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improvement of both xerostomia and xerophthalmia after stopping HAART. All four patients had elevated erythrocyte sedimentation rates, hypergammaglobulinemia, hypocomplementemia, low HIV viral loads, and absent autoantibodies directed against the SSA/Ro and SSB/La antigens. These authors suggested that HAART plays an important role in the etiology of SS among patients with HIV, and that SS may be a new and important complication of long-term HAART regimens [45].
In summary, HIV-related sicca syndrome has many similarities to SS associated with HCV infection. DILS should be considered a viral-related sicca syndrome rather than a disorder separate from HIV infection [46].
4.4Human T-lymphotropic Virus Type I
The clinical significance of human T-lymphotropic virus type I (HTLV-I) infection in patients with SS depends on the geographic area. In Japan, where HTLV-I is endemic, a prevalence of nearly 25% [47, 48] was detected in patients with primary SS, suggesting a possible etiopathogenic role for this retrovirus in a subset of cases. Nakamura et al. [49] reported a low prevalence of ectopic germinal center formation in patients with HTLV-I-associated SS.
In contrast, HTLV-I infection is very rare in European countries, although some studies have detected genomic sequences of HTLV-I in patients with primary SS. Mariette et al. [50] detected the HTLV-I tax gene within the salivary glands of 15 (30%) of 50 SS patients but also in the 28% of controls. Further investigation of the potential relationship between HTLV-I infection and primary SS is required, but it is possible that this retrovirus has a role in Asian populations that is similar to that of HCV in Mediterranean populations.
4.5Coxsackieviruses
Recent evidence suggests a role for Coxsackieviruses in the etiopathogenesis of primary SS. Triantafyllopoulou et al. [51] have detected the presence of the Coxsackievirus genome and the main antigenic capsid protein VP1 in 11 of 12 patients with primary SS, 1 of 13 patients with associated SS, and none of 16 controls, suggesting a latent Coxsackievirus infection within the salivary glands of some patients with primary SS. Although the underlying mechanisms of secondary lymphoid structure formation in primary SS are unclear, the authors have proposed an etiopathogenic model which suggests that, in preclinical stages of the disease, lymphocytes transport the virus to its preferential niche (i.e., the epithelial cells of the exocrine glands). During the course of the disease, the virus is cleared from the systemic circulation, but continues to replicate within epithelial cells that become highly specialized antigen-presenting cells. This initiates the recruitment of T and B lymphocytes into exocrine glands and the secretion of chemokines and cytokines.
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It is probable that the Coxsackievirus per se induces the formation of secondary lymphoid-like follicles and the exocrine gland pathology, which are the histological hallmarks of primary SS. Coxsackievirus infection and replication in the exocrine glands of patients with primary SS may also contribute to the maintenance of the autoimmune reaction by interaction with host cell proteins.
The same group described a 94 base pair gene with full homology to the P2A gene of the Coxsackievirus B4 [52]. In addition, Coxsackievirus sequences have been detected in cultured epithelial cells eluted from the salivary glands of patients with primary SS, but not in those with associated SS [53], suggesting a chronic infection of the epithelial cells by Coxsackievirus. Stathopolou et al. [52] have reported a cross-reaction between antibodies to the major epitope of Ro60 kD autoantigen and a homologous peptide of Coxsackie virus 2B protein. This cross-reaction might play a role in autoantibody formation and in the perpetuation of the autoimmune response against the SSA/Ro and SSB/La antigens. However, Gottenberg et al. [54] failed to identify Coxsackievirus sequences in the salivary glands of both nine SS patients and nine controls. Further studies are required to define the etiopathogenic role of this enterovirus in larger cohorts of patients with primary SS.
4.6Herpes Viruses
Herpes viruses, especially Ebstein–Barr virus (EBV), have also been studied in primary SS [55–59]. Dawson et al. [56] detected EBV-DNA in one of six SS patients with lymphoma, and Inoue et al. [57] suggested a possible role for EBV reactivation in increased apoptotic protease activity in SS. Trimeche et al. detected EBV-DNA by PCR in 3/22 (14%) patients with primary SS in comparison with 2/17 (12%) controls [58].
