Abstract: Dendritic cells (DCs) are pivotal in bridging innate and adaptive immunity through antigen presentation and cytokine signaling. While T cell exhaustion has become a central paradigm in chronic infections and cancer, dendritic cell exhaustion remains under-recognized. In this article, I propose that DC exhaustion is a key perpetuating mechanism in chronic viral syndromes, including Long Covid. Synthesizing classical immunology, recent findings in post-viral syndromes, and millenia of Traditional Chinese Medicine (TCM), I propose a testable model: that Lingering Pathogenic Illnesses(fú xíe)[1], as described in TCM, correlate mechanistically with exhausted antigen-presenting cell states. Through integration of immunological mechanisms and TCM clinical patterns and treatment mechanisms, I argue that immune dysfunction in diseases like Long Covid must be addressed with DC restoration. This hypothesis has far-reaching implications for treatment, vaccine response, and immune resilience in the face of persistent viral threats and complex diseases.
 

1. Introduction Dendritic cells serve as the immune system’s sentinels: capturing, processing, and presenting antigens to T cells while secreting cytokines that direct the nature of the immune response. The paradigm of immune exhaustion has gained prominence, particularly in relation to T cells during chronic infections, cancer, and sepsis. Yet DC exhaustion—a distinct phenotype involving reduced antigen presentation, impaired costimulation, and altered cytokine profiles—remains insufficiently studied. In the context of Long Covid, ME/CFS, HIV, and other persistent viral syndromes, evidence is accumulating that DC dysfunction is both a consequence and a driver of persistent antigen.
 

This manuscript introduces a novel hypothesis: that DC exhaustion represents the immunological correlate of Lingering Pathogenic Illnesses as described in Traditional Chinese Medicine (TCM). Drawing from my clinical experience, where I observed consistent patterns in the therapeutic action of certain herbs, I discovered a link between the efficacy of treatment and the herbs’ ability to support APC function. Conversely, many commonly used antimicrobial herbs impaired recovery, correlating with DC-suppressive effects. This clinical pattern, rooted in empirical use and classical theory, aligns with emerging immunological data. Here, I synthesize these perspectives into a unified, testable framework.
 

2. What Is Lingering Pathogenic Illness? Lingering Pathogenic Illness(fú xíe)[1] is a category of disease in Chinese medicine, the premise of which is that there is an injury to the immune system from which the patient doesn’t recover leading to a deep seated lurking heat in the body. Lingering Pathogenic Illness often presents as a persistent infection but may not always be so obvious or even microbe specific.

Persistent pathogens have been a part of Chinese medicine since the Shang dynasty, 4000 years ago. "Lurking" and "Lingering" pathogens are mentioned in the Huang Di Nei Jing Su Wen, the Shang Han Lun, and the Wen Re Lun. Lingering Pathogenic Illness was introduced by Ye Tian Shi and the Warm School and later expounded upon in greater detail by and Liu Bao-Yi(1842-1901).
 

Biomedical correlaries include: any chronic viral, bacterial, protozoal, or fungal infection, CFS/ME, Long Covid, Post-Vaccination Syndrome, food allergies/intolerances, environmental toxicities, and/or chronic inflammatory and/or autoimmune diseases.
 

Herbs are the primary modality for treating Lingering Pathogenic Illnesses, although acupuncture can be useful for earlier, more superficial stages of pathogen(in the Qi and Shaoyang layer, where it can be "vented").
 

Treatment strategy in TCM is to facilitate the expansion and expulsion of lingering pathogen by tonifying Qi and Yin while encouraging Qi functions such as opening the pores, encouraging bowels and urination, and clearing heat with salty, pungent, and sweet herbs. Cold and overly bitter medicinals are thought to lodge the pathogen deeper into the body and are cautioned against when a patient is chronically ill.

"Nowadays people put Ye Tian-Shi on a pedestal and shelve the idea of lingering pathogens... there is no one to put forward the theory of deep lying pathogens... What a pity! It is recorded in the Nei Jing, Nan Jing, and Shang Han!" -Liu Bao-Yi (1842-1901)

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3. What Is Dendritic Cell Exhaustion? Dendritic cell exhaustion is defined by diminished ability to present antigens, impaired migration, and altered cytokine secretion. Phenotypically, exhausted DCs exhibit:
 

• Reduced MHC-II expression

• Downregulation of costimulatory molecules (CD80/CD86)

• Suppressed IL-12 and IFN-α production

• Upregulation of inhibitory ligands (PD-L1, TIM-3, Galectin-9)

• Skewing toward IL-10 and TGF-β production

• Altered metabolic states (increased fatty acid oxidation, reduced glycolysis)
   

These traits render DCs ineffective at priming T cells, skewing responses toward tolerance or immune anergy.
 

