Neuroinflammation is a critical process in Alzheimer’s disease (AD) development in which different types of cells and cytokines are involved. Proinflammatory cytokine production and the disturbance of anti-inflammatory pathways play critical roles in AD. Neuroinflammation is affected by various factors such as metabolism (metabolic diseases such as obesity), genetics, and immune cells especially resident immune cells in the brain. Moreover, main pro-inflammatory cytokines and inflammatory pathways have different effects on neuroinflammation, neuronal biogenesis, and neuronal apoptosis in AD. Exploration of the relationship between neuroinflammation, risk factors of neuroinflammation and pro-inflammatory cytokines in AD help us to understand AD pathogenesis and select therapeutic targets more efficiently.

Alzheimer’s Disease (AD); Pro-Inflammatory Cytokine; Neuroinflammation

CD4⁺ T helper (Th) cells are part of the adaptive immune system, which are responsible for activating other immune cells, such as B cells, CD8⁺ T cells, macrophages, mast cells, neutrophils, eosinophils, and basophils. Differentiation of CD4⁺ T cells is under the impression of cytokines and stimulation of the T cell receptor by different antigens. The pattern of cytokine secretion can be altered under specific conditions from one cell line to another, indicating that Th cells have plasticity. In fact, active and master regulators collaborate with transcription factors like signal transducer and activator of transcriptions (STATs) in developing the differentiation process. The signals provided by cytokines activate specific transcription factors in each cell line. During this process, epigenetic modifications are actively involved. Epigenetics are defined as heritable alterations in the regulation of gene expression without any change in the DNA strand, and includes DNA methylation, histone modification, and non-coding RNAs. The plasticity of CD4⁺ T cell in differentiation to multiple subsets allows Th cells to exhibit the best immune response possible against the target microorganism. Failure to respond appropriately to multiple types of microorganisms can lead to disease. In this review we have collected recent advances in understanding the role of epigenetic regulatory mechanisms in differentiation of Th cells and, thereby, the commitment of CD4⁺ T cells to a particular lineage to raise an appropriate response against variety of microorganisms.

Multiple sclerosis (MS), an autoimmune chronic inflammatory, demyelinating disease, has affected over 2.5 million people in the world, who are mostly in young adulthood ages. As the burden of this disease would highly influence the socioeconomic status of the societies, as well as the patient’s quality of life, any progress in better understanding the pathophysiology of this disease would be valuable.
MS is caused by a series of cell-mediated immune mechanisms involving CD4+ T-cell reactivation against CNS. Also, as the involvement of both innate and acquired immunities, different risk factors have been proposed for MS. Environmental factors such as smoking, Epstein-Barr virus infection, sun exposure and vitamin D, body mass index, gut microbiota, and melatonin disturbance may affect gene expression patterns through epigenetic changes, and therefore, play roles in disease occurrence. These epigenetic changes could be categorized as alterations in DNA methylation, histone modifications, and non-coding RNAs. Moreover, the reversibility of these epigenetic changes could potentially be considered therapeutic targets. Therefore, several experimental and preclinical studies have investigated medications for reversing the pathologic epigenetic changes in MS. Accordingly, the current review was conducted to gather the current findings on the role of epigenetics in the pathophysiology and also treatment of MS.

Fibromyalgia(FM) is a common rheumatologic syndrome with a wide spectrum of symptoms that can be debilitating. In spite of attempts to discover FM pathogenesis, It is still challenging and poorly understood, and there is no reliable biomarker for the diagnosis of FM. Recent studies showed the role of the immune system in the pathogenesis of FM. So, this review focuses on the immunological aspects of FM pathogenesis, including associated autoimmune comorbidities, autoantibodies, and inflammatory cytokines.

