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Fig. 10.8 Proposed mechanism for the role of antiidiotypic antibodies in CHB. a In CHB pathogenic maternal anti-La autoantibodies enter the fetal circulation via the placenta and bind to the La autoantigen exposed on the surface of apoptotic cardiomyocytes. b The presence of anti-idiotypic antibodies to autoantibodies against La/SSB can protect the fetus by blocking the entrance of pathogenic antibodies to its circulation
presence of anti-idiotypic antibodies to autoantibodies against La/SSB seems to protect the fetus, most probably by blocking the entrance of pathogenic maternal autoantibodies via the placenta (Fig. 10.8) [75].
10.4.2Early Epitope Recognition in Autoimmune Diseases and Epitope Spreading
Autoimmunity typically commences when tolerance to self-antigens is lost, a phenomenon that has fascinated immunologists for more than a century. During the past few decades, innovative methodologies for screening and analyzing cellular and biochemical processes have led
to an extensive body of literature that characterizes human autoimmune diseases on multiple levels. Nevertheless, the precise etiology of most human autoimmune diseases remains largely unexplained, and the initiating immunogens are unclear.
In SLE, the onset and progression of autoantibody development before clinical diagnosis have been studied. Using the US Department of Defense Serum Repository with over 30 million specimens prospectively collected from 5 million US Armed Forces personnel, Arbuckle et al. evaluated serum samples obtained from 130 persons before they received a diagnosis of SLE [76]. They found that in 115 of the 130 patients with SLE (88%), at least 1 SLE autoantibody tested was present before the diagnosis (up to 9.4 years earlier; mean, 3.3 years). ANA, APL, anti-Ro, and anti-La antibodies were present earlier than anti-Sm and anti-snRNP antibodies. Anti-dsDNA antibodies were found later than ANA and earlier than anti-snRNP antibodies. The earliest autoantibodies detected in the pre-clinical period, as individuals progressed toward clinical SLE, were antibodies to Ro60 (mean, 3.7 years before the disease onset).
McClain et al. mapped the initial, pre-disease target of the anti-Ro60 autoantibody response to the region, 169Ð180aa (TKYKQRNGWSHK), of the autoantigen [48]. This region belongs to the SLE-related 169Ð190aa epitope, previously identiÞed by Routsias et al. [47]. This 169Ð180aa epitope was found by McClain and co-workers to cross-react with a peptide (GGSGSGPRHRDGVRR, 58Ð72aa) from the latent viral protein EpsteinÐBarr virus nuclear antigen-1 (EBNA-1) [48]. Notably, no areas of primary sequence homology exist between EBNA-1 58Ð72aa and Ro169Ð180aa although these peptides have similar high isoelectric points (12.0 and 10.5, respectively). However, animals immunized with either the 169Ð180, epitope of Ro60 or the cross-reactive EBNA-1 epitope progressively developed autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens. These animals eventually developed some of the clinical symptoms of lupus, such as leukopenia, thrombocytopenia, or renal
10 B-cell Epitopes of Sjögren’s Syndrome-Related Autoantigens Ro/SSA and La/SSB |
143 |
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dysfunction. Although these experiments indicate a possible cross-reaction between the initial epitope of Ro60 and the 58Ð72aa region of EBNA-1, any involvement of EpsteinÐBarr virus in the pathogenesis of SLE has to be proved. In addition, other possible cross-reactions of Ro60 169Ð180aa epitope with various xenoantigens have to be studied (e.g., the Ro60 169Ð 176aa, TKYKQRNG, with that of L-polymerase 53Ð60aa, TKYKIRNG of human parainßuenza virus 1).
