1 1691 124 DUCTAL CELLS OF MINOR SALIVARY GLANDS IN SJOGREN'S SYNDROME EXPRESS LINE-1 ORF2P AND APOBEC3B. BACKGROUND: TYPE I INTERFERON ACTIVATION IS A HALLMARK EVENT IN SJOGREN'S SYNDROME. L1 RETROELEMENTS STIMULATE PLASMACYTOID DENDRITIC CELLS, ACTIVATING THE TYPE I INTERFERONS, AND ARE REGULATED BY VARIOUS MECHANISMS, INCLUDING THE APOBEC3 DEAMINASES. AS L1S ARE POTENTIAL TRIGGER FACTORS IN AUTOIMMUNITY, WE AIMED TO INVESTIGATE THE IMMUNOHISTOCHEMICAL LOCALIZATION OF L1 ORF2P AND ITS INHIBITOR APOBEC3B PROTEIN IN MINOR SALIVARY GLANDS OF SJOGREN'S SYNDROME PATIENTS. METHODS: TWENTY MINOR SALIVARY GLAND-TISSUE SAMPLES FROM 20 SJOGREN'S SYNDROME PATIENTS, CLASSIFIED ACCORDING TO TARPLEY'S HISTOLOGICAL CRITERIA, AND 10 CONTROLS WERE EVALUATED FOR L1 ORF2P AND APOBEC3B EXPRESSION VIA IMMUNOHISTOCHEMISTRY. RESULTS: L1 ORF2P WAS EXPRESSED IN 17/20 SS PATIENTS AND ALL CONTROLS. APOBEC3B EXPRESSION WAS OBSERVED IN 15/20 SJOGREN'S SYNDROME PATIENTS, 5/5 CHRONIC SIALADENITIS, AND 3/5 NORMAL MINOR SALIVARY GLANDS. BOTH ANTIBODIES STAINED THE CYTOPLASM OF THE DUCTAL EPITHELIAL CELLS. NEGATIVE STAINING WAS OBSERVED IN THE ACINAR CELLS. L1 ORF2P-POSITIVE IMMUNOSTAINING WAS SIGNIFICANTLY LOWER IN TARPLEY IV SJOGREN'S SYNDROME PATIENTS THAN CONTROLS (P = .039), AND APOBEC3B-POSITIVE STAINING WAS SIGNIFICANTLY LOWER IN TARPLEY I COMPARED TO TARPLEY II SJOGREN'S SYNDROME PATIENTS (P = .008) AND CONTROLS (P = .035). CONCLUSIONS: L1 ORF2P AND APOBEC3B ARE EXPRESSED IN THE DUCTAL EPITHELIAL CELLS OF MINOR SALIVARY GLANDS THAT ARE AMONG THE KEY TARGETS IN SJOGREN'S SYNDROME. L1 ORF2P EXPRESSION MAY PROMOTE THE L1 ABILITY TO ACT AS AN INTRINSIC ANTIGEN IN SJOGREN'S SYNDROME. THE POTENTIAL FUTURE USE OF L1 ORF2-REVERSE TRANSCRIPTASE INHIBITORS IN AUTOIMMUNITY SUPPORTS FURTHER INVESTIGATION OF L1 EPIGENETIC REGULATION BY APOBEC3 ENZYMES. 2018 2 2222 36 EPIGENETIC MODIFICATIONS IN SALIVARY GLANDS FROM PATIENTS WITH SJOGREN'S SYNDROME AFFECT CYTOKERATIN 19 EXPRESSION. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS, AND SEVERAL LINES OF EXPERIMENTS INDICATE THAT MULTIFACTORIAL FACTORS CONTRIBUTE TO SALIVARY GLAND EPITHELIAL CELLS (SGEC) DYSFUNCTIONS INCLUDING A COMBINATION OF ENVIRONMENTAL FACTORS, LYMPHOCYTIC INFILTRATIONS, GENETIC PREDISPOSITIONS AS WELL AS EPIGENETIC DEFECTS. SUCH STATEMENT IS REINFORCED BY THE OBSERVATION THAT GLOBAL DNA METHYLATION (5MECYT) IS ALTERED IN MINOR SALIVARY GLANDS FROM PSS PATIENTS AND THAT SUCH DEFECT IS ASSOCIATED CYTOKERATIN 19 (KRT19) OVEREXPRESSION. AN EPIGENETIC DEREGULATION OF THE KRT19 GENE WAS FURTHER TESTED BY TREATING THE HUMAN SALIVARY GLAND (HSG) CELL LINE WITH THE DNA DEMETHYLATING AGENT 5-AZACYTIDIN, AND WITH THE HISTONE ACETYLASE INHIBITOR TRICHOSTATIN A. BLOCKING DNA METHYLATION, BUT NOT HISTONE ACETYLATION, WITH 5-AZACYTIDIN WAS ASSOCIATED WITH KRT19 OVEREXPRESSION AT BOTH TRANSCRIPTIONAL AND PROTEIN LEVEL. NEXT, ANALYSIS OF THE CPG GENOME-WIDE METHYLOME ARRAY IN THE KTR19 LOCUS FROM LONG TERM CULTURED SGEC OBTAINED FROM 8 PSS PATIENTS REVEALED A MORE REDUCED DNA METHYLATION LEVEL IN THOSE PATIENTS WITH DEFECTIVE GLOBAL DNA METHYLATION. ALTOGETHER, OUR DATA, THEREFORE, SUGGEST THAT ALTERATION OF DNA METHYLATION IN SGEC MAY CONTRIBUTE TO PSS PATHOPHYSIOLOGY IN PART BY CONTROLLING THE EXPRESSION OF KRT19. 2016 3 5723 33 SJOGREN'S SYNDROME X-CHROMOSOME DOSE EFFECT: AN EPIGENETIC PERSPECTIVE. