SLEight of hand? Not quite: just misinterpreted “core” signals for a missing tolerance

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Systemic Lupus Erythematosus (SLE) is an autoimmune disease wherein the body’s immune system attacks its own organs and tissues. As a result, inflammation occurs in various parts of the body including the skin, heart, lungs, kidneys, brain, blood cells and joints. Mainly, SLE affects connective tissues such as cartilage and the lining of blood vessels. SLE is difficult to diagnose since the signs and symptoms are like other diseases. The common signs and symptoms vary depending on which part of the body is affected. But, the most distinctive sign of lupus is a facial rash that looks like butterfly wings that unfold across the cheeks. Though the rash occurs in most cases, some patients may not have one. If not detected early, it can affect many body organs. About one-third of people with SLE develop kidney diseases or nephritis. In some patients, they develop heart disease called pericarditis, the inflammation of the pericardium membrane. Others develop problems with their heart valves. Aside from these, SLE may severely affect the nervous system with stroke, cognitive impairment and peripheral neuropathy. In some cases, patients develop respiratory failure.

A new study hints at the possible origin of SLE. A team of researchers at the Emory University School of Medicine show that patients with SLE or lupus, have abnormal activation of B cells, which is part of the body’s immune system. As a result, SLE patients produce more antibodies that mistakenly attack their own tissues, leading to a broad range of symptoms, including rashes, joint pain, kidney problems, and fatigue, among others. The study, published in the journal Nature Immunology, shows that in SLE patients, during the early stages of B cell differentiation, signals that contribute to the expansion and activation are already present. The researchers also determined certain gene activity patterns that can be utilized as biomarkers for the disease process and progression. The study was a result of collaboration among the two Emory laboratories of Ignacio Sanz, head of the division of Rheumatology in the Department of Medicine, and recipient of the 2019 Lupus Insight Prize given by the Lupus Research Alliance, and Jeremy Boss, the chairman of Microbiology and Immunology. Christopher Scharer, assistant professor of Microbiology and Immunology, co-authored the study.

To arrive at these results, the researchers examined blood samples from nine female patients with lupus and 12 individuals who are healthy. Initially, they classified the B cells into subgroups and determined the women’s DNA in their B-cells. During the process, the researchers analyzed the patterns of gene activity. They also determined the DNA methylomes, transcriptomes, and chromatin accessibility profiles from five human B cell subsets from the participants. The researchers observed that patients with SLE have an increase of DN2 B cells and “activated naive”, during flare-ups or when the symptoms are severe. Significantly, an SLE molecular signature has been established in resting naïve cells. These were also dominated by enhancement of accessible chromatin in motifs for AP-1 and EGR transcription factors. Put simply, when the researchers studied epigenetic parameters and gene activity patterns, they saw possible signs of stimulation or activation among resting naïve B cells, which occurs before the activated naive cells. Hence, the researchers note that the study could pave the way to determining when B-cells undergo dysfunction in SLE patients.

The study provides vital information in understanding early antigenic triggers. Also, the study can help future research to determine new potential therapeutic interventions. With the new discovery, the researchers hope that the study could open new paths for future research and investigation. Along with this research, another joint team form the University of Alabama at Birmingham, Birmingham, and again the Emory University, United States, has analyzed in detail the role of gamma-interferon and epigenetic unbalances in the early differentiation of B lymphocytes. These cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet, promote autoimmunity SLE-prone mouse models. Gamma interferon seems to “teach” naïve or early B cells to become secretory, the so called ASC phenotype, by co-working with interleukin-2 (IL-2), an immune activatory protein. The role of ligands for tolerogenic receptors (TLR7/8) seems important as well, since after their activation, the genetic environment around genes like IL-21 and PRDM1 becomes more accessible to specific B cell transcription factors BLIMP-1 and IRF4. Therefore, the molecular picture around SLE is revealing itself twisty. But is coming out nonetheless.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Scharer CD et al., Sanz I, Boss JM. Nat Immunol. 2019 Jul 1. 

Zumaguero E, Stone SL, Scharer CD et al. Elife 2019 May 5; 8.

Okamura T, Yamamoto K, Fujio K. Front Immunol. 2018; 9:340. 

He JS, Subramaniam S et al. Nat Commun. 2017 Sep; 8(1):641.

Informazioni su Dott. Gianfrancesco Cormaci 1716 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it

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