Current Pharmaceutical Biotechnology - Volume 13, Issue 10, 2012

Many important clinical questions concerning primary Sjogren's syndrome (pSS) remain, that can only be adequately addressed by prospective cohorts. Thus, a better knowledge of the clinical outcome, the course of disease activity and the risk factors of lymphoma requires the setting up of cohorts with biobanks. The homogeneous collection of clinical data, disease activity, patient-related outcome, and biological samples, including DNA, RNA and serum, is definitively mandatory to determine new biological prognostic factors and identify disease activity markers. Three large prospective cohorts have already started to enroll patients with pSS. This will be highly invaluable for scientists and clinicians to gain a better insight into the pathogenesis of pSS, as well as to identify prognostic markers and new therapeutic targets.

Sjogren's syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands. SS particularly affects the lacrimal and salivary glands. Dry mouth and dry eyes are frequently proffered as presenting symptoms, but nonspecific symptoms such as malaise and fatigue, and extraglandular manifestations like purpura, polyneuropathy and arthritis are also often present. Moreover, lymphomas develop in about 7.5% of SS patients, mostly marginal zone B-cell lymhomas. Futhermore, SS has a very substantial impact on the patients' quality of life and their daily activities. Recently, many breakthroughs have been seen in salivary diagnostics, which not only can be used for diagnosis but also for monitoring of disease activity and disease progression as well as for objectively scoring the effect of intervention treatment with biologicals. In addition, salivary proteomics, genomics and system biology have been shown to be very promising tools in unravelling the pathophysiology of SS, thus providing in depth insight in its underlying mechanisms which could give clues for intervention therapies with biologicals. The latter is of particular interest as B cell depletion therapy has been shown a very promising therapy for a subgroup of SS patients. When applying salivary diagnostics in combination with instruments to rate disease activity and progression in SS, one might be able to select those SS patients who respond to a particular type of biological. These topics are addressed in this review and promises for the near future are described.

There is growing evidence that epigenetics, the study of heritable changes in gene expression that do not involve mutations in the DNA itself, may play an essential role in autoimmune diseases (AID). In Sjogren's syndrome (SS), a chronic AID characterized by an epithelis of the exocrine glands, epigenetic studies have focused on three mechanisms: DNA methylation and its consequences including human endogenous retrovirus (HERV) expression; microRNA expression; and protein post-translational modifications associated with autoantibody production. Although in its infancy, comprehension of the epigenetic (dys)regulation in SS may help us to understand: why SS affects predominantly middle-aged women; why genetically predisposed individuals develop SS but not others; why flare-ups occur; why treatment responses differ between patients; and why some patients develop lymphoma. From these studies will arise a better comprehension of the pathophysiology of SS as well as development of new diagnostic and prognostic biomarkers, and novel therapeutics for prevention and perhaps early intervention.

Patients with primary Sjogren's syndrome (pSS) have an activated type I interferon (IFN) system that contribute to the etiopathogenesis and clinical manifestations of the disease. The type I IFN system consists of the stimuli for type I IFN production, the receptors, cells and transcription factors involved in the synthesis of type I IFNs, the type I IFN-receptor and the effects on target cells. Increased type I IFN activity has been demonstrated in sera from patients with pSS and IFN-α, the main type I IFN, has been detected in the minor salivary glands. Gene expression profiling of peripheral blood mononuclear cells (PBMCs) and minor salivary glands from pSS patients display an up-regulation of type I IFN-induced genes, an “IFN signature”. The professional IFN-α producing plasmacytoid dendritic cell (pDC) shows a reduced frequency in the peripheral blood, but has been detected in the salivary glands, possibly due to tissue recruitment. Polymorphisms in the interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) genes in the type I IFN system, are associated with increased risk for pSS. A postulated disease model is that an initial viral infection induces type I IFN production in the salivary glands with subsequent activation of the adaptive immune system resulting in the production of autoantibodies against the RNA-binding proteins SSA/SSB/RNP. Interferogenic immune complexes are formed, which trigger the pDCs to an ongoing type I IFN production, which sustain the disease process. Potential therapeutic targets can be identified within the type I IFN system.

Sjogren's syndrome is a systemic autoimmune condition centred around salivary gland dysfunction and atrophy. There are a plethora of antibodies that mark the decline of the salivary glands, most of which relate to apoptopic mediated destruction of acinar cells. The best known of these autoantibodies, anti-Ro and anti-La form part of the diagnostic criteria for the condition. An emerging viewpoint in recent years is that glandular dysfunction precedes rather than follows glandular atrophy and attention has shifted to the interface between the immune system and the secretory process. An autoantibody against the muscarinic type 3 acetylcholine receptor occupies precisely this position because it inhibits the acetylcholine receptor which controls salivary and lacrimal fluid secretion. The consequence of identifying an autoantibody that can cause rather than simply reflect the disease process are manifold and could have a huge impact on development of therapeutic treatments. Furthermore, a “functional” autoantibody directed against an important component of the autonomic nervous system could also account for some of the extraglandular features of Sjogren's syndrome.

T cells have originally occupied central stage of the debate on the type of lymphocytes governing the pathogenesis of Sjogren's syndrome (SS). However, B cells has since been substituted for T cells, and insights into their functions have revealed that they accomplish various tasks. Beyond the paradigm that T lymphocytes maintain strict control over B lymphocytes, these latter cells solicit their own help from the former, release a flurry of cytokines, and act as antigen- presenting cells. In SS, excessive of the B cell-activating factor (BAFF) may cause B-cell quantitative anomalies, such as inflation of mature B (Bm)2/Bm2' cells in the circulation, or accumulation of transitional type 2, marginal zone (MZ) and memory B cells within the exocrine gland infiltrates. These excesses are also associated with B-cell qualitative anomalies, such as the internal synthesis of BAFF, and a default mechanism that promotes the autoantibody production in ectopic germinal centers or MZ equivalents. Thus, SS should rather be conceived as a quintessential model for B cellinduced autoimmunity. Such a view opens novel prospects for treatment, and indeed B cell-ablative therapy has already been shown to be beneficial to these patients.

The strategy for a comparability assessment is developed on a hierarchical risk-based approach. Critical analysis of physicochemical and biological characterization assays is essential for the development of a good comparability protocol. Therefore, selection and sensitivity of these assays is very important. This article discusses a case study to evaluate the sensitivity of various methods in a comparability assessment of three lots of an IgG1 monoclonal antibody (mAb). Analysis with eighteen methods demonstrated that only six of the methods were sensitive enough to show a measurable difference of comparability under accelerated conditions (40°C). Samples stored at 4°C were found to be comparable by all methods. A brief comparison of the results of biochemical and functional assays with biophysical analysis is discussed. Basic principles, applications, strength, and limitations of different biophysical methods are also discussed here.