Articles scientifiques

“Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology


2018/Front Immunol. 2019 May;9;9:966.


Jung S, Gàmez-Diaz L, Projetti M, Grimbacher B.



Primary immunodeficiencies (PIDs) represent a group of mostly monogenic disorders caused by loss- or gain-of-function mutations in over 340 known genes that lead to abnormalities in the development and/or the function of the immune system. However, mutations in different genes can affect the same cell-signaling pathway and result in overlapping clinical phenotypes. In particular, mutations in the genes encoding for members of the phosphoinositide3-kinase (PI3K)/AKT/mTOR/S6 kinase (S6K) signaling cascade or for molecules interacting with this pathway have been associated with different PIDs that are often characterized by the coexistence of both immune deficiency and autoimmunity. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR), which acts downstream of PI3K and AKT, is emerging as a key regulator of immune responses. It integrates a variety of signals from the microenvironment to control cell growth, proliferation, and metabolism. mTOR plays therefore a central role in the regulation of immune cells’ differentiation and functions. Here, we review the different PIDs that share an impairment of the PI3K/AKT/mTOR/S6K pathway and we propose to name them “immune TOR-opathies” by analogy with a group of neurological disorders that has been originally defined by PB Crino and that are due to aberrant mTOR signaling (1). A better understanding of the role played by this complex intracellular cascade in the pathophysiology of “immune TOR-opathies” is crucial to develop targeted therapies.

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Flare of IGA glomerulonephritis under G-CSF stimulation regimen for autologous stem cell transplantation in systemic sclerosis


2020/Rheumatology. 2020 January


Blandine Guffroy, Maxime Ingwiller, Pierre-Edouard Gavand, Bastien Bouldoires, Thierry Krummel, Bruno Lioure, Thierry Martin, Aurélien Guffroy.

SSc is a rare systemic autoimmune disease characterized by microvascular impairment and fibrosis of the skin and other organs, with poor outcomes. Conventional immunosuppressive therapies have a limited impact in diffuse and severe forms of SSc. The best therapeutic strategy to date, demonstrated by two phase III randomized trials, is autologous hematopoietic stem cell transplantation (AHSCT), consisting of immune rebooting with chemotherapy and immune reconstitution by reinjection of autologous hematopoietic stem cells. This procedure requires collection of circulating stem cells after a mobilization step, usually consisting of chemotherapy (often CYC) plus G-CSF stimulation.


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Transitional B cells in quiescent SLE: An early checkpoint imprinted by IFN

2019/J Autoimmun. 2019 Aug;102:150-158.

Dieudonné Y, Gies V, Guffroy A, Keime C, Bird AK, Liesveld J, Barnas JL, Poindron V, Douiri N, Soulas-Sprauel P, Martin T, Meffre E, Anolik JH, Korganow AS.


Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells.


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Hughes-Stovin syndrome: About one case in a young man with recurrent thrombosis and pulmonary artery aneurysm and literature review

2019/Rev Med Interne. 2019 Feb;40(2):120-125.

El Jammal T, Gavand PE, Martin M, Korganow AS, Guffroy A.



First described in 1959, Hughes-Stovin syndrome is a very rare disorder combining vascular aneurysms, especially from pulmonary arteries, and thrombosis. The disease affects mostly the young male and is sometime associated with Behçet’ disease.


Here, we report the case of a 19-year-old man with hemoptysis and dyspnea revealing recurrent pulmonary embolisms despite efficient anticoagulant therapy. The patient subsequently developed fever and an inflammatory syndrome. Physical examination showed ulcers of the tongue. Angio-CT revealed recent pulmonary embolism, femoral vein thrombosis, and a unique threatening aneurysm of a left pulmonary artery segment. The aneurysm was embolized and simultaneously a vena cava filter was inserted.


Hughes-Stovin syndrome requires immediate therapeutic decision, with an important risk of the anticoagulation. High dose steroids and in most cases, intensive immunosuppressive therapies are required such as cyclophosphamide.


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Adolescents and young adults (AYAs) affected by chronic immunological disease: A tool-box for success during the transition to adult care

2018/Clin Immunol. 2018 Dec;197:198-204.

