Langerhans cells regulate immunity in adulthood by regulating postnatal dermal lymphatic development.

The communication between skin and draining lymph nodes is crucial for well-regulated immune responses to skin insults. The skin sends antigen and other signals via lymphatic vessels to regulate lymph node activity, and regulating dermal lymphatic function is another means to control immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, mediate dermal lymphatic expansion and phenotype acquisition postnatally, a function is independent of LC entry into lymphatic vessels. This postnatal LC-lymphatic axis serves in part to control inflammatory systemic T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.

Role of the afferent lymph as an immunological conduit to analyze tissue antigenic and inflammatory load.

The lymphatic fluid is the conduit by which part of the tissue "omics" is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the lymph inflammatory and damage-associated molecular pattern signatures, microbiome-derived by-products, and immunomodulatory molecules, including metabolites of the gut-brain axis, mapped in the afferent mesenteric lymph. Our data point to the relevance of the lymphatic fluid to probe the tissue-specific antigenic and inflammatory load transported to the draining lymph node for immunosurveillance.

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

Vitamin D and SARS-CoV-2 Infection: SERVE Study (SARS-CoV-2 Exposure and the Role of Vitamin D among Hospital Employees).

BACKGROUND: Recognition of the role of vitamin D in immune function has led to interest in its relationship with SARS-CoV-2 infection. Although clinical studies to date have had conflicting results, many individuals currently take high doses of vitamin D to prevent infection. OBJECTIVE: The goal of this study was to investigate the relationship between serum 25-hydroxyvitamin D (25OHD) and vitamin D supplement use with incident SARS-CoV-2 infection. METHODS: In this prospective cohort study, 250 health care workers were enrolled at a single institution and observed for 15 mo. Participants completed questionnaires every 3 mo regarding new SARS-CoV-2 infection, vaccination, and supplement use. Serum was drawn at baseline, 6, and 12 mo for 25OHD and SARS-CoV-2 nucleocapsid antibodies. RESULTS: The mean age of the participants was 40 y, BMI 26 kg/m2, 71% were Caucasian, and 78% female. Over 15 mo, 56 participants (22%) developed incident SARS-CoV-2 infections. At baseline, ∼50% reported using vitamin D supplements (mean daily dose 2250 units). Mean serum 25OHD was 38 ng/mL. Baseline 25OHD did not predict incident SARS-CoV-2 infection (OR: 0.98; 95% CI: 0.80, 1.20). Neither the use of vitamin D supplements (OR: 1.18; 95% CI: 0.65, 2.14) or supplement dose was associated with incident infection (OR: 1.01 per 100-units increase; 95% CI: 0.99, 1.02). CONCLUSION: In this prospective study of health care workers, neither serum 25OHD nor the use of vitamin D supplements was associated with the incident SARS-CoV-2 infection. Our findings argue against the common practice of consuming high-dose vitamin D supplements for the presumed prevention of COVID-19.

Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure.

AIMS: Growing evidence correlate the accrual of the sphingolipid ceramide in plasma and cardiac tissue with heart failure (HF). Regulation of sphingolipid metabolism in the heart and the pathological impact of its derangement remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of endoplasmic reticulum, abundant in the vascular wall, down-regulates the sphingolipid de novo biosynthesis via serine palmitoyltransferase (SPT), first and rate liming enzyme, to impact vascular functions and blood pressure. Nogo-A, a splice isoform of Nogo, is transiently expressed in cardiomyocyte (CM) following pressure overload. Cardiac Nogo is up-regulated in dilated and ischaemic cardiomyopathies in animals and humans. However, its biological function in the heart remains unknown. METHODS AND RESULTS: We discovered that Nogo-A is a negative regulator of SPT activity and refrains ceramide de novo biosynthesis in CM exposed to haemodynamic stress, hence limiting ceramide accrual. At 7 days following transverse aortic constriction (TAC), SPT activity was significantly up-regulated in CM lacking Nogo-A and correlated with ceramide accrual, particularly very long-chain ceramides, which are the most abundant in CM, resulting in the suppression of 'beneficial' autophagy. At 3 months post-TAC, mice lacking Nogo-A in CM showed worse pathological cardiac hypertrophy and dysfunction, with ca. 50% mortality rate. CONCLUSION: Mechanistically, Nogo-A refrains ceramides from accrual, therefore preserves the 'beneficial' autophagy, mitochondrial function, and metabolic gene expression, limiting the progression to HF under sustained stress.

