Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling.

Giant cell arteritis (GCA) is an autoimmune disease affecting large vessels in patients over 50 years old. It is an exemplary model of a classic inflammatory disorder with IL-6 playing the leading role. The main comorbidities that may appear acutely or chronically are vascular occlusion leading to blindness and thoracic aorta aneurysm formation, respectively. The tissue inflammatory bulk is expressed as acute or chronic delayed-type hypersensitivity reactions, the latter being apparent by giant cell formation. The activated monocytes/macrophages are associated with pronounced Th1 and Th17 responses. B-cells and neutrophils also participate in the inflammatory lesion. However, the exact order of appearance and mechanistic interactions between cells are hindered by the lack of cellular and molecular information from early disease stages and accurate experimental models. Recently, senescent cells and neutrophil extracellular traps have been described in tissue lesions. These structures can remain in tissues for a prolonged period, potentially favoring inflammatory responses and tissue remodeling. In this review, current advances in GCA pathogenesis are discussed in different inflammatory phases. Through the description of these-often overlapping-phases, cells, molecules, and small lipid mediators with pathogenetic potential are described.

High-content multimodal analysis supports the IL-7/IL-7 receptor axis as a relevant therapeutic target in primary Sjögren's syndrome.

OBJECTIVE: While the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology. METHODS: An IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies. High-content immunophenotyping using flow and imaging mass cytometry was developed to characterize peripheral and in situ IL-7R expression. RESULTS: We identified a blood 4-gene IL-7 module (IKZF4, KIAA0040, PGAP1 and SOS1) associated with anti-SSA/Ro positiveness in patients as well as disease activity, and a tissue 5-gene IL-7 module (IL7R, PCED1B, TNFSF8, ADAM19, MYBL1) associated with infiltration severity. We confirmed expression of IL-7R on T cells subsets, and further observed upregulation of IL-7R on double-negative (DN) B cells, and especially DN2 B cells. IL-7R expression was increased in pSS compared to sicca patients with variations seen according to the degree of infiltration. When expressed, IL-7R was mainly found on epithelial cells, CD4+ and CD8+ T cells, switched memory B cells, DN B cells and M1 macrophages. CONCLUSION: This exhaustive characterization of the IL-7/IL-7R pathway in pSS pathophysiology established that two IL-7 gene modules discriminate pSS patients with a high IL-7 axis involvement. Their use could guide the implementation of an anti-IL-7R targeted therapy in a precision medicine approach.

Sjögren's syndrome: one year in review 2023.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterised by the T-cell-mediated hyperactivation of B-cells and cytokine production. The condition may evolve from an asymptomatic, indolent course, with glandular involvement, to extra-glandular systemic manifestations up to lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. Recently, increasing research focused on the investigation of mechanisms underlying the complex pathogenesis of the disease and highlighted the multi-factorial nature of SS consisting of concomitant involvement of environmental, genetic, neuroendocrine and immune factors. In particular, many aspects have been investigated regarding genetic and epigenetics, the role of specific B- and T-cell phenotypes and the investigation of disease-specific biomarkers as predictors of disease development, activity, and lymphomagenesis. Surely, a deeper understanding of these multiple mechanisms may facilitate earlier diagnosis, enable subphenotyping of patients and open novel therapeutic possibilities to address the unmet needs of the disease in the upcoming years.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Impact of gender and age at onset on Sjögren's syndrome presentation and outcome: state of the art.

Sjögren's syndrome (SS) is a complex and heterogeneous disease that typically affects middle-aged women. However, while it is rare, the disease may occur in male patients and in females during their childhood/adolescence or in the elderly. Contrasting data have been reported on these three subgroups clinical features and long-term outcomes. Notably, recent studies have pinpointed the severity of the disease in male patients and in both the early and the late-onset subgroups.The aim of this review is, therefore, to summarise the available evidence from the recent literature on these phenotypes. The focus will be on the clinical and laboratory features, and on the lymphoma risk observed in the three subgroups distinct phenotypes: of male patients as well as young-onset SS and elderly-onset SS. Ultimately, an accurate phenotypic stratification may represent the first step towards individualised medical approaches.

