Role of lymphotoxin alpha as a new molecular biomarker in revolutionizing tear diagnostic testing for dry eye disease

Dry eye disease(DED),primarily classified as multifactorial ocular surface disorder,afflicts tens of millions of individuals worldwide,adversely impacting their quality of life.Extensive research has been conducted on tear film analysis over the past decades,offering a range of tests to evaluate its volume,health,and integrity.Yet,early diagnosis and effective treatment for DED continue to pose significant challenges in clinical settings.Nevertheless,by recognizing key phenomena in DED such as ocular surface inflammation,hyperosmolarity,and tear film instability,this article provides a comprehensive overview of both traditional and recently developed methods for diagnosing and monitoring DED.The information serves as a valuable resource not only for clinical diagnosis but also for further research into DED.

Pathological significance and regulatory mechanism of lymphotoxin β receptor overexpression in T cells of patients with systemic lupus erythematosus

Systemic lupus erythematosus（SLE） is a typical autoimmune disease. Lymphotoxin β receptor（LTβR） signaling plays an important role in autoimmune inflammations. LTβR-Ig fusion protein, LTβR blocking agent, has been used to treat SLE, while its mechanism remains to be fully elucidated. In this study, to investigate the expression of LTβR in the T cells of SLE patients and its roles in the pathogenesis of SLE, we isolated the peripheral blood T cells of SLE patients and normal controls to detect expression of LTβR by flow cytometry and RNA assay. T cells were also stimulated with LIGHT, a ligand of LTβR, and then detected for their LTβR expressions and apoptosis by flow cytometry. Also, their expressions of inflammatory factors and receptors were determined by RNA assay. The results showed that LTβR positive cells were 22.75%±6.98% in CD3~＋ cells of SLE patients, while there were almost no LTβR positive cells in CD3~＋ cells of normal persons. Moreover, LTβR expression was remarkably higher in CD3,CD4 and CD8 positive T cells of active SLE patients than non/low active patients（all P〈0.05）, and positively correlated with increased Ig level, decreased complement level and renal damage. Moreover, the stimulation of SLE T cells with LIGHT promoted higher expression of LTβR, IL-23 R and IL-17 A, and apoptosis of T cells. In conclusion,we demonstrated a high expression of LTβR in the T cells of SLE patients which may be associated with pathogenesis of SLE.

THE ANTITUMOR ACTIVITY OF LYMPHOTOXIN AND THE EFFECT OF INTERLEUKIN-2 ON ITS FUNCTION

The effect of lymphotoxin (LT)-containing supernatant produced by lectin-stimulated human lymphocytes on tumor cells and the relation between interleukin-2 (IL-2) and LT were studied in this article. Results showed that LT-containing superna-tants had cytotoxicities on many different kinds of tumor cells from human and mice, that actinomycin D increased the LT activities on target cells and that IL-2 had the ability to increase the cytotoxicity of human PBMC on tumor cells, after being treated with LT, the target cells were more easy to kill by PBMC as well.

Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance

Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of resistance.Here we report that cytokines-activated nuclear IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates p53-directed repression of FAT10.Thus,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.

Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy

Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune diseases.In most cases,the presence of TLS correlates with active immune responses.Because of their proximity to pathological loci,TLS are an intriguing target for the manipulation of immune responses.For several years,it has become clear that lymphotoxin(LT)signalling plays critical roles in lymphoid tissue organogenesis and maintenance.In the current review,we will discuss the role of LT signalling in the development of TLS.With a focus on cancers and autoimmune diseases,we will highlight the correlations between TLS and disease progression.We will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.

Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation

Splenomegaly is a well-known phenomenon typically associated with inflammation.However,the underlying cause of this phenotype has not been well characterized.Furthermore,the splenomegaly phenotype seen in lymphotoxin(LT)signaling-deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils.Splenomegaly,as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues,is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice.We now present evidence that mice deficient in LTα1β2 or LTβR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner.Antibiotic administration to LTα1β2-or LTβR-deficient mice reduces splenomegaly.Furthermore,re-derived germ-free Ltbr−/−mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr−/−mice.By using various LTβ-and LTβR-conditional knockout mice,we demonstrate that retinoic acid-related orphan receptorγT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly.Thus,this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota.

DISTRIBUTION OF AN NcoI POLYMORPHISM IN THE LYMPHOTOXIN α GENE IN DUTCH PATIENTS WITH INFLAMATORY BOWEL DISEASES

An Ncol restriction fragment length polymorphism in the first intron of the lymphotoxin α gene was investigated in 35 patients with Crohn's disease, 40 patients with ulcerative colitis, and 30 unrelated healthy controls, all of Dutch origin. The results showed that no significant differences existed in the genotype frequencies of the Ncol polymorphism in the first intron of the LTα gene between ulcerative colitis patients or Crohn's disease patients and the healthy controls. The study indicates that the Ncol polymorphism in the LTa gene can not be used as a genetic marker for the predisposition to inflammatory bowel diseases. However, since this polymorphism may control the production of tumor necrosis factor, study of this and other related tumor necrosis factor gene polymorphisms may be used as markers to identify patient subgroups and to define patient heterogeneity. Further studies are being carried out on other polymorphisms and on the relevance of LTα and TNFα haplotypes.

Effect of lymphotoxin blockage on different stages of Sjogren's syndrome in an animal model

Background:Lymphotoxin(LT)is an important mediator in Sjogren's syndrome(SS),both in patients and in animal models.Deletion of the LT alpha gene prevented the development of disease manifestations in the interelukin alpha transgenic mouse(IL14αTG)mouse model of SS.Aims:The current study was designed to evaluate the use of LT inhibitors at different stages of the disease in IL14αTG mice.Materials and Methods:IL14αTG mice were treated with anti‐LTa monoclonal antibody,LTb receptor‐immunoglobulin fusion protein(LTBR‐Ig)or isotype control during different stages of disease and analysis of salivary gland function,immunoglobulins,autoantibodies and histology of internal organs performed.Results and Discussion:The inhibitors were very effective in maintaining salivary gland function and preventing infiltration of the glands with lymphocytes when used in the early stages of the disease.Blocking LT at later stages of the disease did not recover salivary gland function but was still effective in limiting extra glandular manifestations including eye disease and tumor development.Some differences were noted in the effectiveness of anti‐LTαversus LTBR‐Ig in limiting particular disease manifestations.Conclusion:LT inhibitors deserve further investigation in the management of SS at whatever stage is identified.