Neural regulation of immune response
Coordinator : N. GAUDENZIO
The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response. On top of their function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) can also directly sense environmental alarms and consequently regulate the development of various type of immune responses. At the IMMCEPTION LAB, Nicolas GAUDENZIO and his team combine unique genetic models and new intravital imaging approaches to study how neuro-immune interactions can regulate the development of inflammatory reactions in various pathological contexts.
AXE 1: Neuro-immuno interactions in health and disease
Communication between brain and immune system plays a critical role in both physiology and pathology. Neuro-immunology is a new emerging field in biomedical research, as crosstalk between the brain and immune system orchestrates different important types of responses, e.g. the response to bacterial infections within several major barrier tissues, including the skin, lung and the intestinal tract. In the skin, cutaneous nerves play an integral role in modulating bacterial host defences. Cutaneous sensory neurons can sense a wide variety of stimuli, such as heat, chemicals, mechanical stimulation, inflammatory cytokines, and microbial products. Despite their primary function of transmission of sensations, sensory neurons (in particular nociceptors) have been shown to be also potent regulators of immune responses.
A major focus of our lab is to identify molecular mechanisms regulating neuro-immune interactions during allergic skin inflammation (such as atopic dermatitis) and to develop new intravital and multiplex imaging methods to probe such interactions in preclinical models.
AXE 2: Skin aging
The project focuses on the biology of skin aging and is part of the INSPIRE Bio-resource Research Platform for Healthy Aging (INSPIRE platform research initiative, RC31/19/0236) which aims to investigate the interplays between biological aging and the severity of burdensome chronic conditions during aging. The skin is the organ where signs of aging are visible, and thus and indicator of an individual’s health. The main objective of the project is to identify key biomarkers in the skin that are representative of healthy or pathological aging by combining different next generation omics in a cohort of patients from different ages.
AXE 3: Rheumatoid autoimmunity: Autoantibodies against citrullinated proteins - physiopathology
Anti-citrullinated protein autoantibodies (ACPA) : pathophysiology of Rheumatoid Arthritis
The goal of our group is to understand the role played by the autoimmune response to citrullinated proteins in the pathophysiology of rheumatoid arthritis (RA).
Such response translates into the production of anti-citrullinated protein autoantibodies (ACPA), which are notably synthesized in RA joints by plasmocytes of the synovial membrane where an autoantigenic target, citrullinated fibrin, is also abundant.
Presently, our studies are devoted to understanding the contribution to RA synovitis of the disease-specific immune complexes (IC) that form in the synovial membrane following the interaction of ACPA with citrullinated fibrin (ACPA IC). In this tissue, macrophages considerably contribute to inflammation and joint destruction notably because they constitute a major source of tumor necrosis factor (TNF)-α which is a key pro-inflammatory cytokine in the disease. We therefore developed a totally human in vitro model in which monocyte-derived macrophages are stimulated by IC formed between patient-derived ACPA and immobilized citrullinated human fibrinogen.
This model contributed to supporting the hypothesis of the pathophysiological involvement of ACPA as it established the inflammatory potential of ACPA IC by showing they induce TNF-α secretion in which the activating FcgγRII IgG receptor has a major contribution.
Our current projects include the study of the influence of another RA-associated autoantibody, rheumatoid factor, and of the macrophage phenotype on the response to ACPA IC.
Photograph and radiograph of the hands and wrists of a patient with rheumatoid arthritis (left and centre)
Schematic representation of the interaction between ACPA IC and synovial macrophages (right)
Anti-citrullinated protein auto-antibodies : diagnosis and specific immunotherapy
Our group is involved in the study of the rheumatoid arthritis (RA)-specific autoantibodies directed to citrullinated proteins (ACPAs). ACPAs have a high diagnostic value. They are present in up to 80% of sera from RA-patients with a specificity > 98%.
Our laboratory has largely contributed to the characterization of the antigenic targets of ACPAs. In 2001, we identified citrullinated forms of the α- and β-chains of fibrin as major targets of ACPA in the synovial tissue of RA patients. However, several other citrullinated proteins have been shown to be reactive with ACPA in vitro and some of them have been proposed as possible in vivo targets. Our current work aims to demonstrate that there is only one family of ACPA, that their major antigenic target corresponds to citrullinated forms of fibrin and that these autoantibodies variously crossreact with other citrullinated proteins depending on the considered patient serum.
