Identification of α-fodrin as a candidate autoantigen in primary Sjögren's syndrome.

Haneji, Norio; Nakamura, Takanori; Takio, Koji; Yanagi, Kumiko; Higashiyama, Hiroyuki; Noji, Sumihare; Sugino, Hiromu; Hayashi, Y

doi:10.1016/s0002-9394(14)70890-6

Cited by 139 publications

(253 citation statements)

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“…The remaining 10 patients produced insufficient saliva for analysis by the described methods. This finding supports evidence from previous studies that the cleaved 120 kDa α-fodrinautoantigen detected in saliva is related to the level of apoptotic cell death and grade of disease in the salivary glands, and as such, this autoantigen, not the autoantibody, may be a useful marker of cell damage [5,7,8,10]. As expected, and shown by multiple previous studies, the autoantibodies against the cleaved α-fodrinfragment are of low diagnostic sensitivity, although, in support of our mechanistic immunologic hypothesis, all patients who produced a positive IgG or IgA autoantibody, also demonstrated the presence of the autoantigen in the salivary tissues by immunohistochemistry [19].…”

Section: Discussionsupporting

confidence: 91%

“…Sjögren syndrome is an autoimmune disease, producing a range of autoantibodiesand cytokines leading to apoptosis of salivary and lacrimal tissues [1][2][3][4][5]. Current diagnostic tests are unable to render a specific diagnosis of SS and thus there is a need for improved diagnostic tools.…”

Section: Introductionmentioning

confidence: 99%

“…The membrane-associated cytoskeleton protein fodrin (also known as non-erythroidspectrin) consists of α-and β-subunits of which the α-subunit is highly conserved and is 90% identical among species [5].The function of fodrin is to provide internal structural support to the lipid bilayer of the cell membrane. Proteolysis of fodrin by caspases during apoptosis isinduced by a variety of stimuli and cytokines, notably tumor necrosis factor α (TNF-α) [11].Apoptotic cleavage of the 240 kDafodrin at several sites can result in the generation of a 150 kDa amino terminal, a 120 kDacarboxy terminal, and a 35 kDa fragment during TNF-α induced apoptosis [4,10,12].In studies reported using the NFS/ sld mouse model of SS, the purified 120 kDa fragment α-fodrin antigen was shown to induce proliferative T cell responses and the production of interleukin-2 and interferon-γ (IFN-γ) in vitro [4].…”

Section: Introductionmentioning

confidence: 99%

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A-fodrinAutoantigen Detection in Saliva and on Salivary Ductal Cells in Sjögren Syndrome

McArthur¹

2016

J. Dent. Sci. Ther

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Background: Sjögren syndrome (SS) is an autoimmune exocrinopathy in which patients produce autoantibodies against the antigen α-fodrin. In the murine model the antigen that elicits the antibody response is a 120 kDacleaved α-fodrin fragment. In a human salivary gland (HSG) ductal cell in vitro model the α-chain of the protein fodrin is cleaved following TNF-induced apoptosis to yield a cleaved product. Cleaved α-fodrin is presented on the cell surface suggesting a mechanism for antigen recognition in vivo as well as a potential antigen of value in diagnosis. The objective of this study was to test the hypothesis that cleaved α-fodrin is expressed in minor salivary gland biopsies and saliva in vivo.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A-fodrinAutoantigen Detection in Saliva and on Salivary Ductal Cells in Sjögren Syndrome

McArthur¹

2016

J. Dent. Sci. Ther

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“…This chronic inflammatory process leads to diminished function of the glands resulting in symptoms of xerophthalmia (dry eyes) or xerostomia (dry mouth). B cell hyper-activation is a predominant feature of SS, which in human patients is characterized by hypergammaglobulinemia and production of autoantibodies [3][4][5][6][7]. The occurrence of SS-A/Ro and SS-B/La, the two most commonly detected autoantibodies in SS patients, has been directly associated with recurrent lymphocyte infiltration of the exocrine glands, tissue damage and secretory dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome

et al. 2008

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CD40L and B lymphocyte‐activating factor (BAFF), members of the TNF superfamily, play critical roles in B cell survival and activation, and in the regulation of humoral immunity. We previously reported that the adaptor molecule Act1 functions as a negative regulator of CD40‐ and BAFF‐mediated B cell survival. Here we demonstrated that mice deficient in Act1 developed systemic autoimmune disease with histological and serological features of human Sjögren's syndrome (SS), in association with systemic lupus erythematosus‐like nephritis. Analyses of Act1−/−CD40−/− and Act1−/−BAFF−/− double‐deficient mice revealed that Act1 regulates different stages of the disease development through its impact on both CD40‐ and BAFF‐mediated pathways. We found that Act1 modulates the survival of autoreactive B cells mainly through its negative regulatory role in BAFF‐mediated cell survival, while the effect of Act1 on autoantibody production is likely through modulation of CD40‐mediated T cell‐dependent antibody response. The impact of Act1 on both BAFF and CD40 pathways establishes Act1‐deficient mice as a unique model to study distinct steps of autoimmunity and regulation of self tolerance.

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“…However, in another report promiscuously expressed genes colocalizing in clusters in functionally mature mTEC appear both Aire dependent and Aire independent [27], suggesting an epigenetic mechanism awaiting its molecular explanation. Recently, in a third independent Aire -/-mouse line, the development of autoantibodies against the salivary gland autoantigen a-fodrin [28], first identified in patients with Sjögren's syndrome was reported [29]. However, the a-fodrin transcript was normally expressed in mTEC from Aire-deficient thymi, suggesting that Aire participates in additional tolerance mechanisms independent of ectopic thymic expression of self antigens [28].…”

mentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Identification of α-fodrin as a candidate autoantigen in primary Sjögren's syndrome.

Cited by 139 publications

References 0 publications

A-fodrinAutoantigen Detection in Saliva and on Salivary Ductal Cells in Sjögren Syndrome

A-fodrinAutoantigen Detection in Saliva and on Salivary Ductal Cells in Sjögren Syndrome

Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

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