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING EXOCRINE GLANDS LEADING TO MOUTH AND EYES DRYNESS. THE EXTENT TO WHICH EPIGENETIC DNA METHYLATION CHANGES ARE RESPONSIBLE FOR AN X-CHROMOSOME DOSE EFFECT HAS YET TO BE DETERMINED. OUR OBJECTIVES WERE TO (I) DESCRIBE HOW EPIGENETIC DNA METHYLATION CHANGES COULD EXPLAIN AN X-CHROMOSOME DOSE EFFECT IN SS FOR WOMEN WITH NORMAL 46,XX GENOTYPE AND (II) DETERMINE THE RELEVANT RELATIONSHIPS TO THIS DOSE EFFECT, BETWEEN X-LINKED GENES, GENES CONTROLLING X-CHROMOSOME INACTIVATION (XCI) AND GENES ENCODING ASSOCIATED TRANSCRIPTION FACTORS, ALL OF WHICH ARE DIFFERENTIALLY EXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN THE SALIVARY GLANDS OF PATIENTS WITH SS. WE IDENTIFIED 58 UPREGULATED X-CHROMOSOME GENES, INCLUDING 22 GENES PREVIOUSLY SHOWN TO ESCAPE XCI, BASED ON THE ANALYSIS OF SS PATIENT SALIVARY GLAND GEO2R GENE EXPRESSION DATASETS. MOREOVER, WE FOUND XIST AND ITS CIS REGULATORS RLIM, FTX, AND CHIC1, AND POLYCOMB REPRESSOR GENES OF THE PRC1/2 COMPLEXES TO BE UPREGULATED. MANY OF THE X-CHROMOSOME GENES IMPLICATED IN SS PATHOGENESIS CAN BE REGULATED BY TRANSCRIPTION FACTORS WHICH WE FOUND TO BE OVEREXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN PATIENTS WITH SS. DETERMINATION OF THE MECHANISMS UNDERLYING METHYLATION-DEPENDENT GENE EXPRESSION AND IMPAIRED XCI IS NEEDED TO FURTHER ELUCIDATE THE ETIOPATHOGENESIS OF SS. 2019 4 1603 34 DNA METHYLATION STUDIES IN SALIVA OF PATIENTS WITH SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A RELATIVELY COMMON SYSTEMIC AUTOIMMUNE DISEASE OF UNKNOWN AETIOLOGY, ALTHOUGH GENETIC, HORMONAL, IMMUNOLOGIC, AND ENVIRONMENTAL FACTORS ARE THOUGHT TO BE INVOLVED IN DISEASE PATHOGENESIS. IT IS ALSO TERMED "AUTOIMMUNE EPITHELITIS", AND AFFLICTS MAINLY THE EPITHELIAL STRUCTURES OF SALIVARY AND LACHRYMAL GLANDS, THROUGH PERIEPITHELIAL LYMPHOCYTIC INFILTRATION RESPONSIBLE FOR THE OCCURRENCE OF DRYNESS SYMPTOMS. SJOGREN'S SYNDROME (SS) IS ALSO CHARACTERISED BY B CELL HYPERACTIVITY AS REFLECTED BY THE PRESENCE OF HYPERGAMMAGLOBULINEMIA AND THE PRODUCTION OF AUTOANTIBODIES, WHICH SEEMS TO BE ASSOCIATED WITH THE PRESENCE OF ECTOPIC GERMINAL CENTRES WITHIN THE INFLAMED MINOR SALIVARY GLANDS. CHRONIC ANTIGENIC STIMULATION MAY LEAD TO EXPANSION OF B CELL AUTOREACTIVE CLONES WITH RHEUMATOID FACTOR ACTIVITY, AND ADDITIONAL MOLECULAR EVENTS MEDIATE MALIGNANT TRANSFORMATION INTO NON-HODGKIN'S LYMPHOMAS OF B CELL ORIGIN. THEREFORE, THE INTERACTION BETWEEN THE IMMUNE CELLS OF THE INFLAMMATORY INFILTRATE AND THE SALIVARY EPITHELIUM SEEMS TO HAVE AN IMPORTANT CONTRIBUTION IN DISEASE PROCESS. RECENT HISTOPATHOLOGIC AND MOLECULAR STUDIES HAVE SHOWN THAT DNA METHYLATION LEVELS OF SS PATIENTS COMPARED TO HEALTHY INDIVIDUALS DIFFER IN EPITHELIAL CELLS OF SALIVARY GLANDS AND PERIPHERAL BLOOD MONONUCLEAR CELLS. IN THE PRESENT STUDY, WE INTEND TO ANALYSE THE EPIGENETIC MODIFICATIONS OF DNA IN THE SALIVA OF SS PATIENTS COMPARED TO HEALTHY CONTROLS. MORE SPECIFICALLY, SALIVARY DNA METHYLATION LEVELS OF SELECTED GENETIC LOCI PREVIOUSLY FOUND TO DIFFER IN OTHER TISSUES, WILL BE COMPARED BETWEEN SS PATIENTS AND HEALTHY CONTROLS. THE STUDY INCLUDES SALIVA COLLECTION FROM SS PATIENTS AND HEALTHY INDIVIDUALS, EXTRACTION OF GENOMIC DNA AND METHYLATION ASSESSMENT. THE EPIGENETIC PROFILE OF EACH GENETIC LOCUS WILL BE CORRELATED WITH SS PATIENTS' CLINICAL CHARACTERISTICS AND THE POSSIBILITY OF GENETIC LOCI WITH DIFFERENTIAL DIFFERENCES IN METHYLATION TO BE USED AS POTENTIAL DIAGNOSTIC BIOMARKERS WILL BE EXPLORED. THE CURRENT STUDY IS ANTICIPATED TO REVEAL POTENTIAL BIOMARKERS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES, OFFERING THE ADVANTAGE TO UTILISE THE EASILY COLLECTED AND HANDLED SALIVA AS THE MAIN BIOLOGIC MATERIAL. 