4. Evidence Across Chronic Conditions
 

4.1 HIV and Hepatitis Viruses Chronic HIV infection reduces plasmacytoid and myeloid DC responsiveness. pDCs exhibit diminished TLR7-mediated IFN-α release, and mDCs express elevated PD-L1, contributing to T cell exhaustion [2]. Similar patterns have been observed in HCV and HBV, where persistent antigen stimulation leads to DC tolerization and impaired costimulation [3].
 

4.2 Long Covid and Post-Viral Syndromes Recent studies suggest that patients with Long Covid display reduced pDC activation, low IFN-I signatures, and decreased HLA-DR on circulating APCs [4]. These features mirror the immunoparalysis seen in chronic viral syndromes. The presence of viral antigen reservoirs in tissue may perpetuate DC exhaustion as seen in Long Ebola.
 

4.3 Other Contexts DC exhaustion has also been observed in tumor microenvironments, where checkpoint ligand expression impairs T cell activation, and in sepsis, where DC apoptosis and tolerization contribute to immune suppression [5].

 

5.1 Herbs That Restore APC Function Through rigorous observation, analysis, and application of Lingering Pathogenic Illness principles, I developed a clinical formula for Long Covid composed of herbs that consistently improved patient outcomes. These herbs were selected not only based on their traditional indications for resolving lingering pathogens, but also for their apparent ability to restore dendritic cell function and counteract immune exhaustion:
 

• Huang Qi (Astragalus): Tonifies Qi. Stimulates dendritic cell maturation by upregulating MHC-II and CD86 expression, enhances IL-12 secretion, and supports Th1-polarizing cytokine balance critical for effective antigen presentation [6].

• Ling Zhi (Reishi): Tonifies Qi. Enhances dendritic cell function through its polysaccharides and triterpenes, activating DCs via toll-like receptors like TLR4. It promotes antigen presentation and balanced cytokine release, helping to restore immune vigilance without triggering excessive inflammation — ideal for reversing chronic immune exhaustion.

• Ge Gen (Pueraria): Vents heat, nourishes fluids. While traditionally used to release the muscle layer and clear residual pathogens, Ge Gen may enhance antigen delivery to lymph nodes by improving microvascular perfusion and tissue drainage, thereby facilitating DC trafficking.

• Sheng Di / Shu Di (Rehmannia): Tonifies Yin. Possesses anti-inflammatory properties that may reduce excessive IL-10 and TGF-β signaling—key mediators of DC tolerization—and helps restore functional DC responsiveness in chronic inflammatory states.

• Fu Ling (Poria): Drains Dampness. Supports the gut-immune axis by improving antigen uptake and endocytosis in DCs, particularly those residing in mucosal-associated lymphoid tissue.

• Neem: Clears Heat. Inhibits dendritic cell-expressed PD-L1, modulates TLR7/9 signaling pathways, and helps rebalance the expression of co-stimulatory and inhibitory molecules [7].

• Black Currant: Tonifies Yin. Rich in anthocyanins and polyphenols, it boosts type I interferon sensitivity and enhances dendritic cell resilience against oxidative stress—supporting sustained antigen presentation in viral syndromes.

• Aloe (Aloe vera): Moves bowels. Supports dendritic cell function through its active polysaccharide, acemannan, which promotes DC maturation and antigen presentation. It increases expression of co-stimulatory molecules (CD80, CD86, MHC II) and stimulates cytokine release (IL-12, TNF-α), enhancing Th1 immune responses and boosting APC activity.
   

Together, these herbs do not simply “tonify Qi” or “clear pathogens,” but appear to act directly on pathways known to be disrupted in dendritic cell exhaustion while fulfilling all the functions necessary to treat Lingering Pathogenic Illness. They promote DC survival, costimulation, cytokine integrity, and antigen-processing capability—thereby restoring the antigen-presenting capacity essential for immune reconstitution.
 

What makes these herbs uniquely valuable is their dual functionality: they are both anti-inflammatory and antigen-presenting cell (APC)-restorative. Unlike many pharmaceuticals that suppress inflammation at the cost of immune vigilance, these botanicals appear to calm overactive immune pathways while simultaneously repairing core immune recognition and presentation machinery. This rare combination is currently unmatched in conventional medicine, where therapies are typically bifurcated into immunosuppressants or immune activators, but rarely both in balance. The herbs described above embody a therapeutic profile that modulates the immune system rather than bluntly inhibiting or stimulating it—making them ideal for the nuanced immune terrain of persistent and post-viral syndromes.
 

