1. Introduction
Apoptosis, or programmed cell death, comes from a Greek term meaning “the falling off of the leaves.” Apoptosis is also known as cell suicide and is a mechanism that is present in most eukaryotic cells to regulate cell numbers. It can be considered as the opposite of mitosis. Apoptosis is a normal part of development and is required during development, creation of the central nervous system, degeneration of the tadpole tail during metamorphosis, and the loss of certain appendages during the larval to pupal metamorphosis in holometabolous insects.
Apoptosis is a major aspect of development and homeostasis. Apoptosis contributes to the sculpting of developing structures in vertebrate and invertebrate embryos. Deletion of interdigital webs in developing limbs (Hammar & Mottet, 1971), development of the fetal intestinal mucosa (Harmon et al., 1984), and retinal development (Penfold & Provis, 1986) all involve apoptosis. Apoptosis serves as a major mechanism for the regulation of cell numbers. For example, in the visual system of developing vertebrates, apoptosis preferentially eliminates neurons that form improper connections (Cowan et al., 1984). In the mammalian embryonic central nervous system, over 1/3 of newly formed cells die (Oppenheim et al., 1982) and during development of
During development, the survival of lymphocytes is mediated by both active signaling and passive processes that regulate survival. These processes are extremely selective resulting in the elimination of the majority of developing lymphocytes (Owen & Jenkinson, 1992). Both T- and B-lymphocytes undergo developmental stages and appear to share many regulatory mechanisms. For example, the early survival of lymphocyte precursors is mediated primarily by cytokines, which both regulate the numbers of progenitors and play critical roles in initiating the rearrangement of the antigen receptor genes (Baird et al., 1999). Developing lymphocytes must create unique antigen receptors by rearrangement to generate the incredible diversity characteristic of an adaptive immune response (Jung et al., 2006). A consequence of the stochastic nature of this process is that only 1/3 of rearrangements are joined appropriately and give rise to a functional antigen receptor (Jung et al., 2006). Although several mechanisms ( use of alternative antigen receptor gene loci and receptor editing) exist to allow further opportunities for successful rearrangement, the majority of lymphocytes fail to generate functional antigen receptors and are thus eliminated by programmed cell death (Berg & Kang, 2001; Nemazee, 2006).
2. Apoptosis and disease
The suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled apoptosis is associated with degenerative diseases. These include acquired immunodeficiency syndrome (AIDS; Ameison & Capron, 1991), cancer (Ling et al., 1993), Parkinson's disease (Walkinshaw & Waters, 1995), and Alzheimer's disease (Landfield et al., 1992). Abnormally elevated levels of apoptosis have been found in the lymph nodes of HIV-infected persons (Muro-Cacho et al., 1995). Indeed a clearer understanding of the regulation of apoptosis may result in better therapies.
In this chapter, we will examine how inappropriate or excessive apoptosis can lead to autoimmune disorders, such as type I diabetes, autoimmune thyroid disease, rheumatoid arthritis, lupus and others. Furthermore, we present data demonstrating that apoptosis-related treatments can be effective against various autoimmune disorders.
3. Type I Diabetes
Type I diabetes (T1D; also known as insulin-dependent or juvenile-onset diabetes) results from a presumed T-cell attack on the insulin-secreting β-cells of the pancreas. Controlled apoptotic cell death contributes to normal T-cell selection and education. Among the regulatory T-cells that actively suppress effector T-cells, the FOXP3+CD4+CD25high T-cells (Tregs) represent one of the best characterized sub-populations. There is accumulating evidence of a deficiency in either the frequency or function of Tregs in various human autoimmune diseases (Bacchetta et al., 2007), as well as in the pathogenesis of T1D (Brusko et al., 2005; Putnam et al., 2005). An increase in Treg apoptosis was found to correlate with a decline in suppressive potential of these cells. The fact that both hyperglycemic T1D subjects and normoglycemic
Therefore, interruption of normal T-cell selection can result in the generation of autoreactive cells (Takuma & Faustman, 2003). However, the mechanisms by which most candidate genes predispose to type 1 diabetes remain unclear. A recent study reports that
4. Autoimmune Thyroid Diseases
The Fas and TRAIL pathways are present and functional in the thyroid, and there is evidence suggesting their involvement in autoimmune diseases of the thyroid (Bretz et al., 1999; Kawakami et al 2000). Giordano et al. (1997) reported the constitutive expression of FasL (Fas ligand) on normal and Hashimoto's thyroiditis (HT) thyrocytes using immunohistochemistry, flow cytometry, and RT-PCR. The percentage of FasL-positive thyrocytes in Graves’ thyroid was less than in normal thyroids (Sera et al., 2000). In contrast, another study was unable to detect FasL in thyrocytes (Xerri et al., 1997).
Although it is widely accepted that thyrocytes express the death receptor Fas, little is known about how this expression is modulated. It has been demonstrated that there is increased expression of Fas in the thyrocytes of patients with Hashimoto’s thyroiditis (Hammond et al., 1997). Fas was also upregulated in the thyrocytes of patients with Graves’ disease (Sera et al., 2000). The thyroid gland of Graves’ disease patients contains TUNEL-positive thyrocytes and PCNA-positive thyrocytes, together with monocuclear cell infiltration (Sera et al., 2000). These data suggest that apoptosis and proliferation of thyrocytes may be abnormally accelerated, however, the proliferation of thyrocytes may outweigh their apoptosis, resulting in hyperplasia. IL-1β-treated thyrocytes become sensitive to apoptosis by anti-Fas IgM and activated T cells (Eguchi, 2001). Moreover, IL-1β-stimulated thyrocytes show reduced cytotoxic activity toward activated T cells. These results indicate that the IL-1β produced in the thyroid gland of Graves’ disease patients might act on the thyroctyes to reduce their resistance to Fas-mediated apoptosis and lose their cytotoxic activity against activated T-cells, thus abolishing the immune-privilege status of the thyroid (Eguchi, 2001). This may provide an explanation for the accumulation of activated T cells in the of Graves’ disease patients.