Guffroy A, Martin T, Korganow AS.


Adolescence is a time of physical, psychological and social changes between childhood and adulthood. All adolescents and young adults (AYAs) are in transition and experience key underlying processes that will influence their later life. It is a critical period, particularly for AYAs with a chronic medical condition. Diseases can start at any point during adolescence. The transition of care will concern health care providers, as well as more unexpected actors such as social workers, teachers, business managers and the family. In this review, we focus on transition in primary immunodeficiencies (PIDs) and autoimmune diseases (AIDs). We describe the challenges and needs of transition in the field. Questions that AYAs with PID and/or AID must face during transition in their familial, professional and personal life are discussed. We expose a practical, AYA centered approach to help physicians in their daily practice, and we propose a position for the future.


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Persitent Acrocyanosis-A Rare Manifestation Revealing Anti-PL-12 Syndrome

2018/Arthritis Rheumatol. 2018 Oct;70(10):1698.

Mertz P, Herber M, Jeannel J, Korganow AS, Guffroy A.

The patient, a 69‐year‐old woman with asthenia, anorexia, and weight loss of several weeks’ duration, was referred for a subacute onset of painful permanent acrocyanosis of the arms and legs without Raynaud’s phenomenon. The patient had concomitantly developed grade I/IV dyspnea. Physical examination revealed livedoid acrocyanosis of distal phalanges of the hands (A), associated with flame‐shaped hemorrhages (B) (arrowheads) and dilated capillaries at the proximal nailfolds (B) (arrow), Gottron’s sign over the metacarpophalangeal and proximal interphalangeal joints, and a discrete heliotrope rash with a palpable V‐shaped rash on the upper chest and forehead. Fine bibasilar crackles were present, and computed tomography showed interstitial lung disease (ILD) (C). Immunodot assay revealed anti–PL‐12 antibodies. Anti–PL‐12 syndrome is usually described as an amyopathic cluster in anti–aminoacyl–transfer RNA synthetase syndrome (ARS). Pulmonary involvement is the most common leading manifestation, with most cases presenting as isolated ILD with dyspnea 1, 2. Acute ischemic phenomena are rare in ARS and are generally associated with a history of Raynaud’s phenomenon. In our case, the discovery of vascular abnormalities of the arms and legs is what led us to the diagnosis of ARS. Little is known about the pathogenesis of subacute vascular manifestations in ARS. It might be due to several causes of immune‐mediated vasculopathy 3. The patient’s clinical manifestations initially responded well to high‐dose steroid therapy and prostaglandin infusion (D), but she experienced a recurrence with cold weather on day 28 (E and F). The treatment regimen was replaced with intravenous pulse cyclophosphamide and bosentan with a satisfactory outcome by day 63 (G–I). In addition to classic dermatologic manifestations, such as Gottron’s papules, mechanic hands, or cuticular overgrowth, physicians should note the existence of uncommon acral manifestations, such as ischemic symptoms, that can also indicate ARS and an increased risk of developing necrosis.


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Trib 1 Is Overexpressed in Systemic Lupus Erythematosus, while It Regulates Immunoglobulin Production in Murine B Cells

2018/Front immunol. 2018 Mars;15;9:373.

Simoni L, Delgado V, Ruer-Laventie J, Bouis D, Soley A, Heyer V, Robert I, Gies V, Martin T, Korganow AS, Reina-San-Martin B, Soulas-Sprauel P.


