Subgroups of Sjögren syndrome patients according to serological profiles
Introduction
Sjögren Syndrome (SS) is a systemic autoimmune disease primarily affecting the exocrine glands. It is clinically characterized by dry eyes (keratoconjuctivitis sicca) and dry mouth (xerostomia), but extraglandular manifestations, such as cutaneous vasculitis, Raynaud phenomenon, arthritis, liver, lung, kidney and rarely peripheral nerve involvement can also develop [1]. The disorder occurs either in a primary form or in association to other autoimmune conditions, more commonly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). SS is relatively common, with a prevalence in the range of 0.1–4.8%, depending on the population examined and the classification criteria used [1]. It affects mostly women, with a 9:1 female to male ratio. The histopathological hallmark of the disease is a progressive periductal lymphocytic infiltration of salivary and lacrimal glands, consisting primarily of T-lymphocytes with a CD4+ cell predominance [1]. Even though the disorder generally follows a mild course, an increased risk for lymphoproliferative disease has been well established among SS patients, with a standardised incidence ratio for non Hodgkin lymphoma of 15.57 (95% Confidence interval: 7.77–27.85) [2]. Palpable purpura, parotid enlargement, low C4 at first visit, neutropenia, cryoglobulinemia, splenomegaly and lymphadenopathy are among the factors that have been associated with an increased risk for lymphoma development [3].
Autoantibodies are of cardinal significance in many autoimmune conditions, usually serving as biomarkers for disease classification and diagnosis, while in some cases their role in the pathogenesis of autoimmune disorders can also be supported. Sjögren syndrome is characterized by a variety of autontibodies, both organ specific and non-specific. The anti-SSA/Ro and anti-SSB/La antibodies are considered typical among them and have been included in the American-European Consensus Group classification criteria [4]. Other autoantibodies encountered in SS patients comprise anti nuclear antibodies (ANA), rheumatoid factor (RF), cryoglobulins and the less typical anti-mitochondrial antibodies (AMA), anti-centromere antibodies (ACA), anti-smooth muscle antibodies (ASMA), anti-Sm, anti-ribonucleoprotein (anti-RNP), antibodies against cyclic citrullinated peptides (anti-CCP) and anti-parietal cell antibodies [5]. In addition, autoantibodies not currently used in the everyday clinical practice such as anti-carbonic anhydrase, anti-alpha fodrin and anti-muscarinic receptor antibodies have been the subject of intense research in SS patients [6]. In the present work we review the existing literature regarding autoantibodies in primary Sjögren Syndrome (pSS) and attempt to characterize pSS patients according to their serological profile. The distinction of patients into subtypes based on the clinical manifestations associated with different antibody reactivities is, of course, schematic. However, a sound knowledge of these associations, as summarized in Table 1, can prove important for the better management of SS (Tables 2 and 3).
Section snippets
Structure and function of the Ro/La complex
Anti-Ro/SSA and anti-La/SSB antibodies are directed against ribonucleoprotein complexes, comprising any of four related small uridine-rich hY RNAs (human cYtoplasmic RNAs) non-covalently associated with at least three proteins, the Ro 52 kDa, the Ro 60 kDa and the La protein [6]. Two additional protein molecules, calreticulin and nucleolin also form constituents of this complex [6]. The localization of the complex is mainly cytoplasmic. Upon assembly in the nucleus the Ro/La RNP is rapidly
Antinuclear antibodies, rheumatoid factor: antibodies associated with younger age, extraglandular manifestations and an active immunological profile
Anti-nuclear antibodies detected by indirect immunofluoresence on HEp-2 cells have been found positive in 59–85% of pSS patients [5], [21], [22], [23], [24], [25]. In a cohort of 445 pSS patients from France, 316 (71%) had ANA at diagnosis (mean dilution 1/2000). Another 31 patients (7%) become ANA positive during follow-up, while in 21 cases ANA disappeared [23], [24]. In another study from Sweden, 62% of the ANA positive pSS patients presented a nuclear fine speckled pattern, 16% displayed a
Cryoglobulins: immunoglobulins that typify Sjögren syndrome patients at a higher risk for lymphoma development and death
Cryoglobulins are immunoglobulins that undergo reversible precipitation at temperatures below 37 °C and resolubilise on warming. Cryoglobulinaemia is classified as type I when caused by a monoclonal immunoglobulin. Mixed cryoglobulinaemia represents 80% of cases and is caused by an IgM, or less commonly an IgG or IgA, immunoglobulin with RF properties, which is either monoclonal (in type II cryoglobulinaemia) or polyclonal (in type III cryoglobulinaemia) and forms complexes with the Fc portion
Anti-cyclic citrullinated peptide antibodies: antibodies possibly defining a subset of Sjögren syndrome patients with articular manifestations
Anti-cyclic citrullinated peptide antibodies are considered specific markers for the diagnosis of RA. Recently, their frequency and clinical significance has been investigated in cohorts of pSS patients. The prevalence of anti-CCP antibodies in pSS, as determined by means of an ELISA assay, ranges from 3 to 10% [51], [52], [53], [54], [55]. The results of Gottenberg et al. and Tobon et al. converge on the conclusion that anti-CCP positive pSS patients did not differ significantly from the
Anti-mitochondrial antibodies: antibodies specific to Sjögren syndrome patients with primary biliary cirrhosis
Anti-mitochondrial antibodies (AMA) were first described by Mackay in 1958 [57] and are considered the serological hallmark of primary biliary cirrhosis (PBC). Indirect immunofluorescence (IIF), complement fixation, immunodiffusion, radioimmunoassay (RIA), ELISA, immunoblotting (IB) and functional assays are among the techniques used for their laboratory detection. In comparison to IIF, ELISA has a slightly better sensitivity but lower specificity [58]. Based on differentially centrifuged
Anti-smooth muscle antibodies/anti-liver kidney microsomal antibodies: antibodies characterizing a subset of Sjögren syndrome patients prone to develop autoimmune hepatitis
Anti-smooth muscle antibodies (ASMA) and ANA are considered the hallmark of type-1 autoimmune hepatitis, while antibodies to a liver kidney microsomal constituent (anti-LKM) characterize patients with type 2 autoimmune hepatitis [72]. It has been shown that the main, although not exclusive target antigen of ASMA is filamentous (F) actin, while anti-LKM1 antibodies are directed against cytochrome P450 IID6 (CYP2D6) [72]. Both antibodies can be detected by means of IIF [72].
