Immunologic Reset and Regenerative Repair: A Precision Medicine Framework for Post-Treatment Lyme Disease

Abstract

Lyme disease, caused by Borrelia burgdorferi, is the most prevalent vector-borne illness in the United States, with nearly half a million cases annually. While most individuals recover after a short course of antibiotics, up to 20% develop post-treatment Lyme disease syndrome (PTLDS), characterized by persistent fatigue, musculoskeletal pain, cognitive impairment, and autonomic dysfunction lasting six months or more. The underlying mechanisms of PTLDS remain incompletely understood, but increasing evidence points to immune dysregulation, molecular mimicry, and persistent inflammatory responses to non-viable bacterial antigens as central contributors to pathogenesis. These immune-mediated sequelae present unique therapeutic challenges, especially in the absence of ongoing infection and the failure of extended antibiotic therapy. This review explores a systems medicine framework for addressing the chronic multisystem impact of PTLDS, emphasizing three interrelated therapeutic strategies: (1) organ- and brain-specific progenitor and stem cell therapies; (2) regenerative peptides with immunomodulatory and metabolic activity; and (3) antigen-adaptive selective immunotherapy (AASI), a novel tolerogenic approach designed to recalibrate immune responses by targeting Borrelia-derived and autoreactive epitopes. We synthesize current preclinical and emerging clinical evidence supporting the use of mesenchymal stem cells (MSCs), neural progenitors, and exosome-based delivery platforms for tissue repair in joints, myocardium, and central nervous system. In parallel, we evaluate a suite of bioactive peptides, including thymosin β4, BPC-157, and mitochondrial-targeted peptides, for their ability to reverse inflammation, support mitochondrial function, and enhance neurocognitive recovery. Finally, we examine the translational potential of AASI as an immune reset tool for post-infectious autoimmunity. By integrating regenerative and immunomodulatory modalities, this precision medicine approach may offer a paradigm shift in the management of PTLDS, particularly for patients with persistent symptoms refractory to antimicrobial therapy.

Keywords:Lyme disease, Peptide, Immune Reset, Regeneration

Introduction

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent tick-borne disease in the United States, affecting an estimated 476,000 individuals annually [1]. Early in infection, B. burgdorferi takes advantage of immunosuppressive proteins in the saliva of the tick to activate genes essential for survival in the mammalian host [2]. Once inside the host, B. burgdorferi possesses multiple mechanisms to evade both the complement system and the adaptive immune response. This invasion effectively delays the production of specific antibodies and surface proteins bind to host complement regulatory factors, thereby temporarily inhibiting opsonization and protecting the bacterium from immune-mediated destruction. Following hematogenous dissemination, neurologic, cardiac, and/or rheumatologic involvement may occur. While most patients recover following a standard 2–4‑week course of antibiotics, approximately 10–20% develop post‑treatment Lyme disease syndrome (PTLDS). PTLDS is characterized by persistent fatigue, musculoskeletal pain, cognitive impairment, and autonomic dysfunction lasting six months or longer [3,4]. Despite appropriate antibiotic therapy, objective culture or polymerase chain reaction (PCR) evidence of ongoing infection is lacking in PTLDS, and extended antibiotic treatment has repeatedly failed to yield benefits while increasing risk [5-7]. Furthermore, central nervous system (CNS) manifestations can have residual neurological symptoms despite antibiotic treatment. Of note, neurologic involvement occurs in up to 15% of untreated individuals, manifesting as cranial neuropathy (particularly facial palsy), lymphocytic meningitis, and radiculoneuritis [8]. When the bacteria enter the heart, Lyme carditis, the infection interferes with the normal movement of electrical signals from the heart’s upper to lower chambers, “heart block.” Moreover, up to 40% of patients experience persistent synovitis after initial treatment, and a subset develop antibiotic-refractory Lyme arthritis despite repeated courses of antibiotics [9]. The multi-organ effects underscore the complex pathophysiology of Lyme disease, particularly in cases involving the nervous system or cardiac tissue, where immune-mediated mechanisms and tissue injury may persist despite microbial clearance. The lack of microbiological evidence of ongoing infection in PTLDS, coupled with the ineffectiveness and risks of prolonged antibiotic therapy, highlights a critical need for research into the host response, persistent inflammation, and potential biomarkers to distinguish post-infectious sequelae from active infection. A deeper understanding of these mechanisms is essential to inform the development of targeted, non-antibiotic therapies and improve long-term outcomes for patients with persistent Lyme-related symptoms.

