Lyme disease - Huaier approach for ARLA patients (Antibiotic-Resistant Lyme Arthritis)

Table of contents

Reading time 17 minutes

Updated - February 2, 2026

Lyme disease is caused by Borrelia burgdorferi, a spiral-shaped bacterium that causes the Lyme borreliosis (also known as Lyme disease).

It is one of the few pathogens that are so scientifically fascinating and at the same time represent the most difficult bacterial infections in immunology and clinical practice:

Unusual genetics: Linear chromosome and complex plasmid system
Master of the immune invasion: VlsE antigenic variation, complement inhibition, biofilm
Multi-organ pathogens: Can affect almost all organ systems
Persistence specialist: Can cause chronic infections that last for years
TLR2 dominance: Triggers massive inflammation (more than Toll-like Receptor 4)
Autoimmune potential: Leads to post-infectious autoimmunity (ARLA)

Most people with Lyme arthritis are cured after antibiotic therapy. However, around 10% do not respond to this treatment and develop what is known as Lyme arthritis. antibiotic-resistant Lyme arthritis (ARLA).

These 10% are divided into

50% with spontaneous remission (temporary or permanent reduction of disease symptoms) in x years
30% to DMARD (Disease-Modifying Antirheumatic Drugs) / Biologics (act against specific target structures of the immune system)
20% chronic and resistant to therapy

First the pathogenesis (cause of the disease), conventional therapy options and then the therapy approach with the active ingredients of the Huaier fungus are explained.

Pathogenesis

Direct invasion:

Collagen/decorin binding via DbpA/B - (enables the pathogen to attach to collagen-rich structures, important for the actual invasion of the host and colonization of the pathogen in the host)
Fibronectin binding via BBK32 - (enables the dynamic strengthening of the binding capacity of the pathogen through the formation of polymerized fibronectin depending on the mechanical load (e.g. in the bloodstream): the higher, the stronger)
Indirect tissue damage due to the triggered immune response

Immune triggering (TLR2-dominant):

Surface lipoproteins (OspA, OspC, OspE) → TLR2/6 activation (early immune response, but also for pathogenesis, as they can trigger excessive inflammatory reactions)
Peptidoglycans → TLR2 activation (leads to a strong inflammatory response and activation of the innate and adaptive immune system)
Leads to massive NF-κB/MAPK activation (results in the strong release of proinflammatory cytokines like TNF-α, IL-6 and IL-1β, which intensifies the inflammatory reaction in Lyme disease)
Massive pro-inflammatory cytokine production

Immune invasion:

Complement inhibition (OspE, OspF - Surface proteins of the bacterium bind to the regulatory protein factor H of the complement system and thus prevent the activation of complement, which would otherwise destroy the bacterium.
OspF appears to play a role in self-protection against its own pathogen in ticks: mice immunized with OspF showed a reduction in spirochetes by up to 90%. Source: Partial destruction of Borrelia burgdorferi within ticks that engorged on OspE- or OspF-immunized mice)
Antigenic variation (VlsE - variable major protein-like sequence Expressed - prevents recognition by the immune system)
Biofilm formation (self-produced extracellular polymeric substance for self-protection of the pathogen)
Intracellular persistence (possible in spirochete-form variants (group of gram-negative, helical, anaerobic or facultatively anaerobic bacteria, including syphilis and leptospirosis pathogens) - hide inside the infected cell and can remain there without symptoms for months and years)

Autoimmunity (post-infectious):

Cross-reactivity between OspA and human proteins (e.g. LFA-1) - (molecular mimicry: leads to an autoimmunologically maintained inflammation, even if the pathogen has already been eliminated.
The strong T-cell response in genetically predisposed patients is associated with excessive production of proinflammatory cytokines (e.g. TNFα, IFNγ), which maintains the inflammatory process)
Epitope Spreading (After an initial immune reaction against Borrelia antigens such as OspA the persistent inflammation leads to tissue decay and the release of the body's own proteins.
These are then also recognized and presented by the immune system, whereby the immune response expands to new, originally foreign-antigen-independent epitopes. This process is triggered by the lack of regulatory IL-10 which can lead to uncontrolled autoimmunity).
Persistent peptidoglycans trigger autoreactive T cells (Components of the bacterial cell wall of the pathogen can remain in tissues such as the liver or joints even after successful antibiotic therapy and continue to stimulate the immune system. They also influence the energy metabolism of immune cells and promote the production of pro-inflammatory proteins, which in turn increases autoimmunity)

Conventional forms of therapy

NSAIDS

Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs that reduce inflammation, relieve pain and lower fever but, unlike corticosteroids, are not steroids.
Unlike steroids, NSAIDs do not increase the infection rate.