2021 5 1985 24 EPIGENETIC ALTERATIONS IN PRIMARY SJOGREN'S SYNDROME - AN OVERVIEW. PRIMARY SJOGREN'S SYNDROME (PSS) IS A CHRONIC AUTOIMMUNE RHEUMATIC DISEASE CHARACTERIZED BY INFLAMMATION OF EXOCRINE GLANDS, MAINLY SALIVARY AND LACRIMAL GLANDS. IN ADDITION, PSS MAY AFFECT MULTIPLE OTHER ORGANS RESULTING IN SYSTEMIC MANIFESTATIONS. ALTHOUGH THE PRECISE ETIOLOGY OF PSS REMAINS ELUSIVE, PSS IS CONSIDERED TO BE A MULTI-FACTORIAL DISEASE, WHERE UNDERLYING GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS CONTRIBUTE TO DISEASE DEVELOPMENT. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS, MAY CONSTITUTE A DYNAMIC LINK BETWEEN GENOME, ENVIRONMENT AND PHENOTYPIC MANIFESTATION BY THEIR MODULATING EFFECTS ON GENE EXPRESSION. A GROWING BODY OF STUDIES REPORTING ALTERED EPIGENETIC LANDSCAPES IN PSS SUGGESTS THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE PATHOGENESIS OF PSS, AND THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS SUGGESTS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC DYSREGULATION IN PSS. THIS ARTICLE REVIEWS OUR CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSS AND DISCUSSES IMPLICATIONS FOR NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2018 6 823 37 CHARACTERIZATION OF COMPREHENSIVE DYNAMIC EPIGENETIC CHANGES DURING HUMAN PRIMARY SJOGREN'S SYNDROME PROGRESSION. BACKGROUND: PRIMARY SJOGREN'S SYNDROME (PSS) IS A SYSTEMIC AUTOIMMUNE DISEASE CHARACTERIZED BY REDUCED EXOCRINE GLAND (PRINCIPALLY THE SALIVARY AND LACRIMAL GLANDS) ACTIVITY CAUSED BY CHRONIC LYMPHOCYTIC INFILTRATION. ALTHOUGH PSS HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, THE DYNAMIC EPIGENETIC CHANGES IN THE GLAND CELLS THAT ACCOMPANY THE PATHOGENESIS ARE NOT ENTIRELY UNDERSTOOD. METHODS: IN THIS STUDY, WE HARVESTED TISSUE SAMPLES FROM THE LABIAL GLAND WITH (LG_PSS) OR WITHOUT PSS (LG_NC) BEFORE MALT DEVELOPMENT, AS WELL AS THE PAROTID GLAND WITH TUMOR TISSUES (PG_MALT) AND PARACANCEROUS TISSUES (PG_NC) OF TWO PSS PATIENTS WITH MALT LYMPHOMA, AND CONDUCTED RNA-SEQ AND CHIP-SEQ FOR TRI-METHYLATED HISTONE 3 LYSINE 4, 9, 27, 36, AND 79 (H3K4/9/27/36/79ME3). RESULTS: TRANSCRIPTOME LANDSCAPES INDICATED TWO OUTCOMES OF PSS PROGRESSION WITH OR WITHOUT MALT LYMPHOMA REPRESENTED BY DISTINCT POPULATIONS OF DIFFERENTIALLY EXPRESSED GENES AND THEIR FUNCTIONS. FURTHERMORE, THE EPIGENETIC ATLAS OF GENOME-WIDE H3K4/9/27/36/79ME3 WAS IN DIFFERENT STAGES FOR VARIOUS SAMPLES, INDICATING THAT THE VARIANCE OF H3K4ME3 WAS THE EARLIEST EVENT, FOLLOWED BY SELECTIVE ALTERATIONS OF H3K9/27/36/79ME3. THESE FOUR EPIGENETIC MODIFICATIONS DETERMINE THE FINAL OUTCOME OF PSS PROGRESSION. CONCLUSIONS: OUR RESULTS NOT ONLY ADVANCE THE UNDERSTANDING OF THE DYNAMICS OF PSS PROGRESSION AND HIGHLIGHT THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN REGULATING TRANSCRIPTION DURING THIS PATHOLOGICAL PROCESS, BUT ALSO IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR PSS TREATMENT AND LYMPHOMA INTERVENTION. 