The complex role of the chemokine CX3CL1/Fractalkine in major depressive disorder:A narrative review of preclinical and clinical studies

Evidence suggests that neuroinflammation exhibits a dual role in the pathogenesis of major depressive disorder (MDD), both potentiating the onset of depressive symptoms and developing as a consequence of them. Our narrative review focuses on the role of the chemokine fractalkine (FKN) (also known as CX3CL1), which has gained increasing interest for its ability to induce changes to microglial phenotypes through interaction with its corresponding receptor (CX3CR1) that may impact neurophysiological processes relevant to MDD. Despite this, there is a lack of a clear understanding of the role of FKN in MDD. Overall, our review of the literature shows the involvement of FKN in MDD, both in preclinical models of depression, and in clinical studies of depressed patients. Preclinical studies (N = 8) seem to point towards two alternative hypotheses for FKN's role in MDD: a) FKN may drive pro-inflammatory changes to microglia that contribute towards MDD pathogenesis; or b) FKN may inhibit pro-inflammatory changes to microglia, thereby exerting a protective effect against MDD pathogenesis. Evidence for a) primarily derives from preclinical chronic stress models of depression in mice, whereas for b) from preclinical inflammation models of depression. Whereas, in humans, clinical studies (N = 4) consistently showed a positive association between FKN and presence of MDD, however it is not clear whether FKN is driving or moderating MDD pathogenesis. Future studies should aim for larger and more controlled clinical cohorts, in order to advance our understanding of FKN role both in the context of stress and/or inflammation.</p

A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon

Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed

Lupus Nephritis: Clinical Picture, Histopathological Diagnosis, and Management

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can affect almost every organ of the body and presents with a great variety of clinical features. SLE effect on kidneys, mostly referred to as lupus nephritis, is of special interest for the rheumatologist and nephrologist for three reasons. First, lupus nephritis is one of the commonest types of organ involvement in this disorder, affecting as up to 45% of all patients with SLE. Second, it presents with a great variety of clinical and histopathological findings, and thus, therapy must be tailored accordingly. Third, it greatly affects the morbidity and mortality of SLE patients. Taking these facts into account, this chapter is centered on lupus nephritis from the perspective of the clinical nephrologist and renal pathologist. This chapter elaborates the diversity of clinical features of lupus nephritis, in relation to the different histopathological forms of the disease and the therapeutic options that are available to date, as well as the pathogenesis, natural history, and prognosis of patients with lupus nephritis

Chemokine pathways in cutaneous melanoma: their modulation by cancer and exploitation by the clinician

The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients

Auto-Antibodies to β-F1-ATPase and Vimentin in Malignant Mesothelioma

Patients with Malignant Mesothelioma (MM) develop unidentified auto-antibodies to MM tumour antigens. This study was conducted to identify the targets of MM patient auto-antibodies in order to try to understand more of the anti-tumour response and to determine if these antibodies might be helpful for diagnosis or prognostication. Using MM patient sera in a Western immunoblott screening strategy, no common immunoreactive proteins were identified. The sera from one long-term survivor recognised a protein band of 50–60 kDa present in cell lysates from four of five MM cell lines tested. The immunoreactive proteins in this band were identified by 2D electrophoretic separation of a MM cell line protein lysate, followed by analysis of excised immunoreactive proteins on a MALDI TOF mass spectrometer and peptide mass fingerprinting. The immunoreactive proteins identified were vimentin (accession gi55977767) and the ATP synthase (F1-ATPase) beta chain (accession gi114549 and gi47606749). ELISA assays were developed for antibodies to these proteins. Neither vimentin (median and 95% CI 0.346; 0.32–0.468 for MM patients, 0.327; 0.308–0.428 for controls) nor ß-F1-ATPase (0.257; 0.221–0.453 for MM patients, 0.263; 0.22–0.35 for controls) showed significant differences in autoantibody levels between a group of MM patients and controls. Using a dichotomized antibody level (high, low) for these targets we demonstrated that vimentin antibody levels were not associated with survival. In contrast, high ß-F1-ATPase antibody levels were significantly associated with increased median survival (18 months) compared to low ß F1 ATPase antibody levels (9 months; p = 0.049). Immunohistochemical analysis on a MM tissue microarray showed cytoplasmic staining in 28 of 33 samples for vimentin and strong cytoplasmic staining in14 and weak in 16 samples for ß-F1-ATPase. Therefore antibodies to neither vimentin nor ß-F1-ATPase are useful for differential diagnosis of MM, however high antibody levels to ß-F1-ATPase may be associated with increased survival and this warrants further investigation

A tool kit for rapid cloning and expression of recombinant antibodies

Over the last four decades, molecular cloning has evolved tremendously. Efficient products allowing assembly of multiple DNA fragments have become available. However, cost-effective tools for engineering antibodies of different specificities, isotypes and species are still needed for many research and clinical applications in academia. Here, we report a method for one-step assembly of antibody heavy- and light-chain DNAs into a single mammalian expression vector, starting from DNAs encoding the desired variable and constant regions, which allows antibodies of different isotypes and specificity to be rapidly generated. As a proof of principle we have cloned, expressed and characterized functional recombinant tumor-associated antigen-specific chimeric IgE/κ and IgG(1)/κ, as well as recombinant grass pollen allergen Phl p 7 specific fully human IgE/λ and IgG(4)/λ antibodies. This method utilizing the antibody expression vectors, available at Addgene, has many applications, including the potential to support simultaneous processing of antibody panels, to facilitate mechanistic studies of antigen-antibody interactions and to conduct early evaluations of antibody functions

Clinical and Translational Significance of Basophils in Patients with Cancer

Despite comprising a very small proportion of circulating blood leukocytes, basophils are potent immune effector cells. The high-affinity receptor for IgE (FcɛRI) is expressed on the basophil cell surface and powerful inflammatory mediators such as histamine, granzyme B, and cytokines are stored in dense cytoplasmic granules, ready to be secreted in response to a range of immune stimuli. Basophils play key roles in eliciting potent effector functions in allergic diseases and type 1 hypersensitivity. Beyond allergies, basophils can be recruited to tissues in chronic and auto-immune inflammation, and in response to parasitic, bacterial, and viral infections. While their activation states and functions can be influenced by Th2-biased inflammatory signals, which are also known features of several tumor types, basophils have received little attention in cancer. Here, we discuss the presence and functional significance of basophils in the circulation of cancer patients and in the tumor microenvironment (TME). Interrogating publicly available datasets, we conduct gene expression analyses to explore basophil signatures and associations with clinical outcomes in several cancers. Furthermore, we assess how basophils can be harnessed to predict hypersensi-tivity to cancer treatments and to monitor the desensitization of patients to oncology drugs, using assays such as the basophil activation test (BAT)