They non-selectively inhibit the prostaglandin and thromboxane-producing COX (cyclooxygenase)-1 and COX-2 enzymes.
While COX-1 is always active (if it is inactive or inhibited, stomach ulcers, kidney problems and a tendency to bleed occur, for example), COX-2 is upregulated during inflammation.
Blocking COX-2 results in the desired effects, e.g. reduction of inflammation and pain, reduction of fever.

Since non-selective NSAIDs inhibit both enzymes equally, they also have the undesirable (side) effects mentioned above.

NSAIDs only have a symptomatic effect. The pathogen is still present and active, the inflammatory mediators (pro-inflammatory cytokines) continue to be produced unhindered and the cartilage erosion continues unabated.

The most common active ingredients of non-selective NSAIDs are

Acetysalicylic acid
Diclofenac
Ibuprofen
Indomethacin
Ketoprofen
Meloxicam
Naproxen
Piroxicam

The most common selective active substances of the (COX-2) inhibitors are

Celecoxib
Etoricoxib

Rofecoxib (due to an increased risk of heart attack) and valdecoxib were withdrawn from the market.

COX-2-selective NSAIDs must not be given to patients with coronary heart disease (CHD) or after a heart attack, as they promote these diseases.

DMARD

The DMARD category includes substances that not only alleviate symptoms (such as NSAIDs), but also actively slow down or stop the progression of the disease and the immune system in the long term.

Example ARLA patient - NSAIDs and DMARDs

Patient: 42-year-old man with ARLA (knee monarthritis after Lyme)

Initial:

Naproxen 500 mg 2x daily
Omeprazole 20 mg once a day (stomach protection)

Pain 7/10
Joint effusion 200 ml

After 2 weeks:

Pain 4/10 (better „well-being“)
Joint effusion still 180 ml
Swelling hardly better

Escalation to DMARD:

+ methotrexate 15 mg/week

+ biologics (TNFi or JAKi)

After 8-12 weeks of combination therapy:

Pain 0-1/10
Joint effusion < 50 ml
Mobility restored
Remission achieved!

Biologics

Biologics are biotechnologically produced, larger molecules modeled on human proteins, nucleic acids or antibodies, which cannot be administered in tablet form due to premature breakdown by stomach acid, but only as subcutaneous injections or infusions. Only JAK inhibitors are taken orally.
They can have a regulating effect on cytokines, receptors or immune cells. Insulin is also a (1982 first) biologic.

In the ARLA context, they are divided into four hierarchies

1st choice - TNF-α inhibitors (TNFi) - Response with 50-70% after 4-8 weeks

Adalimumab
Infliximab
Etanercept

2nd choice - IL-6 inhibitors (IL-6i) - Response at 50-60% after 4-12 weeks

Tocilizumab
Sarilumab

Also effective in TNFi non-responders (~30-50% of patients)

3rd choice - JAK inhibitors (JAKi) - Response already after 2-4 weeks - still in development
They block JAK1 (primary, strong), JAK2 (secondary, weak) and TYK2 (secondary, weak), which is why STAT3 cannot be phosphorylated and therefore remains inactive and IL-6-dependent genes are not transcribed. JAK3, on the other hand, is not blocked, which is positive for an improved defense against infection (source - full text with costs): Chronic Lyme arthritis. Clinical and immunogenetic differentiation from rheumatoid arthritis).

Upadacitinib
Baricitinib
Tofacitinib

4th choice - B-cell depletors - Response at 40-50% - only for TNFi + IL-6i + JAKi non-responders

Rituximab

Huaier mushroom - an alternative?

The Tanaka study sheds light on the effect of Huaier's active ingredients mainly in relation to cancer of any genesis (with the exception of brain tumors, as the large active ingredient molecules are unable to pass the blood-brain barrier).
There is a separate Contribution, also with Dosage instructions and Source of supply of the granules used in the study with 32 % polysaccharides.

Studies have shown that the active ingredients of the Huaier mushroom have a wide range of purely regulatory and programmatic properties. They are able to restore misdirected genes to their original range of functions and even reprogram them towards normal function.

Genes can be switched on or off and up- or down-regulated. All conditions that are not within the normal range result in correspondingly excessive or inhibited reactions to signals. The Huaier active ingredients are able to selectively restore the individually correct regulatory behavior.

