Introduction

The conversion from the Clinical High-Risk (CHR) stage to the onset of psychosis represents a critical period in the trajectory of psychosis [1, 2], characterized by dynamic changes in immune and inflammatory processes [3, 4]. Emerging evidence suggests that immune dysregulation and inflammation play pivotal roles in the pathophysiology of psychosis [5], particularly during the conversion from the CHR stage to the first episode of psychosis [6]. Previous research has indicated that alterations in the serum levels of inflammatory cytokines precede the onset of psychosis in individuals at CHR for psychosis, especially among those who later convert to psychosis [7]. However, it is important to note that changes in inflammatory cytokines are not likely to be a simple unidirectional process but rather may involve a complex interplay or balance [8, 9].

The balance between T helper 1 (Th1) and T helper 2 (Th2) cells [10], known as the Th1-Th2 balance, plays a crucial role in immune regulation. Th1 cells primarily produce pro-inflammatory cytokines, such as interleukin (IL)-1Beta, targeting intracellular pathogens and contributing to autoimmune responses. In contrast, Th2 cells secrete anti-inflammatory cytokines, including IL-6, to counterbalance the pro-inflammatory effects of Th1 cytokines [11]. Imbalances in the Th1-Th2 ratio have been implicated in various immune-related disorders, including psychiatric conditions like psychosis [12, 13]. Notably, this imbalance may interact bidirectionally with complement activation: Th1-derived cytokines (e.g., IL-1β, IFN-γ) could upregulate complement components (e.g., C4, C3) in hepatocytes and immune cells, while Th2 cytokines (e.g., IL-6) might modulate complement regulatory proteins (e.g., factor H) to dampen excessive activation. Complement and T-cell biology are also intricately linked through direct functional interactions, such as complement-mediated regulation of T-cell activation and polarization. Complement components like C4b further influence T cell polarization by enhancing dendritic cell antigen presentation and macrophage signaling to promote Th1 differentiation. Previous studies have reported inconsistent findings regarding the Th1-Th2 balance in schizophrenia, with some studies indicating a decreased Th1-Th2 ratio [14] and others suggesting an increased ratio during psychotic episodes [15]. However, the precise reasons influencing of Th1-Th2 imbalance in psychosis remains unclear, warranting further investigation.

The relationship between complement activation and the onset of psychosis has garnered increasing attention in recent years [16]. Previous studies have indicated that altered complement levels in individuals at CHR are more closely associated with the subsequent conversion to psychosis than inflammatory factors alone [17]. It is important to consider that complement expression—such as Mannose-Binding Lectin (MBL) or classical pathway components—may exhibit ethnic/racial variations that influence these associations. Building on this, the bidirectional interactions between complement and Th1-Th2 balance may represent a key regulatory node in psychosis pathogenesis. Given the classical pathway’s established role in antigen-antibody complex clearance and Th1 cell priming via C4b-mediated dendritic cell activation, we prioritized its components (e.g., C1q, C4b) while also assessing alternative/lectin pathway markers (e.g., factor B, MBL) for comprehensive analysis. The present study aims to investigate the dynamic interplay between complement activation and the Th1-Th2 balance during the progression of psychosis. We hypothesize that complement activation may play a regulatory role in modulating the Th1-Th2 balance, thereby influencing the trajectory of psychosis onset. By exploring the intricate relationship between complement activation, Th1-Th2 balance, and psychosis development, this study seeks to elucidate novel insights into the immunological mechanisms underlying the pathogenesis of psychosis.

