April 2022

Lymphatic Immunopathy and Its Importance in Chronic Wound Healing

By James McGuire, DPM; Avnee Jiten Patel, BS; and Ron Michael Adduru, BSN

Untreated lymphedema can play a significant role in chronic wounds. Manual Lymph Drainage (MLD), performed by a Certified Lymphedema Therapist (CLT) is standard of care for the management of lymphedema of all types, not just advanced disease.

A coordinated immune response to illness, in particular, chronic wound healing, depends on the efficient functioning of the arterial, venous, and lymphatic systems. The lymphatic component of the vascular system in chronic wound healing has received little attention in protocols and guidelines designed to address barriers to healing. Traditionally, the lymphatic system has been thought to function as a passive regulator in our systemic immune response by transporting antigenic cells, materials, and immunologic mediators to regional lymph nodes. Damage to or alteration of the free flow of lymph through local or regional lymphatic vessels in the area of a chronic wound contributes to pathological changes to the lymphatic system that results in a delayed immune response referred to as “lymphatic immunopathy” or what J.A. Carlson referred to as microlymphedema.1

The lymphatic system has been shown to play 2 roles in facilitating an immune response. On a micro level, lymphatic endothelial cells (LECs) regulate immune responses by directly modulating the entry of immune cells into lymphatic capillaries, presenting antigens on major histocompatibility complex proteins, and modulating antigen-presenting cells (APCs).2 On a macro level, the lymphatic fluid flow transports these to regional and central lymph nodes where an immune response is generated. Local edema and tissue scarring in response to chronic inflammation associated with wound chronicity leads to decreases in both micro and macro activity and leads to the development of a “lymphatic immunopathy.”

Lymphatic micro-mechanisms involve cellular-level regulation of immune responses. Immune cell entry, migration of LEC cytokines and chemokines through the lymphatic system, and adhesion molecule expression are a few of the chemical modulations promoted by a functioning lymphatic system. The balance of T-cell inflammation is integral to mitigating fibrosis. CD4 cell differentiation into T-helper 1 (Th1) cells increases the activity of Interferon gamma (IFNγ) which is largely anti-fibrotic versus T-helper 2 (Th2) cells which play a pro-fibrotic role.3 This cycle of T-cell inflammation involving downregulation of CD4+ cell and upregulation of Th2 differentiation leads to lymphatic vessel fibrosis which contributes to lymphedema, a chronic tissue swelling caused by the overwhelming of the lymphatic system.4 Dendritic cells, powerful leukocyte APCs which regulate T-cell responses, upregulate expression of the chemokine cell surface receptor CCR7 whose ligands are expressed by LEC cytokines.2,5 CCR7 ligand gradients guide dendritic cells to the initial lymphatics facilitating entry into the vessel lumen.2,6,7  This activation precedes the chronic cycle of CD4+-mediated inflammation which damages the free flow of fluid through the lymphatic system physically preventing a rapid immune response to bacteria, viruses, and fungal invaders; the efficient removal of accumulated waste products from the tissues; and leads to local or periwound edema or, if extensive, a regional clinical presentation of lymphedema.

“Immune Ignorance”

If the lymphatic system is blocked, the immune system is unaware of an inflammatory process occurring in the afferent tissue and remains unengaged, resulting in immune ignorance.8,9 IFNγ inhibits differentiation of naive T-cells to Th2 cells, serving as a pro-inflammatory, anti-fibrotic cytokine.3 When the influence of IFNγ is weak, the natural killer T-cells produce IL-4 without being affected by dendritic cells. IL-4 causes naive T-cells to differentiate into Th2 cells which promote chronic inflammation with the help of M2 macrophages which promote tissue fibrosis.8 The imbalance of differentiation between Th1 and Th2 is significantly increased in lymphedema. Differentiation of Th1 cells is suppressed in lymphedema, which renders the host prone to severe infection and may cause depression of wound healing activation. In addition, intensive differentiation of Th2 cells causes progression of fibrosis, also leading to disruption of the wound healing process.8 By this mechanism, the immune regulation of the lymphatic system on a micro-scale can manifest itself on a macro-scale.

On a macro-level, the lymphatic system, via lymphatic vessel tone and lymphangion contraction, regulates immune responses by modulating the rate at which extracellular fluid is returned to the vascular system, and antigens and pathologic cells are delivered to regional lymph nodes.2,10-13 Injury to the lymphatic system resulting from direct trauma to the vessels, or a prolonged inflammatory or insufficient reparative process results in blockage of the lymphatic system. Primary or hereditary causes of lymphedema include congenital lymphedema, lymphedema praecox, and lymphedema tarda. Secondary lymphedema causes include: traumatic injury, iatrogenic, oncogenic, or infectious damage to the lymphatic vessels. For the purpose of this paper, we will limit our discussion to secondary lymphedema which may present as a local, regional, or systemic blockage depending on the extent of lymphatic injury.