TSH receptor (TSHR) antibodies may be stimulating, blocking, or neutral in their functional influences and are found in patients with autoimmune thyroid disease, especially Graves’ disease (Morshed et al., 2010). Although neutral TSHR antibodies failed to generate cAMP via Gαs effectors, they initiated unique molecular signaling, possibly via recruitment of multiple G proteins (Laugwitz et al., 1996; Büch et al., 2008), and thus influenced multiple downstream signal transduction cascades including PKC/MAPK, mTOR/S6K, NF-κB, certain cytokines, and oxidative stress signaling and ultimately caused rat thyroid cell apoptosis on chronic exposure. These findings suggest that oxidative stress may play a significant role in such antibody-induced thyrocyte death and thus exacerbate the chronic inflammatory process via antigen-driven mechanisms seen in autoimmune thyroid disease.
Bcl-2 is mitochondiral protein that inhibits apoptosis (Park & Hockenbery, 1996). Increased serum Bcl-2 may be linked to accelerated apoptosis and was observed in patients with malignancies (Tas et al., 2006). In euthyroid Hashimoto’s thyroiditis patients compared with controls and euthyroid Graves’ disease, increased serum Bcl-2 has been reported (Myśliwiec et al., 2006). In a recent study, a tendency towards higher Bcl-2 in Hashimoto’s thyroiditis patients was found (Jiskra et al., 2009). Jiskra et al. (2009) further showed that there was no difference in serum Bcl-2 between hyperthyroid Graves’ disease and when the euthyroid state was achieved.
5. Systemic Lupus Erythematosus
A common feature of autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, and mixed connective tissue disease is the breakdown of tolerance of self antigens, a consequence of which is the production of antibodies reactive with multiple self proteins (von Mühlen & Tan, 1995). In patients with SLE, increased numbers of apoptotic lymphocytes and macrophages have been observed (Emlen et al., 1994). Other proteins have been implicated to play a contributing role in the pathogenesis of SLE. Protein phosphatase 2A (PP2A) is an abundant and ubiquitously expressed, highly conserved enzyme (Janssens et al., 2008). It regulates a variety of cellular processes, including cell cycle progression and cell division, cell death, cytoskeleton dynamics, and signaling pathways (Janssens & Goris, 2001; Sontag, 2001). PP2A is composed of a scaffold subunit (A), a catalytic subunit (C), and a regulatory (B) subunit. A recent study showed that the subunit Bβ is involved in the regulation of programmed cell death triggered by IL-2 deficiency and identified a subset of patients with SLE in which altered regulation of PP2A Bβ is associated with resistance to IL-2 deprivation-induced apoptosis (Crispín et al., 2011). Apoptosis is an essential phenomenon that modulates the duration of immune responses and maintains the diversity of the lymphoid armamentarium. The importance of this process is well known, and the deficiency of central molecules involved in lymphocyte apoptosis causes lymphoproliferative and autoimmune diseases in mice and humans (Turbyville & Rao, 2010; Cohen, 2006). Apoptosis induced by IL-2 deprivation is triggered by intrinsic cellular signals (Lenardo et al., 1999). The balance between anti- and pro-apoptotic Bcl-2 family proteins determines the maintenance of the mitochondrial membrane potential. In the presence of IL-2, Bad is phosphorylated and sequestered in the cytoplasm by 14-3-3 proteins (Zha et al., 1996; Pastorino et al., 1999). Bim, another pro-apoptotic molecule, is absent, and levels of anti-apoptotic Bcl-2 and Bcl-x are high. During IL-2 deprivation, Bad becomes dephosphorylated, dissociates from 14-3-3, and translocates to the mitochondrial membrane where it binds to Bcl-2 and Bcl-x and neutralizes their anti-apoptotic capacity (Zha et al., 1996; Yang et al., 1995). This process results in the loss of the mitochondrial membrane potential and leads to apoptosis. The regulation of T-cell death following activation is known to be altered in patients with SLE (Gergely et al., 2002; Xu et al., 2004). Recent results indicate that the kinetics of apoptosis following IL-2 deprivation is affected in a fraction of patients with SLE (Crispín et al., 2011). Importantly, induction of PP2A Bβ upon IL-2 withdrawal was suboptimal or completely absent in these patients, which confirms the importance of PP2A Bβ as a molecule induced in cytokine withdrawal apoptosis and suggests that its faulty expression may underlie the observed phenotype. Mitochondrial hyperpolarization (MHP) could also contribute to the apoptosis resistance observed in SLE patients upon IL-2 deprivation (Gergely et al., 2002; Fernandez et al., 2006).
6. Apoptosis in rheumatoid arthritis
Fas and FasL both exist in membrane (mFas, mFasL) and soluble (sFas, sFasL) forms, but only engagement of mFas leads to the activation of caspase-8 via the Fas-associated death domain protein (FADD; Okamoto et al., 2000). Activated caspase-8 may lead to apoptosis via at least two well-described pathways: direct activation of caspase-3; and alteration of mitochondrial transmembrane potentials via Bcl-2 homology 3 (BH3)-interacting death-domain agonist (BID), leading to the cytoplasmic translocation of cytochrome c, which leads to activation of caspase-9, which in turn activates caspase-3 (Peng, 2006). Both pathways are regulated at the level of caspase-8 activation by the endogenous inhibitor FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein (FLIP), which may also be recruited by FADD. Interestingly, FLIP may also participate in an alternate signalling pathway, recruiting tumour necrosis factor-associated factor (TRAF) 1, TRAF2, the MAP kinase kinase kinase Raf1 and receptor-interacting protein (RIP) to activate extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB) pathways, leading to proliferation and/or inflammation (Peng, 2006).