Emerging data suggest that PTLDS pathogenesis may be driven by immune dysregulation rather than persistent replication of the spirochete itself. Notably, remnants of B burgdorferi peptidoglycan have been identified in joint and hepatic tissue post-treatment, correlating with ongoing immune activation and chronic inflammation [10,11]. Further, elevated inflammatory cytokines, such as CCL19 and IL‑23 as well as autoantibodies targeting neural and joint antigens have been documented in PTLDS patients. This supports the involvement of molecular mimicry and autoreactive processes10. The multitude of immune-evasive strategies B burgdorferi (e.g., antigenic variation, complement inactivation, and suppression of host antimicrobial pathways) not only facilitate initial dissemination but may also set the stage for sustained inflammation and autoimmunity, presenting unique challenges to effective treatment. The complexity of the immune hyperactivation and breakdown in self-tolerance sets the stage for PTLDS, analogous to other post-infectious and autoimmune syndromes requiring new approaches to explore the host immune response. Given the limitations of antibiotic- based therapy in PTLDS, there is an urgent need to explore regenerative and immunomodulatory interventions to restore immune homeostasis, promote tissue repair, and prevent long-term disability in affected patients [12,13].

A shift toward advanced regenerative and immunomodulatory these advanced therapies could markedly improve outcomes for patients with chronic Lyme-associated inflammation and sequelae. Advanced approaches combining antigen-adaptive selective immunotherapy (AASI) with organ- and brain-targeted precursor stem cells, peptides, and exosome-based therapies could potentially recalibrate the immune system and stimulate tissue repair. The chronic manifestations driven by persistent inflammation, immune dysregulation, and the presence of residual bacterial antigens act as potent immunostimulatory molecules, perpetuating synovial inflammation and contributing to the development of antibiotic- refractory Lyme disease. Furthermore, autoimmunity triggered by molecular mimicry and sustained cytokine activation has been implicated in the chronicity of disease, leading to continued tissue damage even in the absence of viable spirochetes [14]. This review will focus on the integration of targeted regenerative medicine and immune reboot protocols tailored specifically to Lyme disease– related organ and CNS sequelae by evaluating three interrelated strategies for treating Lyme disease and its sequelae:

Organ- and Brain‑Specific Stem/Progenitor Cell Therapies

We will explore the translational potential of mesenchymal stem cells (MSCs) and neural progenitor cells to repair damage in joints, nervous tissue, and other affected organs. Preclinical and emerging clinical data suggest MSCs’ immunomodulatory and regenerative capabilities may attenuate inflammation and restore function in post-treatment Lyme disease (PTLD) patients, although definitive clinical evidence remains limited and requires further investigation.

Peptide-Based Approaches to Support Regeneration

Therapeutic peptides (e.g., BPC‑157, Thymosin β‑4, Thymosin α‑1, KPV, and mitochondrial-targeted peptides) have shown efficacy in promoting tissue repair, enhance angiogenesis, modulate immune activity, and support cognitive and mitochondrial health in Lyme-associated disorders.

AASI Reset Strategies

AASI is a novel, antigen-specific immunomodulatory strategy tailored to Lyme disease. By administering Borrelia-derived and autoreactive peptides using tolerogenic delivery systems, AASI aims to recalibrate the immune response, suppressing autoreactive T cells, boosting regulatory T cells, and restoring tolerance. Insights will be drawn from recent advances in peptide vaccine platforms in autoimmunity and early-phase clinical trials in related inflammatory diseases.

Lyme-Triggered Autoimmunity: Mechanisms & Targets

The persistence of symptoms in a subset of Lyme disease patients following antibiotic treatment has prompted growing interest in autoimmune mechanisms, particularly molecular mimicry, as key drivers of post-infectious sequelae. Borrelia burgdorferi expresses several proteins that share structural or sequence homology with human autoantigens, allowing for epitope mimicry that misdirects host immune responses toward self-tissues [15,16]. Anti-neuronal and ganglionic acetylcholine receptor (gAChR) antibodies have been identified in patients with Lyme neuroborreliosis, suggesting that immune cross-reactivity contributes to neurologic symptoms such as neuropathy, dysautonomia, and cognitive dysfunction [17]. These observations reinforce the role of immune cross-reactivity in Lyme-associated neurological manifestations.

Similarly, in Lyme carditis, autoimmunity may also play a pathogenic role. Autopsy and biopsy studies have demonstrated lymphocytic infiltration and upregulation of MHC class II on cardiac myocytes, implicating T-cell–mediated autoimmune responses even after bacterial clearance [18]. Some cardiac manifestations, such as atrioventricular conduction block, resolve with antibiotics, yet prolonged or recurrent symptoms may involve immune-mediated injury independent of active infection.