There are mechanistic parallels to ARLA, which is why there are four critical molecular intervention points at which Huaier can exert its effect in ARLA pathogenesis:

NF-κB pathway inhibition (plasma membrane signaling)

In post-infectious Lyme arthritis, after successful antibiotic treatment of the borrelia, the so-called persistent peptidoglycans, the cell wall components of the dead borrelia, in the synovial fluid and in the joint tissue. These peptidoglycans are continuously recognized by the immune system, in particular by the Toll-like Receptor 2 (TLR2), which is localized on the surface of macrophages, dendritic cells and other innate immune cells.

When TLR2 recognizes the persistent peptidoglycans, a signaling cascade is set in motion that leads to the activation of the classic NF-κB signaling pathway leads. This occurs through the recruitment of adaptor proteins such as TIRAP and MyD88 to the activated TLR2 receptor.
These adaptor proteins then recruit a complex of kinases, including the IKK complex (Inhibitor of κB kinase), which inhibits the inhibitory protein IκBα phosphorylated and thus marked for proteasomal degradation. With the degradation of IκBα, the Transcription factor dimer p50/p65 is released from NF-κB and can translocate into the cell nucleus.

Once NF-κB is present in the nucleus, it binds to κB DNA binding sites in the promoter regions of pro-inflammatory cytokines and initiates their massive transcription. This leads to the continuous, persistent production of TNF-α, IL-6, IL-1β, IL-8 and other chemokines such as MCP-1 and KC.
In ARLA patients, this process is not self-limiting. It continues for weeks, months and years as long as the peptidoglycans remain present. This is the central problem: there is no new infection that needs to be fought, but the immune system remains stuck in an inflammatory mode.

How Huaier can interrupt this process:

Huaier is rich in β-glucans and others Polysaccharides, that bind to a receptor other than TLR2, namely the so-called Dectin-1 receptor (Dectin-1 is a C-type lectin receptor, which is primarily expressed on macrophages and dendritic cells). When the β-glucans from Huaier bind to Dectin-1, they also activate NF-κB, but via an alternative, less pro-inflammatory signaling pathway.
Instead of the classic TIRAP/MyD88 route As with TLR2 signaling, signaling is performed by Syk kinase and Card9, which leads to a kind of „regulated“ NF-κB signal.

In addition, Huaier works through miRNA-mediated Mechanisms that lead to the reduction of NF-κB components themselves. Specific microRNAs that are upregulated by Huaier (such as miRNA-223, miRNA-146a and others), can directly degrade the mRNA of IKK subunits and of RelA (the p65 subunit of NF-κB). This means that there is less overall NF-κB complex in the cells that can be activated, even if persistent peptidoglycans are still present and stimulate TLR2.

The practical result of this dual intervention by Huaier is that the continuous NF-κB activation by peptidoglycans is greatly reduced. The production of TNF-α decreases, the production of IL-6 decreases and the production of IL-1β decreases. Clinically, this leads to a rapid reduction in C-reactive protein (CRP), which is an NF-κB-induced acute-phase protein.
With less TNF-α and IL-6, which act as chemokines, the joint effusion is also absorbed faster because the recruitment of leukocytes into the joint is reduced. Patients report rapid reduction in swelling and pain in the first 1-2 weeks after Huaier initiation. This is consistent with NF-κB suppression.

JAK/STAT pathway modulation (endosomal signaling + IL-6 feedback)

ARLA is the overproduction of Type I interferons (interferon-α and interferon-β), which is known as „IFN amplification loop“ is labeled. This is not the classic TLR2 signaling that we just discussed with NF-κB. Instead, this occurs through a different pathway: the persistent borrelia are signaled by Macrophages and dendritic cells phagocytized. When they are taken up into the phagosome, they are recognized by endosomal Toll-like receptors, in particular TLR7, TLR8 and TLR9. These receptors are located on the inner surface of endosomal/phagosomal vesicles and recognize Borrelia RNA and DNA.

When TLR7/8/9 are stimulated by bacterial nucleic acids, they recruit the adaptor protein MyD88 and/or TRIF and lead to the activation of interferon-regulatory factors, in particular IRF3 and IRF7. These IRF transcription factors then enter the nucleus and initiate the transcription of type I interferon genes: initially Interferon-β and this is followed by a secondary wave of Interferon-α.

