Objective. Treatment with rituximab depletes B cells from the peripheral blood (PB) and salivary glands (SGs) of patients with primary Sjögren's syndrome (SS). The purpose of this study was to track the repopulation of B cell subsets in PB as well as their subsequent homing into SGs in patients with primary SS treated with rituximab.Methods. A series of 4-color flow cytometry experiments delineated B cell subsets in 15 patients with primary SS. All were tested on days 8 and 15 of treatment. Nine of the patients were followed up monthly for 10 months, and the remaining 6 patients were followed up monthly for 24 months. Enzyme-linked immunosorbent assays were developed to measure serum levels of BAFF and rituximab. SGs were biopsied at the start of the study and 4 months after treatment in 15 patients, 12 months after treatment in 3 patients, and 24 months after treatment in 2 patients.Results. Baseline serum levels of BAFF correlated inversely (r ‫؍‬ ؊0.92, P < 5 ؋ 10 ؊4 ) with the duration of B cell depletion: the higher the BAFF levels, the shorter the duration of B cell depletion. Conclusion. The timing of B cell repopulation is modulated by BAFF and is followed by reconstitution of the preexisting abnormalities.

The pathogenic role of antiendothelial cell antibodies (AECA) remains unclear. They are frequently associated with antibodies to anionic phospholipids (PL), such as phosphatidylserine (PS), which is difficult to reconcile with the distribution of PL molecular species within the plasma membrane. Since it is already known that PS is transferred to the outer face of the membrane as a preclude to apoptosis, the possibility exists that apoptosis is initiated by AECA. AECA-positive/anti-PL antibody-negative sera from eight patients with systemic sclerosis (SS) and 21 control patients were evaluated. Endothelial cells (EC) were incubated with AECA and the exposure of PS was established through the binding of annexin V. Hypoploid cell enumeration, DNA fragmentation, and optical and ultrastructural analyses of EC were used to confirm apoptosis. Incubation of EC with AECA derived from six of eight patients with SS led to the expression of PS on the surface of the cells. This phenomenon was significantly more frequent in SS ( P Ͻ 0.04) than in control diseases. The redistribution of plasma membrane PS preceded other events associated with apoptosis: hypoploidy, DNA fragmentation, and morphology characteristic for apoptosis. Apoptosis-inducing AECA did not recognize the Fas receptor. We conclude that AECA may be pathogenic by inducing apoptosis. (

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IntroductionHuman T-lymphotropic virus-1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). 1,2 Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (ACs), the lifetime cumulative risk of developing ATL or HAM/ TSP is Ͻ 5%. HTLV-1-provirus integrates into the genome of infected cells, predominantly CD4 ϩ CD25 ϩ T lymphocytes, which represent the main reservoir in peripheral blood. 3 HAM/TSP, a central nervous system neuroinflammatory disease, is associated with perivascular and parenchymal infiltration of HTLV-1-infected T cells and activated cytotoxic T lymphocytes (CTLs). 4 A major determinant of HAM/TSP development is the HTLV-1-infected cell burden. The peripheral blood HTLV-1-proviral load is higher in HAM/TSP patients than AC. 5,6 Follow-up studies of HAM/TSP cohorts showed that high provirus loads were associated with rapid disease progression. [7][8][9] Those studies also demonstrated a relative stability of the HTLV-1-proviral load throughout the disease. Set-point provirus load and subsequent HAM/TSP risk are influenced by the cellular immune-response efficiency, 10 although excessive activation of HTLV-1-specific CTLs might become deleterious and contribute to central nervous system tissue damage. 4 Host-pathogen interplay is characterized by very dynamic kinetics, resulting in an equilibrium between the virus-driven clonal expansion of infected T cells 11 and tight control exerted by the immune response. 10 Tax, a transactivator protein encoded by the pX region of the HTLV-1 genome, plays a central role in disease pathogenesis. Tax activates viral transcription and also modulates many cellular signaling pathways involved in T cell activation, cycling, apoptosis or a combination. 12 Tax expression is promitotic and drives CD4 ϩ T-cell proliferation. 13 At the same time, Tax is the immunodominant target recognized by the CTL response. 14 Rapid immune elimination of Tax-expressing cells may explain the poor detection of Tax-gene products (ie, mRNA or protein) in freshly isolated peripheral blood mononuclear cells (PBMCs) from infected patients. 15-18 Short-term culture enables Tax detection and ex vivo conditions might allow Tax-expressing cells to escape immune selective pressure. 19 The current model of HTLV-1 accumulation and persistence supposes 2 steps: first, Tax expression propels CD4 ϩ T cells into cell cycling, which is well documented; and second, silencing of virus expression allows escape from immune surveillance, which remains to be elucidated. Epigenetic mechanisms might participate in silencing of HTLV-1 gene transcription. 20 Use of histone deacetylase (HDAC) inhibitors, such as valproate (2-npropylpentanoic acid, VPA), was postulated to transiently activate virus expression and thereby expose the latent virus reservoir to immune destruction. 21,22 Another avenue of research focuses on negative posttranscriptional regulators of virus expression, eg, pX-encoded Rex and p30 II...

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