Sjogren's syndrome
The Role of Ectopic Germinal Centers in the Immunopathology of Primary Sjögren's Syndrome: A Systematic Review

https://doi.org/10.1016/j.semarthrit.2012.07.003Get rights and content

Objectives

To determine whether the presence of germinal centers (GCs) in salivary glands of patients with primary Sjögren's syndrome (pSS) is related to the severity of disease course and distinct immunopathology features.

Methods

A systematic search was performed in September 2011 for terms and synonyms of Sjögren's syndrome and germinal centers. A total of 80 articles were retrieved, of which 16 were included for (meta-) analysis.

Results

GC morphology was present in a mean ± SD 25.1 ± 5.0% of pSS patients. Mean lymphocyte focus scores were 1.25 points higher in patients with GCs as compared to those without GCs. Saliva production was reduced in patients with GCs, although this did not reach statistical significance. Percentages of patients positive for rheumatoid factor, anti-Sjögren's syndrome A (SSA), and anti-Sjögren's syndrome B (SSB) antibodies were significantly higher in patients with GCs (mean increase, 15%, 18%, and 18%, respectively). Additionally, patients with GCs were characterized by enhanced levels of local and systemic proinflammatory mediators. Importantly, these patients have a higher risk of lymphoma development (14% versus 1%).

Conclusions

Patients with GCs are characterized by more severe disease, although the small number of studies and their design hamper generalizability of results. The precise mechanisms that contribute to the development and persistence of germinal centers in pSS are largely unknown. This and the strongly increased risk of lymphoma development warrant intensive studies for the role of germinal centers in the immunopathology of pSS.

Section snippets

Systematic Review

A systematic search was executed in PubMed (September 2011) for terms and synonyms of “Sjögren's syndrome” and “germinal centers” (Fig. 1). This resulted in 80 articles containing both terms, which were screened on title and abstract for relevance, the availability of a full-text article, and language. Reviews, animal studies, and case reports were not included. Results had to be clarified for pSS. Reference lists of the final 16 studies were screened for missing articles, but this did not lead

Germinal Centers in Primary Sjögren's Syndrome

The literature search resulted in 16 articles reporting on ectopic germinal center formation in patients with pSS (Table 1). One article (15) was later excluded from meta-analysis because patient selection was unclear. It seemed that in this study the patients lacking germinal centers were selected on a high focus score, making the comparison not representative. Results from the recent large study from the Sjögren's International Collaborative Clinical Alliance were not included, because their

Discussion

In this systematic review (using meta-analyses) we show that ectopic GC formation in the exocrine glands, which occurs in one-quarter of patients with pSS, is associated with more severe disease. Although GC assessment was performed in only a limited number of studies and patients, decreasing the generalizability of the outcomes, the results indicate that patients with GCs in salivary gland specimens have a higher lymphocytic focus score, a higher prevalence of autoantibodies, and an increased

References (31)

  • L. Le Pottier et al.

    Ectopic germinal centers are rare in sjogren's syndrome salivary glands and do not exclude autoreactive B cells

    J Immunol

    (2009)
  • M.K. Gatumu et al.

    Nuclear BCL10 in primary Sjögren's syndrome

    J Oral Pathol Med

    (2009)
  • M.V. Jonsson et al.

    Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjögren's syndrome

    J Oral Pathol Med

    (2008)
  • M.N. Manoussakis et al.

    Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: Correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development

    Arthritis Rheum

    (2007)
  • M. Bombardieri et al.

    Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjögren's syndrome

    J Immunol

    (2007)
  • Cited by (0)

    The Dutch Arthritis Association supports the work of JAG van Roon, JWJ Bijlsma, and AA Kruize.

    1

    These authors contributed equally to this article.

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