Once IFN-α and IFN-β are released into the synovial fluid and blood, they bind to the interferon-α/β receptor (IFNAR), which is present on virtually all cells, including T cells, macrophages and synovial fibroblasts.
IFNAR binding recruits two kinases to the receptor: JAK1 and TYK2. These kinases then phosphorylate the STAT proteins STAT1 and STAT2 (not STAT3 in this particular pathway). The phosphorylated STAT1/STAT2 together with IRF9 a transcription factor complex that ISGF3 and goes into the cell nucleus.

In the cell nucleus, ISGF3 binds to Interferon-stimulated Response Elements (ISREs) in the promoter regions of Interferon-stimulated genes (ISGs). These ISGs include genes such as OAS (2′,5′-oligoadenylate synthetase), MxA (Myxovirus Resistance Protein A), PBR (protein kinase R) and many others. These genes are massively upregulated and create an „anti-viral state“ in the cells. This is normal and adaptive in true viral infection, but in ARLA it is maladaptive because there is no active viral infection. It is a kind of „false alarm“.

The problem is made worse by a feedback mechanism: the interferon-producing cells produce more interferon, which triggers an even stronger IFNAR signal in other cells, which in turn leads to more ISG transcription, which in turn increases the likelihood of more IFN production. This is the „IFN amplification loop„, which is characteristic of post-infectious ARLA. This loop is self-perpetuating: even after all living borrelia have been killed, this pathway continues because the dead bacteria and their nucleic acids are still being phagocytosed.

At the same time, this type I IFN state also leads to the activation and proliferation of T cells, in particular Th1 cells and later also Th17 cells. The Th17 cells are activated by a different mechanism: they need IL-6 in combination with TGF-β. And IL-6 is also produced by NF-κB, but also by the interferon-stimulated genes. There are therefore several pathways that lead to IL-6.

As soon as IL-6 is present in significant quantities, something interesting happens: IL-6 binds to its receptor (IL-6R) together with a co-receptor called gp130 on the surface of T cells, synovial fibroblasts and other cells. This binding recruits JAK1 and JAK2 to the receptor. JAK1 and JAK2 then phosphorylate the STAT protein STAT3. With this phosphorylation, STAT3 is activated and enters the nucleus, where it binds to DNA binding sites and initiates the transcription of IL-17 and the transcription factor RORγt.

This leads to a massive expansion of Th17 cells, which in turn produce more IL-17. IL-17 is highly pro-inflammatory and acts on synovial fibroblasts (so-called FLS - fibroblast-like synoviocytes) to produce even more IL-6. This creates a second feedback system: IL-6 → Th17 expansion → IL-17 production → more IL-6 from FLS → even more Th17 → even more IL-17. As with the IFN amplification loop, this is self-perpetuating and gives ARLA its chronic, difficult-to-control nature.

How Huaier can interrupt this process:

Huaier interferes with this JAK/STAT pathway on a more fundamental level than directly blocking JAK1 or JAK2 (as it JAK inhibitors like Upadacitinib do). Instead, Huaier acts through miRNA-mediated transcriptional regulation. Specific microRNAs, which are upregulated by Huaier polysaccharides, destroy or degrade the mRNA of JAK proteins themselves.

This occurs through an elegant regulatory mechanism: when Huaier polysaccharides bind to Dectin-1 and stimulate the cell with signals, not only is a single signaling pathway activated, but miRNA-processing enzymes are also ramped up. These lead to the biogenesis of several canonical and non-canonical miRNAs. Some of these miRNAs, such as miR-223, miR-146a and miR-34a, have binding sites in the 3′-untranslated region (3′-UTR) from JAK1, JAK2 and STAT3 mRNA.
When these miRNAs hybridize with these sequences, they mark the mRNA for RNA interference degradation by the RISC complex (RNA-Induced Silencing Complex). The result is that the mRNA is degraded and these proteins are no longer produced as efficiently.

Within a few days to a week after exposure to Huaier, the cells simply less JAK1-, JAK2- and STAT3 protein. This is more fundamental than just blocking kinase activity. It means that even when the receptor is activated and tries to phosphorylate the JAK, there are fewer JAK molecules to phosphorylate. The Response to JAK-dependent cytokine signaling is therefore greatly reduced.

This reduction in JAK expression interrupts the type I IFN amplification loop. Even when TLR7/8/9 continue to attempt interferon production, the cells producing IFN-α/β have less JAK1/TYK2, so the STAT1/STAT2 can be phosphorylated less efficiently. This leads to less ISGF3 activation, less ISG transcription and thus less „anti-viral state“.

