Immune Dysregulation in Lyme Disease

Lyme disease can alter immune signaling and antibody responses
Some immune changes may persist after antibiotic treatment
Persistent infection, immune effects, coinfections, and other mechanisms may overlap

Can Lyme disease affect the immune system even after treatment? Research suggests that some immune effects associated with Borrelia burgdorferi infection may persist after antibiotic treatment, although the clinical significance remains uncertain.

Immune dysregulation is increasingly recognized as one biologically plausible explanation for persistent symptoms after Lyme disease. Rather than reflecting a simply weakened or overactive immune system, altered immune signaling may contribute to fatigue, brain fog, pain, autonomic dysfunction, sleep disturbance, and other symptoms in some patients.

At the same time, immune dysregulation is not the only possible explanation for persistent illness. Clinicians may also need to consider persistent or recurrent Borrelia burgdorferi infection, other tick-borne infections, persistent bacterial antigens, tissue injury, autonomic dysfunction, treatment effects, and unrelated medical conditions. These possibilities are not necessarily mutually exclusive.

A 2024 review by Snik and colleagues describes inflammatory responses during early and disseminated Lyme borreliosis, prolonged inflammation in later manifestations, changes in B-cell responses and immune memory, and possible autoimmune mechanisms.¹

A separate 2024 experimental study by Williams and colleagues provides additional insight into how B. burgdorferi can alter antibody responses during infection and what happens after antibiotic treatment.²

For a broader clinical framework on how Lyme disease may become chronic, see Preventing Chronic Lyme Disease.

Can the immune system remain altered after Lyme disease?

Possibly. The immune system does not necessarily return immediately to its previous state after an infection. Inflammatory signaling, immune-cell activity, antibody responses, tissue responses, and immune regulation may remain altered for a period of time.

Snik and colleagues reviewed experimental and clinical evidence showing that the host immune response is central to many manifestations of Lyme borreliosis. Early localized disease is associated with proinflammatory immune responses, while disseminated manifestations can involve immune-cell infiltration and altered chemokine signaling. Lyme arthritis and acrodermatitis chronica atrophicans may involve prolonged inflammation, and autoimmune mechanisms have also been investigated.¹

The review also describes evidence that Borrelia infection can disrupt B-cell responses and the development of long-term immune memory.¹

However, evidence of immune abnormalities does not establish why a particular patient remains ill. Different patients may have different or overlapping biological mechanisms contributing to persistent symptoms.

What did the 2024 immune study find?

Williams and colleagues investigated how Borrelia burgdorferi infection affected antibody production in mice.²

The researchers infected mice with B. burgdorferi and then immunized them with an unrelated SARS-CoV-2 spike protein. The SARS-CoV-2 antigen was used as a laboratory tool to determine how well the immune system could respond to something unrelated to Lyme disease.

The infected mice produced substantially less IgG against the unrelated antigen than uninfected mice. This suppression was greatest when immunization occurred approximately two weeks after Borrelia infection and remained detectable throughout the timepoints studied.²

The experiment therefore demonstrated that active B. burgdorferi infection could interfere with antibody responses beyond antibodies directed specifically against Borrelia.

What happened after antibiotic treatment?

The researchers then treated infected mice with ceftriaxone and tested their ability to respond to the same unrelated antigen.²

Following antibiotic treatment, the IgG response returned to levels comparable with those of uninfected mice. Lymph-node architecture that had been disrupted during infection also appeared to return toward normal.²

This is important because it shows that some of the immune abnormalities associated with active infection were reversible after antibiotic treatment in this experimental model.

However, not every immune finding returned to baseline. IgM responses remained elevated after treatment in the mice, suggesting that different components of the immune response may recover on different timelines.² The clinical significance of this finding in humans is unknown.

Why the mouse-study limitation matters

The Williams study was conducted in mice, not patients with Lyme disease.²

The mice were experimentally infected with a defined strain of B. burgdorferi and treated with ceftriaxone under controlled laboratory conditions. The results therefore cannot establish that the same immune changes occur to the same extent in humans.

The study also does not show that these immune abnormalities cause fatigue, brain fog, pain, or other persistent Lyme symptoms.

Its value is more fundamental: it demonstrates a biological mechanism through which B. burgdorferi infection can alter the host’s antibody response and shows that different components of that response may recover differently after treatment.

What does immune dysregulation mean in Lyme disease?

