Focal lymphocytic sialadenitis and ectopic germinal centers in oral reactive lesions and primary Sjögren's syndrome: a comparative study.

Focal lymphocytic sialadenitis (FLS), an important diagnostic criterion for Sjögren's syndrome (SS) diagnosis, can also be observed when assessing minor salivary gland (mSG) biopsies from healthy asymptomatic individuals (non-SS patients). Fifty cases of primary SS (pSS group) and 31 cases of oral reactive lesions (non-SS non-sicca group) containing also typical FLS features, were assessed by morphological and immunohistochemical (CD10, CD23 and Bcl-6) analysis, aiming at the detection of GCs. All pSS cases showed FLS with focus score (FS) ≥ 1. In the non-SS non-sicca group, 12, 10 and 9 cases showed FLS with FS ≥ 1, FLS with FS < 1 and FLS associated with chronic sclerosing sialadenitis with FS < 1, respectively. The morphological analysis revealed similar frequency of GCs in pSS (20%) and non-SS non-sicca group (19%). The area (p = 0.052) and largest diameter (p = 0.245) of GCs were higher in pSS than non-SS non-sicca group. The FS and number of foci were significantly higher in pSS than non-SS non-sicca group with FS < 1. Immunohistochemistry confirmed all morphological findings (GCs showing CD23 and Bcl-6 positivity, with variable CD10 expression) and additionally in 3 and 1 cases of the pSS and non-SS non-sicca group, respectively. Moreover, another 6 and 2 cases of the pSS and non-SS non-sicca group with FS ≥ 1, respectively, showed positivity only for CD23. FLS can also be observed when assessing oral reactive lesions, which showed similar frequency of GCs with those found in pSS patients. Further studies, including functional analysis of lymphocytic populations and GCs in FLS, are encouraged.

B cells in Sjögren's syndrome: from pathophysiology to therapeutic target.

Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sjögren's syndrome. Those patients present abnormal distribution of B lymphocytes in peripheral blood and B cells in exocrine glands. B cells produce auto-antibodies, cytokines and present antigens but can also suppressive functions. In this review, we will summarize current knowledge on B cells in primary Sjögren's syndrome patients, demonstrate their critical role in the immunopathology of the disease and describe the past and current trials targeting B cells.

Biologics in Sjögren's syndrome.

The use of biologic disease modifying antirheumatic drugs (bDMARDs) in systemic autoimmune diseases such as rheumatoid arthritis and at a lesser extent in lupus, has been well established. In Sjögren's syndrome (SS), despite the shared pathogenetic mechanisms with other autoimmune disorders, traditional immunomodulatory drugs have failed to address the main clinical features of the disease and use of biologics has been limited so far. Over the last years, our better understanding in disease pathogenesis has led to an expansion in the number of clinical trials exploring the effect and safety of biological agents with variable results. In the current review, the effect of targeting key molecular mechanisms involved in SS pathogenesis such as antigen presentation, B and T cell activation and germinal center formation is discussed.

Aberrant Humoral Immune Responses in Neurosyphilis: CXCL13/CXCR5 Play a Pivotal Role for B-Cell Recruitment to the Cerebrospinal Fluid.

Background: Previous studies documented that humoral immune responses participated in neurological damage in neurosyphilis patients. However, the mechanisms that trigger and maintain humoral immunity involved in neurosyphilis remain unknown. Methods: Using flow cytometry, expression of B cells was measured in neurosyphilis and non-neurosyphilis. Expression of immunoglobulin indices and chemokine ligand CXCL13 was detected by enzyme-linked immunosorbent assay. The migration and inhibition assays were evaluated by modified chamber assays. The presence of CXCL13+ cells, cluster of differentiation (CD)20+ B cells, CD3+ T cells, CD138+ plasma cells and CD35+ follicular dendritic cells was studied by immunohistochemistry. Results: Enrichment of B cells was observed and activated in the cerebrospinal fluid (CSF) of neurosyphilis patients. Immunoglobulin indices were increased and associated with the progress to neurosyphilis. High expression of CSF CXCL13 mediated B cell migration both in vitro and in vivo. There was a positive correlation among the CSF B cells, immunoglobulin indices, and CSF CXCL13 levels. Ectopic germinal centers (EGCs), important structures for humoral immunity, were observed in the intracranial syphilitic gumma. Conclusions: CXCL13/CXCR5 mediated the aggregation of B cells, that directed the aberrant humoral immune responses via the formation of EGCs, which suggests a molecular mechanism of neurological damage in neurosyphilis.

Catalpol ameliorates Sjögren's Syndrome by modulating interplay of T and B cells.

Catalpol is an active ingredient of Rehmanniae Radix, a medical herb used frequently in treating primary Sjogren's Syndrome (pSS). However, no study has assessed the therapeutic effects of catalpol in treating Sjogren's Syndrome. This study aimed to investigate the therapeutic effects of catalpol for pSS by evaluating the water consumption, stimulated salivary flow rates, sialadenitis, T cell subsets and related cytokine levels. Catalpol treated mice had improved stimulated salivary flow rates and water consumption compared to mice from the control group. Catalpol also reduced the lymphocytic infiltration and prevented the formation of ectopic germinal centers. These effects, especially in the catalpol high dose group, were associated with elevated CD4+ CXC-R5+ PD-1+ Foxp3+ T follicular regulatory (Tfr) cells (1.572 % vs 1.118 %, P = 0.0005) and a higher ratio of Tfr cells to T follicular helper (Tfh) cells (2.137 vs 1.541, P = 0.0007). Downregulated levels of IFN-γ and BAFF in serum and submandibular glands were also noted in catalpol treated groups. Our work indicated that catalpol might be a potential drug for treating pSS by regulating the interplay between T and B cells.

Spontaneous germinal centers and autoimmunity.

Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.

The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases.

TLS, characterized by the formation of ectopic B/T cell follicles with FDCs supporting an ectopic GC response, have been described in the target organs of several autoimmune diseases, including MS, RA, SS, and autoimmune thyroiditis. These structures represent functional niches, whereby autoreactive B cells undergo in situ affinity maturation and differentiation to autoantibody-producing cells, thus contributing to the progression and persistence of autoimmunity. Increasing evidence demonstrates that TLS can also develop in the context of cancer, as well as chronic infections. In this review, we collect recent evidences that highlights the relationship between persistent viral infection and the development of ectopic lymphoid structures in animal models and patients. Furthermore, we shall discuss the concept that whereas in physiological conditions, inducible TLS are critical for viral clearance and the establishment of protective immunity, but in the context of susceptible individuals, persistent viral infections may contribute, directly or indirectly, to the development of breach of tolerance against self-antigens and the development of autoimmunity through the formation of TLS.