This pattern of immune-mediated pathology despite pathogen clearance is also evident in Lyme arthritis, a well-characterized form of late-stage disease, the persistence of synovitis in a subset of patients despite microbiologic cure is attributed to autoimmune mechanisms resembling rheumatoid arthritis [19]. Synovial fluid from antibiotic-refractory Lyme arthritis patients contains autoantibodies and oligoclonal T-cell expansions, with a cytokine profile dominated by IFN-γ, IL-17, and TNF-α, which represent hallmarks of Th1/Th17-driven autoimmunity [20]. HLA-DRB1*0401, an allele associated with rheumatoid arthritis, is also overrepresented in this population, further supporting the role of genetic susceptibility to post-infectious autoimmunity [21]. Collectively, these findings support a multifocal autoimmune model of PTLDS involving antibody- and T cell–mediated responses that target neural, cardiac, and synovial tissues. Advanced immunological profiling and mechanistic studies are urgently needed to identify predictive biomarkers and therapeutic targets capable of distinguishing ongoing infection from autoimmune pathology, a prerequisite for developing non-antibiotic interventions.

Increasing evidence supports a model in which immune cell dysregulation and persistence of bacterial antigens underlie the chronic symptoms observed in PTLDS. Even after microbiologic clearance of Borrelia burgdorferi, components of the bacterial cell wall (i.e., peptidoglycan) have been shown to persist in host tissues, including the synovium, for months to years [22]). These residual antigens act as potent immune stimulants, promoting ongoing activation of innate and adaptive immune pathways that can mimic or evolve into autoimmune-like disease states.

In PTLDS and antibiotic-refractory Lyme arthritis, patients exhibit expansion of inflammatory monocyte subsets, elevated expression of Th1/Th17 cytokines, and enhanced cytotoxic T cell activity, all consistent with chronic immune activation [19,20]. Regulatory T cell (Treg) dysfunction has also been implicated, with studies showing impaired suppression of effector responses in the synovial compartment, a hallmark of immune imbalance similar to that observed in autoimmune diseases such as rheumatoid arthritis [23]. Furthermore, RNA sequencing and flow cytometric analyses have revealed sustained IFN-γ signaling and aberrant expression of costimulatory molecules on antigen-presenting cells, supporting the presence of an unresolved inflammatory milieu [21]. Crucially, these immunological signatures overlap significantly with those seen in classical autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and inflammatory arthritis. Clinical manifestations such as symmetric polyarthritis, fatigue, neurocognitive dysfunction, and dysautonomia often resemble autoimmune syndromes, complicating diagnosis and management, particularly with high risk allelic variants are disproportionately represented in patients with antibiotic-refractory Lyme arthritis, suggesting a shared genetic susceptibility to post-infectious autoimmunity [21]. These findings collectively highlight the need for advanced immunomodulatory therapies that go beyond pathogen eradication to restore immune tolerance, resolve chronic inflammation, and prevent irreversible tissue damage. Targeted interventions aimed at regulating T cell responses, blocking inflammatory monocyte activation, or neutralizing residual peptidoglycan may offer promising new avenues for the treatment.

Regenerative Strategies for Organ & Brain Repair

Advanced regenerative and immunomodulatory strategies are increasingly recognized as essential for restoring function and halting disease progression. B. burgdorferi employs dynamic regulation of its outer surface proteins to evade both innate and adaptive immune responses. It resists complement attack by expressing proteins like OspE-related and CRASP family members that bind host regulators such as factor H, thereby preventing complement activation through C3b inactivation. To avoid antibody-mediated clearance, the bacterium downregulates OspC, which is targeted early by IgM, and switches to expressing VlsE, a functionally similar protein capable of antigenic variation, allowing it to persist within the host. Given B. burgdorferi’s capacity for immune evasion and persistent antigenic stimulation, organ-targeted peptide therapies are a rational approach to promote site-specific immune modulation and tissue repair in the context of chronic inflammation and immune dysregulation seen in post-treatment Lyme disease.

Joint Repair and Synovial Recovery

In antibiotic-refractory Lyme arthritis, synovial inflammation and cartilage degradation may persist long after bacterial clearance. Mesenchymal stromal cells (MSCs) and their secreted peptides offer a promising strategy for targeted joint repair, particularly in chronic inflammatory conditions such as antibiotic-refractory Lyme arthritis. Intra-articular inflammation leads to synovial hyperplasia, cartilage degradation, and fibrosis, processes that MSC-derived factors can counteract through immunomodulatory and regenerative actions. Recent studies highlight specific MSC-derived peptides and secretome components that promote synovial homeostasis, reduce pro-inflammatory cytokine expression, and enhance matrix synthesis and remodeling.

For example, HMGB1-derived peptides, released from MSCs or synthetically mimicked, have been shown to recruit endogenous stem cells and stimulate cartilage repair through CXCR4/SDF-1α signaling [24]. Link N peptide, derived from the N-terminal region of link protein, enhances aggrecan and type II collagen synthesis in chondrocytes and protects cartilage from degradation in models of osteoarthritis [25]. Moreover, TP508, a thrombin peptide analog known to be secreted in the MSC environment, promotes synovial fibroblast proliferation and enhances the repair of collagenous matrices in inflamed joints [26]. Importantly, recent work emphasizes the potential for engineered MSCs or peptide-functionalized hydrogels to provide sustained release of bioactive molecules directly within affected joints, allowing for targeted tissue regeneration without the risks associated with live-cell therapies [27,28]. These approaches can modulate the inflammatory synovial milieu, reduce IL-1β and TNF-α activity, and promote repair of damaged cartilage and synovium [29]. Targeted delivery of MSC-derived peptides represents a scalable and tunable therapeutic avenue for restoring joint integrity and function in chronic inflammatory joint conditions, including Lyme arthritis [30].

