Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with several inflammatory conditions, including pulmonary alveolitis, chronic dermatitis, arthropathy, uveitis, conjunctivitis, and interstitial keratitis (1–5). Although the majority of infected individuals remain asymptomatic, approximately 1–5% progress to adult T-cell leukemia/lymphoma (ATLL) or HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) (6–9). Increasing attention has been devoted to understanding how naturally occurring and infection-driven IgG repertoires are shaped (10–12). Nevertheless, experimental evidence remains insufficient to fully elucidate the molecular principles underlying the “hooks without bait” hypothesis (13). This concept posits that IgG idiotypes arising from environmental exposures, genetic background, and infectious triggers form distinct antibody sets capable of interacting with conserved or clonally expressed molecules on lymphocytes and other immune cells, thereby modulating immune function. Depending on the idiotype–cell interaction, these effects may be regulatory or pro-inflammatory, underscoring the potential relevance of idiotypic networks to disease pathogenesis and therapeutic innovation.

A substantial body of work has demonstrated that discrete IgG idiotype repertoires can independently modulate immune responses in both murine and human lymphocytes (14–17). These influences include alterations in cytokine production by thymic and peripheral αβ T cells, γδ T cells, and B cells, with effects shaped by the immune status of the donor. For instance, IgG from atopic individuals modulates T-cell IFN-γ production (18), while IgG from patients with atopic dermatitis regulates IL-17, IL-22, and IL-10 secretion (19–21). IgG from non-atopic donors affects IL-17, IFN-γ, and IL-10 production (22, 23), and IgG from HIV-1–exposed uninfected and infected individuals can modulate IFN-γ responses in both T and B cells (24). In B cells, IgG from non-atopic individuals has been shown to induce IL-10–producing B cells (B10 cells) in infant thymus and adult PBMCs (25), supporting previous observations in murine allergy models (26, 27).

In HTLV-1 infection, effective control of viral replication depends on multiple effector mechanisms, including IgG antibody production (28). The magnitude and quality of the humoral response may influence clinical outcomes, helping to distinguish asymptomatic carriers from those who develop HAM/TSP or ATLL. Elevated HTLV-1–specific antibody titers have been associated with HAM/TSP (29), suggesting that the breadth or specificity of the IgG response may contribute to inflammatory disease development.

Recent work has shown that IgG from HAM/TSP patients increases IL-17 production by CD4⁺ T cells, decreases IL-4⁺ CD4⁺ T cells, enhances IFN-γ production by CD8⁺ T cells, and reduces IL-4⁺ CD8⁺ T cells. Conversely, IgG from ATLL patients decreases IL-4⁺ CD4⁺ T cells, reduces IFN-γ⁺ γδ T cells, and lowers IL-10⁺ B-cell frequencies. IgG from both groups reduces IFN-γ⁺ B cells (30). Another recent study suggests that HTLV-1 infection may promote the development of distinct IgG repertoires with broad reactivity toward human proteins, potentially contributing to immune dysregulation and offering a partial explanation for divergent clinical trajectories in HAM/TSP and ATLL (31). Together, these findings indicate a wide spectrum of IgG-mediated immune modulation in HTLV-1 infection and raise the possibility that self-protein recognition may occur, although the origins of these repertoires—particularly in the context of environmental exposure—remain unclear.

In the context of a distinct infectious disease, but using methodological approaches comparable to those previously applied in HTLV-1 research, studies in coronavirus disease 2019 (COVID-19) have demonstrated that infection with SARS-CoV-2 can substantially influence the IgG idiotype repertoire of infected individuals. SARS-CoV-2 infection has been shown to modulate IgG recognition profiles against a broad range of host proteins, including molecules associated with major peripheral immune cell populations such as T cells, B cells, and monocytes (32), as well as proteins expressed across multiple organ systems (33). Notably, these alterations have been reported to correlate with disease severity, underscoring the relevance of investigating infection-induced changes in IgG repertoires in relation to clinical status.

In addition, a recent study aligned with the conceptual framework of the present work evaluated the capacity of IgG idiotypes to recognize a broad panel of more than one hundred epitopes derived from several distinct pathogens (34). This study demonstrated that SARS-CoV-2 infection induces a severity-dependent reshaping of the IgG epitope repertoire that extends beyond viral antigens to include epitopes from unrelated pathogens. Collectively, these observations support the notion that infectious diseases may broadly remodel humoral immune recognition through idiotype-driven mechanisms and highlight the potential clinical relevance of IgG repertoire diversity and specificity.

In this context, HTLV-1 infection represents a particularly relevant model, as this retrovirus is associated with a spectrum of inflammatory and immune-mediated conditions whose underlying pathogenic mechanisms remain incompletely understood. Importantly, the distinct clinical phenotypes associated with HTLV-1 infection typically emerge or persist years after primary infection, suggesting that long-term immune modulation may play a critical role in disease development. Drawing parallels with observations from other infectious diseases, including COVID-19, two key questions arise: whether exposure to unrelated pathogens can influence clinical outcomes in HTLV-1–infected individuals, and whether HTLV-1 infection predisposes individuals to distinct patterns of IgG recognition against other pathogens, potentially affecting susceptibility and secondary clinical manifestations.