At the same time, the reduction of JAK1 and JAK2 also interrupts the IL-6 feedback loop. Even if IL-6 is present and binds to IL-6R on T cells, there is less JAK1 and JAK2 to phosphorylate, therefore STAT3 is less phosphorylated. With less active STAT3, less RORγt and IL-17 is produced, and therefore Th17 cells do not expand as aggressively. This means less IL-17 production, less stimulation of FLS to produce IL-6, - and the loop is broken.

In laboratory terms, we see this as a Decrease in IFN-γ levels (marker for Th1 activity, which is also upregulated with type I IFN), Decrease in IL-6 levels (marker for the IL-6 feedback system) and Decrease in IL-17 levels (marker for Th17). This happens more slowly than NF-κB suppression (which occurs within days) - it takes about 2-4 weeks for the miRNA-based effects to fully take effect, but once they do, they are more sustained.

Comparison: JAK1i (like upadacitinib) vs Huaier:

A JAK1 inhibitor like Upadacitinib (trade name Rinvoq) works by a completely different mechanism than Huaier, even though both ultimately modulate JAK/STAT signaling pathways. Upadacitinib is a small molecule that is delivered directly into the ATP binding pocket the JAK1 kinase and physically blocks them. It is a kind of „mechanical inhibitor“.
When JAK1 is blocked, it can no longer phosphorylate the amino acid tyrosine on STAT proteins, regardless of how hard the receptor tries to activate JAK. The effect is rapid: once upadacitinib is absorbed into the bloodstream and reaches the cells, JAK1 is inhibited. This is why JAK inhibitors have a rapid onset, typically 2-4 weeks to noticeable clinical improvements.

However, this direct blockade also has disadvantages. JAK1 inhibitors not only inhibit JAK1, but also other JAK kinases to varying degrees, depending on their selectivity. Even the „JAK1-selective“ inhibitors weakly inhibit JAK2 and TYK2 to a certain degree. This leads to Side effects, especially increased risk of Herpes zoster (shingles), because blocking JAK3 impairs T-cell proliferation and thus the control of latent viruses such as Varicella zoster weakens. Overall, the blockade of JAK2 leads to Thromboembolism activation instead of inhibition (especially baricitinib, which blocks JAK2 more strongly).

Huaier works on a completely different level. It does not directly block the JAK protein. Instead reduced it the amount of JAK protein, that the cell produces at all. This occurs through miRNA-mediated degradation of the JAK mRNA. The advantage is that this mechanism is more subtle and possibly more physiological. The cells simply downregulate how much JAK they produce, rather than a drug forcibly blocking the protein. The downside is that this process is slower. It takes several days to a week for miRNAs to be upregulated in sufficient quantities, and then it takes several more days for enough JAK mRNA to be degraded that JAK protein levels drop noticeably. This is the reason why Huaier has a slower onset, probably 4-8 weeks until noticeable effects on JAK/STAT-dependent processes.

Another important difference is reversibility. When a patient stops taking upadacitinib, the JAK blockade is over within 24-48 hours, as the half-life of upadacitinib is short. JAK1 becomes active again and can phosphorylate STAT. This is useful if a patient is suffering from infections and needs to pause the medication, but it also means that constant daily dosing is necessary. Huaier may have a longer-lasting effect because the miRNA-based regulation lasts longer. The miRNAs themselves have longer half-lives than small molecules, and JAK protein recovery takes longer when Huaier exposure stops.

An even more subtle difference lies in the specificity. Upadacitinib is JAK1-selective, which means that it strongly blocks JAK1, weakly blocks JAK2 and barely blocks JAK3. This is in fact the goal of JAK1 selectivity, namely to avoid blocking JAK3 in order to better preserve T-cell functions.
Huaier probably reduces JAK1, JAK2 and possibly TYK2 more or less proportionally, depending on which miRNAs are upregulated. This could mean that Huaier has a broader JAK suppression which could be good for things like type I IFN signaling (which needs TYK2), but also potentially leads to more JAK2 effects (thromboembolism risk theoretically).

PI3K/AKT activation (mitochondrial restoration + Treg support)

A third major problem with ARLA is not only the persistent production of pro-inflammatory cytokines, but also the breakdown of the systems that would normally limit this inflammation. The most important system that controls inflammation is the population of regulatory T cells (Tregs), in particular CD4+CD25+Foxp3+ Tregs.

In healthy people, Tregs are an integral part of the immune system and act through the production of anti-inflammatory cytokines such as IL-10 and TGF-β, as well as by direct cell-to-cell contact, in order to stimulate pro-inflammatory T cells (Effector T cells) to be suppressed.
Tregs are metabolically very active and rely on oxidative phosphorylation in their Mitochondria This means that they need functioning mitochondria and a constant supply of ATP. They also need the ability to synthesize proteins, especially to produce the Transcription-Regulatory Foxp3 protein and the suppressive cytokines IL-10 and TGF-β.

