Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease

International audienceABSTRACT: INTRODUCTION: T cell abnormalities have been associated with the pathogenesis of systemic sclerosis (SSc). Recently, besides T helper (Th)17 cells the Th22 subset has been identified in humans. Our purpose was to investigate the pattern of cytokines produced and chemokine-receptors expressed by peripheral blood (PB) Th cells in SSc and healthy donors (HD) focusing on cells producing interleukin (IL)-17 and IL-22 and to identify specific clinical associations. METHODS: Clinical data and peripheral blood were collected in 33 SSc individuals and 29 HD. IL-17A, IL-22, interferon gamma (IFN-gamma, IL-4 production, the chemokine receptors CCR4, CCR6, CCR10, CXCR3 expression and the CD161 Th17 cell marker were assessed by multiparametric flow cytometry in PB CD4+ T cells. Intracellular cytokine accumulation was further investigated in CD4+ T cells expanded in vitro for 7 days. RESULTS: The frequency of Th22, Th17, Th2 but not Th1 cells was significantly increased in SSc individuals compared to HD. The percentage of CD161+CD4+ T cells was increased in SSc and correlated with the percentage of IL-17A producing cells. Moreover, the expression of the skin- and lung-homing chemokine receptor CCR6 correlated with the frequency of IL-22 and IL-17A-producing cells in SSc but not in HD. Finally, SSc interstitial lung disease (ILD) was strongly associated with higher numbers of IL-22 and, to a lesser extent, IL-17A-producing cells. CONCLUSIONS: IL-22 and IL-17A-producing T cells with skin- and lung-homing capabilities are characteristically increased in SSc. These findings support the hypothesis that Th22 in addition to Th17 cells may be involved in pathological processes leading to SSc. While the association between IL-22 producing cells and ILD needs to be assessed in larger cohorts of patients, the increased frequency of Th22 cells appears to be a useful novel biomarker in SSc

Case Report Disabling Orthostatic Headache after Penetrating Stonemason Pencil Injury to the Sacral Region

Penetrating injuries to the spine, although less common than motor vehicle accidents and falls, are important causes of injury to the spinal cord. They are essentially of two varieties: gunshot or stab wounds. Gunshot injuries to the spine are more commonly described. Stab wounds are usually inflicted by knife or other sharp objects. Rarer objects causing incidental spinal injuries include glass fragments, wood pieces, chopsticks, nailguns, and injection needles. Just few cases of penetrating vertebral injuries caused by pencil are described. The current case concerns a 42-year-old man with an accidental penetrating stonemason pencil injury into the vertebral canal without neurological deficit. After the self-removal of the foreign object the patient complained of a disabling orthostatic headache. The early identification and treatment of the intracranial hypotension due to the posttraumatic cerebrospinal fluid (CSF) sacral fistulae were mandatory to avoid further neurological complications. In the current literature acute pattern of intracranial hypotension immediately after a penetrating injury of the vertebral column has never been reported

In Vivo Dioxin Favors Interleukin-22 Production by Human CD4+ T Cells in an Aryl Hydrocarbon Receptor (AhR)-Dependent Manner

The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals.This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells

T cell abnormalities in systemic sclerosis with a focus on Th17 cells

Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular alterations and deregulated fibroblast activation leading to fibrosis of the skin and internal organs. SSc is thought to be an autoimmune disease, owning the presence of auto-antibodies. Genetic studies lend support to the critical role exerted by the immune response in the physiopathology of the disease, since several of the SSc-associated polymorphisms have been found in genes involved in the immune response. Oligoclonal T cells, preferentially producing type 2 cytokines, are present in affected tissues and peripheral blood early in the disease course, and their soluble mediators favor the production of pro-fibrotic and pro-angiogenic factors by fibroblasts, most likely participating in the establishment of fibrosis. More recently, we and others have reported an increased expression of additional T cell subsets, including Th17 cells, and their hallmark cytokines in the peripheral blood, serum and skin of SSc individuals. Here, we will review recent data on the presence of various T helper cells in SSc, and discuss the potential role of Th17 cells in promoting inflammatory responses while keeping fibrosis in check. An understanding of the immune abnormalities characteristic of SSc and their significance, represents a critical step towards the identification of novel therapies that could modify the course of the disease

Is there a role for IL-17 in the pathogenesis of systemic sclerosis?

In systemic sclerosis (SSc) immuno-inflammatory events are central to disease development. Amongst other mediators of inflammation, interleukin 17 (IL-17) and Th17 cells have been reported to be increased in the peripheral blood and target organs including involved skin in SSc. They participate and amplify inflammatory responses by inducing the production of cytokines such as IL-6, chemokines such as CCL2 and CXCL8 (IL-8), matrix metalloproteinases-1, -2, -9 and the expression of adhesion molecules in stromal cells including fibroblasts and endothelial cells. In this respect, IL-17 and Th17 cells behave paradigmatically as documented in other autoimmune pathological conditions or infectious diseases. In experimental animal models of skin and lung fibrosis, IL-17 indirectly enhances the fibrotic process by favoring further inflammation by recruiting inflammatory cells, by activating and/or stimulating the production of TGF-β and other pro-fibrotic mediators, by inhibiting autophagy. Whether the findings generated in animal models of fibrosis can be translated to human SSc is unproven. Furthermore, it is controversial whether IL-17 directly promotes the transdifferentiation of human fibroblasts into myofibroblasts and enhances collagen production, with most of the available evidence against this possibility. The reductionist approach in which fibroblast in monolayers are cultured in plastic dishes under the influence of IL-17 limits the relevance of these findings. Further in vitro/ex vivo models with human tissues are being developed to investigate the real effect of IL-17 on extracellular matrix deposition, since agents blocking IL-17 are available for the clinic and it will be important to know whether their use in SSc would be beneficial or detrimental

Lung pathology in non-thoracic trauma

The sequential pathological changesof the respiratory distress syndrome have been studied in patients with monothoracic trauma by percutaneous lung biopsies. The initial ultramicroscopic changes consisted of accumulation and aggregation of platelets and leukocytes in pulmonary vessels. These were followed by marked interstitial edema and later by changes in alveolar lumen. In some patients fat embolism is the predominant lesion. Pathogenesis of these changes is discusse

Prostaglandin I(2) analogues enhance already exuberant Th17 cell responses in systemic sclerosis

Among pleiotropic effects, the capacity of prostaglandin I(2) (PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI(2) analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD)