Pathogenesis Of Immune-mediated Disorders Research Articles

The role of gut microbiota in T cell immunity and immune mediated disorders.

Gut microbiota was only considered as a commensal organism that aids in digestion, but recent studies revealed that the microbiome play a critical role in both physiological and pathological immune system. The gut microbiome composition is altered by environmental factors such as diet and hygiene, and the alteration affects immune cells, especially T cells. Advanced genomic techniques in microbiome research defined that specific microbes regulate T cell responses and the pathogenesis of immune-mediated disorders. Here, we review features of specific microbes-T cell crosstalk and relationship between the microbes and immunopathogenesis of diseases including in cancers, autoimmune disorders and allergic inflammations. We also discuss the limitations of current experimental animal models, cutting-edge developments and current challenges to overcome in the field, and the possibility of considering gut microbiome in the development of new drug.

The impact of circulating preeclampsia-associated extracellular vesicles on the migratory activity and phenotype of THP-1 monocytic cells

Intercellular communication via extracellular vesicles (EVs) and their target cells, especially immune cells, results in functional and phenotype changes that consequently may play a significant role in various physiological states and the pathogenesis of immune-mediated disorders. Monocytes are the most prominent environment-sensing immune cells in circulation, skilled to shape their microenvironments via cytokine secretion and further differentiation. Both the circulating monocyte subset distribution and the blood plasma EV pattern are characteristic for preeclampsia, a pregnancy induced immune-mediated hypertensive disorder. We hypothesized that preeclampsia-associated EVs (PE-EVs) induced functional and phenotypic alterations of monocytes. First, we proved EV binding and uptake by THP-1 cells. Cellular origin and protein cargo of circulating PE-EVs were characterized by flow cytometry and mass spectrometry. An altered phagocytosis-associated molecular pattern was found on 12.5 K fraction of PE-EVs: an elevated CD47 “don’t eat me” signal (p < 0.01) and decreased exofacial phosphatidylserine “eat-me” signal (p < 0.001) were found along with decreased uptake of these PE-EVs (p < 0.05). The 12.5 K fraction of PE-EVs induced significantly lower chemotaxis (p < 0.01) and cell motility but accelerated cell adhesion of THP-1 cells (p < 0.05). The 12.5 K fraction of PE-EVs induced altered monocyte functions suggest that circulating EVs may have a role in the pathogenesis of preeclampsia.

Ustekinumab: Lessons Learned from Targeting Interleukin‐12/23p40 in Immune‐Mediated Diseases

Interleukin (IL)-12 and IL-23 are related cytokines that have been implicated in the pathogenesis of several immune-mediated disorders. IL-12 and IL-23 are heterodimers made up of a common p40 subunit complexed to unique p35 (IL-12) or p19 (IL-23) subunits. Ustekinumab is a human monoclonal antibody that specifically binds the p40 subunit of IL-12/23. Ustekinumab prevents IL-12 and IL-23 from binding their cell surface receptor complexes, thereby blocking the T helper (Th) 1 (IL-12) and Th17 (IL-23) inflammatory pathways. Here, we discuss the preclinical and human translational data supporting a role for IL-12/23 in the pathogenesis of immune-mediated disorders, and how that rationale was challenged in the clinic during the course of the ustekinumab development program in several indications including psoriasis, psoriatic arthritis, Crohn's disease, and multiple sclerosis. We review the key efficacy and safety data in each of these immune-mediated diseases and compare and contrast the safety lessons learned from IL-12/23 genetically-deficient mice and humans in context of the overall clinical trial experience with ustekinumab.

A new era for carnitine?

Early in vitro experiments demonstrated the immunomodulating and anti-apoptotic properties of L-carnitine. More-recent studies have shown that the depletion of this compound plays a role in the pathogenesis of immune-mediated disorders, such as AIDS, septic shock and chronic fatigue syndrome. These data, combined with the safety of L-carnitine, have highlighted the potential for using this compound as an additional therapy to treat such disorders.