5.2 Herbs That Impair DC Function Conversely, herbs with strong “Bitter/Cold”(antimicrobial) energetics, though seemingly beneficial at first, had a depreciating return on patient outcomes. Notably:
 

• Berberine (from Huang Lian): Induces DC apoptosis and inhibits co-stimulatory molecule expression [8]

• Scutellaria (Huang Qin) and Isatis (Ban Lan Gen): Suppress DC maturation and cytokine signaling

• Andrographis: Inhibits NF-κB and T cell priming in chronic use

• Gentiana (Long Dan Cao): Reduces DC survival when used in convalescent states
   

These herbs may be suitable for acute infection, but in chronic, persistent infections they appear to prolong disease by further impairing DCs. Notably, in TCM theory, cold and bitter medicinals are traditionally cautioned against prolonged use in cases of deficient or lingering illness, as they are thought to "drive the pathogen deeper" into the body. This metaphor may reflect the clinical reality of dendritic cell impairment—where aggressive suppressive strategies inadvertently silence antigen presentation and entrench viral persistence. Liu Bao-Yi described Lingering Pathogens as "pressure cookers" in which bitter and cloying herbs would force the pathogen to remain, waiting to be unleashed again. One of Liu Bao-Yi's favorite "venting" herbs for Lingering Pathogenic Illnesses was Dan Dou Chi or fermented black soybean because its preparation, cooking and fermenting, resembled that of a lingering pathogen expanding.
 

6. A Testable Hypothesis: DC Exhaustion Underlies Lingering Pathogenic Illness. Traditional Chinese Medicine (TCM) recognizes a class of disorders known as Lingering Pathogenic Illness, which describes the persistence of unresolved pathogenic influences long after the acute phase of disease. While this category clearly encompasses chronic and post-viral syndromes such as Long Covid, its conceptual reach is much broader. Lingering Pathogenic Illness also includes conditions such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), autoimmunity, food sensitivities, allergies, HIV, somaticized trauma(PTSD), some cancers, and even post-vaccination syndrome. These diverse clinical presentations share an underlying theme in TCM theory: the body is unable to fully expel or resolve external pathogenic factors due to persistent taxation of Qi, Yin, and immunity.
 

In the language of immunology, this may correspond to a failure of antigen-presenting cell (APC) function, especially dendritic cells, to clear antigens, provide appropriate co-stimulation, and restore immune tolerance. The TCM framework thus offers a premodern map of what may now be recognized as dendritic cell exhaustion.
 

The observed herbal patterns suggest that herbs historically used to “tonify Qi and Yin” in order to "expel lingering pathogens" may, in fact, restore APC integrity.

What about glial cells? Glial cells correlate to “Jing”(Essence) in Chinese medicine which is a composite of “Yin” and “Qi,” particularly “pre-natal Qi,” implying embryonic cell origin and respond to precisely the same treatment: “tonifying Qi and Yin.”
 

Testable predictions include:
 

• Patients with Long Covid or ME/CFS will exhibit reduced MHC-II and CD86 on circulating DCs

• Herbs identified as APC-supportive will reverse these changes in vitro
   

7. Discussion: This framework positions dendritic cell exhaustion as a central driver of “Lingering Pathogenic Illnesses.” The convergence between TCM herb energetics and immunological function provides a novel lens through which to evaluate post-viral recovery strategies. More importantly, it offers a testable and mechanistically plausible model for understanding why many patients fail to recover despite the absence of active viral replication.
 

Future studies should measure longitudinal DC phenotype and function in post-viral cohorts, evaluate herbal effects on DC maturation in vitro, and explore combinatory therapies that include both biomedical and botanical interventions. If validated, this model could transform how we approach persistent immune dysregulation, blending traditional frameworks with cutting-edge immunotherapy.
 

More broadly, this hypothesis may serve as the foundation for reimagining the treatment of a spectrum of difficult, complex conditions that fall under the umbrella of Lingering Pathogenic Illness—many of which are currently deemed incurable or untreatable by conventional standards. If dendritic cell exhaustion proves to be the common immunological denominator linking post-viral syndromes, ME/CFS, autoimmunity, and much more, then the implications are profound. It suggests that by restoring the body's most fundamental immune surveillance and coordination system—the dendritic cell network—we may unlock new pathways toward recovery for millions of people worldwide.
 

What is proposed here is not merely a new interpretation of immune dysfunction, but a blueprint for therapeutic renaissance—one that unites ancient clinical wisdom with emerging cellular science to address some of the most challenging conditions of our time.

 

References

1. Maclean, Will, et al. Clinical Handbook of Internal Medicine: The Treatment of Disease with Traditional Chinese Medicine. Vol. 3, Eastland Press, 2018.

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3. Kanto T, Hayashi N. Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med. 2006;45(3):183-191.

4. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2022;327(13):1236-1246.

5. Delano MJ, Scumpia PO, Weinstein JS, et al. MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med. 2007;204(6):1463-1474.

6. Wang D, Feng Y, Liu J, et al. Astragalus polysaccharide enhances the immune response to avian infectious bronchitis virus vaccine in chickens. Microb Pathog. 2017;111:81-85.

7. Kumar S, Narwal S, Kumar V, et al. Neem (Azadirachta indica): Prehistory to contemporary medicinal uses to humankind. Asian Pac J Trop Biomed. 2016;6(7):505-514.

8. Zhou Y, Wang S, Zhang Y, et al. Berberine inhibits dendritic cell maturation and function through triggering apoptosis via the mitochondrial pathway. Mol Immunol. 2012;52(3-4):198-204.