Apoptotic cells are uncommonly observed in rheumatoid arthritis (RA) tissues
7. Sjogren’s Syndrome
Sjogren’s syndrome (SS) is an autoimmune disorder that affects multiple exocrine glands, particular those that produce moisture to coat exposed epithelia such as the oral and ocular surfaces. The role of apoptosis in loss of glandular tissue in SS is less clear (Wang et al., 2006). Environmental and genetic factors appear to contribute to the etiology of SS, although the evidence is relatively premature (Bolstad & Jonsson, 2002; Yamamoto, 2003). T-cell-mediated cytotoxicity (Manganelli & Fietta, 2003; Hayashi et al., 2004) and autoantibodies are important in loss of gland function. There is also a failure to remove autoimmune T-cells at the level of thymic selection, resistance of T-cells within the gland to undergo apoptosis, aberrant expression of increased levels of cell adhesion molecules on glandular epithelial cells (facilitating infiltration of autoimmune lymphocytes to glands), up regulation of human leukocyte antigen (HLA)-DR, and polyclonal activation of B-lymphocytes (Rehman, 2003). Glandular epithelial cells contribute to the autoimmune process by secreting pro-inflammatory cytokines. Specifically, pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and 6 (Roescher et al., 2010) and (Muraki et al., 2004) in the exocrine glands in response to immune-mediated inflammation, are found over-expressed in the SS patients. IL-6, a potent inflammatory cytokine, is involved in acute phase reactions and both B and T-cell responses and the formation of germinal center-like structure (Roescher et al., 2010). It was found to be consistently high in saliva and serum and in the salivary glands of SS patients, not in subjects with xerostomia (dry mouth) only (Roescher et al., 2009). Furthermore, IL-1β is an effective inducer of other inflammatory cytokines such as IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor (Fibbe et al., 1989; Chrousos, 1995). Dry-eye disease is accompanied by an increase in the proinflammatory forms of IL-1 (IL-1 α and mature IL-1 β) and a decrease in the biologically inactive precursor IL-1 β in tear fluid of SS patients (Solomon et al., 2001).
Several studies have analyzed the role of the Fas/FasL system in salivary gland lesions of patients with SS. Bolstad et al. (2003) demonstrated a substantial increase in the salivary gland tissue expression of the negative regulator molecules PD-1 and CTLA-4 and the apoptotic signal molecules Fas and FasL in SS patients compared with controls, suggesting the involvement of the Fas/FasL system in the apoptosis of ductal and acinar epithelial cells. Abu-Helu et al. (2001) showed that salivary gland epithelial cell lines (SGEC) constitutively expressed more membranous Fas and intracellular FasL than controls, while Shibata et al. (2002) detected Fas/FasL expression in ductal and acinar cells of SS patients but not in controls. Other studies have suggested that Fas may accelerate the apoptotic death of peripheral CD4 T cells in SS patients (Zeher et al., 1999; Ohashi et al., 1996). However, Ohlsson et al. (2001) found Fas-induced epithelial cell apoptosis to be a rare event, with a frequency of less than 1% in salivary glands from 18 SS patients.
Loss of p53 activity allows the survival and proliferation of cells that should otherwise be eliminated. In primary SS, the expression of p53 and p21 was analyzed in salivary glands from 10 patients and 10 controls (Mariette et al., 2002). The p53 antigen was detected in the ductal cells of nine SS patients and only one control, and the p21 antigen in eight patients and two controls. Both antigens were located in the ductal cells of SS patients, but not in acinar cells. The expression of p53 and p21 in the ductal cells located around lymphoid infiltrates may represent a defense mechanism allowing DNA repair and thus preventing apoptosis, while the lack of over-expression of p53 and p21 in acinar cells could be one of the mechanisms responsible for acinar destruction by apoptosis in SS salivary glands.
Kong et al. (1997) demonstrated in SS that the expression of Bcl-2 makes them resistant to apoptotic cell death. Nakamura et al. (2000a) showed that Bcl-2 and Bcl-x were preferentially expressed in infiltrating mononuclear cells rather than in the acinar and ductal epithelial cells from salivary glands of 17 SS patients, while Ohlsson et al. (2002)detected Bcl-2 (but rarely Bax) in the infiltrating lymphocytes of salivary glands from SS patients. However, Abu-Helu et al. (2001) found that SGEC cell lines constitutively expressed antiapoptotic proteins, such as Bcl-2 and cFLIP, that might protect them from both spontaneous and anti-Fas mAb-mediated apoptosis. Kamachi et al. (2002) found an inhibitory effect of IFN-γ in Bcl-2 expression, which was enhanced by coadministration of TNFα, leading to an increase in the apoptosis of salivary gland cells. It seems that apoptosis of the epithelial acinar and ductal cells may depend on the imbalance between up-regulated death-promoters (Fas and Bax) and down-regulated apoptosis-suppressor signals (Bcl-2).
A stronger expression of activated caspase-3 and cleaved PARP in the acinar and ductal cells of salivary glands was found in 13/15 (87%) SS patients, while staining for activated caspase-9 was negative. Nakamura et al. (2000b) analyzed the role of the X chromosome-linked inhibitor of apoptosis (XIAP), a member of the IAP family that inhibits the activation of caspases, and found a strong expression in the acinar and ductal epithelial cells of SS patients but not in those of controls. Because caspase-3 and caspase-7 are effector enzymes, XIAP might protect salivary epithelial cells from apoptotic death in SS (Nakamura et al., 2000b). Hayashi et al. (2003) suggested that treatment with caspase inhibitors might prevent the development of the inflammatory process in salivary glands, and Inoue et al. (2001) found that caspase-inhibiting agents could inhibit the cleavage of α-fodrin. Increased caspase cascade activity may be involved in the progression of autoantigen proteolysis and tissue destruction in primary SS. The presence of activated caspase-3 in salivary glands indicates that excessive apoptosis may contribute to epithelial destruction in primary SS.
From the studies above, it can be concluded that the extrinsic apoptotic pathway as well as the intrinsic apoptotic pathway are involved in the pathogenesis of SS. FasL and its receptor, Fas, are essential in the homeostasis of the peripheral immune system. It can be considered that a defect in activation-induced cell death of effector T cells may result in the development of autoimmune exocrinopathy in Sjogren syndrome (Hayashi et al., 2004). Conversely, the increased rate of apoptosis of in epithelial cells in SS may result from either the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducer Bax, via the intrinsic pathway (Manganelli P & Fietta, 2003).
8. Apoptosis-related therapies for autoimmune disorders
Injection of high doses of soluble peptides leads to a state of T‑cell unresponsiveness (referred to as anergy) owing to a block in T‑cell proliferation and/or IL-2 production, or results in activation-induced cell death (AICD) after T-cell re‑stimulation with the cognate peptide (Burstein et al., 1992; Critchfield et al., 1994). It is thought that tolerance induced by soluble peptides may be useful for antigen-specific immunotherapy for the treatment of human autoimmune diseases. Non-obese diabetic (NOD) mice spontaneously develop type 1 diabetes, which is characterized by T‑cell-mediated inflammation of the pancreatic islets (insulitis) and the eventual destruction of the insulin-producing β‑cells7. Prevention of type 1 diabetes in NOD mice can be achieved by inducing specific T‑cell tolerance to pancreatic β‑cell autoantigens prior to the total destruction of all the islet β-cells (Miller et al., 2007).