Neurological Repair

Two species, B. garinii and B. bavariensis can cross the bloodbrain barrier (BBB) and invade the immune-privileged CNS causing Lyme neuroborreliosis (NB) [31]. Antibiotics and antimicrobial peptides have limited biodistribution in the CNS, making neuroinfections difficult to treat. Neurological complications, ranging from cognitive dysfunction to autonomic dysregulation, may persist despite antibiotic therapy in Lyme neuroborreliosis and PTLDS [32]. Neural progenitor cells, amniotic epithelial cells (AECs), and neuroprotective peptides offer an opportunity to reverse CNS injury and neuroinflammation. Targeted MSC-derived peptides represent a promising therapeutic approach for neuro-regeneration, particularly in the context of PTLDS and NB, where neuroinflammation, glial dysregulation, and axonal injury persist despite microbial clearance. MSCs exert neuroprotective effects largely through their secretome, which includes a repertoire of bioactive peptides capable of modulating neuroinflammation, promoting neurogenesis, and enhancing synaptic repair.

Several recent studies have identified key MSC-derived peptides with neurotherapeutic potential. Neurotrophic peptides, such as BDNF-mimetic peptides and NT-3-derived peptides, have been shown to promote neuronal survival, reduce microglial activation, and enhance synaptic plasticity following CNS injury [33]. Thymosin β4 (Tβ4), a naturally secreted peptide by MSCs, facilitates oligodendrocyte differentiation and myelination while exerting anti- apoptotic and anti-inflammatory effects on injured neural tissue [34]. Additionally, LL-37, a cathelicidin peptide found in MSC secretomes, demonstrates potent neuroprotective and immunomodulatory functions by reducing TLR4-mediated neuroinflammation and preserving blood-brain barrier integrity [35].

Advances in peptide delivery systems, such as exosome-encapsulated peptides or scaffold-bound formulations, further enhance CNS targeting and bioavailability while minimizing off-target effects [36]. For example, MSC-derived exosomes enriched with CNS-homing peptides or loaded with synthetic neurotrophic mimetics have shown superior efficacy in restoring cognitive function and reducing neuroinflammation in animal models of neurodegenerative diseases [37].

Given the immune-privileged and often inaccessible nature of the CNS, these cell-free, peptide-based therapies offer a scalable, standardized, and minimally immunogenic platform to repair post-infectious neurological damage and restore cognitive function.

Chronic Fatigue in PTLDS: Mitochondrial Dysfunction and Regenerative Peptide Therapy

Chronic fatigue is a cardinal and debilitating symptom of PTLDS, often persisting for months or years despite microbial clearance. The pathophysiology is multifactorial, with mounting evidence implicating mitochondrial dysfunction, neuroimmune dysregulation, and persistent metabolic inflammation as key drivers. Similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), patients with PTLDS demonstrate reduced ATP production, impaired mitochondrial biogenesis, and a bioenergetic shift toward glycolysis. This metabolic re-direction represents a maladaptive metabolic state exacerbated by systemic inflammation and oxidative stress [38,39].

Studies of mononuclear cells in PTLDS have shown elevated reactive oxygen species (ROS), decreased mitochondrial membrane potential, and impaired mitochondrial DNA (mtDNA) replication, reflecting a chronic energy deficit at the cellular level [40]. Additionally, immune profiling reveals upregulation of inflammatory cytokines (e.g., IL-6, TNF-α), and expansion of non-classical monocytes and exhausted T cell subsets that contribute to metabolic stress and neuroendocrine disruption [41].

Given the limitations of conventional treatments, MSC-derived peptides and exosomes offer a novel, cell-free strategy to reverse fatigue-related pathology. Several regenerative peptides, such as humanin and MOTS-c, derived from mitochondria or MSCs, directly enhance mitochondrial biogenesis, reduce ROS, and restore oxidative phosphorylation efficiency [42,43]. Exosomes derived from MSCs have been shown to carry bioactive lipids, mitochondrial transfer proteins, and antioxidant peptides that modulate redox homeostasis and cellular respiration, leading to improved endurance and reduced fatigue in animal models of chronic inflammation and sepsis [44].

Furthermore, the anti-inflammatory and immunomodulatory effects of MSC-secreted peptides can recalibrate the dysfunctional immune-metabolic axis observed in PTLDS. When targeted to the CNS or muscle via exosome carriers or peptide-conjugated nanoparticles, these therapies offer a precision-based, non-immunogenic option for restoring energy metabolism and improving quality of life.

