Study of the role of BANK1 in antibody production and antibody-independent functions of B cells in SLE

Informations projet

RoBE

N° de convention de subvention: 838548

DOI

10.3030/838548

Projet clôturé

Date de signature de la CE 22 Mars 2019

Date de début 16 Septembre 2019

Date de fin 21 Octobre 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 259 398,72

Contribution de l’UE

€ 259 398,72

Coordonné par

FUNDACION PUBLICA ANDALUZA PROGRESO Y SALUD M.P.
Spain

Periodic Reporting for period 1 - RoBE (Study of the role of BANK1 in antibody production and antibody-independent functions of B cells in SLE)

Période du rapport: 2019-09-16 au 2022-09-15

Résumé du contexte et des objectifs généraux du projet

Lupus is a debilitating, inflammatory autoimmune disease most common in women ages 15-45, or during their reproductive years, in a ratio of 9 women to 1 man. This is a condition where the immune system reacts excessively causing inflammation in different organs and resulting in a broad range of clinical manifestations with periods of remission and flares. Patients affected by lupus have a reduced quality of life and productivity, while the care and treatment of lupus represent a social and economic burden for patients and the health care system. Currently, there is no treatment that cures lupus, in fact, treatments are limited to controlling pain and inflammation to reduce disease activity.
Lupus is a multifactorial disease where genetic susceptibility combined with environmental factors trigger the autoimmune response. The principal characteristic of the disease is the high levels of antibodies against self-nucleic acid structures produced by B cells, which make the basis of the disease. However, B cells have other functions, such as producing inflammatory and anti-inflammatory mediators, called cytokines, and can also help to activate other immune cells. Recent therapies targeting B cells showed positive results, emphasizing the importance of B cells in the pathogenesis of lupus. Therefore, it is important to further investigate the different functions of B cells and their regulation to develop more specific therapies to treat lupus.

It is known that in Europe 1 in 750 women suffer from lupus. These numbers represent a heavy economic and social burden since lupus affects women in their more productive years. Lupus affects every part of a patient´s life, work, school, finances, family, relationships, and mental and emotional well-being. Thus, finding novel and more specific treatments that help to reduce disease progression will reduce the negative impact of lupus in society.

Genetic factors have been associated with lupus development. Among them, a genetic variant of the B cell scaffold protein with Ankyrin repeats 1 (BANK1) has been identified as a genetic risk for developing lupus. BANK1 actively participates in the activation of B cells and in the production of autoantibodies in a lupus model. However, it is not known whether BANK1 regulates the production of either other antibodies or cytokines. Our general objective was to investigate the role of BANK1 signaling in the antibody production and antibody-independent functions of B cells in a mouse model of Lupus.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

To study the role of BANK1 in lupus, we used mice that either develop lupus spontaneously or by inducing lupus activating a receptor in B cells called TLR7. The analysis of the function of B cells in lupus in the absence of BANK1 gene was done in two different organs where B cells are abundant, the spleen and the gut. In the spleen are produced IgG pathogenic autoantibodies, while in the gut IgA antibodies are secreted to de intestinal lumen. We found that in the absence of BANK1 the production of autoantibodies IgG was reduced as well as the organ damage. However, we also found that there was an altered production of IgA in the intestine. Interestingly, changes in the amount of IgA produced in the gut are directly related to changes in the composition of the intestinal commensals (microbiota). We thus studied the microbiota composition of BANK1 deficient mice and found significant changes in the microbiota compared with controls. As a proof of concept, the microbiota of BANK1 mice (that showed reduced disease severity) was shared with control mice before inducing lupus. We found that the severity of lupus in control mice at the level of BANK1 deficient mice, indicating that the microbiota that is supported by the deficiency of BANK1 in B cells in the intestine plays a crucial role in controlling the inflammation in the rest of the organism. We were also able to identify two species of bacteria associated to lower inflammation. We also found that B cells deficient in BANK1 from the intestine were capable of producing more IL-10, which is an anti-inflammatory molecule. Moreover, the inflammation in the intestine caused by lupus enhanced gut permeability, which has been reported to contribute to lupus inflammation negatively.
The results obtained in this work period resulted in one review publication about B cells, microbiota, and autoimmunity. Also, two more manuscripts are in preparation about gut permeability and the role of BANK1 in the intestinal B cell response. We have also presented this work in four international meetings of lupus and autoimmunity and in two local (Spain) meetings, as well as at the European Researcher´s night.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We have advanced in this research by determining that BANK1 not only plays a role in the production of pathogenic autoantibodies but also in the production of IgA antibodies in the gut. IgA antibodies play an important role in determining the abundance of species of commensal microorganisms that inhabit the intestine. The commensal population distribution in turn can modulate the autoimmune response beyond the intestine. In fact, the microbiota composition supported by BANK1 seems to have immunoregulatory properties.
These results shed light on the complex dialog between genes and the environment involved in the pathogenesis of lupus, a topic currently being intensively investigated in patients with lupus. It is being investigated whether changes in the microbiota composition in lupus patients can help to alleviate the disease severity, either by microbiota transplantation or by supplementing the diet with probiotic strains with anti-inflammatory properties.
Gut microbiota modification by providing probiotics can be a novel strategy to help to diminish inflammation in a non-invasive and safe way. By reducing inflammation in lupus patients, it is possible to improve the patient´s life quality and diminish the social and economic burden.
Academically the expected results of this work are at least to obtain two more scientific publications and to continue the research of the molecular mechanisms of the deficient production of IgA in the gut and the study of the immunomodulatory properties of the specific strain of bacteria that we identified.

Participation of BANK1 in the gut B cell response