Methods

Participants and study design

This study was approved by the Research Ethics Committee of the Shanghai Mental Health Center (SMHC). Individuals meeting the criteria for CHR seeking mental health services for the first time were recruited from the SMHC. The SMHC is a leading mental health institution in China, serving patients from diverse backgrounds. The majority of the CHR patients seeking care at SMHC are from urban Shanghai, reflecting the city’s large population and high density. The socioeconomic status of participants varied, with most coming from middle-income households typical of urban Chinese settings, which aligns with the demographics of the greater Shanghai area. Inclusion criteria comprised individuals aged 14–45 years fulfilling the diagnostic criteria for CHR. Exclusion criteria included current or lifetime occurrence of a psychotic episode, symptomatology more aligned with nonpsychotic disorders (e.g., primary anxiety/depressive presentations ruled out via clinical judgment) or substance abuse, prior use of psychotropic medication regardless of dosage, current or historical use of psychoactive substances such as methamphetamine, presence of neurological or endocrine disorders, lack of proficiency in Mandarin, inability to provide informed consent or comprehend the study, and recent intake of anti-inflammatory medications or presence of infectious diseases within the past two weeks, as these factors could potentially affect inflammation levels in individuals. Active autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus) and Acute or subclinical infections at baseline (screened via medical history and serological tests for Epstein-Barr virus, cytomegalovirus, and other common pathogens known to influence immune markers) were excluded as well. The dataset analyzed in this study included 49 individuals classified as CHR and 26 healthy controls (HC) who completed blood collection and clinical assessments. Among them, 38 CHR individuals underwent a blood sample collection at a 1-year follow-up. Written informed consent was obtained from all participants during the recruitment phase, with consent forms for individuals under 18 years of age signed by their parents or legal guardians. The HC group was recruited from local schools and communities through online advertisements. Participants completed the clinical interview to rule out psychiatric disorders. Their demographic characteristics, including age and sex, were meticulously matched with those of the CHR group.

Among the 49 CHR individuals, 35 were male, averaging 18 years old with an educational duration of 10 years. In the HC group of 26 individuals, 18 were male, averaging 17 years old with an educational duration of 11 years. Demographic characteristics did not significantly differ between the groups. Among the 38 CHR individuals who completed both baseline and 1-year follow-up blood collections, 26 were male, averaging 18 years old. No significant differences were observed in demographic characteristics, baseline IL-1Beta, IL-6, and complement components between this group and the 11 CHR individuals who did not participate in the 1-year follow-up blood collection.

Symptomatic assessments and follow-up outcomes

Clinical assessments were conducted to identify individuals meeting the criteria for CHR using the Structured Interview for Prodromal Syndromes (SIPS) [18]. The SIPS encompasses 19 items evaluating four symptom domains: positive symptoms (scales P1-P5), negative symptoms (scales N1-N6), disorganized symptoms (scales D1-D4), and general symptoms (scales G1-G4). Each item is scored from 0–6, with higher scores indicating more severe symptoms. Our research team introduced a Chinese version of the SIPS in previous studies [2, 19], demonstrating its robust inter-rater reliability (intraclass correlation coefficient: r = 0.96, p < 0.01; SIPS total score) and validity (26.4% of participants transitioned to psychosis within the subsequent 2 years) in the Chinese context.

Psychosis conversion, as determined by the criteria for the Presence of Psychotic Symptoms outlined in the SIPS, served as the primary outcome measure in this study. Specifically, CHR-converters were identified by the presence of a positive symptom at level six, which was deemed either dangerous, disorganized, or occurring for at least an hour per day on average over four days a week, totaling a minimum of 16 h. Subsequently, the 38 CHR individuals were divided into two groups: those who later converted to psychosis (CHR-C, n = 14) and those who did not convert (CHR-NC, n = 24).