One of the more promising methods to induce tolerance for the prevention and treatment of autoimmune diseases, and the prevention of transplant rejection, is intravenous treatment with antigen-coupled, ethylene carbodiimide (ECDI)-fixed splenocytes (referred to here as antigen coupled cells). Treatment with antigen-coupled cells can induce anergy
Zauli et al. (2010) showed that recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) ameliorated the severity of streptozotocin (STZ)-induced type 1 diabetes in a mouse model. Specifically, exogenous recombinant TRAIL, co-injected with STZ, significantly reduced the levels of islet damage with respect to animals injected with STZ alone (Zauli et al., 2010). Of note, treatment with recombinant TRAIL does not impair the viability of pancreatic islets, even when overexpressed (Dirice et al., 2009).
Thyroid arterial embolization was shown to effectively enhance the positive expression of pro-apoptotic genes of Fas, FasL, Bax, Bcl-2 and P53 in Grave’s disease (GD) thyroid, thus promoting apoptosis of GD thyroid and restoring the thyroid size and function to normal conditions (Zhao et al., 2009). Furthermore, T lymphocytes from GD patients treated with thyroid hormones accompany reduction of Bcl-2 protein expression, production of reactive oxygen species, and reduction of mitochondrial delta psi, resulting in apoptotic lymphocyte death (Mihara et al., 1999). In a study of patients with Hashimoto’s thyroiditis treated with Simvastatin, it was shown that CD4+ cells and B lymphocytes increased while CD8+ cells, natural killer cells, and activated T lymphocytes decreased significantly (Gullu et al., 2005). This effect is probably mediated via lymphocyte apoptosis as demonstrated with in vitro experiments and is not confined to Simvastatin since Mevastatin, Pravastatin and Cerivastatin also induced apoptosis in lymphocytes (Gullu et al., 2005). Thyroid cells can be sensitized to die via apoptosis by a unique combination of interferon-gamma and IL-1beta cytokines. Interferon-gamma/IL-1beta pretreatment sensitizes human thyroid cells to Fas-mediated apoptosis in a complex manner that overcomes the blockade of initiator caspases through increased expression of cell surface Fas receptor, increases in proapoptotic molecules that result in mitochondrial activation, and late caspase cleavage (Mezosi et al., 2005).
Lupus-prone (NZB x NZW)F1 mice spontaneously develop elevated titers of anti-DNA Abs that contain T cell determinants in their V(H) regions. It has been shown that tolerization with an artificial peptide based on these T cell determinants (pConsensus (pCons)) can block production of anti-DNA Abs and prolong survival of the mice (Singh et al., 1995). These data indicate that clinical suppression of autoimmunity after administration of pCons depends in part on the generation of CD8+ Ti cells that suppress secretion of anti-DNA Ig using mechanisms that include Foxp3, TGFβ, and resistance to apoptosis (Hahn et al., 2005). It is postulated that in the CD8+ Ti cells, secretion of TGFβ, expression of
The above studies strongly suggest that modulation of the Fas pathway may serve as attractive therapeutic targets. Many current RA therapies are in fact known to induce apoptosis in synovial cells, such as methotrexate and TNF-directed therapies, and appear to do so at least in part via Fas, at least in some pathogenic cell populations, such as T cells and/or synovial macrophages (Oshima et al., 2000; Genestier et al., 1998; Catrina et al., 2005). Thus, approaches targeted more specifically against Fas/FasL may be of benefit.
More direct evidence includes one study demonstrating the ability of anti-sense oligonucleotides against FLIP to sensitize RA synoviocytes strongly to Fas-induced apoptosis (Palao et al., 2005). Furthermore, in a model in which severe combined immunodeficient (
A recent study evaluated whether cholinergic autoantibodies contained in IgG purified from Sjogren sera could trigger apoptosis of A253 cell line (Reina et al., 2012). The use of A253 cell lines has revealed that salivary gland epithelial cells are particularly susceptible to Fas-mediated as well as Fas-independent apoptotic death after stimulation with IFN-γ, probably via the downregulation of the apoptosis inhibitor protein c-FLIP (Abu-Helu et al., 2001). Reina et al. (2012) demonstrated that anti-cholinergic autoantibodies in IgG purified from primary SS patient’s sera mediates apoptosis of the A253 cell line in an inositol phosphate, caspase-3 and metalloproteinase-3 dependent manner.
9. Summary
The research reviewed in this chapter clearly demonstrates that there is a delicate balance between death and survival signals in the pathogenesis of autoimmune disorders. The apoptotic pathways involved may be disease-specific or shared in common. Although the precise mechanisms by which apoptosis modulates autoimmune disorders in not fully understood, deciphering the role played by apoptosis in these disorders will lead to improved treatment modalities for patients.
Acknowledgement
This work was supported by a grant from the National Institute of General Medical Sciences (T34 GM 079079) to R.H.
References
- 1.
Abu-Helu RF, Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. Induction of salivary gland epithelial cell injury in Sjogren’s syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression. J Autoimmun.2001 17 141 153 - 2.
Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today.Ameison J. C. Capron A. 1991 12 102 105 - 3.
Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol.Bacchetta R. Gambineri E. Roncarolo M. G. 2007 120 227 235 - 4.
Baird AM, Gerstein RM, Berg LJ. The role of cytokine receptor signaling in lymphocyte development. Curr Opin Immunol.1999 11 157 166 - 5.
Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte-associated antigen 4, and programmed cell death 1 in primary Sjögren’s syndrome. Arthritis Rheum.Bolstad A. I. Eiken H. G. Rosenlund B. ME Alarcón-Riquelme Jonsson. R. 2003 48 174 185 - 6.
Genetic aspects of Sjögren’s syndrome. Arthritis Res.Bolstad A. I. Jonsson R. 2002 4 353 359 - 7.