To begin addressing these hypotheses, the present study applies a high-throughput IgG epitope-profiling platform capable of interrogating 4,345 linear epitopes derived from a wide range of human pathogens—including viruses, bacteria, parasites, and fungi—to generate a comprehensive landscape of pathogen-associated IgG reactivity and corresponding epitope-recognition profiles in HTLV-1 infection.

In this study, we employed a high-density infectious disease epitope microarray to characterize IgG epitope-recognition profiles in individuals with distinct clinical outcomes of HTLV-1 infection. This approach enabled a comprehensive assessment of humoral immune recognition across a broad spectrum of pathogen-derived epitopes while also allowing validation of HTLV-1–specific responses within the same analytical framework.

Before undertaking the broad evaluation of pathogen recognition, our initial analysis of IgG reactivity against HTLV-1–derived epitopes provided clear evidence of the robustness and reliability of the experimental approach. This was demonstrated by the unequivocal discrimination between HTLV-1–infected and non-infected individuals. Moreover, distinct epitope-specific IgG responses were observed among clinically relevant HTLV-1 groups: epitope 21888 was exclusively recognized by IgG from individuals with ATLL, whereas epitopes 39726 and 45727 were selectively recognized by IgG from individuals with HTLV-1–associated HAM/TSP.

According to annotations from the Immune Epitope Database (IEDB) and UniProt databases, epitope 21888 is derived from the HTLV-1 Gag–Pro–Pol polyprotein, which is generated through a translational readthrough event during viral RNA translation. This process produces a single elongated polyprotein that integrates the products of the gag (group-specific antigen), pro (protease), and pol (polymerase) genes. The Gag–Pro–Pol polyprotein plays a critical structural role in the assembly of new viral particles while simultaneously harboring the enzymatic functions required for viral maturation and subsequent infection of new target cells.

In contrast, epitopes 39726 and 45727 are derived from an HTLV-1 envelope glycoprotein that is essential for viral entry, cell-to-cell transmission, and immune evasion. This envelope protein mediates binding to host cells, triggers membrane fusion, promotes syncytium formation, and represents a highly conserved viral component as well as a primary target for neutralizing antibody responses. The selective recognition of these envelope-derived epitopes by IgG from HAM/TSP individuals suggests disease-associated differences in humoral targeting of viral antigens.

Although the present study was not designed to validate individual viral proteins or epitopes as diagnostic markers for HTLV-1–associated clinical conditions, these findings nonetheless highlight the potential biological relevance of disease-specific IgG recognition patterns. Collectively, these observations suggest that epitope-level profiling may capture clinically meaningful differences in humoral immune responses among HTLV-1–infected individuals and may inform future studies aimed at dissecting the relationship between viral antigen recognition, immune dysregulation, and disease pathogenesis.

By quantifying IgG responses to more than 4,300 pathogen-derived linear epitopes, we identified extensive alterations in the breadth, diversity, and intensity of humoral recognition associated with ACs, HAM/TSP, and ATLL. These findings indicate that HTLV-1 infection does not merely elicit virus-specific immune responses but reconfigures the humoral landscape at a systems level.

The immune system of HTLV-1–infected individuals is characterized by persistent activation, even among clinically asymptomatic carriers. The viral regulatory proteins Tax and HBZ chronically stimulate NF-κB, STAT1, AP-1, and IRF signaling, leading to sustained transcription of proinflammatory mediators and abnormal T-cell proliferation (35, 36).

Against this backdrop, the pronounced divergence of IgG repertoires across clinical groups observed in our study is unsurprising. Yet, the extent of divergence—including responses to pathogens unrelated to HTLV-1—reveals a level of systemic immunological remodeling that exceeds previous descriptions.

Our findings further indicate that each clinical phenotype displays a distinctive antibody-recognition signature. HAM/TSP is marked by high proviral load, heightened Th1 activation, and elevated IFN-γ production (37), conditions known to promote broad antigen recognition, enhanced B-cell maturation, and robust inflammatory antibody responses. Consistent with this profile, HAM/TSP participants exhibited greater intensity and diversity of IgG recognition across viral, bacterial, and parasitic epitopes. Conversely, ATLL reflects a profoundly different immunological state, dominated by malignant transformation, transcriptional reprogramming, immunosuppression, and defective antigen presentation (38). Although ATLL patients recognized the largest number of epitopes, their pattern of reactivity was distinct, suggesting dysregulated or atypical B-cell activation. This observation mirrors transcriptomic evidence demonstrating that ATLL cells disrupt immune communication networks and secrete immunosuppressive cytokines that modulate B-cell development and antibody output (36).