Complement, IL-1beta and IL-6 levels measurements

Participants provided blood samples at baseline, usually in the morning following a minimum 3 h fasting period. A volume of 10 mL of venous blood was drawn into tubes without anticoagulant. Subsequently, the samples were left to incubate at room temperature for 1 h. Following incubation, the samples underwent centrifugation at 1710 g for 20 min at 4 °C to isolate the serum. The serum was then divided into aliquots and stored at −80 °C until further analysis. We quantified the levels of thirteen complement proteins (C1q, C2, C3, C3b, C4, C4b, C5, C5a, factor B, D, I, H, and Mannose-Binding Lectin (MBL)) using the MILLIPLEX MAP Human Complement Magnetic Bead Panel 2 - Immunology Multiplex Assay (HCMP2MAG-19K, Merck Millipore, Billerica, MA, USA). Duplicate tests were conducted for standard and reference samples, while participants’ samples were measured individually. The coefficient of variance for all standards and reference materials was less than 20%. Standard curves and equations were generated by fitting the fluorescence detection values from the standard product using the multiparameter mode. Concentrations were reported as nanograms per liter (ng/L). Serum levels of IL-1Beta and IL-6 were measured in duplicate for each sample using an enzyme-linked immunosorbent assay with the Human HS Cytokine Premixed Kit (catalog #: FCSTM09-10, USA) according to the manufacturer’s instructions. Concentrations of IL-1Beta and IL-6 were expressed in pg/mL. These cytokines were selected based on prior studies demonstrating their specific roles in driving Th1/Th2 polarization in psychiatric populations, including their associations with psychotic conversion in CHR individuals [6, 8, 20]. All data were calibrated using standard curves generated for IL-1Beta and IL-6.

Statistical analysis

Participants were categorized into two groups: individuals at CHR and HC. The normality of the distribution of complement, IL-1Beta, and IL-6 variables was assessed using the Kolmogorov-Smirnov test, revealing non-normal distributions for all variables. To facilitate comparisons, serum levels of IL-1Beta and IL-6 were transformed into Z scores across the entire sample. The Th1 > Th2 group was defined as having Z scores of IL-1Beta higher than IL-6, while the Th1 < Th2 group was defined as having Z scores of IL-1Beta lower than IL-6. Th1-Th2 balance (Th1-Th2) was calculated as the difference between the Z scores of serum IL-1Beta and IL-6 levels. Non-parametric analyses were employed for comparisons. A bar plot diagram was generated using GraphPad Prism software to examine differences in the levels of IL-1Beta, IL-6, and complement components between the CHR and HC groups, as well as between the Th1 > Th2 and Th1 < Th2 groups. Spearman’s rank correlations were computed to assess associations between Baseline IL-1Beta, IL-6, Th1-Th2 balance, and complement levels. Non-parametric paired comparisons were conducted to evaluate changes between baseline and follow-up in the 38 CHR individuals. Repeated-measures analysis of variance (ANOVAs) were utilized to explore changes in IL-1Beta (Th1) and IL-6 (Th2) levels, as well as Th1-Th2 balance over one year, and their associations with complement factors, with baseline complement serving as a covariate. Effect sizes (η2) were interpreted as follows: η2 = 0.01 (small), η2 = 0.06 (medium), and η2 = 0.14 (large). Statistical significance was set at a two-tailed p-value of 0.05.

Results

Th1-Th2 balance profiles

As depicted in Fig. 1A, there were no statistically significant differences observed in the baseline serum levels of IL-1Beta and IL-6 between the CHR and HC groups. Figure 1B illustrates the distribution of the IL-1Beta and IL-6 levels in HC and CHR groups, as well as Th1 > Th2 and Th1 < Th2 group. As shown in Fig. 1C, in the CHR group, 45% were Th1 < Th2, whereas in the HC group, Th1 < Th2 constituted 27%.

Fig. 1: Baseline Serum Levels of interleukin (IL)-1Beta and IL-6 Profiles in Clinical High Risk (CHR) and Healthy Control (HC) Individuals.
Fig. 1: Baseline Serum Levels of interleukin (IL)-1Beta and IL-6 Profiles in Clinical High Risk (CHR) and Healthy Control (HC) Individuals.
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A Boxplot illustrating the distribution of IL-1Beta and IL-6 levels in HC and CHR groups. B Scatter plot displaying Z scores of serum IL-1Beta levels with IL-6 levels, segmented by HC and CHR groups, as well as Th1 > Th2 and Th1 < Th2 groups. The levels of IL-1Beta and IL-6 of the HC and CHR groups were converted to Z-scores based on the mean and SD of the overall sample. C Percentages of Th1 > Th2 and Th1 < Th2 groups in the HC and CHR groups.