Suppression of experimental autoimmune thyroiditis in guinea pigs by pretreatment with thyroglobulin-coupled spleen cells. Cell Immunol.Braley-Mullen H. Tompson J. G. Sharp G. C. Kyriakos M. 1980 51 408 413 - 8.
JD, Rymaszewski M, Arscott PL, Myc A, Ain KB, Thompson NW, Baker JR Jr. TRAIL death pathway expression and induction in thyroid follicular cells. J Biol Chem.JD Bretz Rymaszewski. M. Arscott P. L. Myc A. Ain K. B. Thompson N. W. Baker J. R. Jr death T. R. A. I. L. pathway expression. induction in. thyroid follicular. cells 1999 274 23627 23632 - 9.
Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes.2005 54 1407 1414 - 10.
G13-dependent activation of MAPK by thyrotropin. J Biol Chem.Büch T. R. Biebermann H. Kalwa H. Pinkenburg O. Hager D. Barth H. Aktories K. Breit A. Gudermann T. 2008 283 20330 20341 - 11.
Burstein HJ, Shea CM, Abbas AK. Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells. J Immunol.1992 148 3687 3691 - 12.
Deficient Fas ligand expression by synovial lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum.MJ Cantwell Hua. T. Zvaifler N. J. Kipps T. J. 1997 40 1644 1652 - 13.
Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum.Catrina A. I. Trollmo C. af Klint. E. Engstrom M. Lampa J. Hermansson Y. Klareskog L. Ulfgren A. K. 2005 52 61 72 - 14.
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med.1995 332 1351 1362 - 15.
Cohen PL. Apoptotic cell death and lupus. Springer Semin Immunopathol.2006 28 145 152 - 16.
Hum Mol Genet.Colli M. L. Moore F. Gurzov E. N. Ortis F. Eizirik D. L. M. D. A. P. T. P. N. two candidate. genes for. type . diabetes modify. pancreatic beta-cell. responses to. the viral. by-product double-stranded. R. N. A. 2010 19 135 146 - 17.
Cowan WM., Fawcett JW, O’Leary DDM, Stanfield BB. Regressive events in neurogenesis. Science1984 225 1258 1265 - 18.
Crispín JC, Apostolidis SA, Finnell MI, Tsokos GC. Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus. Proc Natl Acad Sci U S A.2011 108 12443 12448 - 19.
Science.Critchfield J. M. Racke M. K. Zúñiga-Pflücker J. C. Cannella B. Raine C. S. Goverman J. MJ Lenardo T. cell deletion. in high. antigen dose. therapy of. autoimmune encephalomyelitis. 1994 263 1139 1143 - 20.
Hum GeneT her.Dirice E. Sanlioglu A. D. Kahraman S. Ozturk S. Balci M. K. Omer A. Griffith T. S. Sanlioglu S. Adenovirus-mediated T. R. A. I. L. gene . Ad5h T. R. A. I. L. delivery into. pancreatic islets. prolongs normoglycemia. in streptozotocin-induced. diabetic rats. 2009 20 1177 1189 - 21.
T-cell protein tyrosine phosphatase is a key regulator in immune cell signaling: lessons from the knockout mouse model and implications in human disease. Immunol Rev.Doody K. M. Bourdeau A. Tremblay M. L. 2009 228 325 341 - 22.
Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C.elegans. Cell.1986 44 817 829 - 23.
Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol.Emlen W. Niebur J. Kadera R. 1994 152 3685 3692 - 24.
Apoptosis in autoimmune diseases. Intern Med.Eguchi K. 2001 40 275 284 - 25.
Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum.Fernandez D. Bonilla E. Mirza N. Niland B. Perl A. 2006 54 2983 2988 - 26.
Exp Hematol.Fibbe W. E. Daha M. R. Hiemstra P. S. Duinkerken N. Lurvink E. Ralph P. Altrock B. W. Kaushansky K. Willemze R. Falkenburg J. H. Interleukin . poly(r I).poly(r. C. induce production. of granulocyte. C. S. F. macrophage C. S. F. granulocyte-macrophage C. S. F. by human. endothelial cells. 1989 17 229 234 - 27.
Apoptosis in rheumatoid arthritis synovium. J Clin Invest.Firestein G. S. Yeo M. Zvaifler N. J. 1995 96 1631 1638 - 28.
Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest.Genestier L. Paillot R. Fournel S. Ferraro C. Miossec P. Revillard J. P. 1998 10 322 328 - 29.
Jr, Niland B, Gonchoroff N, Pullmann R Jr, Phillips PE, Perl A. Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus. J Immunol.Gergely P. Jr Niland B. Gonchoroff N. Pullmann R. Jr Phillips P. E. Perl A. Persistent mitochondrial. hyperpolarization increased. reactive oxygen. intermediate production. cytoplasmic alkalinization. characterize altered. I. L- signaling in. patients with. systemic lupus. erythematosus 2002 169 1092 1101 - 30.
Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science.Giordano C. Stassi G. De Maria R. Todaro M. Richiusa P. Papoff G. Ruberti G. Bagnasco M. Testi R. Galluzzo A. 1997 275 960 963 - 31.
In vivo and in vitro effects of statins on lymphocytes in patients with Hashimoto’s thyroiditis. Eur J Endocrinol.Gullu S. Emral R. Bastemir M. Parkes A. B. Lazarus J. H. 2005 153 41 48 - 32.
Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J Immunol.Hahn B. H. Singh R. P. La Cava A. Ebling F. M. 2005 175 7728 7737 - 33.
Hammar SP, Mottet NK. Tetrazolium salt and electronmicroscopic studies of cellular degeneration and necrosis in the interdigital areas of the developing chick limb. J Cell Sci.1971 8 229 251 - 34.
An ultrastructural study on the "meconium corpuscles" in rat foetal intestinal epithelium with particular reference to apoptosis. Anat Embryol.Harmon B. Bell L. Williams L. 1984 169 119 124 - 35.
Analysis of apoptosis in relation to tissue destruction associated with Hashimoto’s autoimmune thyroiditis. J Pathol.Hammond L. J. Lowdell M. W. Cerrano P. G. Goode A. W. Bottazzo G. F. Mirakian R. 1997 182 138 144 - 36.
Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum.Hasunuma T. Kayagaki N. Asahara H. Motokawa S. Kobata T. Yagita H. Aono H. Sumida T. Okumura K. Nishioka K. 1997 40 80 86 - 37.
Apoptosis and estrogen deficiency in primary Sjögren’s syndrome. Curr. Opin Rheumatol.Hayashi Y. Arakaki R. Ishimaru N. 2004 16 522 526 - 38.
Role of defective apoptosis in type 1 diabetes and other autoimmune diseases. Recent Prog Horm Res.Hayashi T. Faustman D. L. 2003 58 131 153 - 39.
The role of caspase cascade on the development of primary Sjögren’s syndrome. J Med Invest.Hayashi Y. Arakaki R. Ishimaru N. 2003 50 32 38 - 40.
Possible involvement of EBV-mediated alpha-fodrin cleavage for organ-specific autoantigen in Sjogren’s syndrome. J Immunol.Inoue H. Tsubota K. Ono M. Kizu Y. Mizuno F. Takada K. Yamada K. Yanagi K. Hayashi Y. Saito I. 2001 166 5801 5809 - 41.
PLoS One.Jailwala P. Waukau J. Glisic S. Jana S. Ehlenbach S. Hessner M. Alemzadeh R. Matsuyama S. Laud P. Wang X. Ghosh S. Apoptosis of. C. D. D25(high C. cells T. in type. . diabetes may. be partially. mediated by. I. L. deprivation P. Lo 2009 e6527. - 42.
Trends Biochem Sci.Janssens V. Longin S. Goris J. P. P. A. holoenzyme assembly. in cauda. venenum (the. sting is. in the. tail 2008 33 113 121 - 43.
Biochem J.Janssens V. Goris J. Protein phosphatase. . A. a. highly regulated. family of. serine/threonine phosphatases. implicated in. cell growth. signalling 2001 353 417 439 - 44.
The relationship between thyroid function, serum monokine induced by interferon gamma and soluble interleukin-2 receptor in thyroid autoimmune diseases. Clin Exp Immunol.Jiskra J. Antosová M. Límanová Z. Telicka Z. Lacinová Z. 2009 156 211 216 - 45.
Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor alpha and interferon gamma. J Lab Clin Med.Kamachi M. Kawakami A. Yamasaki S. Hida A. Nakashima T. Nakamura H. Ida H. Furuyama M. Nakashima K. Shibatomi K. Miyashita T. Migita K. Eguchi K. 2002 139 13 19 - 46.
Lab Invest.Kawakami A. Matsuoka N. Tsuboi M. Koji T. Urayama S. Sera N. Hida A. Usa T. Kimura H. Yokoyama N. Nakashima T. Ishikawa N. Ito K. Kawabe Y. Eguchi K. C. D. cell-mediated T. cytotoxicity toward. thyrocytes the. importance of. Fas Fas. ligand interaction. inducing apoptosis. of thyrocytes. the inhibitory. effect of. thyroid-stimulating hormone. 2000 80 471 484 - 47.
Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor beta 1. Arthritis Rheum.Kawakami A. Eguchi K. Matsuoka N. Tsuboi M. Kawabe Y. Aoyagi T. Nagataki S. 1996 39 1267 1276 - 48.
Differential regulation of Fas-mediated apoptosis of rheumatoid synoviocytes by tumor necrosis factor alpha and basic fibroblast growth factor is associated with the expression of apoptosis-related molecules. Arthritis Rheum.Kobayashi T. Okamoto K. Kobata T. Hasunuma T. Kato T. Hamada H. Nishioka K. 2000 43 1106 1114 - 49.
Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of apoptosis of rheumatoid synoviocytes but not chondrocytes. Gene Ther.Kobayashi T. Okamoto K. Kobata T. Hasunuma T. Kato T. Hamada H. Nishioka K. 2000 7 527 533 - 50.
Fas and Fas ligand expression in the salivary glands of patients with primary Sjögren’s syndrome. Arthritis Rheum.Kong L. Ogawa N. Nakabayashi T. Liu G. T. D’Souza E. Mc Guff H. S. Guerrero D. Talal N. Dang H. 1997 40 87 97 - 51.
Mechanisms of neuronal death in brain aging and Alzheimer’s disease; role of endocrine-mediated calcium dyshomeostasis. J Neurobiol.Landfield P. W. Thibault O. Mazzanti M. L. Porter N. M. DS Kerr 1992 23 1247 1260 - 52.
The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A.Laugwitz K. L. Allgeier A. Offermanns S. Spicher K. Van Sande J. Dumont J. E. Schultz G. 1996 93 116 120 - 53.
Annu Rev Immunol.Lenardo M. Chan K. M. Hornung F. Mc Farland H. Siegel R. Wang J. Zheng L. Mature T. lymphocyte apoptosis--immune. regulation in. a. dynamic unpredictable antigenic. environment 1999 17 221 253 - 54.
Apoptosis induced by anthracycline inLing Y. H. Waldemar P. Perez-Soler R. 388 parent and multidrug-resistant cells. Cancer Res.1993 - 55.
Apoptosis and Sjögren’s syndrome. Semin Arthritis Rheum.Manganelli P. Fietta P. 2003 33 49 65 - 56.
Antirheumatic effects of humanized anti-Fas monoclonal antibody in human rheumatoid arthritis/SCID mouse chimera. J Rheumatol.Matsuno H. Yudoh K. Nakazawa F. Sawai T. Uzuki M. Nishioka K. Yonehara S. Nakayama J. Ohtsuki M. Kimura T. 2002 29 1609 1614 - 57.
Rheumatology (Oxford).Mariette X. Sibilia J. Roux S. Meignin V. Janin A. A. new defensive. mechanism to. prevent apoptosis. in salivary. ductal cells. from patients. with Sjögren’s. syndrome over-expression. of p. p2 2002 41 96 99 - 58.
J Rheumatol.Matsuno H. Yudoh K. Watanabe Y. Nakazawa F. Aono H. Kimura T. Stromelysin P- . M. M. in synovial. fluid of. patients with. rheumatoid arthritis. has potential. to cleave. membrane bound. Fas ligand. 2001 28 22 28 - 59.
Does triptolide induce lysosomal-mediated apoptosis in human breast cancer cells? Med Hypotheses.ME Messina Jr Halaby. R. 2011 77 91 93 - 60.
Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells. Mol Endocrinol.Mezosi E. Wang S. H. Utsugi S. Bajnok L. JD Bretz Gauger. P. G. Thompson N. W. Baker J. R. Jr 2005 19 804 811 - 61.
Nitric oxide protects cultured rheumatoid synovial cells from Fas-induced apoptosis by inhibiting caspase-3. Immunology.Migita K. Yamasaki S. Kita M. Ida H. Shibatomi K. Kawakami A. Aoyagi T. Eguchi K. 2001 103 362 367 - 62.
Effects of thyroid hormones on apoptotic cell death of human lymphocytes. J Clin Endocrinol Metab.Mihara S. Suzuki N. Wakisaka S. Suzuki S. Sekita N. Yamamoto S. Saito N. Hoshino T. Sakane T. 1999 84 1378 1385 - 63.
Miller SD, Turley DM, Podojil JR. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol.2007 7 665 677 - 64.
Miller SD, Wetzig RP, Claman HN. The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells. J Exp Med.1979 149 758 773 - 65.
Diabetes.Moore F. Colli M. L. Cnop M. Esteve M. I. Cardozo A. K. Cunha D. A. Bugliani M. Marchetti P. Eizirik D. L. P. T. P. N. candidate a. gene for. type . diabetes modulates. interferon-gamma-induced pancreatic. beta-cell apoptosis. 2009 58 1283 1291 - 66.
Neutral antibodies to the TSH receptor are present in Graves’ disease and regulate selective signaling cascades. Endocrinology.Morshed S. A. Ando T. Latif R. Davies T. F. 2010 151 5537 5549 - 67.
Japanese patients with Sjögren’s syndrome and systemic lupus erythematosus. J Rheumatol.Muraki Y. Tsutsumi A. Takahashi R. Suzuki E. Hayashi T. Chino Y. Goto D. Matsumoto I. Murata H. Noguchi E. Sumida T. Polymorphisms of. I. L. beta gene. in Japanese. patients with. Sjögren’s syndrome. systemic lupus. erythematosus 2004 31 720 725 - 68.
Analysis of apoptosis in lymph nodes of HIV-infected persons. J Immunol.CA Muro-Cacho Pontaleo. G. AS Fauci 1995 154 5555 5556 - 69.
Adv Med Sci.Myśliwiec J. Okota M. Nikołajuk A. Górska M. Soluble Fas. Fas ligand. Bcl in autoimmune. thyroid diseases. relation to. humoral immune. response markers. 2006 51 119 122 - 70.
Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum.Nakajima T. Aono H. Hasunuma T. Yamamoto K. Shirai T. Hirohata K. Nishioka K. 1995 38 485 491 - 71.
Relationship between Sjögren’s syndrome and human T-lymphotropic virus type I infection: follow-up study of 83 patients. J Lab Clin Med.Nakamura H. Kawakami A. Tominaga M. Hida A. Yamasaki S. Migita K. Kawabe Y. Nakamura T. Eguchi K. 2000 135 139 144 - 72.
Expression and function of X chromosome-linked inhibitor of apoptosis protein in Sjögren’s syndrome. Lab Invest.Nakamura H. Kawakami A. Yamasaki S. Nakashima T. Kamachi M. Migita K. Kawabe Y. Nakamura T. Koji T. Hayashi Y. Eguchi K. 2000 80 1421 1427 - 73.
Arthritis Rheum.Ohashi H. Ogawa N. Goto Y. Karahashi T. Akamine N. Elevated Fas. . C. D9 bcl protein expression. on T. cells from. patients with. primary Sjogren’s. syndrome 1996 S288. - 74.
Scand J Immunol.Ohlsson M. Szodoray P. Loro L. L. Johannessen A. C. Jonsson R. C. D4 D15 C. Bax Bcl expression in. Sjögren’s syndrome. salivary glands. a. putative anti-apoptotic. role during. its effector. phases 2002 56 561 71 - 75.
Fas-induced apoptosis is a rare event in Sjögren’s syndrome. Lab Invest.Ohlsson M. Skarstein K. Bolstad A. I. Johannessen A. C. Jonsson R. 2001 81 95 105 - 76.
Tumour necrosis factor alpha (TNF-alpha) interferes with Fas-mediated apoptotic cell death on rheumatoid arthritis (RA) synovial cells: a possible mechanism of rheumatoid synovial hyperplasia and a clinical benefit of anti-TNF-alpha therapy for RA. Cytokine.Ohshima S. Mima T. Sasai M. Nishioka K. Shimizu M. Murata N. Yoshikawa H. Nakanishi K. Suemura M. Mc Closkey R. V. Kishimoto T. Saeki Y. 2000 12 281 288 - 77.
Fas-associated death domain protein is a Fas-mediated apoptosis modulator in synoviocytes. Rheumatology (Oxford).Okamoto K. Kobayashi T. Kobata T. Hasunuma T. Kato T. Sumida T. Nishioka K. 2000 39 471 480 - 78.
Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer. Gene Ther.Okamoto K. Asahara H. Kobayashi T. Matsuno H. Hasunuma T. Kobata T. Sumida T. Nishioka K. 1998 5 331 338 - 79.
Oppenheim RW, Maderdrut JL, Wells DJ. Cell death of motoneurons in the chick embryo spinal cord. VI. Reduction of naturally occurring cell death in the thoracolumbar column of Terni by nerve growth factor. J Comp Neurol.1982 210 174 189 - 80.
Owen JJ, Jenkinson EJ. Apoptosis and T-cell repertoire selection in the thymus. Ann NY Acad Sci.1992 663 305 310 - 81.
Park JR, Hockenbery DM. BCL-2, a novel regulator of apoptosis. J Cell Biochem.1996 60 12 17 - 82.
Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. J Biol Chem.Pastorino J. G. Tafani M. Farber J. L. 1999 274 19411 19416 - 83.
An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nat Immunol.Pedotti R. Mitchell D. Wedemeyer J. Karpuj M. Chabas D. Hattab E. M. Tsai M. Galli S. J. Steinman L. 2001 2 216 222 - 84.
Penfold PL, Provis JM. Cell death in the development of the human retina: phagocytosis of pyknotic and apoptotic bodies by retinal cells. Graefe’s Arch Clin Exp Opthalmol.1986 224 549 553 - 85.
