The Kidney in Systemic Autoimmune Diseases (Handbook of Systemic Autoimmune Diseases)
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Our goal is to bring more attention to this under-explored, yet promising, area of study. Lymphatic vessels form an extensive network throughout the body with the exception of only a few tissues including bone, heart myocardium and skeletal muscles, as well as the parenchyma of kidney, liver, and adrenal and thyroid glands. These exceptions either have little interstitial fluid or have an alternative drainage system, such as fenestrated blood vessels 6. The lymphatic system is composed of initial lymphatic capillaries that merge to form collecting lymphatic vessels.
The collecting vessels transport the lymph to and from a series of LNs and eventually drain into the thoracic duct that connects to the blood circulation by draining into the subclavian veins 6. In contrast to the capillaries, collecting lymphatic vessels LVs have intraluminal valves that prevent backflow of lymphatic fluid 8 and several perivascular layers of lymphatic muscle cells, with characteristics of both smooth muscle cells and cardiac striated muscle cells, that provide vascular tone and rhythmic contractions of the vessels, enabling anti-gravity, active fluid transportation 9 , Previously, distinguishing blood endothelial cells from LECs was difficult.
But recent research identified several LEC-specific markers, including Lyve-1, vascular endothelial growth factor receptor-3 VEGFR-3 , podoplanin PDPN , and Prox-1, among others, that enabled tremendous advancements in the study of lymphatic vessel development and function 11 , However, congenital or acquired dysfunction of the lymphatic system result not only in lymphedema and its sequalae such as skin thickening, fibrosis, and adipose degeneration, but also in poor immune function, susceptibility to infections, and impaired wound healing, among other deleterious health effects 8.
These observations point at the greater role lymphatic vessels have than simple fluid transportation. That lymphatic dysfunction exacerbates autoimmune disease is supported by the development of autoantibodies in mice lacking dermal lymphatics 5. Understanding the lymphatic system in the context of autoimmune diseases has the potential to provide insight into disease mechanisms and new approaches to treatment. Rheumatoid arthritis RA is one of the most studied autoimmune conditions, with regards to the role of lymphatics in the context of disease.
RA is an autoimmune systemic disease, affecting 0. Local lymph node enlargement was first described in RA in 21 , but it wasn't until more specific markers of the lymphatic system were discovered that its role could be specifically investigated. It is thought that together with the joint inflammation occurring in RA, the local lymphatics undergo two stages of alterations. This process is important to allow for the resolution of the inflammatory process; if the expansion process is stunted, by inhibition of lymphangiogenesis for example, the joint inflammation becomes more severe and clinical synovitis develops Nevertheless, while the removal of the excess debris is important to allow for inflammation resolution in the acute setting, the inflammatory cells, and catabolic factors that are being removed have been shown to directly damage the LECs and lymphatic muscle cells, both in the afferent lymphatic vessels and the draining lymph nodes The lymphatic vessels are damaged, with increased leakiness and reduced contractions, leading to poor lymphatic clearance, and stasis of the inflammatory fluid within the joint and the afferent lymphatic vessels 23 , 28 — The process is thought to be mediated by several factors, including inflammatory cytokines in the vessels triggering LEC expression of inducible nitric oxide synthase iNOS , as well as iNOS-producing activated myeloid cells, now static within the lymphatic vessels.
The increased local NO production abrogates the constitutive endothelial NOS eNOS activity that is an important mediator of lymphatic vessel contraction 32 , Reduced vessel contraction is likely also due to increased fluid flow and pressure inside the vessels, beyond the vessels' ability to compensate 34 , At the same time, Bin cells in the draining lymph node migrate from the lymph node follicles to the sinuses, as extensively reviewed by Bouta et al.
The resulting impairment in lymphatic drainage contributes to increased joint inflammation and synovial hyperplasia, eventually leading to joint destruction Importantly, known and effective RA treatments, such as tumor necrosis factor TNF inhibition and anti-CD20 therapy, have both shown to also have a beneficial effect on lymphatic flow. Inhibition of TNF has been shown to restore lymphatic vessel contractility 28 , and anti-CD20 therapy, i.
Preliminary work with indocyanine green near-infrared ICG-NIR fluorescence imaging has been promising in providing sensitive, real-time non-invasive means to evaluate the layout and function of the lymphatic vasculature 31 , 38 , 39 , and the first study of lymphatic flow in RA patients with this modality is currently being performed ClinicalTrials.
Meanwhile, the change in size of the local draining lymph nodes has been shown to reflect joint inflammatory activity, as well as response to therapy Even prior to clinical lymphadenopathy, evaluation of draining lymph nodes of inflamed joints by power Doppler ultrasound PDUS , demonstrated hypertrophy of the lymph node cortex, in addition to power Doppler signal amplification in cortical and hilar regions likely indicating increased flow.