Profiles of complement factors in Th1/Th2 balance groups

As shown in Table 1, there were no significant differences in demographic and clinical characteristics between the Th1 > Th2 group and Th1 < Th2 group, except in the HC group, where the Th1 > Th2 group had slightly longer years of education compared to the Th1 < Th2 group (p = 0.046). The differences between the two groups in cytokines and complement factors were relatively consistent. Mainly, IL-6 (HC, p = 0.001 vs. CHR, p < 0.001), C4b (HC, p = 0.069 trending towards significance vs. CHR, p = 0.004), C5 (HC, p = 0.019 vs. CHR, p = 0.019), I (HC, p = 0.099 trending towards significance vs. CHR, p = 0.033), C4 (HC, p = 0.022 vs. CHR, p = 0.019), and B (HC, p = 0.004 vs. CHR, p = 0.054 trending towards significance).

Table 1 Demographic, clinical, cytokine, and complement factor characteristics and comparisons between Th1 > Th2 and Th1 < Th2 groups.
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Correlations

The IL-1Beta levels exhibited significant positive associations with component D (r = 0.291, p = 0.043) in the CHR group, while significant positive associations with component C2 (r = 0.462, p = 0.017) were observed in the HC group (Fig. 2A). Conversely, the IL-6 levels were significantly positively associated with components C4b, C5, I, C3, C4, B, and H in the CHR group, but no significant correlation was found between IL-6 levels and component factors in the HC group (Fig. 2B). Additionally, in the CHR group, the correlation coefficients between Th1-Th2 balance and complement factors were significantly negatively associated with components C4b, C5, I, C3, C4, and B, while significant correlations with C5, I, and B were found in the HC group (Fig. 2C).

Fig. 2: Correlations between Baseline Interleukin (IL)-1Beta (Th1), IL-6 (Th2) and Th1-Th2 balance and Complement Factors.
Fig. 2: Correlations between Baseline Interleukin (IL)-1Beta (Th1), IL-6 (Th2) and Th1-Th2 balance and Complement Factors.
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A Correlations between IL-1Beta (Th1) and Complement Factors; (B) Correlations between IL-6 (Th2) and Complement Factors; (C) Correlations between Th1-Th2 and Complement Factors. Th1-Th2 indicates Z score of serum level of IL-1Beta minus Z score of serum level of IL-6. MBL represents Mannose-Binding Lectin. Nonparametric Spearman’s correlation tests were conducted separately for Clinical High Risk (CHR) and Healthy Control (HC) groups separately, with statistical significance set at a two-tailed p-value of 0.05. Statistically significant p-values are denoted above the correlation values (r). *p < 0.05; **p < 0.01.

Th1-Th2 balance and conversion

Out of the 49 CHR cases, 38 completed a retest of IL-1Beta and IL-6 levels after one year, among which 14 (36.8%) cases were confirmed to have converted to psychosis during the 1-year follow-up period from baseline. In the total sample, paired-sample Wilcoxon tests (Fig. 3A, B) indicated that serum levels of IL-1Beta and IL-6 did not change significantly. However, in the CHR-C group, IL-6 tended to increase significantly (p = 0.084) from baseline to 1 year later. When grouped as Th1 > Th2 and Th1 < Th2, at follow-up, there were 11 cases of CHR-C in the Th1 < Th2 group, whereas the Th1 > Th2 group had only 5 cases, a proportion significantly higher than that of the Th1 > Th2 group (χ2 = 12.09, p = 0.001) (Fig. 3C).