2021 7 6050 30 THE CONTRIBUTION OF EPIGENETICS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS THAT COMBINES EXOCRINE GLAND DYSFUNCTIONS AND LYMPHOCYTIC INFILTRATIONS. WHILE THE PATHOGENESIS OF SS REMAINS UNCLEAR, ITS ETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC PREDISPOSITIONS, ENVIRONMENTAL FACTORS, AND EPIGENETIC FACTORS. RECENTLY, INTEREST HAS GROWN IN THE INVOLVEMENT OF EPIGENETICS IN AUTOIMMUNE DISEASES. EPIGENETICS IS DEFINED AS CHANGES IN GENE EXPRESSION, THAT ARE INHERITABLE AND THAT DO NOT ENTAIL CHANGES IN THE DNA SEQUENCE. IN SS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION THAT PREDOMINATES IN EPITHELIAL CELLS, AN ABNORMAL EXPRESSION OF MICRORNAS, AND ABNORMAL CHROMATIN POSITIONING-ASSOCIATED WITH AUTOANTIBODY PRODUCTION. LAST BUT NOT LEAST, EPIGENETIC MODIFICATIONS ARE REVERSIBLE AS OBSERVED IN MINOR SALIVARY GLANDS FROM SS PATIENTS AFTER B CELL DEPLETION USING RITUXIMAB. THUS EPIGENETIC FINDINGS IN SS OPEN NEW PERSPECTIVES FOR THERAPEUTIC APPROACHES AS WELL AS THE POSSIBLE IDENTIFICATION OF NEW BIOMARKERS. 2014 8 207 39 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS. 2010 9 1165 28 CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SJOGREN'S SYNDROME: A REVIEW. SJOGREN'S SYNDROME (SS) IS A CHRONIC SYSTEMIC DISEASE CHARACTERISED BY SALIVARY AND LACRIMAL GLAND DYSFUNCTION WITH SEVERE IMPLICATIONS FOR THE WELL-BEING OF BEARING INDIVIDUALS. ALTHOUGH ITS ORIGIN HAS NOT YET BEEN FULLY ELUCIDATED, IT IS KNOWN THAT GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF THIS SYNDROME. DNA METHYLATION IS A RELEVANT, WIDELY STUDIED EPIGENETIC FACTOR THAT IS POSSIBLY RELATED TO THE ESTABLISHMENT OF SS. THE AIM OF THE PRESENT STUDY WAS TO PERFORM A SYSTEMATIC REVIEW OF THE LITERATURE TO COMPILE STUDIES ON THE CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SS. A LITERATURE SEARCH WAS PERFORMED IN 4 DATABASES (PUBMED, WEB OF SCIENCE, LILACS, AND SCOPUS) USING PREVIOUSLY SELECTED MEDICAL SUBJECT HEADINGS (MESH) DESCRIPTORS, AND ARTICLE SELECTION CONSIDERED OBSERVATIONAL STUDIES ONLY. AFTER A FULL-TEXT READING OF THE SELECTED ARTICLES, 15 STUDIES WERE IN ACCORDANCE WITH THE ELIGIBILITY CRITERIA FOR DATA EXTRACTION. METHYLATION DETECTION APPROACHES INCLUDED GLOBAL METHYLATION, GENOME-WIDE ASSESSMENT OF DIFFERENTIALLY METHYLATED REGIONS, AND SITE-SPECIFIC METHYLATION. FOURTEEN ARTICLES REPORTED ASSOCIATIONS OF DNA METHYLATION PROFILES IN SS PATIENTS, BOTH GLOBALLY AND IN SEVERAL GENES IN SALIVARY GLANDS AND BLOOD CELLS. THUS, DNA METHYLATION MAY CONTRIBUTE TO THE PATHOGENESIS OF SS. THE FINDINGS REINFORCE THE IMPORTANCE OF EPIGENETIC MARKERS IN THE DYNAMICS OF SS AND MAY DIRECT EFFORTS TOWARD THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2022 10 1261 25 CURRENT VIEWS ON THE PATHOGENESIS OF SJOGREN'S SYNDROME. PURPOSE OF REVIEW: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN INSIGHT INTO THE PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE PATHOGENESIS OF PRIMARY SJOGREN'S SYNDROME (PSS), HIGHLIGHTING RECENT FINDINGS WITH POTENTIAL THERAPEUTIC REPERCUSSIONS. RECENT FINDINGS: IN THE LAST 2 YEARS, EPIGENETIC ANALYSES PROVIDED NEW INSIGHTS INTO PSS PATHOGENESIS. CHARACTERIZATION OF DNA METHYLATION PATTERNS, CHROMATIN STRUCTURES AND MICRORNA CONFIRMED THE IMPORTANCE OF ABERRANT INTERFERON AND B-CELL RESPONSES