Interstitial lung disease (ILD) is a major extra-articular manifestation of systemic sclerosis (SSc), significantly contributing to morbidity and mortality. Early detection and close monitoring of patients at high risk of progression are critical for establishing the need for targeted treatment with immunomodulatory and antifibrotic drugs that have the potential to alter the course of the disease. Although the predictive value of high-resolution computed tomography (HRCT) is undeniable, it increases the risk of cancer in SSc-ILD patients with a propensity for developing cancer due to medication overuse and radiation exposure. Lung ultrasonography (LUS) is an intriguing alternative technology in this context, providing a non-invasive and non-radiating evaluation that can be performed prior to other imaging techniques, such as a CT scan, to detect interstitial abnormalities within the subpleural space. Vertical artifacts such as B lines and pleural line modifications have a strong link with the presence of ILD on HRCT and the extent and severity of the disease, with sensitivity and negative predictive values of up to 100%. In the past decades, LUS has been shown to be a cost-effective and repeatable procedure when combined with pulmonary function tests as a primary assessment, limiting the frequency of HRCT application and minimizing radiation exposure that contributes to the probability of cancer development and progression. In this review, we have provided an etiological background for pulmonary involvement in SSc, screening modalities for ILD in SSc, and a thorough description of LUS findings and scoring systems as a point-of-care diagnostic tool in SSc-ILD.

Toll-like Receptors in Multiple Sclerosis: From Immunobiology to Therapeutics

Background: Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory disease of the intestinal tract. Tumor necrosis factor-alpha (TNF-α) signaling plays a major role in the pathogenesis of IBD and is commonly targeted for therapeutic purposes. Results on the contribution of TNF-α -308 and -238 single nucleotide polymorphisms (SNP) to the susceptibility to IBD have been contradictory in different populations.
Methods: Allele frequency and genotype status of TNF-α -308 and -238 SNPs were investigated in 75 unrelated patients with IBD [40 Crohn’s disease (CD) and 35 ulcerative colitis (UC)] and 140 healthy controls by polymerase chain reaction with sequence-specific primers (PCR-SSP). We also conducted a systematic review and meta-analysis of the published reports.
Results: TNF-α -238 GG was detected at a higher frequency in CD and UC. TNF-α -308 GG was more frequently detected in UC compared to control. There was no significant association between TNF-α -238 or -308 gene polymorphisms and patients’ demography (i.e., gender and age) or disease phenotype (i.e., extraintestinal manifestations, treatment, activity index, age at onset, and duration of the disease). In the meta-analysis, TNF-α -238 (AA/AG) genotype tended to be less frequent in patients with UC compared to healthy controls. There was no association between TNF-α -238 gene polymorphisms (AA/AG or GG genotypes) and either form of IBD.
Conclusion: TNF-α -308 and -238 SNPs are associated with IBD in Iranian patients. The TNF-α -308 AA genotype is positively correlated with UC in this meta-analysis.

Background: Growing evidence supports that changes in the expression of the suppressor of cytokine signaling 3 (SOCS3) protein contribute to the pathogenesis of types of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC). Despite the importance of the currently known genetic risk map, an increasing number of observations reveal that epigenetic modifications, including DNA methylation, are considered as or even more important for IBD pathogenesis than genetic predisposition. We investigated the hypothesis that alterations in DNA methylation status at the promoter region within the SOCS3 gene in colorectal tissue specimens may be involved in the susceptibility to UC.

Methods: WWe studied extracted DNA from colorectal biopsies of 15 ulcerative colitis cases and 15 age—and sex-matched healthy controls and performed genotype analyses of the promoter methylation status of the SOCS3 gene, using the real-time quantitative multiplex methylation-specific PCR (QM-MSP) assay to show evidence of differential methylation between cases of ulcerative colitis and healthy controls.

Results: Based on methylation assay data profiling, we found that the mean CpG island methylation levels at the SOCS3 gene promoter region in colorectal mucosa of patients with UC was significantly higher than mucosa from healthy controls (ulcerative colitis vs. healthy controls; 0.00007±0.0018 vs. 0.07±0.142, P<0.000).

Conclusion: Our data provide an important insight into the influence of epigenetic aberrances in the SOCS3 gene such that the inactivation of the SOCS3 gene by promoter hypermethylation might be a risk factor for inflamed mucosa of UC. It might also fundamentally contribute to the initiation of the inflammatory process and development of UC.