Fig. 3: Baseline and Follow-up Comparisons of Serum Inflammatory Cytokine Levels and Th1/Th2 Subset Proportions in CHR-C and CHR-NC Groups.
Fig. 3: Baseline and Follow-up Comparisons of Serum Inflammatory Cytokine Levels and Th1/Th2 Subset Proportions in CHR-C and CHR-NC Groups.
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A Self-controlled comparison of serum interleukin (IL)-1β levels between baseline and follow-up, stratified by clinical high-risk converters (CHR-C) and clinical high-risk non-converters (CHR-NC). B Self-controlled comparison of serum IL-6 levels between baseline and follow-up, stratified by CHR-C and CHR-NC. C Proportions of participants with Th1 Th2 and Th1 Th2 at baseline and follow-up, stratified by CHR-C and CHR-NC. The paired Wilcoxon test was used for self-controlled analysis of serum inflammatory factor levels across time points. Statistical significance was defined as a two-tailed p-value 0.05. IL interleukin, CHRC clinical high-risk converter, CHR-NC clinical high-risk non-converter.

Changes of Th1-Th2 balance and complement factors

Repeated-measures ANOVAs examined changes in IL-1Beta (Th1) and IL-6 (Th2) levels and Th1-Th2 balance over one year and their association with complement factors, using baseline complement as a covariate. Table 2 demonstrates a significant time effect of IL-1Beta associated with C4b (F = 11.514, p = 0.002, effect size (η2) = 0.324). The alterations in the Th1-Th2 balance linked with C4b (F = 15.081, p = 0.001, η2 = 0.396) and C4 (F = 6.933, p = 0.015, η2 = 0.232) exhibited a notable time effect.

Table 2 Repeated-measures ANOVAs were performed for IL-1Beta (Th1), IL-6 (Th2) and Th1-Th2.
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Discussion

Key findings

The dynamic relationship between complement and inflammatory factor balance in the onset of psychosis remains poorly understood. To our knowledge, this study is the first to investigate the relationship between complement and Th1-Th2 balance in CHR individuals and its impact on subsequent psychotic episodes. Our major findings are as follows: 1) There are differences in complement characteristics between Th1 > Th2 and Th1 < Th2 balance states, with variations in complement factors between CHR and HC groups; 2) The correlation features between Th1 and Th2 inflammatory factors and complement are evident in CHR individuals but less so in HC individuals; 3) Over the longitudinal follow-up, the proportion of Th1 < Th2 balance in the CHR-C group significantly increased compared to the CHR-NC group, indicating a potential right shift in Th1-Th2 balance during the onset of psychosis; 4) The right shift in Th1-Th2 balance appears to be associated with baseline complement C4b and C4 levels. These results suggest that changes in complement and inflammatory status may be related to the onset of psychosis.

Th1-Th2 balance and psychosis

In our study, we observed a trend towards a right shift in Th1 < Th2 balance in CHR individuals compared to HC, with a more pronounced shift observed in the CHR-C group during follow-up. This finding is consistent with our previous preliminary research with small sample [8], particularly in relation to the observed shift in the Th1/Th2 balance. In both studies, we noted alterations in serum IL-1Beta (Th1) and IL-6 (Th2) levels in CHR individuals. Specifically, in our previous study, CHR-C (n = 8) exhibited increased IL-1Beta and IL-6 levels over time, leading to a normalization of Th1/Th2 ratios comparable to those of CHR-NC and HC groups. The inconsistency lies in the nature of the Th1/Th2 balance shift. While both studies observed a shift towards Th1 < Th2 balance in CHR individuals, the previous study highlighted an increase in Th1/Th2 ratios over time in CHR-C. This discrepancy may stem from differences in the study methodology that current approach of using Z scores to assess balance shifts provides a more robust methodological framework compared to ratio-based comparisons. Using ratios for comparison poses methodological challenges, as it can be influenced by various factors such as differences in baseline levels and individual variability. Instead, we employed Z-score transformation to examine the balance relationship between Th1 and Th2 distributions. This approach provides a standardized measure, allowing for a more accurate assessment of the balance between Th1 and Th2 responses while minimizing the impact of individual variations [21].