IN THE DEVELOPMENT OF THE DISEASE. THE FORMATION OF ECTOPIC B-CELL FOLLICLES WITH GERMINAL CENTERS IS NOW A WELL RECOGNIZED PATHOGENIC MECHANISM WITHIN SALIVARY GLANDS OF PSS. IN THE CONTEXT OF ECTOPIC GERMINAL CENTERS REACTION, T/B-CELL INTERACTIONS, THAT IS REGARDING T-HELPER 17 AND T-FOLLICULAR HELPER CELLS, AND THEIR RESPECTIVE COUNTERPARTS, T-REGULATORY AND T-FOLLICULAR REGULATORY CELLS, APPEAR PARTICULARLY RELEVANT IN PSS PATHOGENESIS AS THEIR IMBALANCE IS ASSOCIATED WITH A DYSREGULATION OF B-CELL DYNAMICS AND THE PRODUCTION OF AUTOANTIBODIES. SUMMARY: ADVANCES IN THE UNDERSTANDING OF PSS PATHOGENESIS HAVE PAVED THE WAY FOR CLINICAL TRIALS WITH NOVEL BIOLOGIC AGENTS TARGETING IMMUNE PATHWAYS REGULATING T/B-CELL INTERACTIONS AND DOWNSTREAM B-CELL ACTIVATION. REVERSE TRANSLATION FROM THESE STUDIES PROVIDES INVALUABLE NOVEL INFORMATION OF THE MECHANISMS SUSTAINING AUTOIMMUNITY AND CHRONIC INFLAMMATION IN PSS. 2018 11 2515 28 EPIGENETICS AND SJOGREN'S SYNDROME. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS IN THE DNA ITSELF, MAY PLAY AN ESSENTIAL ROLE IN AUTOIMMUNE DISEASES (AID). IN SJOGREN'S SYNDROME (SS), A CHRONIC AID CHARACTERIZED BY AN EPITHELIS OF THE EXOCRINE GLANDS, EPIGENETIC STUDIES HAVE FOCUSED ON THREE MECHANISMS: DNA METHYLATION AND ITS CONSEQUENCES INCLUDING HUMAN ENDOGENOUS RETROVIRUS (HERV) EXPRESSION; MICRORNA EXPRESSION; AND PROTEIN POST-TRANSLATIONAL MODIFICATIONS ASSOCIATED WITH AUTOANTIBODY PRODUCTION. ALTHOUGH IN ITS INFANCY, COMPREHENSION OF THE EPIGENETIC (DYS)REGULATION IN SS MAY HELP US TO UNDERSTAND: WHY SS AFFECTS PREDOMINANTLY MIDDLE-AGED WOMEN; WHY GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP SS BUT NOT OTHERS; WHY FLARE-UPS OCCUR; WHY TREATMENT RESPONSES DIFFER BETWEEN PATIENTS; AND WHY SOME PATIENTS DEVELOP LYMPHOMA. FROM THESE STUDIES WILL ARISE A BETTER COMPREHENSION OF THE PATHOPHYSIOLOGY OF SS AS WELL AS DEVELOPMENT OF NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, AND NOVEL THERAPEUTICS FOR PREVENTION AND PERHAPS EARLY INTERVENTION. 2012 12 2552 30 EPIGENETICS IN PRIMARY SJOGREN'S SYNDROME. PRIMARY SJOGREN'S SYNDROME (SJS) IS A CHRONIC AND SYSTEMIC AUTOIMMUNE EPITHELITIS WITH PREDOMINANT FEMALE INCIDENCE, WHICH IS CHARACTERIZED BY EXOCRINE GLAND DYSFUNCTION. INCOMPLETELY UNDERSTOOD, THE ETIOLOGY OF SJS IS MULTI-FACTORIAL AND EVIDENCE IS GROWING TO CONSIDER THAT EPIGENETIC FACTORS ARE PLAYING A CRUCIAL ROLE IN ITS DEVELOPMENT. INDEPENDENT FROM DNA SEQUENCE MUTATIONS, EPIGENETICS IS DESCRIBED AS INHERITABLE AND REVERSIBLE PROCESSES THAT MODIFY GENE EXPRESSION. EPIGENETIC MODIFICATIONS REPORTED IN MINOR SALIVARY GLAND AND LYMPHOCYTES FROM SJS PATIENTS ARE RELATED TO (I) AN ABNORMAL DNA METHYLATION PROCESS INDUCING IN TURN DEFECTIVE CONTROL OF NORMALLY REPRESSED GENES INVOLVING SUCH MATTERS AS AUTOANTIGENS, RETROTRANSPOSONS, AND THE X CHROMOSOME IN WOMEN; (II) ALTERED NUCLEOSOME POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION; AND (III) ALTERED CONTROL OF MICRORNA. RESULTS FROM EPIGENOME-WIDE ASSOCIATION STUDIES HAVE FURTHER REVEALED THE IMPORTANCE OF THE INTERFERON PATHWAY IN DISEASE PROGRESSION, THE CALCIUM SIGNALING PATHWAY FOR CONTROLLING FLUID SECRETIONS, AND A CELL-SPECIFIC CROSS TALK WITH RISK FACTORS ASSOCIATED WITH SJS. IMPORTANTLY, EPIGENETIC MODIFICATIONS ARE REVERSIBLE THUS OPENING OPPORTUNITIES FOR THERAPEUTIC PROCEDURES IN THIS CURRENTLY INCURABLE DISEASE. 