Mammalian Target of Rapamycin Pathway Assessment in Antiphospholipid Antibody-Positive Patients with Livedo.

OBJECTIVE: In antiphospholipid antibody (aPL) nephropathy, activation of the mammalian target of rapamycin (mTOR) contributes to endothelial cell proliferation, a key finding of aPL microvascular disease. Here, we examined mTOR activation in the skin of aPL-positive patients with livedo. METHODS: Three patient groups with livedo were studied: (1) persistently aPL-positive with systemic lupus erythematosus (SLE); (2) persistently aPL-positive without SLE; and (3) aPL-negative SLE (control). After collecting aPL-related medical history, two 5-mm skin biopsies of livedo were performed on each patient: (1) peripheral (erythematous-violaceous lesion); and (2) central (nonviolaceous area). We stained specimens for phosphorylated protein kinase B (p-AKT) and phosphorylated S6 ribosomal protein (p-S6RP) as mTOR activity markers, CD31 to identify endothelial cells, and Ki-67 to show cellular proliferation. We counted cells in the epidermis and compared mTOR-positive cell counts between peripheral and central samples, and between patient groups, using Freidman test and Wilcoxon signed-rank test. RESULTS: Ten patients with livedo reticularis were enrolled: 4 aPL-positive without SLE (antiphospholipid syndrome [APS] classification met, n = 3), 4 aPL-positive SLE (APS classification met, n = 3), and 2 aPL-negative SLE (control). In all aPL-positive patients, epidermal p-AKT and p-S6RP staining were significantly increased in both peripheral and central skin samples when compared to aPL-negative SLE controls; both were more pronounced in the lower basal layers of epidermis. CONCLUSION: Our study demonstrates increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE, with more prominent activity in the lower basal layers of the epidermis. These findings may serve as a basis for further investigating the mTOR pathway in aPL-positive patients.

Advances in understanding and examining lymphatic function: relevance for understanding autoimmunity.

PURPOSE OF REVIEW: The aim of this review is to give insights into how novel lymphatics functions may influence autoimmunity. RECENT FINDINGS: The lymphatic system connects peripheral tissues to draining lymph nodes to regulate adaptive immunity and directly interfaces with leukocytes in lymph vessels and in the lymph node. Here, we discuss recent findings showing evidence of dysfunctional lymphatics in autoimmune disease, new understanding of how afferent lymphatic regulation can modulate immunity, lymph node lymphatic heterogeneity and how these lymphatics can directly modulate lymphocyte function, how this understanding can be harnessed for new therapeutics, and new tools for the investigation of lymphatic and immune biology. SUMMARY: Lymphatics have an active role in the regulation of inflammation and the adaptive immune response. Here, we review recent findings in lymphatics biology in peripheral tissues and lymph nodes and emphasize the relevance for better understanding autoimmune diseases.

Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.

Exogenous administration of lymphangiogenic growth factors is widely used to study changes in lymphatic function in pathophysiology. However, this approach can result in off-target effects, thereby generating conflicting data. To circumvent this issue, we modulated intracellular VEGF-C signaling by conditionally knocking out the lipid phosphatase PTEN using the Vegfr3 promoter to drive the expression of Cre-lox in lymphatic endothelial cells (LECs). PTEN is an intracellular brake that inhibits the downstream effects of the activation of VEGFR3 by VEGF-C. Activation of Cre-lox recombination in adult mice resulted in an expanded functional lymphatic network due to LEC proliferation that was independent of lymphangiogenic growth factor production. Furthermore, compared with lymphangiogenesis induced by VEGF-C injection, LECPTEN animals had mature, nonleaky lymphatics with intact cell-cell junctions and reduced local tissue inflammation. Last, compared with wild-type or VEGF-C-injected mice, LECPTEN animals had an improved capacity to resolve inflammatory responses. Our findings indicate that intracellular modulation of lymphangiogenesis is effective in inducing functional lymphatic networks and has no off-target inflammatory effects.