The rightward shift in Th1-Th2 balance observed in the context of psychotic episodes may offer insights into the pathophysiological mechanisms underlying the onset of psychosis. This shift suggests a relative increase in Th2 responses compared to Th1 responses, potentially leading to immune dysregulation and inflammation [22, 23], which are implicated in the pathogenesis of psychosis [24, 25]. Biologically, Th1 and Th2 cells play critical roles in regulating immune responses [26]. Th1 cells primarily mediate cellular immunity, defending against intracellular pathogens [27], while Th2 cells orchestrate humoral immunity, promoting antibody production and defense against extracellular pathogens [28]. In the context of psychosis, dysregulation of Th1-Th2 balance may disrupt the delicate equilibrium of inflammatory responses [29]. Of particular relevance are the roles of IL-1Beta and IL-6 in immune-inflammatory processes. IL-1Beta, predominantly produced by Th1 cells, plays a key role in initiating and amplifying inflammatory responses [30]. It contributes to the recruitment of immune cells to sites of infection or injury and promotes the synthesis of other pro-inflammatory cytokines [31]. On the other hand, IL-6 is a pleiotropic cytokine involved in modulating immune responses, acute-phase reactions, and inflammation [32]. While both cytokines play essential roles in immune defense, dysregulated production or prolonged exposure to IL-1Beta and IL-6 can lead to chronic inflammation and tissue damage [33], which have been implicated in the pathogenesis of psychosis [34, 35]. Excessive immune activation and chronic inflammation may disrupt the blood-brain barrier, allowing immune cells and inflammatory mediators to enter the central nervous system and induce neuroinflammation [36]. Additionally, dysregulated cytokine signaling may impact neurotransmitter systems, such as the dopaminergic and glutamatergic systems, which are implicated in the pathophysiology of psychosis [37]. Moreover, chronic inflammation may lead to oxidative stress, neurodegeneration, and synaptic dysfunction, contributing to the emergence of psychotic symptoms [38].

Th1-Th2 balance and complement factors

The different complement characteristics observed between Th1 > Th2 and Th1 < Th2 balance states, particularly in CHR individuals compared to HC, may underscore the intricate relationship between Th1-Th2 balance and complement activation. Notably, this close association was predominantly evident in CHR participants, suggesting that clinical high-risk status primes a context where complement-Th1/Th2 interactions are dysregulated. This close association and heightened correlation may stem from the pivotal role of complement in regulating immune responses and inflammation. The observed associations may involve C4b-mediated dendritic cell activation, where C4b opsonizes antigens to enhance Th1 polarization via MHC class II presentation. In CHR, dysregulated C4b could disrupt this pathway, skewing responses toward Th2 dominance despite classical pathway activation, highlighting complement’s role in T-cell priming dysregulation.

Complement activation is closely intertwined with the immune system, playing a crucial role in the clearance of pathogens, modulation of inflammatory responses, and maintenance of immune homeostasis. In the context of Th1-Th2 balance, complement activation may serve as a key mediator of immune regulation, influencing the balance between pro-inflammatory and anti-inflammatory pathways [39].

The intimate relationship between C4 and C4b and Th1-Th2 balance may be attributed to the diverse functions of complement components in immune modulation. C4 and C4b are pivotal players in the classical pathway of complement activation, which can be triggered by antigen-antibody complexes and pathogens [39]. Activation of C4 leads to the generation of C4b, which, in turn, plays a crucial role in opsonization, facilitating the clearance of immune complexes and pathogens by phagocytic cells. In the context of Th1-Th2 balance, dysregulation of complement activation, particularly aberrant levels of C4 and C4b, may disrupt immune homeostasis and contribute to the pathogenesis of psychosis [40, 41]. Notably, our findings align with prior research demonstrating that C4 gene polymorphisms (e.g., C4A/C4B copy number variations) are associated with schizophrenia risk, likely via altered complement-mediated synaptic pruning and immune dysregulation [42].