2020 13 1873 28 EMERGING ROLE OF MICRORNAS AND LONG NON-CODING RNAS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISEASE. IT IS CONSIDERED A MULTIFACTORIAL PATHOLOGY, IN WHICH UNDERLYING GENETIC PREDISPOSITION, EPIGENETIC MECHANISMS AND ENVIRONMENTAL FACTORS CONTRIBUTE TO DEVELOPMENT. THE EPIGENETIC REGULATIONS REPRESENT A LINK BETWEEN GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. RECENT STUDIES SUGGESTED A REGULATORY ROLE FOR NON-CODING RNAS IN CRITICAL BIOLOGICAL AND DISEASE PROCESSES. AMONG NON-CODING RNAS, MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS) PLAY A CRITICAL ROLE IN THE POST-TRANSCRIPTIONAL MRNA EXPRESSION, FORMING A COMPLEX NETWORK OF GENE EXPRESSION REGULATION. THIS REVIEW AIMS TO GIVE AN OVERVIEW OF THE LATEST STUDIES THAT HAVE INVESTIGATED THE ROLE OF MIRNAS AND LNCRNAS IN THE SS. WE INCLUDED PAPERS THAT INVESTIGATED THE EXPRESSION OF NON-CODING RNAS ON DIFFERENT TISSUES, IN PARTICULAR ON PERIPHERAL BLOOD MONONUCLEAR CELLS AND SALIVARY GLANDS. HOWEVER, REGARDING THE INVOLVEMENT OF NON-CODING RNAS GENETIC VARIABILITY IN SS SUSCEPTIBILITY VERY FEW DATA ARE AVAILABLE. FURTHER RESEARCH COULD HELP TO ELUCIDATE UNDERLYING PATHOGENIC PROCESSES OF SS AND PROVIDE NEW OPPORTUNITIES FOR THE DEVELOPMENT OF TARGETED THERAPIES. 2021 14 1422 33 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS. 2023 15 4268 37 MICROBIAL AGENTS AS PUTATIVE INDUCERS OF B CELL LYMPHOMA IN SJOGREN'S SYNDROME THROUGH AN IMPAIRED EPIGENETIC CONTROL: THE STATE-OF-THE-ART. INTRODUCTION: UNDERSTANDING THE MECHANISMS UNDERLYING THE PATHOGENESIS OF SJOGREN'S SYNDROME (SS) IS CRUCIALLY IMPORTANT IN ORDER TO BE ABLE TO DISCRIMINATE THE STEPS THAT LEAD TO B CELL TRANSFORMATION AND PROMPTLY IDENTIFY THE PATIENTS AT RISK OF LYMPHOMAGENESIS. THE AIM OF THIS NARRATIVE REVIEW IS TO DESCRIBE THE EVIDENCE CONCERNING THE ROLE THAT INFECTIONS OR DYSBIOSIS PLAYS IN THE EPIGENETIC CONTROL OF GENE EXPRESSION IN SS PATIENTS AND THEIR POSSIBLE INVOLVEMENT IN B CELL LYMPHOMAGENESIS. MATERIALS AND METHODS: WE SEARCHED THE PUBMED AND GOOGLE SCHOLAR DATABASES AND SELECTED A TOTAL OF 92 ARTICLES PUBLISHED DURING THE LAST 25 YEARS THAT DESCRIBE EXPERIMENTAL AND CLINICAL STUDIES OF THE POTENTIAL ASSOCIATIONS OF MICROBIOTA AND EPIGENETIC ABERRATIONS WITH THE RISK OF B CELL LYMPHOMA IN SS PATIENTS. RESULTS AND DISCUSSION: THE GENETIC BACKGROUND OF SS PATIENTS IS CHARACTERIZED BY THE HYPEREXPRESSION OF GENES THAT ARE MAINLY INVOLVED IN REGULATING THE INNATE AND ADAPTIVE IMMUNE RESPONSES AND ONCOGENESIS. IN ADDITION, SALIVARY GLAND EPITHELIAL CELLS AND LYMPHOCYTES BOTH HAVE AN ALTERED EPIGENETIC BACKGROUND THAT ENHANCES THE ACTIVATION OF PROINFLAMMATORY AND SURVIVAL PATHWAYS. DYSBIOSIS OR CHRONIC LATENT INFECTIONS MAY TUNE THE IMMUNE RESPONSE AND MODIFY THE CELL EPIGENETIC MACHINERY IN SUCH A WAY AS TO GIVE B LYMPHOCYTES AN ACTIVATED OR TRANSFORMED PHENOTYPE. IT IS ALSO WORTH NOTING THAT TRANSPOSABLE INTEGRATED RETROELEMENTS MAY PARTICIPATE IN THE PATHOGENESIS OF SS AND B CELL LYMPHOMAGENESIS BY INDUCING DNA BREAKS, MODULATING CELL GENE EXPRESSION, OR GENERATING ABERRANT TRANSCRIPTS THAT CHRONICALLY STIMULATE THE IMMUNE SYSTEM. CONCLUSIONS: MICROORGANISMS MAY EPIGENETICALLY MODIFY TARGET CELLS AND INDUCE THEIR TRANSCRIPTOME TO GENERATE AN ACTIVATED OR TRANSFORMED PHENOTYPE. THE OCCURRENCE OF LYMPHOMA IN MORE THAN 15% OF SS PATIENTS MAY BE THE END RESULT OF A COMBINATION OF GENETICS, EPIGENETICS, AND DYSBIOSIS OR LATENT INFECTIONS. 