Inflammation and fibrosis in human pathophysiology

Our aim is to explain how the local microenvironment of affected tissues can shape the immune response to promote an altered reparation process and fibrosis during systemic sclerosis.

Inflammation and fibrosis are two symptoms that appear in many very diverse diseases. We use three different medical environments to analyze the mechanisms behind these conditions: systemic sclerosis, pregnancy-related pathologies, and chronic graft versus host disease (cGVHD).

In each of these pathologies, the onset and manifestations of inflammation and fibrosis are different. They occur on a systemic level in systemic sclerosis, they are localized in pregnancy-related diseases and they are induced by an external graft in cGVHD. These different approaches and the close collaboration between our different work groups, allow us to get an overall picture of what is causing, driving, and sustaining inflammation and fibrosis.

Groupe 1: Systemic sclerosis

Systemic sclerosis (SSc) is a severe autoimmune disease, characterized by fibrosis, vascular abnormalities and autoimmunity. It is difficult to estimate the prevalence of systemic sclerosis. According to studies, the figures vary between 1/1300 people to 1/5000 people on average, but there are vast geographic variations. In France, an estimated 6000 to 9000 people are affected.
Our major scientific question is to explain how the local microenvironment of affected tissues can shape the immune response to promote an altered reparation process and fibrosis during SSc. We previously identified KLRG1 negative ILC2 as potential key players in skin fibrosis in SSc patients. However, their precise mechanisms of action remain to be determined. We, therefore, plan to:

  1. Study whether ILC2 contributes to fibrotic processes in other tissues, such as the lung.
  2. Decipher the mechanisms by which ILC2 promotes tissue fibrosis using innovative approaches, such as bio-imprinted reconstituted skin.

Apart from ILC, alternatively activated macrophages have emerged as important players in tissue fibrosis during SSc, but the underlying mechanisms of action have not been elucidated yet. We observed that IL-1β-activated microvascular endothelial cells from SSc patients induce monocytes to differentiate into DC-SIGN+-, alternatively activated macrophages producing high levels of CCL18, CCL2 and CXCL8, but no IL-10.
In the skin of SSc patients, DC-SIGN+ macrophages are enriched in the perivascular region and their numbers correlate to skin fibrosis. Our ongoing and future studies aim to characterize immune functions of endothelial cell-induced DC-SIGN+ alternatively activated macrophages and to test whether DC-SIGN targeting could alter these functions both in vitro and in mouse models of SSc.

Group 2: Pregnancy-related pathologies

Pregnancy-related pathologies (in particular vascular-placental pathologies such as intrauterine growth retardation (IUGR), pre-eclampsia and fetal death in utero (FDIU)) are increasingly frequent in France and worldwide for multiple reasons: pregnancy at an advanced maternal age, increase in the incidence of obesity, environmental and socio-economic factors. They are the cause of significant maternal and especially neonatal morbidity and mortality and therefore constitute a major public health issue.

In France, 6 pregnancies per 1000 are affected by fetal death in utero and 10.8 per 100 children from single pregnancies have a low weight for gestational age, i.e., < 10th percentile (2016 national perinatal survey). The incidence of both conditions increases especially if the pregnancy is no longer considered low risk (advanced maternal age, obesity, autoimmune pathology, essential hypertension, nephropathy…). Not only is the incidence of IUGR unfortunately still frequent, even at term, and represents a family tragedy with a prolonged psychological impact on the family, but children born with IUGR event at term have an increased risk throughout their life (compared to those born with a normal weight for gestational age), of neurodevelopmental disorders, but also of metabolic disorders, obesity, diabetes, hypertension, stroke, with possible trans-generational effects.

The causes of IUGR and IUGR are multiple and often interrelated, including congenital and placental anomalies, congenital infections (CMV), vascular, immunological and environmental/toxic causes. However, 30-50% of these IUGRs remain unexplained, which greatly hinders the development of prevention strategies and justifies active research in this area.

It, therefore, seems essential that human and financial resources be made available for research on maternal and fetal health to improve physiopathological knowledge. This will make it possible to optimize patient care and to develop means of prevention to improve perinatal health in France. One of the identified obstacles to fundamental and clinical research on these themes is that it requires excellent cross-disciplinary collaboration by health actors who are not always accustomed to working together daily: gynecologists-obstetricians, internists or immunologists specialized in pregnancy, fetal pathologists, physicians specialized in environmental issues and pregnancy.

All these teams of excellence are now united within the Bordeaux University Hospital and have for the past 5 years initiated collaborative projects in fundamental and clinical research on IUGR/FDIU around two different axes:

  • understand the factors associated with IUGR
  • improve the management of patients with a history of IUGR.

Groupe 3: Chronic Graft versus Host Disease

Chronic Graft versus Host Disease (cGVHD) is a major complication of allogeneic stem cell transplantation performed for hematological malignancies. cGVHD is occurring in 30-60% of patients responsible for major morbidity and mortality, but it also reflects the alloreactive potential of the graft and the cancer curative effect.

We intend to decipher cGVHD pathogenesis to develop new prophylactic and curative options, and also because cGVHD represents a model sharing clinical and biological similarities with SSc. We previously showed the role of a T cell population with a mixed signature (Th1/Th17) with enhanced trafficking capacities and interrogated the role of Germinal Center-like reaction in cGVHD pathogenesis through the analysis of T follicular helper cells from the blood (cTFH), showing increased activation, decreased number in the blood, a skewed Th2/Th17 phenotype, and increased capacity to help B cells promoting B cell maturation and differentiation into antibody-secreting B cells, a hallmark of cGVHD pathogenesis. The role of TFH and GC reaction in the fibrosis observed during cGVHD remains to be elucidated.

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