The Role of the Akt Signaling Pathway in Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder with diverse clinical picture and high prevalence of B-cell non-Hodgkin lymphoma (NHL), that possibly raises from the chronic activation of B-cells. The mechanisms underlying the development of neoplasia in pSS remain elusive. Activated Akt/mTOR pathway is a uniform finding in cancer, whereas its significance in haematologic malignancies is highlighted by the plethora of inhibitors with promising therapeutic efficacy. PI3K-Akt activation has been involved in the TLR3-induced apoptosis of cultured salivary gland epithelial cells (SGECs), whereas upregulated expression of the phosphorylated ribosomal S6 protein (pS6), an end-result of PI3K signalling, has been detected in the infiltrating T and B lymphocytes at the MSG lesions of pSS patients; nevertheless, without specifying if this was mediated by the Akt/mTOR or Ras/ERK pathways. To this end, the role of Akt/mTOR pathway in pSS and associated lymphomagenesis, will be investigated by the immunohistochemical detection of the entire and phosphorylated protein forms of Akt kinase and two of its substrates, namely the FoxO1 transcription factor and the proline-rich Akt substrate of 40-kDa (PRAS40) in MSGs of pSS patients with variable histological and clinical phenotype, as well as sicca-complaining controls. Subsequently, the role of this pathway will be evaluated in in-vitro inhibition experiments, studying the effect of specific inhibitors in the phenotype, function, and interaction of SGECs and B cells. The current proposal is expected to promote the understanding of pSS pathogenesis, enlighten the mechanisms underlying related lymphomagenesis and possible therapeutic targets.

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording.

OBJECTIVE: Parotid swelling (PSW) is a major predictor of non-Hodgkin's lymphoma (NHL) in primary SS (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localization was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. METHODS: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localization of NHL at onset. RESULTS: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to >12 months. NHL was prevalently localized in the parotid glands of the cases. CONCLUSION: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localizes in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.

The clinical phenotype of primary Sjögren's syndrome patients with lymphadenopathy.

OBJECTIVES: Previous cohort studies have shown that around 10% of patients with primary Sjögren's syndrome (pSS) develop lymphadenopathy during their disease course. However, no studies have described their clinical phenotype. The present study aims to describe the clinical manifestations and laboratory findings of pSS patients presenting long-standing lymphadenopathy. METHODS: From a total of 1234 consecutive pSS patients fulfilling the 2016 ACR-EULAR criteria, those with stable lymphadenopathy unrelated to lymphoma were identified (lymphadenopathy group). Their clinical data were collected and compared with 2 control groups: a) the remaining unmatched pSS patients without lymphadenopathy (unmatched non-lymphadenopathy group) and b) pSS patients without lymphadenopathy matched for age, sex, and disease duration, in an approximately 1:1 ratio (matched non-lymphadenopathy group). RESULTS: One hundred and sixty-five (13.37%) patients presented persistent, stable lymphadenopathy. They were characterised by younger age at both pSS onset and diagnosis, and by shorter disease duration. Compared to the unmatched nonlymphadenopathy group, patients with lymphadenopathy had more frequently salivary gland enlargement (p<0.001), higher focus score at first salivary gland biopsy (p=0.017), palpable purpura (p<0.001), peripheral nervous system involvement (p=0.012), glomerulonephritis (p<0.001), and leukopenia (p<0.001), while the results of the matched comparison were similar. Regarding the serological profile, the comparison with the unmatched group demonstrated higher frequency of ANA (p=0.013), anti-Ro/SSA (p=0.001), and anti-La/SSB (p<0.001) positivity for the lymphadenopathy group, while in the matched comparison only higher rates of anti-Ro/SSA positivity (p=0.002) remained statistically significant. CONCLUSIONS: pSS patients presenting non-lymphoma related stable lymphadenopathy constitute a subgroup of younger individuals with B-cell hyperactivation.

Sjögren's syndrome: one year in review 2022.