2019 16 1059 16 CLINICAL PERSPECTIVES OF NON-CODING RNA IN ORAL INFLAMMATORY DISEASES AND NEUROPATHIC PAIN: A NARRATIVE REVIEW. NON-CODING RNAS (NCRNAS) REPRESENT A RESEARCH HOTSPOT BY PLAYING A KEY ROLE IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF DIVERSE BIOLOGICAL FUNCTIONS AND DUE TO THEIR INVOLVEMENT IN DIFFERENT DISEASES, INCLUDING ORAL INFLAMMATORY DISEASES. BASED ON NCRNAS' SUITABILITY FOR SALIVARY BIOMARKERS AND THEIR INVOLVEMENT IN NEUROPATHIC PAIN AND TISSUE REGENERATION SIGNALING PATHWAYS, THE PRESENT NARRATIVE REVIEW AIMS TO HIGHLIGHT THE POTENTIAL CLINICAL APPLICATIONS OF NCRNAS IN ORAL INFLAMMATORY DISEASES, WITH AN EMPHASIS ON SALIVARY DIAGNOSTICS, REGENERATIVE DENTISTRY, AND PRECISION MEDICINE FOR NEUROPATHIC OROFACIAL PAIN. 2022 17 1227 26 CRITICAL ROLE OF MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: OVEREXPRESSION OF THE ONCOGENE PLAG1 BY DEREGULATED MIRNAS. MICRORNAS (MIRNAS) ARE SMALL, GENE ENCODED RNAS WHICH ARE ABLE TO INFLUENCE GENE EXPRESSION IN BINDING TO THE 3'UTR OF MRNAS. COMPARED TO HEALTHY TISSUES, THE GLOBAL EXPRESSION OF MIRNAS IN CANCEROUS TISSUE IS FREQUENTLY DOWN-REGULATED. LIKEWISE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DOWN-REGULATION OF SEVERAL MIRNAS HAS BEEN REPORTED. ANALYSIS OF MIRNA PROMOTERS FOR EPIGENETIC MODIFICATIONS REVEALED A STRONGER METHYLATION OF DOWN-REGULATED MIRNAS IN CLL. TO DATE, SEVERAL TARGET GENES AFFECTED BY DEREGULATED MIRNAS HAVE BEEN IDENTIFIED THAT HAVE IMPACT ON CLL PATHOGENESIS. THE BEST-DESCRIBED CONSEQUENCE OF MIRNA DEREGULATION IS FOR MIRNA-15/16 CLUSTER DELETION, WHICH IS FREQUENTLY DOWN-REGULATED IN A SUBGROUP OF PATIENTS WITH CLL CARRYING 13Q14 DELETION. SO FAR, MODELS FOR MIRNA DEREGULATION HAVE ADDRESSED JUST SINGLE MIRNAS. FOR ASSESSMENT OF COMPLETE MIRNA DEREGULATION, FURTHER EVALUATION OF THE RESULTS FROM MICROARRAY STUDIES IS NEEDED. PREVIOUSLY WE IDENTIFIED THE ONCOGENE PLAG1, WHOSE EXPRESSION IS AFFECTED BY VARIOUS MIRNAS DEREGULATED IN CLL. THE INVOLVEMENT OF MIRNAS IN PLAG1 EXPRESSION WAS SHOWN TO BE RELEVANT IN PLEOMORPHIC ADENOMAS OF THE SALIVARY GLAND, TOO. AS PLAG1 IS HIGHLY OVEREXPRESSED, AND ITS TARGET GENES APPEAR TO BE DEREGULATED IN CLL, E.G. BCL-2, PLAG1 IS A PUTATIVE NEW RELEVANT ONCOGENE INVOLVED IN THE PATHOGENESIS OF CLL. 2010 18 6242 30 THE MATRICELLULAR PROTEIN SPARC DECREASES IN THE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. PURPOSE: SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC) IS A MATRICELLULAR GLYCOPROTEIN ABUNDANTLY EXPRESSED IN BASEMENT MEMBRANES AND CAPSULES SURROUNDING A VARIETY OF ORGANS AND TISSUES. IT MEDIATES EXTRACELLULAR MATRIX ORGANIZATION AND HAS BEEN IMPLICATED IN CELL CONTRACTION. HERE, WE EVALUATED THE EXPRESSION OF SPARC IN THE MURINE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. METHODS: LACRIMAL GLANDS OF YOUNG MICE (4-6 WEEKS OLD) AND ADULT MICE (32-40 WEEKS OLD) WERE USED FOR EXTRACTION OF DNA, RNA, AND PROTEIN. THE PRESENCE OF SPARC WAS ASSESSED BY QUANTITATIVE PCR, ELISA, AND IMMUNOFLUORESCENCE MICROSCOPY. 