Lymphostatic Dermopathy

As previously discussed, a wound can lead to a local lymphatic immunopathy with dysfunction of chemical modulators leading to a prolonged inflammatory response, tissue breakdown, and loss of dermal integrity. Lymphostatic dermopathy, or failure of immune function of the skin, contributes to all wounds and skin dysfunction and can even lead to expansion of the wound.1 Primary dermal breakdown from underlying circulatory system failure can be called dermal disruption ulceration and presents as small coalescent ulcerations that quickly expand and form larger more obvious wounds if not addressed. This vascular injury presents as lymphatic vessel lumen enlargement, valve dysfunction, and loss of smooth muscle cell coverage. If this inflammatory process is prolonged, it promotes interstitial fluid retention and tissue edema, followed by tissue fibrosis and adipose deposition.14

The cascade of immune responses leads to physical degenerative changes to the lymphatic system. At a macro-level, the fibrosis related to collagen deposition causes stasis and increased fluid accumulation in the lymphatic system. Immunologically, this results in stagnation of immune cells surrounding the area of blockage while the inflammatory cells accumulate within the area. Clinically, this may present as a lymphatic dermopathy. The ability to heal wounds is significantly decreased and the risk of developing wounds significantly increased when this inflammatory cycle becomes chronic.

A thorough understanding of how the lymphatic system functions is critical to improve wound healing outcomes. Most chronic non-healing wounds observed in podiatric wound care have been complicated by obesity, diabetes, and uncontrolled lymphedema. Wound healing is affected by lymphedema both pathophysiologically and immunologically. The pathophysiological effects result from impaired tissue remodeling due to excessive accumulation of interstitial fluid, microvascular ischemia caused by internal tissue pressure, and cell damage by accumulation of cell debris. The immunological effects of lymphedema contribute to immunodeficiency and chronic inflammation of wounds.8,15

To Promote a Healing Environment

An understanding of the underlying immune response is integral to the treatment of wounds. To create an environment that promotes wound healing and epithelialization, the underlying edema must be recognized, and treatment modalities utilized to address this fluid stagnation. Edema is generally classified as being high-protein or low-protein. Lymphedema is a high-protein edema which results from damage to or the absence of a normal lymphatic system. Proteins are deposited in the interstitial tissues when lymphatic capillaries are unable to transport them back into the venous system resulting in a change in osmotic and hydrostatic pressure. The change in interstitial pressure attracts more water into the interstitial tissue alongside the trapped proteins leading to fibrosis and edema. Unlike lymphedema, venous insufficiency is initially a low-protein edema characterized by an accumulation of water not resulting in tissue fibrosis. Chronic venous insufficiency causes high filtration pressure and increased fluid in the tissue leading to venous hypertension and an increased lymphatic water load. When either the venous or lymphatic system is overburdened, it can lead to fatigue of the other system.

Most wounds which develop in edematous legs have venous insufficiency as a primary initial cause which leads to secondary phlebolymphedema, the major cause of lymphedema in the US.16 Phlebolymphedema develops from longstanding venous insufficiency which frequently is inadequately addressed in its early stages and allowed to progress without compression or other simple interventions such as weight loss, elevation, and exercise. When both the venous and lymphatic systems are overwhelmed, a lymphatic overload occurs. Activation of inflammatory cytokines results in an influx of inflammatory cells, a change from a watery transudative edema to a protein-rich exudative edema, and a local lymphatic immunopathy. Inflammatory skin changes and skin breakdown lead to ulceration and delayed healing when the developing immunopathy is left unaddressed.17,18 In many ways, the progression of skin changes seen reflected in the categories of the CEAP classification are a measure of the degree of lymphatic immunopathy present in the tissues and what leads to ulceration and poor healing.19

Recent research supports the treatment of lymphedema with complete decongestive therapy, including manual lymph drainage, graduated compression garments, lymphedema wraps, therapeutic exercises, meticulous skin care, and the addition of intermittent pneumatic compression.20 The combination of these treatments promotes fluid return from interstitial tissues to the vascular space and mobilizes immune cells from the area of blockage, which reduces swelling and eliminates the static immunopathy associated with lymphedema.