Immune dysregulation refers to impaired control or coordination of immune signaling rather than a single abnormal laboratory value or diagnosis.

In Lyme disease, proposed immune abnormalities include prolonged cytokine signaling, altered T-cell activity, disrupted B-cell responses, impaired development of immune memory, persistent antigenic stimulation, and altered communication between the immune system and nervous system.^1-3

Importantly, immune dysregulation does not necessarily mean that routine blood tests will remain abnormal. Many research findings involve cytokines, chemokines, antibodies, immune-cell populations, gene expression, or tissue-level processes that are not measured by standard laboratory panels.

Can Lyme disease affect B cells and immune memory?

Yes. B cells produce antibodies and help establish long-term immune memory.

Experimental studies have found that Borrelia infection can interfere with normal germinal-center responses. Germinal centers are structures within lymph nodes that are important for producing high-affinity antibodies, long-lived plasma cells, and memory B cells.^1,2

Williams and colleagues observed disruption of lymph-node organization during active infection, while lymph-node structure appeared more normal following antibiotic treatment.²

Human studies have also identified changes involving plasmablasts and memory B-cell responses, although the long-term clinical implications remain incompletely understood.¹

These findings may help explain why infection with Lyme disease does not necessarily generate dependable long-term protective immunity.

Does Lyme disease weaken the immune system?

Not necessarily. Lyme disease does not generally weaken the immune system in the same way as chemotherapy, advanced HIV infection, or powerful immunosuppressive medications. A patient with Lyme disease should not automatically be considered globally immunocompromised.

The evidence instead suggests that Borrelia can alter or redirect particular immune responses. Some pathways may be suppressed, others activated, and some may remain altered after treatment.^1-3

The Williams experiment illustrates this distinction. Active infection suppressed an IgG response to an unrelated antigen, while other aspects of the antibody response behaved differently.²

That pattern is better described as immune dysregulation than simply a weak immune system.

Can Lyme disease trigger autoimmune responses?

Autoimmune mechanisms have been investigated in Lyme disease, particularly in Lyme arthritis.

Snik and colleagues describe molecular mimicry as one proposed mechanism. Molecular mimicry occurs when an immune response directed against a microbial target also recognizes a similar host protein.¹

A 2026 review by Pine and colleagues also discusses molecular mimicry, persistent antigens, altered inflammatory pathways, and other mechanisms that may contribute to infection-triggered immune dysregulation.³

However, the presence of autoreactivity or an autoantibody does not prove that it is responsible for a particular patient’s symptoms. Lyme disease itself remains an infectious disease rather than an autoimmune disease.

What symptoms may accompany immune dysregulation?

There is no single symptom pattern or laboratory test that confirms immune dysregulation after Lyme disease.

Patients with persistent Lyme symptoms may report fatigue, brain fog, slowed processing speed, sleep disruption, widespread pain, sensory sensitivity, dizziness, orthostatic intolerance, exercise intolerance, gastrointestinal symptoms, temperature dysregulation, and symptoms that fluctuate with exertion, sleep, illness, or stress.

These symptoms are not specific to immune dysregulation or Lyme disease. Infectious, inflammatory, endocrine, neurologic, cardiovascular, sleep-related, psychiatric, medication-related, and other medical explanations may need to be considered.

Neuroinflammation and immune dysregulation in Lyme disease

The immune system and nervous system communicate continuously. Cytokines and other inflammatory mediators can influence sleep, cognition, pain processing, neuroendocrine activity, and autonomic function.^4,5

Altered neuroimmune communication is therefore being investigated as one possible contributor to brain fog, slowed cognitive processing, heightened pain sensitivity, sleep disturbance, and other neurologic symptoms.

These mechanisms do not necessarily imply permanent structural brain injury.

For a focused discussion of cognitive effects, see Brain Fog and Cognitive Dysfunction in Lyme Disease.

Immune dysregulation and autonomic dysfunction

The immune and autonomic nervous systems also interact closely.

The autonomic nervous system helps regulate heart rate, blood pressure, gastrointestinal motility, sweating, temperature control, and other involuntary functions.

A 2024 review by Adler, Chung, Rowe, and Aucott examined dysautonomia following Lyme disease and its possible relationship to post-treatment Lyme disease. The authors noted substantial overlap between PTLD symptoms and other infection-associated chronic illnesses involving autonomic dysfunction, while emphasizing that direct research establishing dysautonomia as a complication of Lyme disease remains limited.⁶

Patients with autonomic dysfunction may experience orthostatic intolerance, palpitations, dizziness, gastrointestinal symptoms, temperature dysregulation, non-restorative sleep, and fatigue disproportionate to exertion.