Peng SL. Fas (CD95)-related apoptosis and rheumatoid arthritis. Rheumatology (Oxford).2006 Jan;45 1 26 30 - 86.
Programmed cell death in the Mullerian duct induced by Mullerian inhibiting substance. Am J Anat.Price J. M. Donahoe P. K. Ito Y. Hendren W. H. 3rd 1977 149 353 375 - 87.
J Autoimmun.Putnam A. L. Vendrame F. Dotta F. Gottlieb P. A. C. D. D25high C. regulatory T. cells in. human autoimmune. diabetes 2005 24 55 62 - 88. Rehman HU. Sjögren’s syndrome. Yonsei Med J. 2003;44:947-954.
- 89.
Cell Immunol.Reina S. Sterin-Borda L. Borda E. Anti-M( peptide Ig. G. from Sjögren’s. syndrome triggers. apoptosis in. A2 cells 2012 Apr 3. [Epub ahead of print] - 90.
Cytokines in Sjogren’s syndrome: potential therapeutic targets. Ann Rheum Dis.Roescher N. Tak P. P. Illei G. G. 2010 69 945 948 - 91.
Cytokines in Sjögren’s syndrome. Oral Dis.Roescher N. Tak P. P. Illei G. G. 2009 15 519 526 - 92.
J Clin Invest.Salmon M. Scheel-Toellner D. Huissoon A. P. Pilling D. Shamsadeen N. Hyde H. D’Angeac A. D. Bacon P. A. Emery P. Akbar A. N. Inhibition of. T. cell apoptosis. in the. rheumatoid synovium. 1997 99 439 446 - 93.
Diabetes.Santin I. Moore F. Colli M. L. Gurzov E. N. Marselli L. Marchetti P. Eizirik D. L. P. T. P. N. candidate a. gene for. type . diabetes modulates. pancreatic β-cell. apoptosis via. regulation of. the B. H3-only protein. Bim 2011 60 3279 88 - 94.
Clin Exp Immunol.Sera N. Kawakami A. Nakashima T. Nakamura H. Imaizumi M. Koji T. Abe Y. Usa T. Tominaga T. Ejima E. Ashizawa K. Yokoyama N. Ishikawa N. Ito K. Eguchi K. Fas Fas. L. mediated apoptosis. of thyrocytes. in Graves’. disease 2001 124 197 207 - 95.
Involvement of Fas/Fas ligand in the induction of apoptosis in chronic sialadenitis of minor salivary glands including Sjögren’s syndrome. Hum Cell.Shibata Y. Hishikawa Y. Izumi S. Fujita S. Yamaguchi A. Koji T. 2002 15 52 60 - 96.
Singh RR, Ebling FM, Sercarz EE, Hahn BH. Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus. J Clin Invest.1995 96 2990 2996 - 97.
Smith CE, Eagar TN, Strominger JL, Miller SD. Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A.2005 102 9595 9600 - 98.
Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. NatureCA Smith Williams. G. T. Kingston R. Jenkinson S. J. Owen J. J. T. 1989 337 181 184 - 99.
Cell Signal.Sontag E. Protein phosphatase. . A. the Trojan. Horse of. cellular signaling. 2001 13 7 16 - 100.
Serum vascular endothelial growth factor (VEGF) and bcl-2 levels in advanced stage non-small cell lung cancer. Cancer Invest.Tas F. Duranyildiz D. Oguz H. Camlica H. Yasasever V. Topuz E. 2006 24 576 580 - 101.
Fas antigen expression on synovial cells was down-regulated by interleukin 1 beta. Biochem Biophys Res Commun.Tsuboi M. Eguchi K. Kawakami A. Matsuoka N. Kawabe Y. Aoyagi T. Maeda K. Nagataki S. 1996 218 280 285 - 102.
Turbyville JC, Rao VK. The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance. Autoimmun Rev.2010 9 488 493 - 103.
von Mühlen CA, Tan EM. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum.1995 24 323 358 - 104.
Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson’s disease. J Clin Invest.Walkinshaw G. Waters C. M. 1995 95 2458 2464 - 105.
Detectionof cleaved alpha-fodrin autoantigen in Sjögren’s syndrome: apoptosis and co-localisation of cleaved alpha-fodrin with activated caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) in labial salivary glands. Arch Oral Biol.Wang Y. AS Virji Howard. P. Sayani Y. Zhang J. Achu P. Mc Arthur C. 2006 51 558 566 - 106.
Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol.Xerri L. Devilard E. Hassoun J. Mawas C. Birg F. 1997 50 87 91 - 107.
Nat Med.Xu L. Zhang L. Yi Y. Kang H. K. Datta S. K. Human lupus. T. cells resist. inactivation escape death. by upregulating. C. O. X- 2004 10 411 415 - 108.
Yamamoto K. 2003 Pathogenesis of Sjögren’s syndrome. Autoimmun Rev. 2003;2 13 18 - 109.
Cell.Yang E. Zha J. Jockel J. Boise L. H. Thompson C. B. Korsmeyer S. J. Bad a. heterodimeric partner. for-X Bcl. L. Bcl- displaces Bax. promotes cell. death 1995 80 285 291 - 110.
Treatment with recombinant tumor necrosis factor-related apoptosis-inducing ligand alleviates the severity of streptozotocin-induced diabetes. Diabetes.Zauli G. Toffoli B. di Iasio M. G. Celeghini C. Fabris B. Secchiero P. 2010 59 1261 1265 - 111.
Correlation of increased susceptibility to apoptosis of CD4+ T cells with lymphocyte activation and activity of disease in patients with primary Sjögren’s syndrome. Arthritis Rheum.Zeher M. Szodoray P. Gyimesi E. Szondy Z. 1999 42 1673 1681 - 112.
Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell.Zha J. Harada H. Yang E. Jockel J. Korsmeyer S. J. 1996 87 619 628 - 113.
Apoptotic study in Graves disease treated with thyroid arterial embolization. Endocr J.Zhao W. Gao B. L. Yi G. F. Jin C. Z. Yang H. Y. Shen L. J. Tian M. Yu Y. Z. Li H. Song D. P. 2009 56 201 211