Primary Sjögren’s Syndrome of Early and Late Onset: Distinct Clinical Phenotypes and Lymphoma Development

Goules, Andreas V.; Argyropoulou, Ourania D; Pezoulas, Vasileios C.; Chatzis, Loukas; Critselis, Elena; Gandolfo, Saviana; Ferro, Francesco; Binutti, Marco; Donati, Valentina; Callegher, Sara Zandonella; Venetsanopoulou, Aliki; Zampeli, Evangelia; Mavrommati, Maria; Voulgari, Paraskevi V.; Exarchos, Themis P.; Mavragani, Clio P.; Baldini, Chiara; Skopouli, Fotini N.; Fotiadis, Dimitrios I.; Vita, Salvatore De; Moutsopoulos, Haralampos Μ.; Tzioufas, Athanasios G.

doi:10.3389/fimmu.2020.594096

Cited by 55 publications

(50 citation statements)

References 19 publications

(34 reference statements)

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“…The histopathology of salivary glands in pSS is of particular interest as several clinical, biological, and immunological aberrations have been directly attributed to changes that occur in the patients’ glandular tissue ( 3 , 4 , 22 , 23 ). At the same time, only a few published studies have concerned the extent of atrophy and adipose tissue in the disease target organ, although both features represent important degenerative changes where functional acinar cells are damaged or replaced ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Stratification in Primary Sjögren’s Syndrome Reveals Novel Immune Cell Alterations in Patients’ Minor Salivary Glands

et al. 2021

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There is a critical need to deconvolute the heterogeneity displayed by the minor salivary glands of primary Sjögren’s syndrome (pSS) patients. This is challenging primarily because the disease etiology remains unknown. The hypothesis includes that initial events in the disease pathogenesis target the salivary glands, thereby triggering the development of focal infiltrates (≥50 mononuclear cells) and finally germinal center-like structures. However, the proportion of key mononuclear immune cells residing at these sites, in combination with the overall ratio of morphometric tissue atrophy and adipose infiltration within the minor salivary glands (MSG) parenchyma at distinct phases of inflammatory disease establishment and progression have not been quantified in detail. In this cross-sectional study, we intended to address this problem by stratifying 85 patients into mild (S1), moderate (S2), and severe (S3) stages using the Inflammatory severity index. We found that mild (<3%) and marked (≥3%) levels of atrophy were accompanied by the respective levels of adipose infiltration in the non-SS sicca controls (p <0.01), but not in pSS patients. The percentage of adipose infiltration significantly correlated with the age of patients (r = 0.458, p <0.0001) and controls (r = 0.515, p <0.0001). The CD4+ T helper cell incidence was reduced in the focal infiltrates of the MSG of S2 patients compared to S1 (p <0.01), and in S2 compared to S1 and S3 combined (p <0.05). CD20+ B cells increased from S1 to S3 (p <0.01) and S2 to S3 (p <0.01), meanwhile CD138+ plasma cells diminished in S3 patients compared to both S1 and S2 groups combined (p <0.01). The proportion of patients with anti-Ro/SSA+, anti-La/SSB+, and RF+ increased over the course of inflammatory disease progression and they were significantly more common in the S3 group relative to S1 (p <0.05). On the other hand, S2 patients measured a higher mean salivary flow relative to S1 and S3 patients combined (p <0.05). Our results demonstrate how the proposed Inflammatory severity index stratification revealed pathological cell and tissue-associated aberrations in the salivary component over the course of inflammatory progression, and their correlations to clinical outcomes. This could be directly transferred to the optimization of available diagnostic strategies applied for pSS patients.

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Section: Discussionmentioning

confidence: 99%

Inflammatory Stratification in Primary Sjögren’s Syndrome Reveals Novel Immune Cell Alterations in Patients’ Minor Salivary Glands

et al. 2021

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“…The association of the LILRA3 functional variant with lymphoma development in the context of younger onset SS patients, together with the heightened LILRA3 serum levels in SS individuals with a younger age of disease onset (≤40 years old), reinforce our previous observations at both clinical and genetic grounds. Thus, a growing body of evidence supports an aggressive phenotype among SS patients with younger disease onset, indicating strong immunological activity and a highly inflammatory background [ 30 , 31 , 32 , 33 , 34 ]. Moreover, the rs2230926 exonic variant of the Tumor Necrosis Factor, Alpha-Induced Protein 3 (TNFAIP3) gene, encoding a defective A20 protein, along with the BAFF-R His159Tyr mutation, have been detected in increased frequency among young SS patients (≤40 years) complicated with lymphoma [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome

Argyriou

Nezos

Ρούσσος

et al. 2021

JCM

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Background: Primary Sjogren’s syndrome (SS) is an autoimmune disease with a strong predilection for lymphoma development, with earlier disease onset being postulated as an independent risk factor for this complication. Variations of the Leukocyte immunoglobulin-like receptor A3(LILRA3) gene have been previously shown to increase susceptibility for both SS and non-Hodgkin B-cell lymphoma (B-NHL) in the general population. We aimed to investigate whether variations of the LILRA3 gene could predispose for lymphoma development in the context of SS. Methods: Study population, all of Greek origin, included 101 SS cases with a current or previous diagnosis of lymphoma (SS-lymphoma, SS-L) and 301 primary SS patients not complicated by lymphoma (SS-non-lymphoma, SS-nL). All SS patients fulfilled the 2016 SS American College of Rheumatology/European league against Rheumatism (ACR/EULAR) classification criteria. A total of 381 healthy controls (HC) of similar age/sex/race distribution were also included. On the basis of the age of SS onset and the presence or absence of adverse predictors for lymphoma development, SS patients were further stratified into younger (≤40 years) and older (>40 years) age of disease onset, as well as into high/medium and low risk groups. Polymerase chain reaction (PCR) was implemented for the detection of the following LILRA3 gene variants: homozygous non-deleted or functional wild type (+/+) heterozygous (+/−) and homozygous deleted (−/−). LILRA3 serum protein levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 85 individuals (29 SS-L, 35 SS-nL patients and 21 HC). Results: While no statistically significant differences were detected in the overall frequency of LILRA3 gene variants between SS-L, SS-nL and HC groups, LILRA3 serum protein levels were increased in the SS-L group compared to HC (1.27 ± 1.34 vs. 0.38 ± 0.34 ng/mL, p-value: 0.004). After stratification according to the age of SS onset and history of lymphoma, as well as the presence or absence of adverse predictors for lymphoma development, the prevalence of the functional LILRA3 gene variant was found to be significantly increased in the young onset SS-L group compared to the HC of similar age and sex distribution (100% vs. 82.9%, p = 0.03), as well as in the high/medium risk SS compared to the low risk SS (91.3 vs. 78.3%, p = 0.0012). Of note, young onset SS-L and SS-nL groups displayed higher LILRA3 serum levels compared to their older counterparts (p-values: 0.007 and 0.0005, respectively). Conclusion: The functional LILRA3 gene variant increases susceptibility to SS-related lymphoma development in patients with a disease onset of <40 years old, implying that genetically determined deranged immune responses in younger SS individuals could underly their pronounced risk for lymphoma development.

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“…Furthermore, we have shown that A allele carriers are younger at disease diagnosis, display lower monocyte absolute numbers and Hgb, as well as increased IGFIEa mRNA expression in MSG tissues and serum BAFF protein levels compared to non-carriers. Taken into consideration that serum anti-Ro/SSA [57], earlier disease onset [58], lower HGB values [59], and heightened serum BAFF levels [4] have all been previously associated with lymphoma development among SS patients, it seems that alterations of the IGF1/IGF1R axis could be significant contributors of severe inflammation and malignant transformation in the setting of SS.…”

Section: Discussionmentioning

confidence: 99%

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren’s Syndrome: Potential Clinical and Pathogenetic Implications

Skarlis

Marketos

Nezos

et al. 2021

JCM

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Background: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren’s syndrome (SS) pathogenesis and explores potential functional implications. Methods: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1β, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. Results: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1β at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. Conclusions: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.

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Primary Sjögren’s Syndrome of Early and Late Onset: Distinct Clinical Phenotypes and Lymphoma Development

Cited by 55 publications

References 19 publications

Inflammatory Stratification in Primary Sjögren’s Syndrome Reveals Novel Immune Cell Alterations in Patients’ Minor Salivary Glands

Inflammatory Stratification in Primary Sjögren’s Syndrome Reveals Novel Immune Cell Alterations in Patients’ Minor Salivary Glands

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren’s Syndrome: Potential Clinical and Pathogenetic Implications

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