Mechanisms of autoantibody production and the relationship between autoantibodies and the clinical manifestations in Sjögren’s syndrome

doi:10.1016/j.trsl.2006.07.003

Translational Research

Volume 148, Issue 6, December 2006, Pages 281-288

https://doi.org/10.1016/j.trsl.2006.07.003 Get rights and content

The major target organs of Sjögren’s syndrome (SS) are lacrimal glands and salivary glands where prominent lymphocytic infiltration occurs, which may induce varying levels of autoantibody production. Multiple factors, including environmental stress, viral infection, hormonal imbalance, and apoptosis, are thought to be involved in the pathogenesis of SS. Production of anti-SS-A/Ro and anti-SS-B/La antibodies is thought to be regulated by the presentation of autoantigens in context with an aberrant expression pattern of human leukocyte antigen (HLA) in situ. Molecular mimicry with some viral sequences is also hypothesized. The apoptosis-resistance phenotype of B cells in labial salivary glands (LSGs) of SS is important in autoantibody production. CD40/CD40L (CD40 ligand) and Bcl-2 family proteins, in tandem with B cell-activating factor (BAFF), are supposed to protect infiltrating lymphocytes from apoptosis. Anti-muscarinic3 receptor antibody plays an important role in cholinergic hyperresponsiveness in SS. Fragmentation of autoantigens such as SS-B/La or alfa-fodrin during the process of apoptosis causes the redistribution of these autoantigens, leading to the production of autoantibodies in SS. In this review, the role of autoantibodies found in SS, corresponding to clinical aspects of each antibody as well as the mechanisms of production, is discussed.

Section snippets

Anti-SS-A/Ro and anti-SS-B/La autoantibodies in SS

Anti-SS-A/Ro antibody and anti-SS-B/La antibody are well-known autoantibodies usually detected by an ELISA in the sera of the patients with SS. Franceschini et al¹⁶ have reported that some techniques exist to detect these autoantibodies. One of these techniques, the RNA precipitation assay, has the highest sensitivity and specificity and is usually considered to be the reference method. They have also reported that CIE is the most reliable method for routinely detecting anti-Ro/SS-A antibodies,

ACA in SS

The ACA has also been reported as an autoantibody found in SS. Hsu et al³⁴ recently reported that 17 of 62 (27.4%) sera of primary SS patients are positive for ACA and anti-CENP-H antibodies (Table I). Interestingly, sera from SS patients with anti-CENP-H and ACA antibodies do not contain anti-SS-A/Ro or anti-SS-B/La antibodies, suggesting that SS can be serologically divided into two groups in which the groups have anti-SS-A/SS-B antibodies or ACA/anti-CENP-H antibody. The data support the

Anti-alpha-fodrin antibodies in the pathogenesis of SS

Haneji et al³⁷ identified 120-kd alpha-fodrin as an organ-specific autoantigen from the salivary gland of NFS/sld mouse, a model mouse of human SS (Table I). An in vitro experiment demonstrated that purified alpha-fodrin antigen could induce proliferative T cell responses as well as production of IL-2 and IFN-gamma. As sera from patients with SS reacted with purified or recombinant human alpha-fodrin protein, alpha-fodrin appears to be crucial to the development of primary SS. Yanagi et al³⁸

Anti-type M3R autoantibodies in SS

Bacman et al⁴⁴ initially reported that when using a 25-mer peptide corresponding to the extracellular domain of human M3R, anti-M3R autoantibodies can be detected by ELISA in sera from SS patients with dry eye (Table I). They reported that anti-M3R autoantibodies can serve as a new marker distinguishing SS from nonSS dry eye. Regarding LSG of SS, Beroukas et al⁴⁵ detected granular staining of M3R using an affinity-purified polyclonal antibody raised against the C-terminal sequence of human M3R,