The prevalence of
Anti-centromere antibodies: antibodies associated with a clinical phenotype overlapping between Sjögren syndrome and systemic sclerosis
Anti-centromere antibodies (ACA) are usually detected by means of IIF and are considered highly specific for the subset of patients with limited cutaneous systemic sclerosis (lcSSc). The centromere proteins CENP-A (17 kDa), CENP-B (80 kDa) and CENP-C (140 kDa) have been identified as the major antigenic targets of ACA in patients with SSc, although sera from a small percentage of ACA positive patients recognize other proteins, such as the 50 kDa CENP-D, the 312 kDa CENP-E, the 400 kDa CENP-F,
Antibodies against carbonic anhydrase: functional antibodies possibly associated with renal tubular acidosis
Carbonic anhydrase is a zinc containing metalloenzyme, important for the regulation of acid base equilibrium. It is widely distributed in mammalian tissues. Up to now a total of 13 active isoenzymes of carbonic anhydrase have been described in mammals [90]. Autoantibodies against the carbonic anhydrase isoenzyme II (anti-CAII) have been detected in the serum of patients with several autoimmune conditions, such as SLE, SS, SSc, dermatomyositis [91], RA [92], PBC [93], autoimmune cholangiitis [94]
Anti-muscarinic receptor antibodies: functional antibodies detected by functional assays and associated with particular disease manifestations but not with disease subgroups
Muscarinic receptors (MRs) are acetylcholine receptors coupled to G-proteins; they can be detected in plasma membranes of certain neuronal and non-neuronal cells [100]. Acetylcholine released from postganglionic fibers in the parasympathetic nervous system stimulates MRs to express a certain function in the target [101]. Their higher sensitivity to muscarin- a toxin produced by amanita muscaris- rather than nicotine, lent these receptors their name. While the nicotinic receptors on the
Other autoantibodies in SS of uncertain pathological significance and poor performance in predicting disease subgroups
Antibodies to alpha and beta fodrin, to islet cell autoantigen, to poly(ADP) polymerase to nuclear mitotic apparatus (NuMA), to golgins, to lipoactin and to 90 kDa nucleolar organizer region protein (reviewed in Routsias et al., [6]). The methods for their detection, their prevalence in large patient cohorts and their performance in predicting disease subgroups or particular disease characteristics have not been validated. Their pathologic significance is uncertain.
Summary
Sjögren syndrome is a systemic autoimmune exocrinopathy characterized by the presence of a variety of autoantibodies. Most typical among them are the ones directed against the Ro/La ribonucleoprotein complexes, which form part of the recently proposed American-European Consensus Group classification criteria. Primary Sjögren syndrome patients positive for anti-Ro/SSA and anti-La/SSB are younger at diagnosis, present more severe dysfunction of the glands and have a higher prevalence of
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2022, Seminars in Arthritis and RheumatismCitation Excerpt :SS patients with anticentromere antibodies have been shown to share overlapping features with SSc such as RP [7,12,21,23,26,27], dysphagia [7,12,27], sclerodactyly [12,27], telangiectasias [12,27], in addition to sicca phenotype [13,26,27]. Compared to their SS counterparts, they have seldom hypergammaglobulinemia [21], display reduced frequency of antibodies against Ro/SSA and/or La/SSB [12,20,25,26] but share similar histopathological findings [12,25,26] in MSG tissues. While a more severe clinical phenotype [21] conferring higher lymphoma risk [23] was previously reported, this was not confirmed in other studies [28,29].
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2022, Journal of Translational AutoimmunityCitation Excerpt :Autoantibodies that have been predictors of an overlapping autoimmune condition include anti-centromere (Raynaud's phenomenon), anti-mitochondrial (liver involvement) and anti-aquaporine-4 (NMOSD). Moreover, anti-carbonic anhydrase 2 antibodies have been associated with renal tubular acidosis [40,42,96–100]. Autoantibodies that have not been reported as useful diagnostic tool yet, but may have added value for phenotype identification include autoantibodies against interferon-inducible protein-16 (IFI16), NR2 and mouse double minute 2 (MDM2).
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