More recently, we identified two peptides α36-50 and β60-74 as bearing the immunodominant epitopes of citrullinated fibrin. Then, we defined three 4- and 5-amino acid-long minimal epitopes that together almost entirely encompass the reactivity of ACPA to citrullinated fibrin for a vast majority of RA-sera. We underwent to develop tests for the detection of each subfamily of ACPA directed to each of those 3 minimal epitopes. These tests will allow to define different groups of patients according to the reactivity of their sera to the 3 minimal epitopes and to evaluate the prognostic value and the predictive value for the response to treatment of ACPA directed to each immunodominant epitope. We are also studying the evolution of the ACPA titer and specificity in response to treatment by anti-CD20 antibodies.
Position of immunoreactive peptides on a schematic ribbon representation of the 3D structure of the fibrinogen molecule
(Eur J Immunol 2006, 36:2250).
Mas-related G protein-coupled receptors (Mrgprs) - Key regulators of neuroimmune interactions Journal Article
Neuroscience Letters, 2021, ISSN: 03043940.
IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus. Journal Article
Immunity, 53 (4), pp. 793–804.e9, 2020, ISSN: 1097-4180 (Electronic).
Omalizumab in the treatment of adult patients with mastocytosis: A systematic review. Journal Article
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 50 (6), pp. 654–661, 2020, ISSN: 1365-2222 (Electronic).
Rapid identification of human mast cell degranulation regulators using functional genomics coupled to high-resolution confocal microscopy. Journal Article
Nature protocols, 15 (3), pp. 1285–1310, 2020, ISSN: 1750-2799 (Electronic).
Nociceptor-Mast Cell Sensory Clusters as Regulators of Skin Homeostasis. Journal Article
Trends in neurosciences, 43 (3), pp. 130–132, 2020, ISSN: 1878-108X (Electronic).
MRGPRX2 sensing of cationic compounds—A bridge between nociception and skin diseases? Journal Article
Experimental Dermatology, 2020, ISSN: 16000625.
Annual Review of Immunology, 5 , 2020.
Peripheral neurons: Master regulators of skin and mucosal immune response. Journal Article
European journal of immunology, 49 (11), pp. 1984–1997, 2019, ISSN: 1521-4141 (Electronic).
A Connective Tissue Mast-Cell-Specific Receptor Detects Bacterial Quorum-Sensing Molecules and Mediates Antibacterial Immunity. Journal Article
Cell host & microbe, 26 (1), pp. 114–122.e8, 2019, ISSN: 1934-6069 (Electronic).
House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation Journal Article
Nature Immunology, 2019, ISSN: 15292916.
Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity. Journal Article
Frontiers in immunology, 9 , pp. 1275, 2018, ISSN: 1664-3224 (Print).
Human mast cells as antigen-presenting cells: When is this role important in vivo? Miscellaneous
2018, ISSN: 1097-6825 (Electronic).
Imaging protective mast cells in living mice during severe contact hypersensitivity. Journal Article
JCI insight, 2 (9), 2017, ISSN: 2379-3708 (Electronic).
Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. Journal Article
The Journal of experimental medicine, 214 (5), pp. 1249–1258, 2017, ISSN: 1540-9538 (Electronic).
Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling. Journal Article
Cell, 168 (6), pp. 1041–1052.e18, 2017, ISSN: 1097-4172 (Electronic).
Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis. Journal Article
The Journal of allergy and clinical immunology, 139 (3), pp. 889–899.e11, 2017, ISSN: 1097-6825 (Electronic).
Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. Journal Article
The Journal of allergy and clinical immunology, 139 (2), pp. 584–596.e10, 2017, ISSN: 1097-6825 (Electronic).
Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. Journal Article
The Journal of clinical investigation, 126 (12), pp. 4497–4515, 2016, ISSN: 1558-8238 (Electronic).