Other autoantibodies detected in SS

Except for the above autoantibodies, some other autoantibodies have been reported. With regard to RF, Markusse et al⁵⁰ reported that IgA-RF was locally produced in salivary gland and measurement of IgA-RF and IgM-RF was useful as diagnosis for primary SS. Atkinson et al⁵¹ also reported that salivary flow rate was inversely correlated with serum IgA-RF concentration. Molnar et al⁵² reported the presence of anti-thyroid antibodies. They measured some of anti-thyroid antibodies in patients with

Conclusions and future directions

SS is a multifactorial disorder that can be induced by environmental stress, stimulation of autoantigens, and hormonal responses. However, the primary pathogenesis of SS remains unclear. In this article, the possible autoantigens related to the pathogenesis of SS were reviewed. The correlation of the autoantigen-antibody system in SS is illustrated in Fig 1. Newly suggested autoantigens were also included, such as alpha-fodrin and M3R. As autoantigens, some parts of components of viruses or

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The initial phase of the human T cell leukemia virus-1 (HTLV-1) infection of salivary gland epithelial cells (SGECs) was examined. SGECs of patients with Sjögren’s syndrome (SS) and non-SS subjects were co-cultured with the HTLV-1-infected cell line HCT-5 or MOLT-4, then immunofluorescence (IF), scanning and transmission electron microscopy (SEM/TEM) were employed.
The extracellular matrix and linker proteins galectin-3, agrin, and tetherin were expressed on the surfaces of both HCT-5 and MOLT-4 cells. HTLV-1 Gag-positive spots were observed on adjacent SGECs after 1 h of co-culture with HCT-5. Both in subjects with and those without SS, agrin and tetherin were co-expressed with HTLV-1 Gag on SGECs after co-culture with HCT-5, although no polarization of HTLV-1 Gag and relevant molecules was observed. SEM showed HTLV-1 virions that were found on HCT-5 were observed in the interfaces between HCT-5 cells and SGECs. TEM imaging showed that HTLV-1 virions were transmitted to SGECs at the interface with thin film-like structure, while HTLV-1 virions were released from the surface of HCT-5 cells. No endogenous retroviruses were observed. These results showed that the initial phase of HTLV-1 infection toward SGECs of SS was mediated not by viral synapses, but by biofilm-like components.
Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjögren's syndrome
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It is necessary to conduct further research using objective indicators of salivary gland function. HTLV-1 has been reported to be involved in the pathogenesis of pSS in endemic areas, including Nagasaki city in Japan, one of the districts in which the present study was conducted [34–36]. However, the associations between HTLV-1 infection and pulmonary involvement in patients with SS are still unknown.
Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjögren's syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjögren's syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases.
We performed a retrospective cohort study of patients with primary Sjögren's syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjögren's syndrome with initial HRCT examinations were enrolled.
Higher age, dry mouth, and higher labial gland biopsy focus scores (≥4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026–1.102, OR 8.795 CI 2.317–33.378 and OR 3.261 CI 1.100–9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (≥4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032–1.127, OR 12.178 CI 1.121–132.307 and OR 3.954 CI 1.423–10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases.
This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjögren's syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjögren's syndrome.
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These autoantibodies target nuclear or cytoplasmic antigens, cell membrane, phospholipid-associated antigens, plasma or matrix proteins, neural, blood or endothelial cells, and other miscellaneous targets [12,18]. Although the causes of autoantibody production are not entirely understood, mosaic of multiple factors, including infection, exposure to toxic chemicals, hormonal imbalance, and genetic predisposition combined with environmental triggers (adjuvants, medicines etc.) are thought to be involved in autoantibody production [12,19]. Previous research has suggested that the activation of B cells and the lack of clearance of apoptotic cells containing self-antigens play a key role in autoantibody production [20,21].