Importantly, these findings reversed with treatment At the same time, low PDUS signal at baseline despite active arthritis, likely representing a collapsed lymph node, predicts poor clinical response to therapy The LNs with the more notable reduction in size are the ones that are more likely to have undergone collapse, leading to inadequate inflammation resolution and reduced pain relief Scleroderma is an autoimmune connective tissue disease characterized by abnormalities in vasculature, immune function, and extracellular matrix that ultimately manifest as fibrosis of the cutaneous, vascular, musculoskeletal, gastrointestinal, pulmonary, cardiac, and renal systems.
Although the etiology of the disease is poorly understood, vascular injury and abnormal endothelial cell function are hypothesized to be among the primary defects responsible for disease pathogenesis 43 , Studies into vascular abnormalities leading to fibrosis have generally been more focused on blood endothelial cells BECs , while the roles of LECs and lymphatic dysfunction have been less well-studied.
In , Leu et al. Similar findings using immunohistochemical staining of scleroderma skin recently showed a decrease in lymphatic vessels and increased cross-sectional area of the remaining vessels, suggesting vessel dilatation and a block in lymphatic flow downstream The changes were most significant in the reticular dermis, with a similar trend found in the papillary dermis.
Lymphatic changes have been found in other fibrosing conditions as well Table 1 , further supporting the idea that lymphatic dysfunction may be a therapeutic target in scleroderma. Systemic lupus erythematosus SLE is the prototypical systemic autoimmune disease, affecting between in 6. There have been no systematic studies of lymphatic function in SLE to date. There are, however, hints that there might be lymphatic dysfunction in SLE, as there are case reports of chylous ascites or pleural effusions, lymph fluid found in the abdomen or thoracic cavity, respectively, that can result from lymphatic obstruction in the mesentery 59 — Lymphedema from peripheral lymphatic obstruction has also been described These occurrences are rare, however, and whether more subtle problems with lymphatic flow that could perhaps result from the lymphadenopathy commonly found in SLE 64 , 65 are not known.
Similarly, lymphatic function in dermatomyositis, a group of autoimmune diseases primarily directed against the muscle and skin 66 , has not been systematically studied. Dermatomyositis patients can rarely present with generalized edema, which may reflect poor lymphatic function and lymphedema Interestingly, benign lymphadenopathy is less frequent in dermatomyositis than in SLE or RA, and, because of the association of cancer with dermatomyositis in adults, lymphadenopathy in dermatomyositis has to be evaluated carefully for metastatic cancer or lymphomas As we begin to understand the role of lymphatic dysfunction in autoimmune diseases, it is also time to consider how we might improve lymphatic function as part of disease treatment.
Schwarz and colleagues have recently outlined molecularly targeted therapies that are currently being investigated In contrast to pharmacologic approaches, manual therapies have been used since ancient times and are currently the mainstay in improving lymphatic flow in diseases. Below, we briefly discuss some of these approaches to consider their potential utility in improving lymphatic function in autoimmune diseases. Manual lymphatic drainage MLD is a specific light pressure massage technique that moves from the trunk to the distal portion of the affected limb to stimulate lymph flow away from the peripheral tissue Indeed, hand edema is observed in systemic sclerosis patients in the early edematous phase, and MLD has been shown to significantly reduce the swelling and improve hand function in these patients Similarly, a dry brushing massage technique used in Ayurvedic medicine that originated in India 5, years ago is meant to relieve lymphatic congestion that is thought to contribute to stress and disease.
It has also been used to reduce lymphedema and inflammation from lymphatic filariasis Interestingly, the sports industry, which has been interested in promoting post-training recovery and reducing edema, is investigating the utility of peristaltic pulse dynamic compression PPDC devices that simulate manual lymphatic therapies. Recently, PPDC was shown to increase the pressure-to-pain threshold in elite athletes 74 and also to induce expression of anti-inflammatory genes 75 , although it is yet unclear whether these effects are attributable to improving lymphatic flow.
Potentially, then, lymphatic massage techniques could be used to improve lymphatic function to help reduce tissue inflammation in autoimmune diseases. Interestingly, acupuncture, a component of traditional Chinese medicine, may potentially have a lymphatic basis. Acupoints are specific points on the body that practitioners target in an attempt to mobilize stagnant qi , thought to be a form of energy that flows through the meridian system and enhance well-being Recent analysis of acupoints demonstrates that they co-localize with tissue planes rich in nerves, blood and lymphatic vessels, and mast cells.
Acupuncture involves insertion of metal needles into the skin and spinning the needle between the acupuncturist's fingers.
Part I: Introduction
It has been proposed that this process disturbs local tissues and transmits a biomechanical signal to surrounding cells and structures 77 that can stimulate lymphatic vessels. Additionally, activation of the nerves or mast cells in the area could result in release of vasoactive cytokines that can then stimulate lymphatic vessels to better mobilize fluid and inflammatory cells from the area 77 — There are observational trials showing efficacy of acupuncture on breast cancer-associated lymphedema, supporting the idea that acupuncture can modulate lymphatic function 81 — A recent randomized controlled trial examining the ability of acupuncture to further reduce lymphedema on top of current standard therapies such as lymphatic massage drainage and compression sleeves did not show additional benefits However, whether acupuncture alone is at least as good as current standard therapies is not yet known.
