Aberrant T-cell phenotypes in a cohort of patients with post-treatment Lyme disease, 2025, Girgis et al

[forestglip]

Aberrant T-cell phenotypes in a cohort of patients with post-treatment Lyme disease

Alexander A. Girgis, Raffaello Cimbro, Ting Yang, Alison W. Rebman, Thelio Sewell, Daniela Villegas de Flores, Aarti Vadalia, William H. Robinson,, Andrea L. Cox, Erika Darrah, Mark J. Soloski, John Aucott

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Abstract
Post-treatment Lyme Disease (PTLD) is a poorly understood complication of Borrelia burgdorferi infection with significant patient morbidity. Characterized by fatigue, generalized myalgias, and cognitive impairment, PTLD symptomatology closely resembles long COVID and other post-acute infection syndromes. While prior studies suggest immune dysregulation as a factor in PTLD pathogenesis, the mechanisms underlying its heterogeneous presentation and severity remain unclear.

To associate symptom burden with discrete immune phenotypes, we applied factor analysis to self-reported symptom data from 272 PTLD patients to generate patient subgroups. We then immunophenotyped peripheral blood cells of these individuals and 28 healthy controls through 19-parameter flow cytometry and cytokine profiling to associate PTLD status and the newly defined subgroups with specific immune states.

Our PTLD cohort had fewer circulating CXCR5+ CD4+ naïve T cells relative to healthy controls (5.2% vs. 8.3%, Padj < 0.001). These cells were positively associated with musculoskeletal pain in PTLD participants, but not healthy controls.

This and additional immunophenotypic alterations, including an increased prevalence of CXCR3+ CCR4- CCR6- CD8 T cells (43.1% vs. 25.7%, Padj < 0.01), permitted the creation of an elastic net classifier which identified PTLD with moderate efficacy (AUC 0.83). Measurement of cytokines did not reveal associations with PTLD and did not improve the performance of the model.

While we could not identify immune features which distinguished all patient subgroups, we did observe a female-specific increase in central memory CD8 T cells restricted to one high-fatigue patient subgroup. Additionally, factor analysis revealed multiple associations between immune cell frequency and the severity of specific symptoms.

Collectively, our findings add to growing evidence of immune dysfunction as a prominent feature of PTLD.

Web | PDF | Frontiers in Immunology | Open Access

 

[forestglip]

Univariate testing did not reveal differences between PTLD patient subgroups. However, multiple features varied between healthy controls and PTLD participants (Table 2).

CXCR5+ Naive CD4 T cells were reduced in PTLD compared to healthy controls (8.8% vs. 5.2%, Padj. < 0.001).

CD4+ effector memory CD45RA+ (EMRA) cells were increased in the PTLD cohort (5.1 vs. 1.6%, Padj < 0.01, Figure 4B).

We also examined CXCR3, CCR4, and CCR6 on CD8 T cells and identified CD8+ Th1-like cells (CXCR3+ CCR6- CCR4-) which were markedly increased in PTLD relative to healthy controls (43.1% vs. 25.7%, Padj < 0.01), with a corresponding decrease in CD8+ Th1/17-like cells, defined as CXCR3- CCR6+ and CCR4+ (3.9% vs. 13.4%, Padj < 0.01).

Lastly, CD4+ EMRA cells were increased in the PTLD cohort (5.1 vs. 1.6%, Padj < 0.01, Figure 4B).

 

[forestglip]

CXCR5 on Wikipedia:

Other studies highlight the role of CXCR5 in T cells, as they are unable to access B cell follicles without CXCR5 expression.[9][10] This is a key step in the production of high affinity antibodies as B cells and T cells need to interact in order to activate the Ig class switch.[9]

CXCR5 has been shown to be expressed on both CD4[11] and CD8[12] T cells, though it is often regarded as the defining marker for T Follicular Helper (Tfh) cells.[13]

 

[hotblack]

A lot of his reminds me of the papers for ME/CFS showing changes in T cell populations, but me not really understanding what that means. And it possibly just not being very clear what it means.

But this stood out

While we could not identify immune features which distinguished all patient subgroups, we did observe a female-specific increase in central memory CD8 T cells restricted to one high-fatigue patient subgroup.

A bit more from the discussion section

Our sole sex-specific observation is the female-specific increase in CD8 TCM cells within patient subgroup 3. This subgroup was characterized by high fatigue/cognitive factor scores and a high incidence of flu-like illness upon initial infection. Increased TCM cells may suggest a greater capacity for durable, proliferative responses following an inflammatory insult (49). Why this observation is restricted to the females of patient subgroup 3, but not males, is unclear and requires future study.

 

[forestglip]

But this stood out

A bit more from the discussion section

That result doesn't feel very strong. Higher CD8 in only one of five six symptom-based subgroups, and not even in both sexes.

Edit:

 

[duncan]

While prior studies suggest immune dysregulation as a factor in PTLD pathogenesis

Other prior studies suggest persistence as a factor.

Wonder why I feel the influence of a rheumatologist in this. Wonder which group from Johns Hopkins. Oh, and why is someone from AstraZeneca out of the UK involved?

the mechanisms underlying its heterogeneous presentation and severity remain unclear.

As they do in the various stages of Lyme. So I think this could represent a valuable exercise despite somewhat dubious wording.

 

[hotblack]

That result doesn't feel very strong.

Oh it doesn’t does it. Oh well. Thanks @forestglip