We additionally observed heightened IgG responses to pathogens frequently associated with co-infections in HTLV-1. Elevated reactivity against Mycobacterium tuberculosis, Strongyloides stercoralis, Toxoplasma gondii, and Plasmodium species aligns with clinical data showing that HTLV-1 infection predisposes individuals to severe strongyloidiasis, tuberculosis, and toxoplasmosis (39). These amplified antibody responses may reflect repeated exposure, impaired pathogen control, or chronic antigenic stimulation; however, in the absence of corresponding clinical or microbiological testing, these possibilities cannot be definitively established. The IFN-γ–driven environment characteristic of HTLV-1 infection facilitates intracellular pathogen persistence, likely contributing to sustained IgG production.

For pathogens such as SARS-CoV-related viruses, HCV, EBV (HHV-4), and influenza, the group-specific IgG differences may partly reflect heterogeneous exposure histories. However, the magnitude and consistency of divergence are more consistent with altered B-cell selection, activation thresholds, or memory-cell maintenance driven by HTLV-1–mediated immune dysregulation.

Beyond known co-infections, our results provide compelling evidence for heterologous immunity—whereby immune responses to one pathogen shape subsequent responses to unrelated antigens (40). Heterologous immunity can have protective or pathogenic consequences depending on context (41). In HTLV-1 infection, chronic antigenic stimulation, dysregulated costimulatory signaling, and persistent inflammation may collectively prime B-cell memory pools, generating widespread alterations in epitope recognition—even against pathogens not recently encountered.

Analogous patterns have been described in other chronic viral infections. HIV, for example, induces hypergammaglobulinemia, clonal B-cell expansion, and diversification of antibody repertoires (42). Although HTLV-1 operates through distinct mechanisms, our findings suggest that it similarly contributes to increased immune turnover and activation of noncanonical B-cell pathways.

A particularly notable finding is that IgG responses within each group comprised hundreds of clusters with minimal sequence similarity. This observation argues against simple linear cross-reactivity and instead points toward altered B-cell selection dynamics, impaired tolerance, clonal expansions, and systemic perturbations of antibody homeostasis.

This broader perspective aligns with idiotypic network theory, first proposed by Jerne (43) and later expanded into modern models describing antibody–antibody regulatory circuits (44). Recent large-scale sequencing studies further demonstrate that healthy individuals maintain highly structured and self-regulated antibody repertoires (45). HTLV-1, by altering lymphocyte homeostasis and inducing chronic immune activation, may destabilize these regulatory networks.

This interpretation also resonates with the “hooks without bait” hypothesis (13), which proposes that pathological states associated with infections such as HIV (24) and COVID-19 (16, 32, 33) can generate IgG idiotype repertoires capable of interacting with self-proteins expressed on immune cells or in soluble form, thereby modulating immune responses. Notably, IgG-mediated immunomodulatory effects have also been documented in non-infectious conditions, including atopic dermatitis (19–21, 46–49), allergic diseases such as dust-mite allergy (15, 18, 22, 23, 25, 50–52), and in HTLV-1 infection itself—where distinct clinical phenotypes have been shown to associate with divergent autoreactive IgG repertoires possessing immunomodulatory potential (30). Our observations strongly parallel these findings, suggesting that shifts in idiotype networks may contribute to the clinical heterogeneity of HTLV-1 disease.

Collectively, our results demonstrate that HTLV-1 infection drives widespread remodeling of IgG epitope recognition that cannot be attributed solely to antigen exposure. Instead, these patterns likely arise from the intersection of chronic infection, persistent inflammation, B-cell dysregulation, and impaired idiotypic network regulation.

These findings carry several important implications. First, distinct IgG repertoires across ACs, HAM/TSP, and ATLL patients may serve as biomarkers capable of stratifying clinical phenotypes. Second, enhanced IgG recognition of specific pathogens corresponds to known clinical vulnerabilities and may support improved co-infection surveillance strategies. Third, the low sequence similarity among epitopes highlights the need to investigate structural, conformational, and post-translational determinants of antibody binding in HTLV-1. Fourth, therapeutic strategies aimed at reducing chronic inflammation or restoring B-cell regulatory circuits may prove beneficial. Finally, future studies integrating epitope profiling with deep BCR sequencing, single-cell immunophenotyping, and longitudinal sampling will be essential to determine how humoral signatures evolve over time and whether they can predict progression to HAM/TSP or ATLL.

This study was designed to provide a comprehensive descriptive analysis of IgG epitope-recognition patterns across distinct clinical outcomes of HTLV-1 infection. While the cross-sectional nature of the cohort limits causal inference and longitudinal interpretation, the standardized experimental conditions and consistent group-level patterns support the robustness of the observed findings. Future studies incorporating longitudinal sampling and functional assays may further clarify the mechanistic implications of these humoral signatures.