T2B or not to B: Calming neutrophils offshore.

In this issue of JEM, Podstawka et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210409) show that B cells can limit neutrophil responses within the lung microvasculature by marginating and acting on marginated neutrophils. This study provides a new view of B cells and reveals a novel mechanism of cell-mediated intravascular regulation.

Targeted truncation of the ADAM17 cytoplasmic domain in mice results in protein destabilization and a hypomorphic phenotype.

A disintegrin and metalloprotease 17 (ADAM17) is a cell-surface metalloprotease that serves as the principle sheddase for tumor necrosis factor α (TNFα), interleukin-6 receptor (IL-6R), and several ligands of the epidermal growth factor receptor (EGFR), regulating these crucial signaling pathways. ADAM17 activation requires its transmembrane domain, but not its cytoplasmic domain, and little is known about the role of this domain in vivo. To investigate, we used CRISPR-Cas9 to mutate the endogenous Adam17 locus in mice to produce a mutant ADAM17 lacking its cytoplasmic domain (Adam17Δcyto). Homozygous Adam17Δcyto animals were born at a Mendelian ratio and survived into adulthood with slightly wavy hair and curled whiskers, consistent with defects in ADAM17/EGFR signaling. At birth, Adam17Δcyto mice resembled Adam17-/- mice in that they had open eyes and enlarged semilunar heart valves, but they did not have bone growth plate defects. The deletion of the cytoplasmic domain resulted in strongly decreased ADAM17 protein levels in all tissues and cells examined, providing a likely cause for the hypomorphic phenotype. In functional assays, Adam17Δcyto mouse embryonic fibroblasts and bone-marrow-derived macrophages had strongly reduced ADAM17 activity, consistent with the reduced protein levels. Nevertheless, ADAM17Δcyto could be stimulated by PMA, a well-characterized posttranslational activator of ADAM17, corroborating that the cytoplasmic domain of endogenous ADAM17 is not required for its rapid response to PMA. Taken together, these results provide the first evidence that the cytoplasmic domain of ADAM17 plays a pivotal role in vivo in regulating ADAM17 levels and function.

Immune Cell-Stromal Circuitry in Lupus Photosensitivity.

Photosensitivity is a sensitivity to UV radiation (UVR) commonly found in systemic lupus erythematosus (SLE) patients who have cutaneous disease. Upon even ambient UVR exposure, patients can develop inflammatory skin lesions that can reduce the quality of life. Additionally, UVR-exposed skin lesions can be associated with systemic disease flares marked by rising autoantibody titers and worsening kidney disease. Why SLE patients are photosensitive and how skin sensitivity leads to systemic disease flares are not well understood, and treatment options are limited. In recent years, the importance of immune cell-stromal interactions in tissue function and maintenance is being increasingly recognized. In this review, we discuss SLE as an anatomic circuit and review recent findings in the pathogenesis of photosensitivity with a focus on immune cell-stromal circuitry in tissue health and disease.

Fibroblast subtypes in tissues affected by autoimmunity: with lessons from lymph node fibroblasts.

The recent advent of single-cell technologies has fast-tracked the discovery of multiple fibroblast subsets in tissues affected by autoimmune disease. In recent years, interest in lymph node fibroblasts that support and regulate immune cells has also grown, leading to an expanding framework of stromal cell subsets with distinct spatial, transcriptional, and functional characteristics. Inflammation can drive tissue fibroblasts to adopt a lymphoid tissue stromal cell phenotype, suggesting that fibroblasts in diseased tissues can have counterparts in lymphoid tissues. Here, we examine fibroblast subsets in tissues affected by autoimmunity in the context of knowledge gained from studies on lymph node fibroblasts, with the ultimate aim to better understand stromal cell heterogeneity in these immunologically reactive tissues.

Lymph node stromal CCL2 limits antibody responses.