Several things have gone wrong in ARLA patients. First, due to continuous TLR2 and TLR7/8 stimulation, the Mitochondria chronically stressed. The continuous production of ROS (reactive oxygen species) by the activated inflammatory cells oxidizes the inner mitochondrial membrane and damages complexes in the electron transport chain. Mitochondrial DNA can be oxidized, leading to defective transcription. The mitochondria simply cannot produce enough ATP to supply all the cells in the chronic inflammatory state.

Secondly, through the chronic ER stress situation (because inflammatory cells constantly produce large quantities of cytokines and the Protein folding capacity of the endoplasmic reticulum is overwhelmed), the Protein synthesis capacity of the cells is reduced globally.
Ribosomes are the tool of protein production, and when the ER is under stress, the ribosomes are also under stress. As a result, important proteins such as Foxp3, IL-10 and TGF-β cannot be optimally produced.

Thirdly, through all these metabolic problems are Tregs simple dysfunctional. Although Tregs can still be detected (they are often even increased in number), their ability to have a suppressive effect is greatly reduced. They cannot produce enough IL-10. Tregs are therefore unable to adequately suppress Th17 and Th1 cells. With less IL-10 in the environment, the anti-inflammatory „braking“ of the immune system cannot take place, and the Pro-inflammatory „acceleration“ remains activated.

How Huaier activates/restores this process:

Huaier tackles this problem via the PI3K/AKT signal path on. When Huaier polysaccharides bind to the Dectin-1 receptor, they not only activate NF-κB and interferon pathways, but also PI3K (phosphoinositide 3-kinase). PI3K catalyzes the phosphorylation of phosphatidylinositol-(4,5)-bisphosphate (PIP2) to phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). PIP3 is a „second messenger“ - an intracellular signaling molecule that attracts other proteins.

The protein that is attracted by PIP3 is ACT (also called protein kinase B). AKT is synthesized by 3-phosphoinositide-dependent protein kinase 1 (PDK1) is phosphorylated and activated. Once activated, AKT is a „master regulator“ of many cellular processes. In the context of ARLA, two functions of AKT are particularly important:

First, AKT activates mTOR (mechanistic Target Of Rapamycin), a large protein complex that controls mRNA translation and ribosome biogenesis.
When AKT activates mTOR, two things happen: (1) mTOR phosphorylates S6K (ribosomal S6 kinase), which phosphorylates S6 proteins in ribosomes, leading to an increase in translation efficiency. (2) mTOR also phosphorylates 4E-BP1 (4E-Binding Protein 1), which enables the binding of 4E-BP1 to eIF4E and thereby increases the translation of eIF4E-dependent mRNAs.
The net result is that the cell can produce more proteins in less time. For Tregs this means that they can now can optimally produce IL-10 and Foxp3, the proteins they need, to have a suppressive effect.

Secondly, AKT activates the biogenesis of new mitochondria. This is partly due to the activation of the PGC1α gene by AKT.
PGC1α is a so-called „master regulator“ of mitochondrial biogenesis. It is a coactivator that works together with several transcription factors to activate the genes that code for mitochondrial proteins.
With active PGC1α new mitochondria are created in the cells. Over several weeks, this means that the Tregs can renew their mitochondrial populations, old, damaged mitochondria are replaced by new, functional ones, and the ability of the Tregs to produce ATP is restored.

With improved mitochondrial function and better protein synthesis, Tregs regain the ability to work effectively. They can produce significant amounts of IL-10 again. With IL-10 in the synovial fluid, Th17 cells can be suppressed, Th1 cells can be inhibited, and chronic autoimmunity can be resolved.

This is a slow process, biogenesis of new mitochondria takes weeks, but sustainable. While NF-κB suppression by Huaier works quickly (days) and JAK/STAT modulation works in the medium term (weeks), the PI3K/AKT activation a long intervention, which will not change the fundamental restores metabolic conditions for immune tolerance.

Specific effects with ARLA:

In an ARLA patient in the basal state before Huaier therapy, there are several pathological features. Firstly, the mitochondria in the synovial cells, macrophages and T cells are chronically attacked. The electron transport chain does not function optimally and ATP synthesis is reduced. This can be demonstrated by metabolic tests such as Seahorse analyses (which measure real ATP production rates). ARLA patients had lower OXPHOS rates than control subjects.