It should be of interest to better study whether acupuncture could modulate lymphatic function to aid in the treatment of autoimmune diseases.
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While the objective of these manual therapies in lymphedema is to improve lymphatic flow and reduce inflammation and swelling in the affected tissues, improving lymphatic flow has the potential to also modulate immune cell activity in a number of ways. First, as mentioned in section Overview of the Lymphatic System, LECs can directly regulate immune cell function, and stimulation of lymphatic flow can modulate the ability of LECs to regulate immune cells Second, lymphatic flow, by means of transporting antigen from the periphery, can impact the tolerance and activation of lymph node lymphocytes 5.
Third, cytokines expressed in peripheral tissues can impact immune function in lymph nodes 86 , potentially in part by lymphatic transport to the lymph nodes Thus, in the study mentioned above examining the effects of MLD on hand edema in scleroderma patients 72 , it would be interesting to understand whether MLD reduced autoantibody levels when edema was reduced.
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Manual therapies to improve lymphatic flow, then, may be a well-tolerated, relatively low-cost method to improve many facets of lymphatic function to reduce inflammation and autoimmunity in rheumatic diseases. The lymphatic system has not been well-studied in autoimmune diseases generally, but the existing evidence, especially in RA and, to a more limited extent, in systemic sclerosis suggests that there is at least dysfunction of lymphatic flow.
Further studies focused on the consequences of dysfunctional flow as well as alterations in the direct effects of lymphatic vessels and LECs on innate and adaptive immune cells should provide insights into how best to target the lymphatics in autoimmune rheumatic diseases. Additionally, understanding the causes of lymphatic dysfunction in these diseases may help us better target upstream mediators and perhaps reveal that lymphatic targeting is a mechanism of action of some medications.
Finally, as we consider new approaches to targeting lymphatics in autoimmune diseases, there may be value in better understanding older approaches in the context of Twenty-First century biomedical understanding of lymphatic and immune function to expand our therapeutic armamentarium for autoimmune diseases.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The lymphatic system: a historical perspective. Clin Anat. Oliver G, Detmar M. This handbook will prove useful to clinicians and researchers alike.
It covers practical points, ranging from which anti-rheumatic medications are safe in pregnancy to how to counsel women with scleroderma contemplating pregnancy. Pulmonary Involvement in Systemic Autoimmune Diseases. In this book is found the information essential to diagnosing, managing and treating the lung complications of connective tissue diseases.
This is a notoriously difficult area, which continues to puzzle clinicians, despite the fact that these disorders are increasingly frequent as a result of longer survival in connective tissue disease. In separate chapters, the major connective tissue diseases are reviewed, with detailed discussion of a variety of lung abnormalities, including pleural disease, parenchymal lung disease and pulmonary vascular disease.
There are also invaluable overviews of lung histological and CT appearances in these disorders, and a deeply.. Pediatrics in Systemic Autoimmune Diseases.
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Many of the systemic autoimmune diseases seen in children are different from those seen in adults making them a special problem for physicians and scientists who care for the affected children and study their diseases. Benefiting both pediatric and adult rheumatologists, as well as physicians from other specialties, this volume covers the latest advances in pathogenesis and clinical management of common conditions seen in pediatric rheumatology practices. ANCA vasculitis and glomerulonephritis.
Anti-glomerular basement membrane anti-GBM disease is the best-defined renal organ-specific autoimmune disease.
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The disease is strongly associated with autoantibody formation to a specific target found in the glomerular and alveolar basement membranes and is characterized by a rapidly progressive glomerulonephritis RPGN which is often associated with pulmonary hemorrhage, though either may occur alone. Six alpha chains of type IV collagen are known and these chains form triple helical molecules protomers. Diagnosis is based on the demonstration of anti-GBM antibodies, either in the circulation or fixed to basement membrane of affected organs on biopsy.
The majority of these antibodies are of the IgG1 subtype, with only few IgG4 antibodies. Systemic lupus erythematosus SLE is the prototypic systemic autoimmune disease with widespread clinical manifestations. The prevalence of renal involvement depends strongly on the definition. Renal involvement is one of the most serious complications, since nephritis may progress into end stage renal disease ESRD and is associated with increased mortality. Changing classifications were applied over past decades. Not all of these antibodies seem to mediate renal damage or indicate renal involvement.
For nephrologists, antibodies to anti-C1q and to nucleosomes are of particular interest. Nucleosomes consist of DNA and histones. Some primary immunodeficiency diseases are, however, associated with more severe eczema. In these disorders, the eczema may be quite resistant to typical therapies. Psoriasis is another type of autoimmune skin disease that is more severe than eczema.
Psoriasis plaques are typically red, raised, itchy and painful.