Analyses of circulating Treg population

in the salivary glands [76]. Their count was found to inversely correlate with the degree of glandular inßammation and certain risk factors for lymphoma development [77]. Regulatory mechanisms are discussed in Section 15.3.4.

15.1.4 B cells

Phenotypical analyses of B cells from patients with SS have revealed decreased numbers of circulating CD27+ memory B cells [78, 79], which selectively overexpressed C-X-C motif receptors (CXCR)3 and CXCR4 [80]. In contrast, the fraction of CD27+ memory B cells within the glands was enlarged [79]. Extensive analyses of mature B-cell subsets (Bm1ÐBm5) in blood further showed altered proportions of most mature B-cell subsets in primary SS compared to healthy donors and patients with RA [81].

The percentage of B cells expressing mutated V(H) genes has been found to be signiÞcantly higher in B cells isolated from parotid glands compared to B cells in circulation [82]. Furthermore, V(L) gene analysis of B cells isolated from the glands revealed biased usage of V(L) chain genes [83]. However, if these alterations result from disturbed B-cell maturation and abnormal selection processes or if the biased repertoire reßects a normal antigen-driven local immune response is unclear. Polyclonal B-cell activation may develop into an oligoclonal or monoclonal B-cell expansion during disease progression. Such expansion may provide a basis for the initiation of a malignant lymphoproliferative disease [84, 85].

Patients with SS often present increased levels of polyclonal IgG in the serum [2]. Augmented production of IgM and IgG compared to IgA was further detected within labial salivary glands from patients with SS [86]. Autoantibodies speciÞc for Ro and La are associated with SS and of major importance in SS diagnosis and patient classiÞcation [1]; 60Ð80% of the patients present anti-Ro and 40Ð60% present anti-La antibodies in the serum [2]. Even though the role of Ro

and La in the pathogenesis of SS is still elusive, recent research efforts suggested new molecular mechanisms, by which Ro52 may directly contribute to the induction of autoimmune T cells and B cells in SS [87]. Rheumatoid factor (RF) is produced in approximately 60% of the patients [88], whereas anti-cyclic citrullinated peptide (CCP) antibodies are rarely found in patients with SS [89]. Other antibodies found in patients with SS are anti-α-fodrin [90, 91] and anti-phospholipid antibodies [92]. The latter antibody could not be associated with any of the typical clinical manifestations of SS [93] and anti-α-fodrin autoantibodies are a controversial issue [94], also since the original Þndings were difÞcult to verify [95]. Autoantibodies potentially inhibiting neuronal innervation of acinar cells are discussed in more detail in Section 15.2.1 and for more insight about autoantibodies in SS in general please see Chapter 9.

15.1.5Lymphoid Organization and Germinal Center-Like Structure Formation

Histological and immunohistological investigations of minor salivary gland specimens identiÞed germinal center (GC)-like structures, also known as tertiary lymphoid tissue, in approximately every fourth patient with primary SS [48]. Interestingly, generation of the SS patientÕs individual cytokine and chemokine proÞle revealed biomarker signatures in serum indicative for the presence of GC-like structures in the salivary glands [17]. Among 25 biomarkers B-cell- activating factor (BAFF), CCL11, and IFN-γ levels were found to discriminate best between patients with and without GC-like structure formation [17].

In secondary lymphoid tissues GCs develop dynamically after the activation of B cells by T-cell-dependent antigen [12]. Interestingly, within the salivary glands affected by SS T and B cell proportions vary signiÞcantly among different foci [48]. In GCs of the secondary lymphoid tissue B cells begin monoclonal expansion in close proximity to DCs. In a state of activated apoptosis B cells compete for survival signals