The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100 years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression. The idea that autoantibodies are directly involved in tumour progression gains special support by the findings that some antibodies secreted by a variety of cancer cells can promote their proliferation and metastasis. Because the cancer cells generate cell antigenic changes (neoantigens), which trigger the immune system to produce autoantibodies, serum autoantibodies against tumour-associated antigens have been established as a novel type of cancer biomarkers and have been extensively studied in different types of cancer. The autoantibodies as biomarkers in cancer diagnosis are not only more sensitive and specific than antigens, but also could appear before clinical evidences of the tumours, thus disclosing them. The observations that cancer risk is lower in patients with some autoimmune diseases suggest that certain autoantibodies may be protective from certain cancers. Moreover, the presence of autoantibodies in healthy individuals implies that it could be safe to employ autoantibodies to treat cancer. Of note, an autoantibodies derived from lupus murine model received much attention due to their selective cytotoxicity for malignant tumour cell without harming normal ones. These studies showed the therapeutic value of autoantibodies in cancer. In this review, we revisited the pathological or protective role of autoantibodies in cancer progression, summarize the application of autoantibodies in cancer diagnosis and prognosis, and discuss the value of autoantibodies in cancer therapy. The studies established to date suggest that autoantibodies not only regulate cancer progression but also promise to be valuable instruments in oncological diagnosis and therapy.
The Pathophysiology of Dry Eye Disease: What We Know and Future Directions for Research
2017, Ophthalmology
Citation Excerpt :
The hallmarks of SS are lymphocytic infiltration of the lacrimal and salivary glands, serum autoantibodies, keratoconjunctivitis sicca, and dry mouth.134 Mouse models of SS and aging have identified a pathogenic role for CD4+T98,132,135–137 and B cells.138–141 Mouse SS models that develop dacryoadenitis tend to be Th1 skewed,142–146 whereas those that develop sialadenitis are Th17 skewed.147–150
Clinical and laboratory studies performed over the past few decades have discovered that dry eye is a chronic inflammatory disease that can be initiated by numerous extrinsic or intrinsic factors that promote an unstable and hyperosmolar tear film. These changes in tear composition, in some cases combined with systemic factors, lead to an inflammatory cycle that causes ocular surface epithelial disease and neural stimulation. Acute desiccation activates stress signaling pathways in the ocular surface epithelium and resident immune cells. This triggers production of innate inflammatory mediators that stimulate the production of matrix metalloprotease, inflammatory cell recruitment, and dendritic cell maturation. These mediators, combined with exposure of autoantigens, can lead to an adaptive T cell–mediated response. Cornea barrier disruption develops by protease-mediated lysis of epithelial tight junctions, leading to accelerated cell death; desquamation; an irregular, poorly lubricated cornea surface; and exposure and sensitization of epithelial nociceptors. Conjunctival goblet cell dysfunction and death are promoted by the T helper 1 cytokine interferon gamma. These epithelial changes further destabilize the tear film, amplify inflammation, and create a vicious cycle. Cyclosporine and lifitegrast, the 2 US Food and Drug Administration–approved therapies, inhibit T-cell activation and cytokine production. Although these therapies represent a major advance in dry eye therapy, they are not effective in improving discomfort and corneal epithelial disease in all patients. Preclinical studies have identified other potential therapeutic targets, biomarkers, and strategies to bolster endogenous immunoregulatory pathways. These discoveries will, it is hoped, lead to further advances in diagnostic classification and treatment.
Degradation of proteoglycan 4/lubricin by cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's syndrome
2017, Experimental Eye Research
Citation Excerpt :
