CCL19-Positive Lymph Node Stromal Cells Govern the Onset of Inflammatory Arthritis via Tropomyosin Receptor Kinase.

Objective: The study objective was to assess the role of CCL19 lymph node stromal cells of the joint-draining popliteal lymph node (pLN) for the development of arthritis.

Methods: CCL19 lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19-immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results.

Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease.

Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC).

Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets.

Bone turnover is finely tuned by cells in the bone milieu, including osteoblasts, osteoclasts, and osteocytes. Osteoclasts are multinucleated giant cells with a bone-resorbing function that play a critical role in regulating skeletal homeostasis. Osteoclast differentiation is characterized by dramatic changes in morphology and gene expression following receptor activator of nuclear factor-kappa-Β ligand (RANKL) stimulation.

Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive.

RANKL-Induced Btn2a2 - A T Cell Immunomodulatory Molecule - During Osteoclast Differentiation Fine-Tunes Bone Resorption.

Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins' role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts.

Dietary Short-Term Fiber Interventions in Arthritis Patients Increase Systemic SCFA Levels and Regulate Inflammation.

Chronic inflammatory diseases are often initiated and guided by the release of proinflammatory mediators. Rheumatoid arthritis (RA) is caused by an imbalance between the pro- and anti-inflammatory mediators in the joints, thereby favoring chronic inflammation and joint damage. Here, we investigate if short-term high-fiber dietary intervention shifts this towards anti-inflammatory mediators.

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis.

Ethanol consumption inhibits T cell responses and the development of autoimmune arthritis.

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (T) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties.

Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss.

While the role of T cells in the regulation of bone homeostasis is well defined, little is known about the role of innate lymphoid cells (ILCs) on bone. ILCs are innate immune cells that share cytokine expression patterns with T cells but lack the T cell receptor. In this study we show that type 2 ILCs (ILC2) potently inhibit the generation of bone resorbing osteoclasts in vitro as well as favorably influence bone homeostasis under steady state conditions in vivo using loss and gain of function models.

Free Fatty Acids in Bone Pathophysiology of Rheumatic Diseases.

Obesity-in which free fatty acid (FFA) levels are chronically elevated-is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases.

The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study.

Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut-joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis.

Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice.

Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number.

Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss.

Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo.

Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites.

Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory-secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro.

Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes.

Evidence has recently emerged that butyrophilins, which are members of the extended B7 family of co-stimulatory molecules, have diverse functions in the immune system. We found that the human and mouse genes encoding butyrophilin-2A2 (BTN2A2) are regulated by the class II trans-activator and regulatory factor X, two transcription factors dedicated to major histocompatibility complex class II expression, suggesting a role in T cell immunity. To address this, we generated Btn2a2-deficient mice.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production.

Autoantibodies against galectins are associated with antiphospholipid syndrome in patients with systemic lupus erythematosus.

The presence of autoantibodies against immunoregulatory effectors can be relevant for onset and/or the progression of autoimmune disease. Emerging insights into an immunological activity profile including a role as opsonins give reason to systematically monitor sera of patients for immunoglobulin G (IgG) autoantibodies, preferably for several galectins at the same time. Here, we report on a study of chronic inflammatory rheumatic diseases, i.

12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance.

Noninflammatory clearance of apoptotic cells (ACs) is crucial to maintain self-tolerance. Here, we have reported a role for the enzyme 12/15-lipoxygenase (12/15-LO) as a central factor governing the sorting of ACs into differentially activated monocyte subpopulations. During inflammation, uptake of ACs was confined to a population of 12/15-LO-expressing, alternatively activated resident macrophages (resMΦ), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner.

Autoimmunity and chronic inflammation - two clearance-related steps in the etiopathogenesis of SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease with very prominent chronic inflammatory aspects that render into multiple symptoms and clinical signs. The precise etiology of SLE remains elusive; however, it is known that its etiopathogenesis is of multifactorial nature. The production of autoantibodies (AAb) targeting double stranded DNA (dsDNA) and other nuclear autoantigens is the main characteristic of this disease.

Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation.

Objective: Immune activation triggers bone loss. Activated T cells are the cellular link between immune activation and bone destruction. The aim of this study was to determine whether immune regulatory mechanisms, such as naturally occurring Treg cells, also extend their protective effects to bone homeostasis in vivo.

Treatment with DNAse I fosters binding to nec PBMC of CRP.

CRP is an important inflammatory marker, however, CRP levels are relatively low in patients with SLE. In addition patients with SLE often display low activities and serum levels for DNase I and complement, respectively. Here we show that DNase I treatment of nec PBMC increased their binding of CRP.

The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis.

Objective: The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis.

Methods: Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis.

Detection and chromatographic removal of lipopolysaccharide in preparations of multifunctional galectins.

The functional spectrum of human galectins is currently explored, with a wide range of activities being described. The role of galectin-3 as adhesin for bacteria is based on its strong binding to lipopolysaccharides (LPSs), which brings the possibility of such a contamination in galectin preparations to awareness. This assumption was verified in three independent functional assay systems using polymyxin B as inhibitor of LPS-dependent effects.

Human galectins as sensors for apoptosis/necrosis-associated surface changes of granulocytes and lymphocytes.

Changes in the glycomic profile can significantly affect the cells' communication with the environment. Plant lectins have so far been used to address the issue as to whether the courses of apoptosis or necrosis are associated with such alterations. We, here, initiate the study of members of the family of functionally pleiotropic human galectins in this respect.