After the initial response against Ro60 autoantigen, autoantibody targets can be expanded to the whole Ro60 by a procedure known as epitope spreading. The term epitope spreading was introduced in the early 1990s to describe the ability of the B-cell and T-cell immune response to diversify, at the level of speciÞcity, from a single determinant to many sites on an autoantigen [77]. This process is not a feature restricted to systemic autoimmune diseases but is a common characteristic of the natural immune response mounted against some pathogens. Our studies with rabbit immunizations revealed that immunization with a single synthetic epitope of La/SSB produced epitope spreading to other B-cell epitopes of the molecule. Yiannaki et al. showed that immunization of rabbits with an antigenic peptide of La autoantigen led to antibodies to multiple epitopes of La [78]. These results demonstrate that loss of tolerance to a single antigenic determinant of the autoantigen can begin an autoimmune response that virtually recreates the humoral autoimmune speciÞcity seen in human SLE. Clues to the mechanisms involved in the aforementioned production of cross-reactive antibodies to the common spliceosomal proteins have been reported by Monneaux et al. [79, 80]. According to their model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar, and cytoplasmic antigens plays the role of a ÒdriverÓ epitope. Cross-reactive autoantibodies targeting this epitope have the potential to spread the autoimmune response to other RNA-binding proteins through molecular mimicry. Subsequently, intramolecular spreading to these speciÞc proteins can occur. This hypothesis is based on the
observation that this ÒdriverÓ epitope sequence in the RNP motif is recognized by CD4+ T cells from lupus mice and is often targeted by autoantibodies very early during the course of the disease [79, 81]. Remarkably, this sequence is present in components of Ro/La RNP, such as Ro60 (119Ð131aa), La (146Ð158aa), and nucleolin (346Ð358aa, 517Ð529aa) as well as in spliceosomal proteins, such as RNP70 (139Ð151aa) and RNP A (47Ð59aa, 239Ð251aa). Several other sequences might also be considered as important ÒinitiatorÓ sequences, e.g., the recurring proline-rich sequence, PPPGMRPP, present in several snRNPs or the dimethylargininemodiÞed CRG repeats present on the B, D1, and D3 autoantigens [82].
10.4.3Post-translational Modifications (PTMs) of B-cell Epitopes
The majority of mammalian proteins have PTMs, which potentially can be recognized by the immune system as self-neoepitopes. PTMs are either driven by enzymes or occur spontaneously, but the extent of protein modiÞcation varies in inßammatory and autoimmune disorders. These associations have been known for sometime, but their effects on disease etiology are still unclear. Two amino acid modiÞcations have been described as targets of systemic autoimmunity.
1.Arginine modifications. Arginine residues are susceptible to three forms of modiÞcation: methylation, deimination, and citrullination. Two of them have been correlated with systemic autoimmunity.
a.Dimethylation: The Sm proteins D1, D3, and B/B contain a C-terminal rich in argi-
nine and glycine residues that is conserved in most eukaryotic organisms. Studies using mass spectrometry and sequencing of the C terminus of these Sm proteins have shown that repeated RG dipeptide
regions in Sm D1 and Sm D3 and repeated GRG triplets in Sm B/B contain sym-
metric dimethylarginine residues [83, 84]. Dimethylation of arginine residues of the major Sm D1 and Sm D3 autoepitopes
144
remarkably increases binding by SLE autoantibodies. Moreover, a particular Sm D3 peptide represents a highly speciÞc substrate for detecting a subclass of anti-Sm antibodies by ELISA [85]. Thus, symmetrical dimethylarginine residues act as targets for autoantibodies in SLE. It was recently shown that the same autoantigens contain asymmetric dimethylarginine in addition to the already-reported symmetric dimethylarginine residues [86]. The effect of this modiÞcation in autoantibody binding has not been studied yet.
b.Citrullination: Removal of the imine group from an arginine residue produces cit-
rulline, which lacks the positive charge |
10.5 Summary and Future |
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of arginine. This reaction is catalyzed by |
Directions |
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the peptidylarginine deiminase (PAD) fam- |
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ily of enzymes. Citrulline has recently |
The extensive study of B-cell epitopes of intra- |
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attracted interest as an autoantibody target |
cellular autoantigens provides useful insights into |
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in RA [87]. One of the major autoanti- |
the diagnosis, classiÞcation, and prognosis of |
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gens |
in |
RA, Þlaggrin, |
is citrullinated |
autoimmune diseases. The successful develop- |
by PAD and provides several targets for |
ment of diagnostic assays is hindered by a num- |
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autoantibody binding. However, citrullina- |
ber of factors concerning epitope recognition in |
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tion of B-cell epitopes of Ro 60, span- |
autoimmune disorders, such as cross-reactivity, |
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ning the sequence 212Ð232aa, in the argi- |
epitope spreading, epitope masking, and epitope |
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nine residues, did not reveal alterations in |
modiÞcation. Issues regarding the simultaneous |
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antibody-binding capacity [88]. |
analysis of a large number of autoantibody speci- |
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2. Serine/Threonine Phosphorylation: Phospho- |
Þcities in a single test also have to be considered. |
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rylation is the most common and ubiqui- |
The analysis of B-cell epitopes of autoantigens |
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tous form of enzyme-mediated PTM. It has |
provides clues to overcome these problems. |
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been implicated in the recognition of nuclear |
1. Autoantibody screening test methodologies |