The associated reduction in tear volume causes an increase in tear osmolarity that alters the phenotype of the ocular surface epithelium to generate a series of inflammatory cytokines and effectors including interleukin-1-alpha, interleukin-1-beta, tumor necrosis factor alpha and matrix metalloproteinase-9 (MMP-9) (Baudouin et al., 2016; De Paiva et al., 2006). Inflammatory activation in these glands leads to the expression of autoantigens at the surface of epithelial cells (Nakamura et al., 2006) and an accumulation of CD4+ and CD8+ T-cells (Hayashi et al., 2003) in the conjunctiva and stroma. Reduced lacrimal secretion also alters the mechanical environment of the ocular surface.
Sjögren's syndrome (SS) is an autoimmune disease affecting the lacrimal and salivary glands with hallmark clinical symptoms of dry eye and dry mouth. Recently, markedly increased cathepsin S (CTSS) activity has been observed in the tears of SS patients. Proteoglycan 4 (PRG4), also known as lubricin, is an effective boundary lubricant that is naturally present on the ocular surface. While PRG4 is susceptible to proteolytic digestion, the potential effect of CTSS on PRG4 remains unknown. The objective of this study was to assess the ability of CTSS to enzymatically degrade purified PRG4, and PRG4 naturally present in human tears, and alter ocular surface boundary lubricating properties. To assess the potential time course and dose-dependency of PRG4 digestion by CTSS, full-length recombinant human PRG4 (rhPRG4) was incubated at 37 °C with or without CTSS in an enzymatic digestion buffer. Digestion of PRG4 by CTSS was also examined within normal human tear samples, both with and without supplementation by rhPRG4. Finally, digestion of endogenous PRG4 by CTSS, and the effect of a CTSS inhibitor, was examined in SS tears on Schirmer strips. Digestion products were separated on 3–8% SDS-PAGE and visualized by protein staining and western blotting. The boundary lubricating ability of rhPRG4 samples was assessed using an in vitro human eyelid-cornea friction test. Finally, SDS-PAGE protein stain bands resulting from rhPRG4 digestion were submitted for tandem mass spectrometry analysis to confirm their identity as PRG4 and identify non-tryptic cleavage sites. CTSS digested rhPRG4 in a time and dose dependent manner. CTSS digestion of rhPRG4 at 1% (where % is the mass ratio of CTSS to rhPRG4) resulted in a time dependent decrease in the full-length, ∼460 kDa, monomeric rhPRG4 band, and an appearance of lower MW fragments. After 20 h, no full-length rhPRG4 was observed. Furthermore, with an increased relative enzyme concentration of 3%, no protein bands were observed after 2 h, indicating complete digestion of rhPRG4. Western blotting demonstrated PRG4 is present in normal human tears, and that rhPRG4, tears, and tears supplemented with rhPRG4 incubated with 3–9% CTSS demonstrated decreased intensity of high MW PRG4 bands, indicative of partial degradation by CTSS. Similarly, western blotting of PRG4 in SS tears incubated with CTSS demonstrated decreased intensity of high MW PRG4 bands, which was reversed in the presence of the CTSS inhibitor. CTSS treatment of rhPRG4 resulted in an increased friction coefficient, compared to untreated controls. Lastly, the lower MW bands were confirmed to be PRG4 fragments by tandem mass spectrometry, and 6 non-tryptic cleavage sites were identified. rhPRG4 is susceptible to proteolytic digestion by CTSS, both alone and in human tears, which results in diminished ocular surface boundary lubricating ability. Moreover, endogenous PRG4 is susceptible to proteolytic digestion by CTSS, both in normal and SS tears. Given the elevated activity of CTSS in SS tears, and the role intact PRG4 plays in ocular surface health and lubrication, degradation of PRG4 by CTSS is a potential mechanism for diminished ocular surface lubrication in SS. Collectively these results suggest that tear supplementation of PRG4 may be beneficial for SS patients.
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2023, Journal of Clinical Medicine

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Review articleMechanisms of autoantibody production and the relationship between autoantibodies and the clinical manifestations in Sjögren’s syndrome

Section snippets

Anti-SS-A/Ro and anti-SS-B/La autoantibodies in SS

ACA in SS

Anti-alpha-fodrin antibodies in the pathogenesis of SS

Anti-type M3R autoantibodies in SS

Other autoantibodies detected in SS

Conclusions and future directions

Lancet

Lancet

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Am J Pathol

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Expression of CD40/CD40 ligand and Bcl-2 family proteins in labial salivary glands of patients with Sjögren’s syndrome

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Review article
Mechanisms of autoantibody production and the relationship between autoantibodies and the clinical manifestations in Sjögren’s syndrome