Perrot et al. [55] analysed the prevalence of herpesviruses DNA sequences using degenerated consensus PCR primers in salivary gland biopsies from primary and associated SS. Herpesviruses DNA sequences were isolated from 9/55 (16%) salivary gland specimens (EBV sequences in six cases and herpes simplex virus HSV sequences in the remaining three). With respect to other herpes viruses, Klussman et al. [59] isolated sequences and antigens of HHV-8 in one patient with SS and MALT lymphoma. Due to the high seroprevalence of the herpes viruses in the healthy adult population, a discriminative etiopathogenic role is usually difficult to demonstrate, limiting the significance of isolating sequences of ubiquitous viruses in patients with primary SS.
4.7Human Parvovirus B19
In 1998, a preliminary study showed that serological evidence of past B19 infection in SS patients was associated with the presence of leukopenia and thrombocytopenia, suggesting a possible relationship between B19 and cytopenia [60]. Two
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subsequent studies have focused on the etiopathogenic role of B19 in primary SS. De Re et al. [61] analyzed six primary SS patients who had monoclonal lymphoproliferation and detected no B19-DNA within parotid specimens. De Stefano et al. [62] studied salivary gland specimens from ten patients with SS and detected B19DNA in one (10%), who had a high titer of anti-B19 IgG antibodies but negative IgM assays. Thus, although the presence of B19-DNA in salivary glands of SS patients seems to be infrequent, B19 might persist in some cases.
4.8Conclusion
In recent decades, many research groups have focused on the role of viral infection in the etiopathogenesis of primary SS, the so-called viral hypothesis. The main earlier candidates were herpesviruses such as EBV and CMV, which have a high seroprevalence in the general population, with more than 90% of adults presenting IgG against these viruses. Recent studies have suggested that other viruses (mainly hepatitis viruses, retroviruses, and enteroviruses) may play a key etiopathogenic role in SS. However, the mechanisms that lead to the aberrant autoimmune responses related to chronic viral infection are not clearly understood.
Because primary infection by these viruses is not always recognized, etiopathogenic studies performed after acute infection are difficult to interpret. Molecular changes induced by first contact with the virus are not susceptible to analysis when the etiopathogenic situation previous to the primary infection is not known. However, the search will be always for the external agent that could trigger the autoimmune response and the development of primary SS. The viral causal agent of SS has not yet been discovered, but many interesting findings on the complex interactions between viruses and SS patients in clinical practice have been made.
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44. Panayiotakopoulos GD, Aroni K, Kyriaki D, et al. Paucity of Sjögren-like syndrome in a cohort of HIV-1-positive patients in the HAART era. Part II. Rheumatology (Oxford). 2003;42:1164–7.