Cardiac Recovery

Involvement of the heart, though somewhat rare (estimated incidence 4-10% in the US [45]), can lead to significant morbidity through Lyme carditis, most notably presenting as atrioventricular block (AVB) [46]. Severe forms are characterized by the presence of syncope, dyspnea, and chest pain. Although this condition typically resolves with antibiotics, immune-mediated injury due to possible cross-reaction between Borrelia burgdorferi antigens and cardiac epitopes does occur. Residual conduction abnormalities or myocardial inflammation may benefit from regenerative therapy. Cardiac progenitor cells, MSCs, and peptides such as thymosin β4 and angiogenic mimetics have been studied for their ability to enhance vascular remodeling and myocardial repair [47,48]. Given the immunologic contributions to myocardial injury in Lyme disease, combined cell–peptide therapies may help promote recovery of electrical conduction and reduce fibrosis.

MSC-derived peptides also represent a novel frontier in cardiac repair. MSC-derived peptides offer a targeted means of modulating inflammation, promoting cardiomyocyte survival, and stimulating endogenous cardiac regeneration through paracrine signaling pathways. Several key bioactive peptides secreted by MSCs or engineered into MSC mimetics have demonstrated cardioprotective potential. Thymosin β4 (Tβ4), a highly conserved actin-sequestering peptide secreted by MSCs, plays a central role in cardiac repair by promoting endothelial migration, angiogenesis, and epicardial activation, facilitating the recruitment of cardiac progenitor cells [49]. Tβ4 also reduces myocardial fibrosis and preserves ventricular geometry post-injury [50]. Neuregulin-1 (NRG1)–derived peptides, which can be released or upregulated in MSC-conditioned media, activate ErbB4 signaling to enhance cardiomyocyte proliferation and contractile function in ischemic or inflamed myocardium [51]. Moreover, C21, an angiotensin II type 2 receptor agonist peptide found in MSC-derived exosomes, exerts anti-fibrotic and anti-apoptotic effects, particularly in autoimmune and post-infectious myocarditis models [52]. ^4^ Delivery systems using hydrogels or exosome carriers have further improved the bioavailability and retention of these peptides in cardiac tissue, leading to sustained improvements in ejection fraction and reduced arrhythmic burden in preclinical models [53]. Collectively, MSC-derived peptides offer a scalable, cell-free regenerative therapy platform for myocarditis and conduction disorders associated with Lyme carditis. Their ability to engage reparative pathways without provoking alloimmune responses makes them particularly suitable for use in post-infectious cardiac syndromes. Compared to cellular therapies, exosomes offer key translational advantages: standardizable manufacturing, minimal risk of tumorigenicity, ease of storage and transport, and reduced immunogenicity. As such, MSC-derived exosomes are increasingly recognized as next-generation biologics for immune-mediated and degenerative disorders.

Peptide-Based Regenerative Therapies

Synthetic peptides provide a complementary and highly targeted approach to promote tissue regeneration and modulate immune signaling. Peptides can be engineered to mimic endogenous repair factors or signaling motifs, enhancing tissue-specific regeneration. In musculoskeletal applications, peptides such as P-15, CK2.1, and link N have been shown to promote cartilage matrix synthesis, reduce inflammation, and enhance synovial healing, particularly relevant for patients with antibiotic-refractory Lyme arthritis [54,55]. In neurological contexts, neuroprotective peptides (e.g., including NAP (davunetide), Semax, and tetrapeptide mimetics of neurotrophins) have demonstrated efficacy in promoting axonal outgrowth, stabilizing microtubules, and reducing excitotoxicity and neuroinflammation [56,57]. These agents are especially promising for treating cognitive and autonomic sequelae of PTLDS, where persistent neuroimmune activation may underlie clinical symptoms despite microbial clearance. Together, cell-free exosome therapies and peptide-based biologics constitute an emerging class of precision therapeutics capable of addressing the multi-organ immune dysregulation and tissue damage associated with PTLDS as well as other post-infectious syndromes. In summary, while persistent symptoms remain a significant clinical challenge, increasing evidence suggests sustained immune activation, molecular mimicry, and residual bacterial components, in driving chronic inflammation and tissue-specific dysfunction even after pathogen clearance. These pathophysiological insights underscore the need for adjunctive therapies that go beyond antimicrobials to address long-term tissue damage and immune dysregulation.

Emerging regenerative strategies leveraging organ-specific precursor cells and bioactive peptides offer a promising avenue to restore tissue integrity and modulate immune responses across multiple systems affected. In Lyme arthritis, where persistent synovitis and cartilage degradation may occur despite microbial clearance, mesenchymal stem cell (MSC)-derived secretomes and targeted chondrogenic peptides have demonstrated the ability to promote cartilage repair while suppressing pro-inflammatory cytokine signaling and matrix-degrading enzymes [58]. In the context of neurologic sequelae, neural progenitor cells, MSCs, and amniotic epithelial cell-derived factors have shown potential to restore neurovascular integrity, attenuate glial activation, and reverse cognitive dysfunction, particularly when administered alongside neuro- regenerative peptides such as cerebrolysin and PACAP [59-61].

Cardiac manifestations of PTLDS, including conduction abnormalities and myocardial fibrosis, may benefit from cell-based approaches utilizing cardiopoietic stem cells or exosome-bound mitochondrial proteins, which have been shown to enhance myocardial repair and reduce arrhythmogenic remodeling [62]. A growing body of evidence implicates mitochondrial dysfunction, including impaired oxidative phosphorylation, elevated oxidative stress, and dysregulated immunometabolism, as a major contributor to chronic fatigue in PTLDS [63]. MSC-derived exosomes and mitochondrial-targeted peptides such as MOTS-c and humanin have demonstrated efficacy in reversing these deficits by restoring mitochondrial bioenergetics and reducing systemic inflammation in preclinical models [64-66]. Together, these findings provide a compelling mechanistic basis for the use of targeted, cell-free, or peptide-based regenerative therapies to address the multisystem manifestations of PTLDS. Future investigations should focus on validating these interventions in well-controlled clinical trials, assessing long-term safety, and optimizing delivery platforms to enhance tissue specificity and therapeutic persistence. Given the heterogeneous and multifactorial nature of PTLDS, personalized regenerative approaches that concurrently modulate immune dysregulation and metabolic dysfunction may represent the most effective path toward durable recovery.

AASI Immunotherapy in Lyme

While regenerative approaches offer promising avenues to repair organ-specific damage and restore homeostatic function in PTLDS, they do not directly address the underlying immune dysregulation and potential autoimmune mechanisms perpetuating chronic symptoms. Notably, accumulating evidence supports the role of molecular mimicry, persistent antigenic stimulation, and immune cell dysregulation in the pathogenesis of post-infectious sequelae in Lyme disease. AASI immunotherapy represents a novel precision-targeted strategy designed to recalibrate immune tolerance, clear residual autoantibodies, and suppress aberrant inflammatory responses. The following section explores the mechanistic rationale, emerging evidence, and translational potential of AASI immunotherapy as an adjunct to antimicrobial and regenerative therapies in Lyme disease and related autoimmune syndromes.

AASI Mechanistic Approach

Chronic Lyme manifestations is increasingly linked to dysregulated adaptive immune responses, including expansion of effector T cells (Teff), impaired regulatory T cell (Treg) function, and production of autoantibodies triggered by molecular mimicry [39,67,68]. AASI is an emerging precision immunotherapy strategy that leverages low-dose, controlled exposure to disease-relevant antigens (i.e., B. burgdorferi peptides, conserved peptidoglycan fragments, and self-antigens) to induce immune tolerance and reset aberrant immune profiles [69-71].

Chronic Lyme manifestations is increasingly linked to dysregulated adaptive immune responses, including expansion of effector T cells (Teff), impaired regulatory T cell (Treg) function, and production of autoantibodies triggered by molecular mimicry [39,67,68]. AASI is an emerging precision immunotherapy strategy that leverages low-dose, controlled exposure to disease-relevant antigens (i.e., B. burgdorferi peptides, conserved peptidoglycan fragments, and self-antigens) to induce immune tolerance and reset aberrant immune profiles [69-71]. The immunologic basis of AASI parallels the concept of antigen- specific tolerance induction seen in allergen immunotherapy and autoimmune desensitization but is tailored to chronic infection– associated autoimmunity. In PTLDS, sustained presentation of Borrelia lipoproteins and bacterial cell wall remnants can perpetuate a maladaptive immune response even after pathogen clearance, characterized by elevated pro-inflammatory cytokines (e.g., IFN-γ, IL-17), memory T-cell activation, and antigen spreading [55,72,73]. AASI aims to selectively suppress this pathogenic cascade by shifting the balance from Teff to Treg cells, promoting anergy or deletion of autoreactive clones, and reestablishing immune homeostasis [74].

Pilot studies using antigen-specific immune modulation have shown success in related conditions, such as rheumatoid arthritis and type 1 diabetes, where peptide-based or tolerogenic antigen therapy reduced autoreactive T-cell responses and cytokine production [75,76]. In the context of Lyme disease, peptides derived from Borrelia outer surface proteins (e.g., OspA, VlsE) and ganglioside- mimicking epitopes implicated in neuroborreliosis could serve as rational AASI targets [77]. The inclusion of peptidoglycan fragments, shown to persist in synovial fluid and drive innate activation, may further enhance tolerance reprogramming [78].