A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. Journal Article
Nature communications, 7 , pp. 13696, 2016, ISSN: 2041-1723 (Electronic).
Neutrophils are not required for resolution of acute gouty arthritis in mice. Miscellaneous
2016, ISSN: 1546-170X (Electronic).
Different activation signals induce distinct mast cell degranulation strategies. Journal Article
The Journal of clinical investigation, 126 (10), pp. 3981–3998, 2016, ISSN: 1558-8238 (Electronic).
Melanoma cell lysosome secretory burst neutralizes the CTL-mediated cytotoxicity at the lytic synapse. Journal Article
Nature communications, 7 , pp. 10823, 2016, ISSN: 2041-1723 (Electronic).
IgE antibodies, Fc$epsilon$RI$alpha$, and IgE-mediated local anaphylaxis can limit snake venom toxicity. Journal Article
The Journal of allergy and clinical immunology, 137 (1), pp. 246–257.e11, 2016, ISSN: 1097-6825 (Electronic).
Impact on society
Atopic dermatitis is an inflammatory skin disease that affects up to 20% of children and 5% of adults in Western countries. The quality of life of these people is affected by pain and severe itching. Our research activity aims to create a synergy between several disciplines to better understand the causes of the disease and to assess how immune cells interact with other components, in particular with nerve fibers.
Xinzhong Dong, Johns Hopkins University, USA
Stephen J Galli & Mindy Tsai, Stanford University, USA
Christophe Altier, University of Calgary, Canada
Rebecca Gentek, University of Edinburg, Scotland
Thomas Marichal, University of Liege, Belgium
Gunnar Pejler, Uppsala University, Sweden
Vassilis Pachnis, The Francis Crick Institute, King’s College, London, UK
Philipp Starkl, University of Vienna, Austria
Nicolas Cenac & Gilles Dietrich, IRSD Inserm, Toulouse, France
Claude Knauf, IRSD Inserm, Toulouse, France
Jean François Nicolas & Audrey Nosbaum, Lyon University Hospital, France
Genoskin Inc, Toulouse, France
Pierre Fabre, Toulouse, France
Laurent Reber, Infinity, Toulouse, France
Michel Simon, Infinity, Toulouse, France
Nicolas Fazilleau, Infinity, Toulouse, France
Nicolas Blanchard, Infinity, Toulouse, France
Carle Paul, Toulouse University Hospital & Infinity, France
We are thrilled to announce that our PhD student, Nadine Serhan from Lebanon, just received the L’Oreal-Unesco Award for Women in Science for her brilliant PhD. Congrats Nadine!
Thanks a lot to the media « La Dépêche » for this nice article about atopic eczema destined to an audience of non specialist.
Our last invited review on the role of mast cells in inflammation and disease is now out in the Annual Review of Immunology !
Atopic dermatitis: allergens are playing with your nerves !
We are thrilled to see our last study published in Nature Immunology. Congratulations to Nadine Serhan and Lilian Basso for their fantastic work selected for the cover of November issue !
Lab data gallery
Whole mouse skin 3D staining of peripheral neurons (PGP9.5 yellow) and cells nucleus (DAPI cyan)
Claudin 1 expression (red) and cells nucleus (DAPI cyan) in mouse epidermis
3D image of a human primary mast cell degranulated in a matrigel (exteriorized granules are stained using fluorochrome-labeled avidin, red)
Mouse lymph node section stained with a combination of 7 antibodies to identify different populations of immune cells. Confocal microscopy.
Modeling of substance P expression (green) and mast cell granules (red) in whole mounted skin. Confocal Microscopy and computational analysis.
Dorsal root ganglia (DRG) neurons, subtypes of neurons (red) and nucleus (DAPI, Cyan). 3D confocal microscopy.
Activated TRPV1+ sensory neurons (genetically-encoded calcium tracer, cyan) and degranulated mast cells (avidin, red). Intravital two-photon microscopy of mouse ear dermis.
Video 3. Monitoring of mast cell granules (red) and blood flow (green) in living mice sensitized with DNP-specific IgE and injected with vehicle. Intravital two-photon microscopy of the skin. Reber et al. JCI Insight 2017.