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Chapter 5
Etiopathogenic Role of B Cells in Primary
Sjögren’s Syndrome
Jacques-Olivier Pers, Sophie Hillion, Gabriel Tobón,
Valérie Devauchelle, Alain Saraux, and Pierre Youinou
Contents |
|
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5.1 |
The Role of T Cells in SjS............................................................................................... |
69 |
5.2 |
The Role of B Cells in SjS............................................................................................... |
70 |
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5.2.1 The Impact of B Cell Cytokines........................................................................... |
70 |
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5.2.2 Ontogeny of B Lymphocytes................................................................................ |
71 |
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5.2.3 Subpopulations of B Cells .................................................................................... |
72 |
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5.2.4 B Cell Monoclonal Expansion.............................................................................. |
74 |
5.3 |
B Cells Are Not Dispensable .......................................................................................... |
74 |
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5.3.1 B Cell Chemokines and Antibody Production ..................................................... |
74 |
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5.3.2 Peculiarities of B Cell Products: Cytokines and IgA Autoantibodies.................. |
75 |
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5.3.3 Intrinsic Abnormalities of B Cells in Primary SjS ............................................... |
76 |
5.4 |
Conclusion ....................................................................................................................... |
77 |
References................................................................................................................................. |
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Sjögren’s syndrome (SjS) is an autoimmune epithelitis [1], the hallmarks of which are a disruption of epithelial cells and the infiltration by lymphocytes of lacrimal and salivary glands. The epithelitis and salivary gland infiltration typically lead to profound salivary gland dysfunction. SjS can develop as a primary disorder or against a background of other readily identified connective tissue disorders [2]. Among the permissive autoimmune settings are rheumatoid arthritis (RA), systemic sclerosis
J.-O. Pers • S. Hillion • G. Tobón • V. Devauchelle • A. Saraux
EA 2216 “Immunology and Pathology” and IFR 148 ScInBioS,
the European University of Brittany and the University of Brest,
and the Brest University Medical School Hospital, Brest, France
P. Youinou (*)
EA 2216 “Immunology and Pathology” and IFR 148 ScInBioS,
the European University of Brittany and the University of Brest,
and the Brest University Medical School Hospital, Brest, France
Laboratory of Immunology, Brest University Medical School Hospital, Brest, France
M. Ramos-Casals et al. (eds.), Sjögren’s Syndrome, |
67 |
DOI 10.1007/978-0-85729-947-5_5, © Springer-Verlag London Limited 2012 |
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68
Table 5.1 Arguments for Sjögren’s syndrome as a “T-cell disease”
J.-O. Pers et al.
•Predominance of T cells in salivary gland infiltrates
•Limited heterogeneity of the T-cell antigen receptors
•Impaired proliferative potential of circulating T cells
•Requirement of T cells for antibody class switching
•Importance of T cells in the formation of germinal centers
•T helper 1 profile of cytokines in the exocrine glands
(SSc), and systemic lupus erythematosus (SLE). Popular theories regarding the pathogenesis of SjS are that the condition is triggered by viruses [3] and modulated by sex hormones [4]. Its etiologic pathways appear to include a combination of environmental agents and genetic factors [5].
Lymphocytes are central to the pathogenesis of SjS. The epithelial structures of inflamed tissues in SjS are wrapped within a sheath of lymphocytes. However, controversy persists over which lymphocyte subtype initiates the process. Studies beginning in the 1980s focused upon disturbances in the T-cell compartment. SjS patients demonstrate a number of features that imply a greater role for T cells than B cells in the disease (Table 5.1). For example, T-cell infiltrates predominate within the salivary glands of SjS patients [6], have a restricted antigen repertoire, and display impaired proliferative capacity. Regulatory T cells (Treg cells) have been detected in salivary glands from SjS patients more recently [7]. Their presence correlates positively with lesion severity and negatively with their number in the blood [8]. However, the function of circulating Treg cells is believed to be normal in SjS [9]. In summary, one school of thought with regard to SjS pathogenesis holds that the influence of T cells is predominant, and the role of B lymphocytes is confined to antibody production.
Nonetheless, clinical and experimental evidence has sparked substantial interest in the possibility that B cells play critical roles in the pathogenesis of SjS. This greater appreciation of the importance of B cells does not necessarily imply that T cells are not also instrumental in SjS. Major breakthroughs in the understanding of B lymphocytes in health and disease are:
•The widespread availability of targeted recombinations in knock-out mice
•The dissection of B cell developmental stages [10]
•The profiling of B-cell-related gene expression using microarray technology [11]
•The dissection of candidate biomarkers by applying proteomic technologies [12]
•The discovery of two representatives of the tumor-necrosis factor (TNF) ligand family in the late 1990s [13]: A Proliferation-Inducing Ligand (APRIL), and the B-cell-Activating Factor (BAFF) of the TNF Family.
The clinical benefits obtained from the use of anti-B cell monoclonal antibodies have been ascribed to the purging of autoreactive B lymphocytes. It is conceivable that such autoreactive cells are the prime effectors in SjS, as it is known that T cells predominate in mild lesions but B cells become dominant in severe lesions [14].