Secondly, the regulatory T cells (Tregs) are numerous. They can be identified by means of Flow cytometry by looking at CD4+CD25+Foxp3+ markers. ARLA patients often have an increased absolute number of Tregs, sometimes even higher than in healthy individuals. One would expect that more Tregs would lead to better suppression, but the opposite is the case because these Tregs are dysfunctional. They produce less IL-10 per cell, their suppressive activity is low and therefore cannot effectively control autoreactive T cells.

Thirdly, the IL-10/IFN-γ ratio is highly imbalanced. In healthy people, IL-10 is typically at least as high as IFN-γ, if not higher. In ARLA patients, IFN-γ is highly elevated (hundreds of times higher in synovial fluid than in healthy people) and IL-10 is low. This imbalance is probably one of the best biological markers of ARLA severity.

Fourthly, autoantibody titers are elevated. These can be Anti-OspA antibodies (against the Borrelia antigen, but the reaction persists), antibodies against the body's own cartilage proteins such as Type II collagen and Aggrecan, sometimes also the Rheumatoid factor and Anti-CCP antibodies.

After starting the Huaier therapy with 20 g/day and several weeks to months, we see the following changes:

The mitochondrial respiration normalizes. This can be measured by Seahorse analysis. The Basal respiration and the ATP production rate increase to normal values. This is measurable and reproducible. The mechanism is PI3K/AKT-mediated mitochondrial biogenesis through PGC1α induction, as described above.

The Tregs become functional. This is more subtle to measure, but there are several pathways: IL-10 production per Treg increases (can be measured by intracellular cytokine staining and flow cytometry). Foxp3 expression increases (more Foxp3 protein per cell). Suppressive function in vitro can be measured by suppression assays. When ARLA patient Tregs are co-cultured with autoreactive T cells, the Tregs suppress T cell proliferation better after Huaier therapy.

The IL-10/IFN-γ ratio normalizes dramatically. The IFN-γ level often decreases by 50-70%, and the IL-10 level increases by 100-200%. This leads to a ratio that looks normal again, no longer a pathological 1:100 ratio, but closer to 1:1 or even IL-10 dominant.

The Decreasing autoantibody titers. This takes longer, often 8-12 weeks, but the titres fall consistently. Anti-OspA falls first, antibodies against endogenous cartilage proteins fall later. This is a sign that the B-cell response is declining due to normalized T-cell control (Tregs inhibit B-cell responses).

The Joint effusion is reduced. This is the most visible sign and can be measured by clinical examination, circumferential measurement or ultrasound. With more IL-10 and less TNF-α/IL-6, the chemotaxis of leukocytes into the joint is reduced and the existing effusion is absorbed. An effusion of 200-300 mL can decrease to 50-100 mL or disappear completely.

The clinical symptoms improve accordinglyPain decreases, mobility increases, patients can use their joints again. The quality of life improves dramatically. Many ARLA patients describe that they can do normal everyday activities again for the first time in years (climbing stairs, going shopping, doing sport).

Ribosomal homeostasis (Tanaka main finding)

The fourth intervention point is subtle but potentially critical, based on the Tanaka studies on ribosomal dysfunction. Here is the hypothesis: in ARLA, chronic, persistent TLR2 and TLR7/8 signaling leads to chronic ER stress. The endoplasmic reticulum (ER) must constantly fold and release large amounts of new cytokines and chemokines, so that its proteostatase systems are constantly overloaded.

When the ER is under chronic stress, the cell reacts with the so-called „unfolded protein response“ (UPR). The UPR is a survival mechanism, but if it is chronically activated, it can become problematic.
One part of the UPR is the phosphorylation of eIF2α (eukaryotic initiation factor 2 alpha) by HRI (Heme-Regulated Inhibitor Kinase) or other kinases. When eIF2α is phosphorylated, the global rate of protein synthesis is reduced. This is adaptive because the cell should not fold more proteins if the ER is already overloaded.

When the Protein synthesis rate is reduced overall, the proteins that normally have to be produced continuously in order to maintain immune tolerance are also not produced optimally. These include IL-10, TGF-β and Foxp3. These are relatively large and structurally complex proteins that require special ribosomal quality in order to be optimally folded.

In addition, the ribosomes themselves can be damaged under ER stress. The large ribosomal subunits (60S) and small ribosomal subunits (40S) have a complex structure and composition.
When the ER is stressed and the cell produces too many misfolded proteins, misfolded proteins can interact with and damage ribosomal proteins, which in turn leads to abnormal ribosomal RNA structures, as Tanaka described in his mRNA vaccination study.