For more detail, see Autonomic Dysfunction in Lyme Disease.

Why can symptoms fluctuate?

Immune and autonomic activity can change over time. Symptoms may worsen during intercurrent illness, poor sleep, physiologic stress, emotional strain, hormonal changes, or physical overexertion.

These fluctuations do not automatically indicate disease progression or a new infection. They may reflect changes in immune and nervous-system signaling.

However, significant or sustained changes should not automatically be attributed to immune dysregulation either. Reinfection, recurrent or persistent infection, another tick-borne infection, medication effects, and unrelated medical conditions may need to be considered.

Immune dysregulation and pain

Persistent inflammatory or neuroimmune signaling may influence pain-processing pathways and contribute to increased sensitivity in some patients.

Central sensitization is another proposed mechanism. It describes changes in how the central nervous system processes sensory input and should not automatically be assumed to result from immune dysregulation alone.

For more detail, see Pain Processing and Central Sensitization in Lyme Disease.

Immune dysregulation and gastrointestinal symptoms

The gastrointestinal tract is highly responsive to immune, neurologic, and autonomic signaling. Changes in these systems can influence gut motility, sensation, and coordination.

This may contribute to constipation, bloating, early satiety, abdominal discomfort, nausea, and other gastrointestinal symptoms in some patients.

These symptoms are nonspecific and should not automatically be attributed to Lyme disease or immune dysregulation when other explanations are possible.

For more detail, see Gastrointestinal Dysregulation in Lyme Disease.

Can immune dysregulation be treated?

There is currently no single established treatment that specifically reverses immune dysregulation after Lyme disease.

Management depends on the individual’s clinical presentation and on which mechanisms appear most relevant.

When active Lyme disease or another tick-borne infection is clinically suspected, appropriate evaluation remains important. In other patients, management may include addressing autonomic dysfunction, sleep disturbance, pain, physical deconditioning, nutritional problems, medication effects, or other coexisting medical conditions.

Research continues to investigate treatments directed at abnormal immune regulation and inflammation. At present, treatment should be individualized rather than based on one proposed mechanism alone.

How does immune dysregulation relate to PTLDS?

Post-Treatment Lyme Disease Syndrome (PTLDS) describes persistent symptoms that develop or continue after treatment for Lyme disease. Fatigue, pain, and cognitive difficulties can significantly affect function in affected patients.⁷

Immune dysregulation provides one biologically plausible framework for understanding these symptoms.

Snik and colleagues discuss immune abnormalities reported in studies of patients with persistent symptoms, including differences involving inflammatory mediators and B-cell responses.¹ Pine and colleagues review additional proposed mechanisms involving persistent immune activation and antigenic stimulation.³

None of these findings establishes one universal immune mechanism responsible for persistent symptoms in every patient.

A broader discussion is available in Post-Treatment Lyme Disease Syndrome (PTLDS).

Does immune dysregulation prove that the infection is gone?

No.

Evidence of immune dysregulation does not prove that Borrelia remains present, but it also does not independently establish that every viable organism has been eliminated.

The Williams study illustrates why these questions should be separated. In the experimental mice, several immune measures improved after ceftriaxone treatment while another component of the antibody response remained altered.²

Researchers continue to investigate post-infectious immune mechanisms, persistent bacterial antigens, bacterial persistence, tissue reservoirs, immune escape, and other possible explanations for persistent symptoms.

There is currently no routinely available clinical test that can definitively determine which of these mechanisms is responsible for persistent symptoms in an individual patient.

Why this matters clinically

Research on immune dysregulation helps explain why Lyme disease cannot always be reduced to a simple choice between “infection present” and “infection gone.”

Infection can alter immune function, and different components of the immune response may recover on different timelines.

At the same time, immune findings should not become another one-size-fits-all explanation for persistent illness.

Persistent symptoms can have multiple possible contributors, including immune changes, persistent infection, other tick-borne infections, persistent bacterial material, neurologic and autonomic dysfunction, tissue injury, medication effects, and unrelated medical problems.

The goal clinically is to determine which possibilities best fit the individual patient’s history, examination, testing, treatment response, and course over time.

Frequently Asked Questions

Can Lyme disease affect the immune system after treatment?