The biological mechanisms underlying the involvement of complement in Th1-Th2 balance are multifaceted. Complement components, including C4 and C4b, can interact with various immune cells, cytokines, and signaling pathways, modulating immune responses and inflammation. For example, complement activation products can stimulate the production of pro-inflammatory cytokines, such as IL-1Beta and IL-6, further exacerbating immune dysregulation and inflammation [39]. In CHR, these interactions may be uncoupled due to baseline immune activation, leading to dysfunctional complement-T cell crosstalk. Additionally, complement activation can directly influence T cell differentiation and polarization [43], potentially affecting the balance between Th1 and Th2 responses. Overall, the intricate interplay between complement activation and Th1-Th2 balance underscores the multifaceted nature of immune dysregulation in psychosis. Further elucidating the biological mechanisms underlying complement involvement in Th1-Th2 balance may provide novel insights into disease pathogenesis and inform the development of targeted therapeutic strategies aimed at restoring immune homeostasis and mitigating the risk of psychosis.

Limitations

While this study represents the first investigation into the relationship between Th1-Th2 cytokine balance and complement in CHR individuals, with a longitudinal follow-up of one year, exploring the dynamics of cytokines and complement during the onset of psychosis, there are several limitations to consider. Firstly, the sample size is relatively small, particularly the limited number of cases in the CHR-C group. Future studies should aim to expand the sample size to validate these findings. Secondly, the one-year follow-up only included clinical outcomes and cytokine measurements, without reassessment of complement levels. Therefore, the specific changes in complement levels during the onset of psychosis remain unclear. Additionally, the one-year follow-up period is relatively short, and some CHR-NC individuals may develop psychosis after one year [44], potentially affecting the accuracy of the CHR-C and CHR-NC grouping. Future studies should consider longer follow-up periods to address this limitation. Lastly, during the one-year follow-up period, some CHR individuals received psychotropic medications, which may influence cytokine levels [45]. However, due to the limited sample size, stratified analysis based on medication status was not feasible. Additionally, the study excluded CHR participants with current substance abuse (e.g., cannabis, amphetamines), which are prevalent in international CHR cohorts and may independently modulate immune profiles via inflammation or direct effects on complement pathways. This exclusion introduces selection bias, potentially limiting generalizability to diverse CHR populations with high substance use rates. Lastly, the study did not account for the influence of comorbid conditions (e.g., metabolic syndrome, autoimmune disorders) and family history of autoimmune/infectious diseases on complement and cytokine profiles. Such conditions could independently modulate immune responses, introducing confounding variables. Future research should incorporate comprehensive assessments of comorbidities to disentangle their effects on the complement-Th1/Th2 axis in CHR populations.

Conclusion

Our study sheds light on the dynamic interplay between complement and inflammatory factor balance in the onset of psychosis, an area that remains poorly understood. Our findings highlight significant differences in complement characteristics between Th1 > Th2 and Th1 < Th2 balance states, particularly observed variations between CHR and HC groups. Moreover, the evident correlation between Th1 and Th2 inflammatory factors and complement in CHR individuals underscores the complexity of immune dysregulation in psychosis. Importantly, the observed right shift in Th1-Th2 balance, particularly associated with baseline complement C4b and C4 levels, suggests a potential role of complement in the pathogenesis of psychosis. Overall, these findings contribute to a better understanding of the immune-inflammatory mechanisms underlying psychosis onset and underscore the importance of further research in this area. By elucidating these intricate relationships, we not only advance fundamental knowledge but also open new avenues for developing targeted diagnostic and therapeutic strategies in the early detection and prevention of psychosis.