5-METHYLCYTOSINE AND DNA METHYLATION WERE EVALUATED USING ELISA AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. THE EFFECTS OF CYTOKINES AND INFLAMMATION IN SPARC EXPRESSION WERE EVALUATED IN VITRO AND IN THE NON-OBESE DIABETIC (NOD) MOUSE MODEL OF SJOGREN'S SYNDROME. RESULTS: THE MRNA AND PROTEIN LEVELS OF SPARC WERE DOWNREGULATED IN LACRIMAL GLANDS OF MATURE ADULT MICE PRESENTING AGE-RELATED HISTOLOGICAL ALTERATIONS SUCH AS INCREASED DEPOSITION OF LIPOFUSCIN AND LIPIDS. EPIGENETIC ANALYSES INDICATED THAT GLANDS IN ADULT MICE CONTAIN HIGHER LEVELS OF GLOBAL DNA METHYLATION AND SHOW INCREASED HYPERMETHYLATION OF SPECIFIC CPG SITES WITHIN THE SPARC GENE PROMOTER. ANALYSIS OF SMOOTH MUSCLE ACTIN (SMA)-GREEN FLUORESCENT PROTEIN (GFP) TRANSGENIC MICE REVEALED THAT SPARC LOCALIZES PRIMARILY TO MYOEPITHELIAL CELLS WITHIN THE GLAND. TREATMENT OF MYOEPITHELIAL CELLS WITH IL-1BETA OR TNF-ALPHA AND THE DEVELOPMENT OF INFLAMMATION IN THE NOD MICE LED TO DECREASED TRANSCRIPTION OF SPARC. CONCLUSIONS: SPARC IS A NOVEL MATRICELLULAR GLYCOPROTEIN EXPRESSED BY MYOEPITHELIAL CELLS IN THE LACRIMAL GLAND. LOSS OF SPARC DURING ADULTHOOD AND CHRONIC INFLAMMATION MIGHT HAVE DETRIMENTAL CONSEQUENCES ON MYOEPITHELIAL CELL CONTRACTION AND THE SECRETION OF TEAR FLUID. 2022 19 5843 26 STUDIES ON THE CARCINOGENICITY OF POTASSIUM IODIDE IN F344 RATS. A CHRONIC TOXICITY AND CARCINOGENICITY STUDY, IN WHICH MALE AND FEMALE F344/DUCRJ RATS WERE GIVEN POTASSIUM IODIDE (KI) IN THE DRINKING WATER AT CONCENTRATIONS OF 0, 10, 100 OR 1000 PPM FOR 104 WEEKS, AND A TWO-STAGE CARCINOGENICITY STUDY OF APPLICATION AT 0 OR 1000 PPM FOR 83 WEEKS FOLLOWING A SINGLE INJECTION OF N-BIS(2-HYDROXYPROPYL)NITROSAMINE (DHPN), WERE CONDUCTED. IN THE FORMER, SQUAMOUS CELL CARCINOMAS WERE INDUCED IN THE SALIVARY GLANDS OF THE 1000 PPM GROUP, BUT NO TUMORS WERE OBSERVED IN THE THYROID. IN THE TWO-STAGE CARCINOGENICITY STUDY, THYROIDAL WEIGHTS AND THE INCIDENCE OF THYROID TUMORS DERIVED FROM THE FOLLICULAR EPITHELIUM WERE SIGNIFICANTLY INCREASED IN THE DHPN+KI AS COMPARED WITH THE DHPN ALONE GROUP. THE RESULTS OF OUR STUDIES SUGGEST THAT EXCESS KI HAS A THYROID TUMOR-PROMOTING EFFECT, BUT KI PER SE DOES NOT INDUCE THYROID TUMORS IN RATS. IN THE SALIVARY GLAND, KI WAS SUGGESTED TO HAVE CARCINOGENIC POTENTIAL VIA AN EPIGENETIC MECHANISM, ONLY ACTIVE AT A HIGH DOSE. 2000 20 5663 20 SEZARY SYNDROME COEXISTING WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA: CASE REPORT AND REVIEW OF THE LITERATURE. INTRODUCTION: THE SIMULTANEOUS PRESENTATION OF CHRONIC B-CELL LYMPHOCYTIC LEUKEMIA (B-CLL) AND CUTANEOUS T-CELL LYMPHOMA (CTCL) IS EXTREMELY RARE. CASE REPORT: WE DESCRIBE A PATIENT WITH B-CLL AND SEZARY SYNDROME (SS), AN ERYTHRODERMIC AND LEUKEMIC VARIANT OF CTCL. DESPITE TREATMENT, THE SS PROGRESSED TO INVOLVE INTERNAL ORGANS AND EVENTUAL DEATH OF THE PATIENT FROM SEPSIS. THIS IS THE FIRST REPORTED CASE OF SS COEXISTING WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN WHICH AN ANTI-V BETA 13.6 ANTIBODY WAS USED TO SERIALLY TRACK CHANGES IN CIRCULATING NEOPLASTIC T CELLS VIS-A-VIS NEOPLASTIC B CELLS AND TO DETECT NEOPLASTIC T CELLS IN ASCITIC FLUID NEAR THE END OF THE PATIENT'S LIFE. DISCUSSION: WE SPECULATE THAT THE COEXISTENCE OF B-CLL AND CTCL IS THE RESULT OF AN INITIATING GENETIC OR EPIGENETIC DEFECT AT THE LEVEL OF THE COMMON LYMPHOID STEM CELL THAT PREDISPOSES BOTH B-CELL AND T-CELL LINEAGES TO ADDITIONAL ONCOGENIC CHANGES AT A MORE ADVANCED STAGE OF DIFFERENTIATION. 2008