If the ribosomes are damaged at the structural level, they can still function, but not optimally. This could result in

Translation errors
inefficient protein synthesis
defective proteins, especially structurally complex proteins such as IL-10

This makes the problem self-perpetuating: poor ribosomes → poor IL-10 synthesis → less IL-10 in the environment → less immune tolerance → more inflammation.

How Huaier fixes this process:

Huaier addresses ribosomal homeostasis through miRNA-mediated regulation. Tanaka described that Huaier through the upregulation of specific miRNAs the ribosomal RNA composition and structure normalized. This works through the following mechanisms:

First, Huaier induces specific miRNAs that inhibit the expression of proteins implicated in ribosome dysfunction. For example, miRNAs can reduce the expression of proteins that accumulate misfolded proteins in the ribosomes.

Secondly, Huaier activates autophagy and the proteasome, to degrade damaged ribosomal proteins and old ribosomes. This occurs in part through miRNA regulation of autophagy genes. With activated autophagy, old, damaged ribosomes are removed from the cells.

Third, the PI3K/AKT activation by Huaier (which we discussed in the last point) Activates mTOR, which not only stimulates translation, but also stimulates new ribosome biogenesis. This means that while old ribosomes are removed by autophagy, new, functional ribosomes through mTOR-dependent rRNA synthesis and ribosomal protein expression be produced.

The result after several weeks is a Normalization of the ribosome population. The cells now have functional ribosomes with the correct structure. This means that IL-10, TGF-β and Foxp3 can be optimally synthesized again. The Proteins, that are produced are Structurally correct and functionally effective.

This is Huaier's most subtle and probably slowest intervention. It takes 4-8 weeks or longer to fully restore ribosomal quality. This is fundamental because it restores the cells' ability to produce the very proteins that are necessary for immune tolerance.

Mechanistic comparison of Huaier to biologics

Aspect	TNFi	IL-6i	JAK1i	HUAIER
NF-κB blocked	Indirect (↓TNF)	Indirect (↓IL-6)	Indirect (↓JAK1)	Direct (NF-κB suppression)
JAK/STAT blocked	No	Partial (IL-6 route)	YES (very strong)	JA (via miRNA, weaker)
PI3K/AKT activated	No	No	No	YES (STRONG!)
Ribosomal quality	No	No	No	JA (miRNA regulation)
Treg support	Weak	Weak	Weak (JAK3 not blocked)	STARK (via PI3K/AKT + ribosomes)
IL-10 increase	Minimal	Minimal	Low	STARK (via ribosomes + Treg support)
Onset	4-8 Wo	4-12 Wo	2-4 Wo	4-8 Wo (estimated)
Risk of infection	Increased	Moderate	Moderate	LOW (no immunosuppression!)

Dosage recommendation for ARLA at an advanced stage

ARLA at an advanced stage with multi-organ infestation corresponds in severity and systemic burden to the most severe cases of cancer:

Chronic multi-organ inflammation
Autoimmune component
Multiple self-perpetuating feedback loops
Mitochondrial dysfunction
Ribosomal damage

Proposal for ARLA dosing

Recommendation: 50-60g/day
divided into 3 receipts at intervals of 8 hours each
As with all preparations, the concentration of active ingredients is essential for the intended effect. As the active ingredients are broken down more or less quickly by the body over time, it is essential that the time interval between doses is strictly adhered to in order to maintain a constant level of active ingredients throughout the day!

Why 50 - 60 g/d instead of e.g. 40 g/d:

Severity: Multi-organ involvement corresponds to stage IV cancer in the Tanaka study
Multiple mechanisms of action: All 4 mechanisms must be addressed simultaneously
Dose dependenceTanaka shows clear dose dependence without toxicity
Time factor: Higher doses could enable faster onset

Dosing regimen (suggestion):

Phase 1 (weeks 1-4)
60g/day (divided into 3x20g)
Focus: NF-κB suppression, start of JAK/STAT modulation
Costs / month (approx.) 568,- Euro
Phase 2 (weeks 5-12)
50g/day (3×16-17g)
Focus: JAK/STAT effects fully established, PI3K/AKT activation
Costs / month (approx.) 473,- Euro
Phase 3 (months 4-6)
40g/day (3x13g)
Conservation, ribosomal restoration
Costs / month (approx.) 379,- Euro
Long-term preservation
20-30g/day (3x 7 .. 3x 10g)
Costs / month (approx.) 189 ... 284,- Euro