Primary Sjögren's syndrome (pSS) is a complex disabling systemic autoimmune disorder. The hallmark of pSS is the T-cell-mediated hyperactivation of B-cells, evolving from asymptomatic conditions to systemic complications and lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. B-cells show multiple possible roles in disease pathogenesis, from autoantibody production, to antigen presentation, and cytokine production. B-cells hyperactivation is supported by genetic risk factors, T-cell dependent and independent mechanisms, and the presence of different pathogenic B-cell subsets must be reminded.Many aspects have been investigated in the last year regarding genetic and epigenetics, B- and T-cell role in pSS pathogenesis, their interaction with salivary gland epithelial cells (SGECs) and in their direct or indirect use as biomarkers and predictors of disease development, activity, and lymphomagenesis.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities.

A vital function of the immune system is the modulation of an evolving immune response. It is responsible for guarding against a wide variety of pathogens as well as the establishment of memory responses to some future hostile encounters. Simultaneously, it maintains self-tolerance and minimizes collateral tissue damage at sites of inflammation. In recent years, the regulation of T-cell responses to foreign or self-protein antigens and maintenance of balance between T-cell subsets have been linked to a distinct class of cell surface and extracellular components, the immune checkpoint molecules. The fact that both cancer and viral infections exploit similar, if not the same, immune checkpoint molecules to escape the host immune response highlights the need to study the impact of immune checkpoint blockade on viral infections. More importantly, the process through which immune checkpoint blockade completely changed the way we approach cancer could be the key to decipher the potential role of immunotherapy in the therapeutic algorithm of viral infections. This review focuses on the effect of programmed cell death protein 1/programmed death-ligand 1 blockade on the outcome of viral infections in cancer patients as well as the potential benefit from the incorporation of immune checkpoint inhibitors (ICIs) in treatment of viral infections.

Clinical and laboratory findings of primary Sjögren's syndrome patients without sicca symptoms.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterised by oral and eye dryness. A minority of patients can present without dryness but studies on their clinico-laboratory manifestations are scarce. Our purpose was to describe the clinical phenotype of pSS patients lacking sicca symptoms. METHODS: From a total of 1738 consecutive pSS patients fulfilling the 2016 ACR-EULAR criteria, those who presented without sicca symptoms were identified (non-dryness group). Their medical data was collected and compared with 2 control groups: a) the remaining unmatched sicca pSS patients with both oral and eye dryness (unmatched dryness group) and b) matched sicca pSS patients according to age, sex, and disease duration, in 1:2 ratio (matched dryness group). RESULTS: Thirty-eight (2.19%) patients lacked sicca manifestations presenting mainly with arthralgias (47%), parotid enlargement (24%), Raynaud's phenomenon (11%) and persistent lymphadenopathy (11%) that led them to be evaluated for pSS. Non-dryness pSS patients were younger than the unmatched sicca controls, displaying a higher frequency of anti-Ro/SSA antibodies (100% vs. 79.7%, p<0.001), ANA positivity (100% vs. 90.4%, p<0.001), neutropenia (20.8% vs. 7.5%, p=0.04) and thrombocytopenia (13.8% vs. 4.2%, p=0.04). They also had lower frequency of positive ocular tests compared to both unmatched and matched dryness patients. No differences were found between non-dryness pSS patients and both control groups regarding focus score or any other extraglandular manifestation. CONCLUSIONS: pSS patients without sicca complaints constitute a distinct phenotype involving younger patients, sharing common immunopathologic mechanisms with typical sicca patients.

Liver Fibrosis in Primary Sjögren's Syndrome.

Background: Primary Sjögren syndrome (pSS) is a systemic autoimmune epithelitis, potentially affecting salivary epithelium, biliary epithelium, and hepatocytes. Common immunological mechanisms might cause clinically silent liver inflammation, and combined with non-alcoholic fatty liver disease (NAFLD), liver fibrosis (LF) may occur. No studies have explored the occurrence of LF in the context of NAFLD among pSS patients. Methods: Consecutive pSS patients from the rheumatology outpatient clinic of the Department of Pathophysiology and individuals evaluated in the hepatology outpatient clinic for possible NAFLD serving as comparators underwent transient elastography (TE) to assess LF and liver steatosis (LS). All participants had no overt chronic liver disease. Clinical, demographic, and laboratory data were collected from all participants at the time of TE. Results: Fifty-two pSS patients and 198 comparators were included in the study. The median age (range) of pSS and comparators was 62.5 (30-81) and 55 (19-86) years, respectively. Both groups had similar prevalence regarding type 2 diabetes mellitus, hyperlipidemia, and similar body mass index (BMI). Patients with pSS had less frequently high LS (S2, S3) (27% vs. 62%, p < 0.001) and significant LF (F2-4) [2 (3.8%) vs. 34 (17.2%), p = 0.014] than comparators. Univariable analysis showed that advanced LF was significantly associated with older age, higher LS, greater BMI, and disease status (comparators than pSS); of these, only age was identified as an independent LF risk factor in the multivariable logistic regression analysis. Conclusion: Liver fibrosis among pSS patients is most likely not attributed to the disease per se.

Patient-centered approaches for patients with systemic autoimmune rheumatic diseases: development and evolution.

INTRODUCTION: European Reference Networks (ERNs) are dedicated to rare complex diseases. Systemic autoimmune rheumatic diseases (SARDs) comprise a group of disorders, some of which are rare, complex, and chronic, characterized by relapsing-remitting course and requiring targeted treatments for long periods; SARDs are also associated with various co-morbidities and therefore health-care infrastructures, at the highest level of expertise are required. AREAS COVERED: For the current work, literature on the basic characteristics of a center of excellence dedicated to SARDs, its advantages over the existing health infrastructures in order to improve health and social care, its contribution to the education of health-care workers, and the related research opportunities are presented. In addition, our experience, vision, and initiatives as a new member of the ERNs are reported. EXPERT OPINION: A restructure in healthcare policy and resource allocation, based on centers of expertise, is necessary to improve the medical care of patients with SARDs.

Clinical picture, outcome and predictive factors of lymphoma in primary Sjögren's syndrome: results from a harmonized dataset (1981-2021).

OBJECTIVES: Primary Sjögren's Syndrome (pSS) carries the highest risk for non-Hodgkin's lymphoma (NHL) development among systemic autoimmune diseases. However, the paucity of data on the long-term survival of those patients and the lack of established predictors for each lymphoma histologic subtype prompted our present study. METHODS: We retrospectively analysed 121 patients diagnosed with NHL according to the WHO classification criteria. All patients fulfilled the 2016 ACR-EULAR classification criteria for pSS. Cumulative clinical, laboratory, radiologic, treatment regimens and histologic data were recorded, harmonized and analysed. Overall survival (OS) and event-free survival (EFS) curves were calculated. A mucosa-associated lymphoid tissue lymphoma (MALTL) prediction model was developed by applying innovative data-driven analysis of clinical features present at the time of pSS diagnosis. RESULTS: MALTLs constituted the majority of lymphomas (92/121, 76.0%) followed by diffuse large B-cell lymphomas (DLBCL) (11/121, 9.0%) and nodal marginal zone lymphomas (NMZL) (8/121, 7%). MALTLs show salivary glands localization, limited disease and often bone marrow and nodal involvement. The 10-year OS and EFS rates were 79% and 45.5% for MALTLs, 40.9% and 24.2% for DLBCL and 46% and 31% for NMZL. Cryoglobulinemia, focus score and the total EULAR SS Disease Activity Index (ESSDAI) composite index at pSS diagnosis were proven independent MALTL predictors. Even though MALTLs have a comparatively good survival outlook, they are accompanied by frequent events throughout their clinical course. CONCLUSIONS: Common features of pSS, present at diagnosis, can predict future lymphomagenesis meriting a more intensive follow-up plan.

One year in review 2021: Sjögren's syndrome.