Design of AASI for Lyme

The design of AASI specifically for Lyme disease is rooted in the need to restore immune tolerance by selectively modulating antigen- specific immune responses, rather than broadly suppressing immunity. This precision immunotherapy strategy hinges on two key components: rational antigen selection and innovative delivery platforms to ensure targeted, durable immunomodulation. AASI for Lyme is structured around a dual-antigen strategy to address both pathogen-associated immune activation and post-infectious autoimmunity:

a) Borrelia-specific antigens: Select peptides derived from B. burgdorferi, notably conserved components such as outer surface proteins (e.g., OspA, VlsE) and cell-wall peptidoglycan fragments, are the central focus. These bacterial remnants persist in tissues (especially joints) and are recognized drivers of chronic inflammation, even post-pathogen clearance [55,78].

b) Self-peptides implicated in molecular mimicry underlie AASI incorporation of neural and synovial autoantigens implicated in Borrelia-induced autoimmunity, including ganglioside-like peptides and neural surface antigens linked to Lyme neuroborreliosis and arthritis [68,77].

The goal is to retrain autoreactive T cells while preserving host defense mechanisms tailored to the patient. By tailoring antigen selection to the patient’s clinical phenotype and serologic profile, AASI holds potential to resolve chronic inflammation without broad immunosuppression. Future translational studies are warranted to optimize antigen dosing, delivery platforms (e.g., intra-lymphatic, subcutaneous), and biomarker-guided stratification to enhance safety and efficacy in chronic Lyme and other infection-associated autoimmune conditions.

Delivery Platforms

To induce durable immune tolerance and minimize off-target effects, AASI relies on next-generation delivery systems that provide controlled, tissue-targeted release. For example, peptide-loaded nanoparticles are engineered to deliver tolerogenic antigens to lymphoid organs or antigen-presenting cells (APCs). The nanoparticles can be functionalized to co-deliver immunomodulators or surface ligands to bias toward Treg induction [79,80]. In addition, tolerogenic dendritic cells (tolDCs) either autologous or ex vivo generated pulsed with Borrelia and autoantigen peptides can present antigen in a non-inflammatory context, promoting regulatory T cell expansion and anergy of autoreactive clones [66,81]. Further, biodegradable scaffolds or hydrogels allow for sustained, localized antigen release and have shown promise in autoimmune models to reverse chronic inflammation without global immunosuppression [82]. Together, these elements of AASI offer a rational strategy to selectively downregulate chronic post-infectious immune activation in Lyme disease, with potential to mitigate persistent symptoms while reducing the need for extended antibiotic or immunosuppressive therapy. This approach gains further relevance considering emerging evidence that implicates infection-mediated autoimmunity as a key driver of chronic Lyme manifestations, often potentiated by host genetic susceptibility.

Emerging evidence implicates infection-mediated autoimmunity as a key driver, often facilitated by host genetic susceptibility, particularly certain HLA-DR alleles that skew antigen presentation toward autoimmune activation [83]. The resulting imbalance between effector T cells (Teff) and regulatory T cells (Tregs) fosters a pro-inflammatory immune profile that mimics patterns seen in classic autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) [84]. Mechanistically, molecular mimicry, epitope spreading, and persistence of bacterial antigens such as peptidoglycan further perpetuate tissue-targeted immune responses [85].

The AASI Framework: Precision Immunotherapy for Immune Reset

AASI is a next-generation immunomodulatory strategy designed to reestablish immune tolerance by selectively presenting pathogenic antigens in a tolerogenic context [86]. The AASI framework does this by employing customized peptide libraries incorporating microbial antigens (e.g., Borrelia surface proteins, peptidoglycan fragments) and self-peptides known to drive autoimmunity (e.g., myelin, synovial, or ganglioside-related epitopes) [87]. Delivering antigens via tolerogenic platforms (i.e., biodegradable nanoparticles, tolerogenic dendritic cells, or immunologically inert hydrogels) engineered to expand Tregs, suppress autoreactive T cells, and recalibrate systemic immunity [87]. This targeted approach avoids the pitfalls of global immunosuppression by selectively re-educating the immune system, offering a safe and durable alternative for chronic inflammatory conditions with post-infectious or idiopathic etiologies. In autoimmune disorders such as multiple sclerosis and rheumatoid arthritis AASI has the potential to induce antigen-specific Treg expansion, restoring immune homeostasis. Co-administration of MSCs or their secretome may enhance efficacy by fostering an immunomodulatory microenvironment [88]. AASI enables targeted removal of autoreactive lymphocyte clones activated via Borrelia-driven mimicry [89]. This helps halt progression to antibiotic-refractory Lyme arthritis or Lyme-associated neuroimmune dysfunction. Additionally, antigen-specific tolerance may facilitate recovery of commensal microbiota, restoring gut-immune homeostasis [90]. AASI reduces tissue damage and improves host receptivity to organ-specific cell therapies, such as MSCs for joints, neural progenitor cells for CNS repair, and cardiac progenitors, by quelling persistent immune activation [91]. AASI may also synergize with cell-free biologics (e.g., MSC-derived exosomes, tolerogenic peptides) to create a pro-regenerative, anti-inflammatory milieu that ensures durable functional recovery and immune stability [92]. Collectively, AASI establishes a pro-regenerative, immune-quiescent state conducive to sustained functional recovery and longterm immunologic stability.