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autoantigens by the immune system in SLE. |
can be improved using large-scale arrays with |
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In fact, phosphorylated components of U1 |
speciÞc autoantigen epitopes. These arrays |
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snRNP particles are speciÞcally recognized |
are able to perform large-scale multiplex |
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by autoantibodies of SLE patients and CD4+ |
characterizations of autoantibody responses |
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T cells from lupus-prone mice (MRL/lpr |
against structurally diverse autoantigens [92]. |
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mice). |
La |
protein can be |
phosphorylated |
Chemical modiÞcations of autoepitopes can |
at position 366. La phosphorylated at ser- |
provide better antigenic substrates mimick- |
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ine 366 is nucleoplasmic and is associated |
ing naturally occurring PTMs. The lesson of |
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with nascent RNA polymerase III transcripts |
citrullinated peptides taught us that recom- |
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while non-phosphorylated La is cytoplasmic |
binant proteins are not always the preferred |
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and is associated with a subset of mRNAs |
substrate for autoantibody detection and that |
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that contain 5 -terminal oligopyrimidine (5 - |
synthetic peptides can be successfully used in |
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TOP) [89]. Thus, La exists in distinct states |
diagnostic assays if the exact structure of the |
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that differ in subcellular localization and is |
autoantibody target is known [3]. |
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associated with RNAs, which can be dis- |
2. Complementary peptides can efÞciently neu- |
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criminated |
by serine 366 |
phosphorylation. |
tralize anti-idiotypic antibodies, enhancing |
|
10 B-cell Epitopes of Sjögren’s Syndrome-Related Autoantigens Ro/SSA and La/SSB |
145 |
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the interaction of the idiotypic autoantibodies with their target epitope. The analysis of B-cell epitopes of autoantigens provides a better understanding of the origin and evolution of autoimmune response. In this regard, foreign epitopes, mimicking complementary epitopes or post-translationally modiÞed peptides, could be the initiating agents of autoimmune disease. In addition, the spreading of autoimmune response from the initial epitope to others can be utilized for monitoring the evolution of autoimmune disease. Finally, the analysis of B-cell epitopes of autoantigens can provide potential therapeutic regimens, using epitopes with high speciÞcity as vaccines, as tolerogens, or as modiÞers of the autoimmune response via the idiotypicÐ anti-idiotypic network.
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10 B-cell Epitopes of Sjögren’s Syndrome-Related Autoantigens Ro/SSA and La/SSB |
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Bozic B, Pruijn GJ, Rozman B, van Venrooij WJ. |
52-kd Ro(SS-A) antigen by sera from patients with |
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primary biliary cirrhosis and primary SjogrenÕs syn- |
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nize different epitope regions on the 52-kD Ro/SS- |
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Neurobiology and Hormonal |
11 |
Control of Lacrimal and Salivary |
Gland Function
Yrjö T. Konttinen, Alberto Vivó Porcar, Pauliina
Porola, Katja Koskenpato, María Lorés Rodriguez,
Raimo Pöllänen, Vasily Stegaev, Liisa Virkki,
Michelle Spaan, and Beata D. Przybyla
Abstract
SjšgrenÕs syndrome (SS) is characterized by diminished production of secretes from exocrine glands and sicca complex, which occur in an autoimmune context; 90% of patients are women, usually developing the disease when they are 40Ð50 years old. This characterization comprises several neuroimmunoendocrine aspects. The sympathetic, parasympathetic, vascular, acinar, and myoepithelial systems normally work in a co-ordinated fashion in two phases, resting and stimulated phases, corresponding to the secretion of resting and stimulated saliva. Stimulation of the exocrine ßow with acetylcholine is coupled with a proportional local release of acinotrophic vasoactive intestinal peptide (VIP) from post-ganglionic parasympathetic nerve terminals, which helps to recover and repair the acinar cell during the ÒrestingÓ (recovery) phase. Lost (dead and detached) acinar cells are replaced by remodeling based on an asymmetric division of the intercalated duct progenitor cells, which as a result are able to maintain their unipotent stemness and at the same time able to replace the lost acinar cells. This remodeling is maintained by dehydroepiandrosterone (DHEA) produced in the reticular zone of the endocrine adrenal gland in an endocrine process, but is locally in exocrine glands converted to dihydrotestosterone (DHT) in an intracrine process. SS is characterized by deranged intracrine enzymatic machinery and impaired DHEA-to-DHT conversion. This impairment leads particularly in women to acinar cell atrophy/loss and a reciprocal ductal cell hyperplasia. Men are protected because they feed the intracrine machinery also with testosterone, only one step away from DHT. Abnormally processed self antigens are released from dying
Y.T. Konttinen ( )
Department of Medicine, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki,
Finland; ORTON Orthopaedic Hospital of the ORTON Foundation, Helsinki, Finland; COXA Hospital
for the Joint Replacement, Tampere, Finland e-mail: yrjo.konttinen@helsinki.Þ
R.I. Fox, C.M. Fox (eds.), Sjögren’s Syndrome, DOI 10.1007/978-1-60327-957-4_11, |
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cells and break the immunologic tolerance so that autoantibodies are formed against previously hidden endotopes. Immune inßammation leads to synthesis and release of tumor necrosis factor-α, interleukin-1§, and other cytokines, which impair signal transduction in acinar cells and add to the burden of the inßammatory functio laesa.