Nonhematopoietic stromal cells in lymph nodes such as fibroblastic reticular cells (FRCs) can support the survival of plasmablasts and plasma cells [together, antibody-forming cells (AFCs)]. However, a regulatory function for the stromal compartment in AFC accumulation has not been appreciated. Here, we show that chemokine ligand 2 (CCL2)-expressing stromal cells limit AFC survival. FRCs express high levels of CCL2 in vessel-rich areas of the T cell zone and the medulla, where AFCs are located. FRC CCL2 is up-regulated during AFC accumulation, and we use lymph node transplantation to show that CCL2 deficiency in BP3+ FRCs and lymphatic endothelial cells increases AFC survival without affecting B or germinal center cell numbers. Monocytes are key expressers of the CCL2 receptor CCR2, as monocyte depletion and transfer late in AFC responses increases and decreases AFC accumulation, respectively. Monocytes express reactive oxygen species (ROS) in an NADPH oxidase 2 (NOX2)-dependent manner, and NOX2-deficient monocytes fail to reduce AFC numbers. Stromal CCL2 modulates both monocyte accumulation and ROS production, and is regulated, in part, by manipulations that modulate vascular permeability. Together, our results reveal that the lymph node stromal compartment, by influencing monocyte accumulation and functional phenotype, has a regulatory role in AFC survival. Our results further suggest a role for inflammation-induced vascular activity in tuning the lymph node microenvironment. The understanding of stromal-mediated AFC regulation in vessel-rich environments could potentially be harnessed to control antibody-mediated autoimmunity.

Adaptive and innate immune cell responses in tendons and lymph nodes after tendon injury and repair.

Tendon injuries are a common clinical condition with limited treatment options. The cellular components of the innate immune system, such as neutrophils and macrophages, have been studied in tendon injuries. However, the adaptive immune system, comprising specialized lymphocytes, plays an important role in orchestrating the healing of numerous tissues, but less is known about these cells in tendon healing. To gain a greater understanding of the biological processes that regulate tendon healing, we determined how the cellular components of the adaptive and innate immune system respond to a tendon injury using two-month-old male mice. We observed that lymphatic vasculature is present in the epitenon and superficial regions of Achilles tendons, and that the lymphatics drain into the popliteal lymph node. We then created an acute Achilles tenotomy followed by repair, and collected tendons and popliteal lymph nodes 1, 2, and 4 wk after injury. Tendon injury resulted in a robust adaptive immune cell response that followed an initial innate immune cell response in tendons and lymph nodes. Monocytes, neutrophils, and macrophages initially accumulated at 1 wk after injury in tendons, while dendritic cells and CD4+ T cells peaked at 2 wk after injury. B cells and CD8+ T cells progressively increased over time. In parallel, immune cells of the popliteal lymph node demonstrated a similarly coordinated response to the injury. These results suggest that there is an adaptive immune response to tendon injury, and adaptive immune cells may play a role in regulating tendon healing.NEW & NOTEWORTHY While the innate immune system, consisting of macrophages and related hematopoietic cells, has been studied in tendon injury, less is known about the adaptive immune system. Using a mouse model of Achilles tendon tenotomy and repair, we observed an adaptive immune cell response, consisting of CD4+ and CD8+ T cells, and B cells, which occur through 4 wk after tendon injury. This response appeared to be coordinated by the draining popliteal lymph node.

Role of type I interferons and innate immunity in systemic sclerosis: unbalanced activities on distinct cell types?

PURPOSE OF REVIEW: The role of type I IFNs (IFN-I) in the promotion of autoimmunity has been well established. However, its role in the skin fibrosis of systemic sclerosis (SSc) is less clear. IFN-I can participate to tissue repair, and, here, we will consider the extent to which IFN-I's role in SSc skin fibrosis may reflect in part IFN-I functions during wound healing. RECENT FINDINGS: Studies are beginning to delineate whether IFN-I has a protective or pathogenic role and how IFN-I affects tissue biology. Recent support for a pathogenic role came from a study depleting plasmacytoid dendritic cells during bleomycin-induced skin fibrosis. The depletion reduced the bleomycin-induced IFN-I-stimulated transcripts and both prevented and reversed fibrosis. Additionally, two recent articles, one identifying SSc endothelial cell injury markers and one showing repressed IFN signaling in SSc keratinocytes, suggest the possibility of unbalanced IFN-I activities on distinct cells types. SUMMARY: Recent results support a pathogenic role for IFN-I in skin fibrosis, and recent studies along with others suggest a scenario whereby SSc skin damage results from too much IFN-I-activity driving vasculopathy in combination with too little IFN-I-mediated epidermal integrity and antifibrotic fibroblast phenotype.