Sjögren's syndrome (SS) is a multifactorial systemic autoimmune disease of unknown aetiology characterised by a wide spectrum of different clinical manifestations and scattered complications. Recently, great efforts have been made to elucidate mechanisms involved in the pathogenesis of the disease in order to identify exploitable therapeutic targets in SS. Similarly, novel insights have enabled to better define disease phenotypes and different outcomes. Ultimately, the discovery of new potential therapeutic targets and a better stratification of patients are paving new avenues for novel treatment options and treat-to-target therapeutic approach. In this review, we will provide a critical digest of the recent literature published in 2020 on SS pathogenesis, clinical manifestations and novel treatment options.

Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets.

A prospective multicenter study assessing humoral immunogenicity and safety of the mRNA SARS-CoV-2 vaccines in Greek patients with systemic autoimmune and autoinflammatory rheumatic diseases.

OBJECTIVES: To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. METHODS: A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. RESULTS: Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. CONCLUSIONS: In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

Combined seronegativity in Sjögren's syndrome.

OBJECTIVES: To describe the clinical spectrum of Sjögren's syndrome (SS) patients with combined seronegativity. METHODS: From a multicentre study population of consecutive SS patients fulfilling the 2016 ACR-EULAR classification criteria, patients with triple seronegativity [anti-Ro/SSA(-), anti-La/SSB(-), RF(-) and ANA(+)] and quadruple seronegativity [anti-Ro/SSA(-), anti-La/SSB(-), RF(-) and ANA(-)] were identified retrospectively. Both groups were matched in an 1:1 ratio with 2 distinct control SS groups: i) classic anti-Ro/SSA seropositive patients [SS(+)] and ii) classic anti-Ro/SSA seropositive patients with negative rheumatoid factor [SS(+)/RF(-)] to explore their effect on disease expression. Clinical, laboratory and, histologic features were compared. A comparison between triple and quadruple seronegative SS patients was also performed. REESULTS: One hundred thirty-five SS patients (8.6%) were identified as triple seronegative patients and 72 (4.5%) as quadruple. Triple seronegative patients had lower frequency of peripheral nervous involvement (0% vs. 7.2% p=0.002) compared to SS(+) controls and lower frequency of interstitial renal disease and higher prevalence of dry mouth than SS(+)/RF(-) controls. Quadruple seronegative patients presented less frequently with persistent lymphadenopathy (1.5% vs. 16.9 p=0.004) and lymphoma (0% vs. 9.8% p=0.006) compared to SS(+) controls and with lower prevalence of persistent lymphadenopathy (1.5% vs. 15.3% p=0.008) and higher frequency of dry eyes (98.6% vs. 87.5% p=0.01) and autoimmune thyroiditis (44.1% vs. 17.1% p=0.02) compared to SS(+)/RF(-) SS controls. Study groups comparative analysis revealed that triple seronegative patients had higher frequency of persistent lymphadenopathy and lymphoma, higher focus score and later age of SS diagnosis compared to quadruple seronegative patients. CONCLUSIONS: Combined seronegativity accounts for almost 9% of total SS population and is associated with a milder clinical phenotype, partly attributed to the absence of rheumatoid factor.

Searching for the "X factor" in Sjögren's syndrome female predilection.

Sjögren's syndrome is typified by a strong female predilection which is also observed in other systemic autoimmune diseases. Although many factors may be contributing to this phenomenon, the exact underlying mechanisms remain unclear. Apart from the traditionally considered hormonal and environmental factors, lately the role of sex chromosomes and especially of the X chromosome has drawn much attention. In the current review, we focus on the inherent genetic imbalance between the sex chromosomes and their influence and role on gender-discordant disease presentation. To compensate for this imbalance, nature has created a defective epigenetic mechanism to silence the second rich in immune related genes X chromosome. Genes escaping silencing, transfer the genetic imbalance into the transcriptional and protein level, contributing to gender differences as reflected in functions of the innate and adaptive immunity. Under this prism, recent research data on SS, regarding specific immune X-linked loci are being presented and analysed. The "X Factor" in the search for an explication of women's predilection in autoimmunity, may lie behind these unique properties of the X chromosome.