Compressive treatments are used for both venous mediated and lymphatic edema. Compressive devices include single- or multi-layer elastic or inelastic short or long stretch bandages, stockings, VelcroTM closure systems, or several types of segmental compression pumps. Compression can also be classified as either passive or active. Passive systems include most wraps and bandages; active systems include various intermittent pneumatic compression devices designed for venous or lymphatic edema. Dressings containing elastic or long stretch components are able to function in both ambulatory and non-ambulatory conditions while short stretch dressings function best in patients who are ambulatory.21 Manual Lymph Drainage (MLD) performed by a Certified Lymphedema Therapist (CLT) is standard of care for the management of lymphedema of all types, not just advanced disease. Segmental devices attempt to use sequential application of compressive forces to move venous blood and low protein transudate from surface vessels to deeper ones. Multiple chambered light pressure lymphatic pumps are used to facilitate movement of exudative lymphatic fluid through existing open lymphatic channels to larger more proximal lymphatic vessels.22

Too often patients are referred only after symptoms of skin breakdown and edema have reached significant levels. Rarely are CLTs used for periwound microedema or phlebolymphedema which would significantly improve healing of chronic wounds. Unaddressed lymphostatic microlyphedema leads to the development of a wider periwound lymphostatic dermopathy, or skin failure.20 For many of the chronic wounds we treat, this mechanism is why they fail to heal or expand in size during our initial therapies. In combination with advanced wound healing, complete decongestive therapy, and edema mitigating technologies, counseling patients on the importance of early intervention with exercise, diet, and compressive hosiery could prove invaluable to improving both the quality and efficiency of our attempts at wound healing.

  1. Carlson JA. Lymphedema and subclinical lymphostasis (microlymphedema) facilitate cutaneous infection, inflammatory dermatoses, and neoplasia: A locus minoris resistentiae. Clin Dermatol. 2014;32(5):599-615.
  2. Kataru RP, Baik JE, Park HJ, et al. Regulation of Immune Function by the Lymphatic System in Lymphedema. Front Immunol. 2019;10:470.
  3. Zhang M, Zhang S. T Cells in fibrosis and fibrotic diseases. Front Immunol. 2020;11:1142.
  4. Avraham T, Zampell JC, Yan A, et al. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J. 2013;27(3):1114-1126.
  5. Garcia Nores GD, Ly CL, Cuzzone DA, et al. CD4(+) T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema. Nat Commun. 2018:9(1):1970.
  6. Weber M, Hauschild R, Schwarz J, et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science. 2013;339(6117):328–32.
  7. Teijeira A, Rouzaut A, Melero I. Initial afferent lymphatic vessels controlling outbound leukocyte traffic from skin to lymph nodes. Front Immunol. 2013;4:433.
  8. Yoshida S, Koshima I, Hamada Y, et al. Lymphovenous anastomosis aids wound healing in lymphedema: relationship between lymphedema and delayed wound healing from a view of immune mechanisms. Adv Wound Care (New Rochelle). 2019;8(6):263-269.
  9. Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6(6):686–688.
  10. Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The lymphatic system: integral roles in immunity. Annu Rev Immunol. 2017;35:31–52.
  11. Liao S, Cheng G, Conner DA, et al. Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci USA. 2011;108:18784–9.
  12. Lee KM, McKimmie CS, Gilchrist DS, et al. D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood. 2011;118(23):6220–9.
  13. Kuan EL, Ivanov S, Bridenbaugh EA, et al. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J Immunol. 2015;194(11):5200–10.
  14. Jiang X, Nicolls MR, Tian W, Rockson SG. Lymphatic dysfunction, leukotrienes, and lymphedema. Annu Rev Physiol. 2018;80:49-70.
  15. Mallon EC, Ryan TJ. Lymphedema and wound healing. Clin Dermatol 1994;12(1):89-93.
  16. Farrow W. Phlebolymphedema–a common underdiagnosed and undertreated problem in the wound care clinic. J Am Col Certif Wound Spec. 2010;2(1):14-23.
  17. Herrman EC, Knapp CF, Donofrio JC, et al. Skin perfusion responses to surface pressure-induced ischemia: Implications for the developing pressure ulcer. J Rehabil Res Dev 1999;36(2):109-120.
  18. Paek R, Chang DS, Brevetti LS, et al. Correlation of a simple direct measurement of muscle pO(2) to a clinical ischemia index and histology in a rat model of chronic severe hindlimb ischemia. J Vasc Surg. 2002;36(1):172-179.
  19. Lurie F, Passman M, Meisner M, et al. The 2020 update of the CEAP classification system and reporting standards. J Vasc Surg Venous Lymphat Disord. 2020;8(3):342-352.
  20. Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg. 2007;59(4):464-472.
  21. O’Donnell TF Jr, Passman MA, Marston WA, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery® and the American Venous Forum. J Vasc Surg. 2014;60(2 Suppl):3S-59S.
  22. Partsch H. Intermittent pneumatic compression in immobile patients. Int Wound J. 2008;5(3):389-397.

Leave a Reply

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.