Keywords
SjšgrenÕs syndrome ¥ Salivary glands ¥ Acinus ¥ Acetylcholine ¥ Neuropeptide ¥ DHEA ¥ Cytokines
11.1Introduction to Sjögren’s Syndrome
SjšgrenÕs syndrome (SS), originally mostly deÞned according to the Copenhagen criteria [1], is nowadays usually deÞned using the EuropeanÐ American inclusion and exclusion criteria and classiÞcation rules [2], although this praxis can in the clinical setting also be questioned [3]. Emphasis is on lacrimal and salivary gland dysfunction and mucosal membrane drying, which, however, must occur in an autoimmune setting. Half of the patients have circulating SS-A/Ro and/or SS-B/La autoantibodies, in the rest focal adenitis is often the clue. Basically all known causes for somewhat similar histopathology and/or clinical manifestations form exclusions, Òpseudo-SjšgrenÕs syndromes.Ó The ÒtrueÓ syndromes occur as Òprimary SjšgrenÕs syndromeÓ (pSS) or develop to complicate some underlying disease, like rheumatoid arthritis (Òsecondary SjšgrenÕs syndrome,Ó sSS). Because its cause and even pathomechanisms are largely unknown, creation of such relatively widely accepted diagnostic classiÞcation criteria can be considered as a major policy achievement. At the same time, these widely cited criteria represent nothing but our consensus what we believe, without actually knowing, is SS.
SS is also characterized by non-ocular and non-oral sicca symptoms, general symptoms, and visceral manifestations and complications, all nicely described in the so-called wheel
of Oxholm [4]. Apart from keratoconjunctivitis sicca and xerostomia, also nose, throat, vagina, and skin are dry. General symptoms comprise fatigue, often in patient-centered studies experienced as the most difÞcult individual disease manifestation, arthralgia/arthritis, myalgia/myositis, lymphadenopathy, and RaynaudÕs phenomenon. Internal organ changes include involvement of the central and peripheral nervous systems, thyroiditis, interstitial lung disease, chronic atrophic gastritis, celiac disease, primary biliary cirrhosis and other liver manifestations, interstitial nephritis, lymphocytic and collagen colitis, and interstitial cystitis. Complications include caries, candidiasis, middle ear infections, dry cough and bronchoconstriction, respiratory tract, and other infections associated with the sicca syndrome, congenital heart conduction abnormalities, and neonatal subacute lupus as a result of SS antibodies (transferred via the placenta from the mother to the developing fetus) and, last but not least, lymphoma associated with the B-cell hyperreactivity [5]. These lymphomas are usually extranodal, mucosal-associated lymphatic tissue tumors (MALTomas) [6, 7] often developing in pre-existing lymphocyte inÞltrates in lacrimal, salivary, or thyroid gland, interstitial lung tissue, or chronic atrophic gastritis lesions. They can present as Òpremalignant lesions,Ó myoepithelial sialadenitis (MESA) or lymphoepithelial sialadenitis (LESA), characterized by clustered B cells interdigitating with ductal epithelial cells, epimyoepithelial islands [8].