Systemic lupus erythematosus (SLE) is a severe and heterogeneous autoimmune disease with a complex genetic etiology, characterized by the production of various pathogenic autoantibodies, which participate in end-organ damages. The majority of human SLE occurs in adults as a polygenic disease, and clinical flares interspersed with silent phases of various lengths characterize the usual evolution of the disease in time. Trying to understand the mechanism of the different phenotypic traits of the disease, and considering the central role of B cells in SLE, we previously performed a detailed wide analysis of gene expression variation in B cells from quiescent SLE patients. This analysis pointed out an overexpression of TRIB1. TRIB1 is a pseudokinase that has been implicated in the development of leukemia and also metabolic disorders. It is hypothesized that Trib1 plays an adapter or scaffold function in signaling pathways, notably in MAPK pathways. Therefore, we planned to understand the functional significance of TRIB1 overexpression in B cells in SLE. We produced a new knock-in model with B-cell-specific overexpression of Trib1. We showed that overexpression of Trib1 specifically in B cells does not impact B cell development nor induce any development of SLE symptoms in the mice. By contrast, Trib1 has a negative regulatory function on the production of immunoglobulins, notably IgG1, but also on the production of autoantibodies in an induced model. We observed a decrease of Erk activation in BCR-stimulated Trib1 overexpressing B cells. Finally, we searched for Trib1 partners in B cells by proteomic analysis in order to explore the regulatory function of Trib1 in B cells. Interestingly, we find an interaction between Trib1 and CD72, a negative regulator of B cells whose deficiency in mice leads to the development of autoimmunity. In conclusion, the overexpression of Trib1 could be one of the molecular pathways implicated in the negative regulation of B cells during SLE.


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Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus


2018/JCI Insight. 2018 Mars 8;3(5).


Gies V, Schickel JN, Jung S, Joublin A, Glauzy S, Knapp AM, Soley A, Poindron V, Guffroy A, Choi JY, Gottenberg JE, Anolik JH, Martin T, Soulas-Sprauel P, Meffre E, Korganow AS.


B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.


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Primary immunodeficiencies and lymphoma: a systematic review of literature.

2019/Leuk Lymphoma. 2019 Oct 3:1-11.

Herber M, Mertz P, Dieudonné Y, Guffroy B, Jung S, Gies V, Korganow AS, Guffroy A.


The management of lymphoma in patients with primary immunodeficiency (PID) is challenging because of its poor prognosis and complex therapeutic approaches. We conducted a systematic literature review of case-reports, case-series, and cohorts indexed in MEDLINE reporting the association of lymphoma and PID. One hundred and eighty-two articles were selected out of 787. We identified 386 cases. Median age at diagnosis of PID and lymphoma was 9.5 and 12 years old, respectively. T-cell deficiencies were the main PIDs associated with lymphoma (57%). The most prevalent lymphoma was diffuse large B-cell lymphoma (33.5%). Epstein-Barr Virus-driven lymphomas were mostly observed in innate immunodeficiencies (when reported). Complete response to treatment was observed in 65.8% of the cases. Death occurred in 38.2%. Few allogenic stem cell transplantations were performed (29 cases). Our detailed analysis of the literature provides a landscape of lymphoma’s occurrence in PID. Devoted studies in specific sub-groups of patients at risk are needed to develop dedicated protocols.


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Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement-A new target for lupus treatment.

2019/ Sci Adv. 2019 Jul 10;5(7):eaav9019.


Smith N, Rodero MP, Bekaddour N, Bondet V, Ruiz-Blanco YB, Harms M, Mayer B, Bader-Meunier B, Quartier P, Bodemer C, Baudouin V, Dieudonné Y, Kirchhoff F, Sanchez Garcia E, Charbit B, Leboulanger N, Jahrsdörfer B, Richard Y, Korganow AS, Münch J, Nisole S, Duffy D, Herbeuval JP.


Type I interferons are highly potent cytokines essential for self-protection against tumors and infections. Deregulations of type I interferon signaling are associated with multiple diseases that require novel therapeutic options. Here, we identified the small molecule, IT1t, a previously described CXCR4 ligand, as a highly potent inhibitor of Toll-like receptor 7 (TLR7)-mediated inflammation. IT1t inhibits chemical (R848) and natural (HIV) TLR7-mediated inflammation in purified human plasmacytoid dendritic cells from blood and human tonsils. In a TLR7-dependent lupus-like model, in vivo treatment of mice with IT1t drives drastic reduction of both systemic inflammation and anti-double-stranded DNA autoantibodies and prevents glomerulonephritis. Furthermore, IT1t controls inflammation, including interferon α secretion, in resting and stimulated cells from patients with systemic lupus erythematosus. Our findings highlight a groundbreaking immunoregulatory property of CXCR4 signaling that opens new therapeutic perspectives in inflammatory settings and autoimmune diseases.

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