Immunopathogenesis of Juvenile Systemic Sclerosis.

Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.

The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair.

Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

Disruption of the Gut Microbiome Increases the Risk of Periprosthetic Joint Infection in Mice.

BACKGROUND: Periprosthetic joint infection (PJI) is one of the most devastating complications of total joint arthroplasty. Given the mortality and morbidity associated with PJI and the challenges in treating it, there has been increased interest in risk factors that can be modified before surgery. In this study, we used a novel mouse model to consider the role of the gut microbiome as a risk factor for PJI. QUESTIONS/PURPOSES: (1) Does the state of the gut microbiota before surgery influence the likelihood of developing an established infection in a mouse model of PJI? (2) How does the state of the gut microbiota before surgery influence the local and systemic response to the presence of an established infection in a mouse model of PJI? METHODS: Male C57Bl/6 mice were divided into two groups: those with modified microbiome [INCREMENT]microbiome (n = 40) and untreated mice (n = 42). In [INCREMENT]microbiome mice, the gut flora were modified using oral neomycin and ampicillin from 4 weeks to 16 weeks of age. Mice received a titanium tibial implant to mimic a joint implant and a local inoculation of Staphylococcus aureus in the synovial space (10 colony forming units [CFUs]). The proportion of animals developing an established infection in each group was determined by CFU count. The local and systemic response to established infection was determined using CFU counts in surrounding joint tissues, analysis of gait, radiographs, body weight, serum markers of inflammation, and immune cell profiles and was compared with animals that received the inoculation but resisted infection. RESULTS: A greater proportion of animals with disrupted gut microbiota had infection (29 of 40 [73%]) than did untreated animals (21 of 42 [50%]; odds ratio, 2.63, 95% CI, 1.04-6.61; p = 0.035). The immune response to established infection in mice with altered microbiota was muted; serum amyloid A, a marker of systemic infection in mice, was greater than in mice with disrupted gut microbiota with infection (689 µg/dL; range, 68-2437 µg/dL, p < 0.05); infection associated increases in monocytes and neutrophils in the spleen and local lymph node in untreated mice but not were not observed in mice with disrupted gut microbiota. CONCLUSIONS: The findings from this in vivo mouse model suggest that the gut microbiota may influence susceptibility to PJI. CLINICAL RELEVANCE: These preclinical findings support the idea that the state of the gut microbiome before surgery may influence the development of PJI and justify further preclinical and clinical studies to develop appropriate microbiome-based interventions.

Immunopathogenesis of Pediatric Localized Scleroderma.

Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, also affects extracutaneous tissues ranging from muscle to the central nervous system. Although developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA Sequencing and tissue staining. Research is underway to identify the key players in the pathogenesis of LS, but close approximation of inflammatory lymphocytic and macrophage infiltrate with collagen and fibroblasts deposition supports the notion that LS is a disease of inflammatory driven fibrosis. The immune system is dynamic and undergoes changes during childhood, and we speculate on how the unique features of the immune system in childhood could potentially contribute to some of the differences in LS between children and adults. Interestingly, the immune phenotype in pediatric LS resembles to some extent the healthy adult cellular phenotype, possibly supporting accelerated maturation of the immune system in LS. We discuss future directions in better understanding the pathophysiology of and how to better treat pediatric LS.

Lymphatic Function in Autoimmune Diseases.

Lymphatic vessels are critical for clearing fluid and inflammatory cells from inflamed tissues and also have roles in immune tolerance. Given the functional association of the lymphatics with the immune system, lymphatic dysfunction may contribute to the pathophysiology of rheumatic autoimmune diseases. Here we review the current understanding of the role of lymphatics in the autoimmune diseases rheumatoid arthritis, scleroderma, lupus, and dermatomyositis and consider the possibility that manual therapies such as massage and acupuncture may be useful in improving lymphatic function in autoimmune diseases.