

A dry eye may result from a deficiency in any of the three layers of the tear film: the outer lipid layer produced by the meibomian glands, the middle aqueous layer secreted by the lacrimal glands, and the inner mucous layer derived from the conjunctival goblet cells. Dry mouth and its complications are the product of reduced salivary flow, as well as changes in the concentrations of salivary electrolytes and proteins. Fatigue, which is the most prevalent extraglandular symptom, often has a multifactorial basis and may arise from disease-related mechanisms, depression, anxiety, fibromyalgia, sleep disturbance, or medication side effects.