Synergy with Regenerative Therapies

AASI functions to specifically halt ongoing autoimmune inflammation, creating an immunological milieu conducive to tissue repair. This immunomodulatory effect complements the regenerative capacity of MSCs and MSC-derived exosomes, which promote repair of damaged joint, neural, and cardiac tissues through anti-inflammatory and trophic mechanisms [93,94]. Moreover, tailored peptide cocktails can be designed to concurrently recalibrate immune responses while directly stimulating cellular pathways involved in tissue regeneration, thus offering a multifaceted therapeutic approach that addresses both immune dysregulation and structural restoration. This integrated strategy holds significant potential to enhance clinical outcomes in Lyme-associated chronic disease and related autoimmune conditions.

Therapeutic Evidence

Emerging early-phase clinical investigations have begun to explore tolerogenic peptide immunotherapy and intravenous immunoglobulin (IVIG) as targeted interventions for PTLDS and associated autonomic dysfunction [95]. These approaches aim to recalibrate immune tolerance by modulating pathogenic T cell responses without broad immunosuppression. For instance, pilot studies utilizing peptide-based tolerance induction targeting Borrelia and autoantigen epitopes demonstrate promising immunomodulatory effects with favorable safety profiles [96]. IVIG has also shown potential benefit in select patients with dysautonomia secondary to immune dysregulation post-Lyme, plausibly via Fc receptor-mediated modulation of autoreactive lymphocytes and inflammatory cytokines [97]. Preclinical models and limited clinical data underscore the potential of MSCs and related cell therapies in addressing immune dysfunction and tissue damage associated with Lyme disease sequelae. MSCs’ immunomodulatory properties, mediated through secretion of anti-inflammatory cytokines, exosomes, and cell-cell contact, have been shown to restore Treg function and inhibit Teff expansion in autoimmune and infectious contexts. Notably, recent Kentucky-based case series have documented preliminary safety and immune restoration in immunodeficient patients with a history of Lyme disease treated with allogeneic MSCs, though controlled trials remain lacking. In antibiotic-refractory Lyme arthritis, immunosuppressive therapies traditionally used in autoimmune arthritis (i.e., disease-modifying antirheumatic drugs (DMARDs) and biologics targeting TNF-α or IL-6 pathways), have demonstrated clinical efficacy in reducing synovitis and restoring joint function. This clinical responsiveness corroborates the autoimmune nature of persistent arthritis post-Borrelia clearance and suggests that adjunct immunotherapy may be necessary for complete remission. Accumulating evidence underscores the critical need for combined immunomodulatory and regenerative approaches to achieve durable recovery. However, the promising findings necessitate further rigorous evaluation in Lyme-associated immune dysregulation.

Future Directions

Despite significant advances in understanding Lyme disease immunopathogenesis, several critical challenges remain in the development of effective targeted therapies. Chief among these is the precise identification of the key antigenic drivers responsible for sustaining immune dysregulation and autoimmunity post-Borrelia infection. Given the heterogeneity of immune responses among patients, individualized antigen profiling will be essential to optimize specificity and minimize off-target effects, thereby enhancing therapeutic efficacy and safety. There is a pressing need for validated biomarkers to enable real-time monitoring of immune modulation during therapy. Candidate biomarkers include expansions of inflammatory monocyte subsets, Treg cell functionality, circulating autoantibodies, and quantifiable levels of bacterial peptidoglycan fragments. These biomarkers could serve not only as surrogate endpoints in clinical trials but also as tools for patient stratification and treatment personalization.

Continued investigations are warranted to evaluate the combinatorial effects of AASI and MSC-derived exosomes on both joint and CNS repair, particularly the assessment of immunological resetting alongside functional and histological outcomes, providing critical mechanistic insights. Subsequently, studies designed to assess safety, tolerability, and preliminary efficacy of integrated peptide immunotherapy coupled with secretome administration in patients with PTLDS merit attention to lay the groundwork for innovative, multi-modal therapeutic strategies that address both immune dysregulation and tissue regeneration, ultimately improving long-term outcomes for patients affected by Lyme disease.

In conclusion, Lyme-induced autoimmunity is driven by persistent peptidoglycan-mediated inflammation, molecular mimicry, and dysregulation of regulatory T cells, which collectively sustain chronic immune activation. AASI offers a promising strategy to restore immune tolerance by specifically targeting autoreactive lymphocytes, thereby enabling subsequent regenerative interventions to repair joint and neurological damage. This integrated immunomodulatory and regenerative approach provides a viable and innovative roadmap for the effective management of chronic Lyme disease and its persistent sequelae, PTLDS.

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