Possibly. Experimental and clinical research suggests that some immune changes associated with Lyme disease may persist after treatment. A 2024 mouse study found that some immune responses normalized following antibiotic treatment while another component of the antibody response remained altered. The significance of these findings in humans remains uncertain.

Does Lyme disease weaken your immune system?

Not necessarily. Most patients with Lyme disease are not globally immunocompromised. Research suggests that Lyme disease may alter the regulation of particular immune pathways and B-cell responses rather than simply weakening the entire immune system.

Can Lyme disease affect B cells and immune memory?

Yes. Experimental research has identified disrupted germinal-center responses and impaired development of durable B-cell memory during Borrelia infection. Human studies have also reported changes in B-cell responses, although their clinical significance is still being investigated.

Why can routine blood tests be normal if immune dysregulation is present?

Routine blood tests do not measure many of the cytokines, chemokines, immune-cell populations, gene-expression changes, and tissue-level responses investigated in immune research. Normal routine laboratory results therefore do not determine whether immune dysregulation is contributing to persistent symptoms.

Does immune dysregulation mean the Lyme infection is still active?

No. Immune dysregulation by itself does not prove persistent infection. Conversely, demonstrating immune dysregulation does not independently prove that infection has been eradicated. These are separate biological questions.

Can immune dysregulation cause brain fog and fatigue?

Altered immune and inflammatory signaling is one biologically plausible contributor to fatigue, cognitive difficulties, sleep disruption, and other persistent symptoms. These symptoms are nonspecific, however, and immune dysregulation cannot be assumed to be their cause in an individual patient.

Is Lyme disease an autoimmune disease?

No. Lyme disease is an infection caused by Borrelia species. Autoimmune mechanisms have been investigated in certain manifestations, particularly Lyme arthritis, but this does not make Lyme disease itself an autoimmune disease.

Clinical Takeaway

Immune dysregulation is one biologically plausible contributor to persistent symptoms after Lyme disease, but it should not be treated as a single explanation for every patient.

The 2024 Williams study adds an important experimental observation: active Borrelia burgdorferi infection altered antibody responses and lymph-node organization in mice. Some of these abnormalities returned toward normal after ceftriaxone treatment, while another component of the immune response remained altered.²

The findings do not establish that these immune changes cause persistent symptoms in humans. They do show that B. burgdorferi infection can have complex effects on immune regulation and that different aspects of the immune response may recover differently after treatment.

Immune dysregulation expands our understanding of persistent Lyme disease without resolving the larger question of why every individual patient remains ill.

Related Articles

These articles explore related questions involving persistent symptoms, recovery, and overlapping mechanisms:

Persistent Lyme Disease: Why Symptoms Continue After Treatment
Why Do Lyme Symptoms Last So Long?
Lyme Disease Symptoms: Why They Come and Go
Lyme Disease Recovery: Timeline, Challenges, and Long-Term Outlook
Lyme Disease Co-Infections: What You Need to Know

References

1. Snik ME, Stouthamer NEIM, Hovius JW, van Gool MMJ. Bridging the gap: Insights in the immunopathology of Lyme borreliosis. European Journal of Immunology. 2024;54(12):e2451063.
2. Williams MT, Zhang Y, Pulse ME, Berg RE, Allen MS. Suppression of host humoral immunity by Borrelia burgdorferi varies over the course of infection. Infection and Immunity. 2024;92(4):e00018-24. doi:10.1128/iai.00018-24. PMID: 38514468; PMCID: PMC11003232.
3. Pine K, Pine V, Negrut N, Ferician A, Marian P. Infection-Triggered Immune Dysregulation and Immunopathology in Lyme Disease: Mechanisms and Clinical Implications. Journal of Clinical Medicine. 2026;15(8):2922. doi:10.3390/jcm15082922.
4. Irwin MR. Sleep and inflammation: partners in sickness and in health. Nature Reviews Immunology. 2019;19(11):702-715. doi:10.1038/s41577-019-0190-z.
5. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clinic Proceedings. 1993;68(10):988-1001. doi:10.1016/S0025-6196(12)62272-1.
6. Adler BL, Chung T, Rowe PC, Aucott J. Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome? Frontiers in Neurology. 2024;15:1344862. doi:10.3389/fneur.2024.1344862.
7. Aucott JN, Rebman AW, Crowder LA, Kortte KB. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Quality of Life Research. 2013;22(1):75-84. doi:10.1007/s11136-012-0126-6.

Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention