Letter to the Editor: Unlinking lymphocyte counts from disease severity in patients with acute-on-chronic liver failure

Abstract

We have carefully reviewed the recent study by Peng et al published in World Journal of Gastroenterology. Studies have indicated the presence of widespread lymphopenia in patients with acute-on-chronic liver failure (ACLF), along with rapid reconstitution of natural killer cells and B cells following liver transplantation. Furthermore, the absolute counts of peripheral blood lymphocyte subsets are not significantly correlated with the etiology of ACLF, multiple disease severity scores, or long-term prognosis after liver transplantation. This “negative result” may suggest that the immunopathology of ACLF cannot be fully captured by simple cell counts alone. We need to focus on the functional status of peripheral blood lymphocyte subsets and implement dynamic monitoring based on these subsets.

Key Words: Peripheral blood lymphocyte subset; Acute-on-chronic liver failure; Liver transplantation; Dynamic monitoring; Functional status

Core Tip: Commenting on the study by Peng et al, we offer insights into the finding that absolute counts of peripheral blood lymphocyte subsets are not significantly correlated with the etiology of acute-on-chronic liver failure, severity scores across multiple diseases, or long-term outcomes after liver transplantation. We believe that greater emphasis should be placed on monitoring the functional status of peripheral blood lymphocytes to better understand disease progression.

TO THE EDITOR

We have carefully reviewed the recent study by Peng et al[1] published in World Journal of Gastroenterology. Through detailed data, the authors systematically described the dynamic changes in peripheral blood lymphocyte subsets (PBLSs) before and after liver transplantation (LT) in patients with acute-on-chronic liver failure (ACLF). These findings confirmed the widespread lymphopenia occurring in patients with ACLF and demonstrated the rapid reconstitution of natural killer cells and B cells following LT. Notably, the key finding reported by the authors was that the absolute counts of PBLSs were not significantly correlated with the etiology of ACLF, multiple disease severity scores, or long-term prognosis after LT. In particular, the authors foresightedly mentioned the limitations of the current study in the Discussion section, including the lack of assessment of lymphocyte function, which may precisely be the key factor in explaining this “negative result”. Certainly, this outcome could also stem from the relatively small sample size included in the study, incomplete PBLS retrieval data, and the single-center retrospective nature of the study, along with the lack of external validation. Nevertheless, this study offers a novel perspective. Specifically, the finding of “irrelevance” should not be simplistically interpreted as “immunodeficiency being a fundamental feature of ACLF”; rather, it should be viewed as an opportunity to explore the complexity of the disconnection between quantity and function in ACLF immune dysregulation. Static, single-time-point absolute counts may be insufficient to capture the true state of the immune system, thus potentially explaining the limitations of their prognostic predictive capacity.

MECHANISTIC UNDERPINNINGS OF IMMUNE DYSFUNCTION

Key pathways to T-cell exhaustion

Liver failure profoundly affects the immune system, thus leading to dysregulation of the innate and adaptive immune responses[2]. This mechanism may involve T-cell mitochondrial dysfunction, among other factors (Figure 1)[3,4]. Under severe stress and chronic antigen exposure [such as hepatitis B virus (HBV) infection], lymphocytes often enter into a state of exhaustion or dysfunction. At this point, even if cell numbers remain unchanged, their functions (such as cytokine secretion, proliferation, and killing capacity) are severely impaired[5]. Therefore, in the study by Peng et al[1], the lack of an association between the lymphocyte count and prognosis can be reasonably explained by the possibility that lymphocytes in all ACLF patients (regardless of disease severity) may be in a state of profound functional suppression to varying degrees. T cells at normal numbers but with functional exhaustion may exhibit significantly lower immune efficacy than those with reduced numbers but preserved function. At this point, single counts of PBLSs fail to reflect the true state of the disease and are even less suitable as priority assessment criteria for the LT waiting list. Studies have indicated that the number of depleted T cells significantly increases during the pathogenesis of ACLF, thus suggesting that T-cell exhaustion is associated with immune dysfunction in patients with HBV-associated acute liver failure[6]. The acute onset of ACLF triggers systemic inflammation and cytokine storms, thereby leading to sustained T-cell activation. This activation causes T cells to overexpress inhibitory receptors (such as programmed death 1 and Tim-3). Persistent overexpression, combined with mitochondrial dysfunction and a rapidly deteriorating immunosuppressive microenvironment, results in T-cell dysfunction (including impaired proliferation, killing capacity, and cytokine secretion). This dysfunction then fails to control infection and liver damage, thereby releasing more antigens and exacerbating inflammation, which further intensifies T-cell exhaustion[3,5,7]. This scenario effectively creates a vicious cycle. Future research should explore whether novel therapeutic targets can interrupt this cycle, thus potentially offering new treatment strategies for ACLF patients. Additionally, lymphocytes are classified into numerous distinct types. In addition to the roles of various T cells, the roles of B cells[8] and natural killer cells[9] in ACLF warrant further investigation. Similarly, attention must be given to the functional status of these cells, which requires ongoing dynamic monitoring. PBLSs may be associated with the natural prognosis of patients with ACLF who have not undergone LT. Studies have indicated that a decrease in CD8+ T-cell counts may be associated with lower survival rates in patients with HBV-associated ACLF[10]. Peng et al[1] also support this view, thus further underscoring the necessity of investigating the functional status of PBLSs.

Figure 1 Possible mechanisms underlying T-cell immune exhaustion in acute-on-chronic liver failure include persistent antigenic stimulation, metabolic abnormalities (such as mitochondrial damage), increased numbers of immunosuppressive cells, increased expression of inhibitory receptors, and elevated levels of immunosuppressive cytokines. These factors ultimately lead to uncontrolled infection and inflammation, thus creating a vicious cycle. Created with http://biogdp.com. CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; HBV: Hepatitis B virus; IL-10: Interleukin-10; MDSCs: Myeloid-derived suppressor cells; PD-1: Programmed death 1; TGF-β: Transforming growth factor-beta; Tregs: Regulatory T cells.

CLINICAL AND TRANSLATIONAL IMPLICATIONS

Relevance across patient subgroups

It is important to clarify the translational relevance of our perspective across different clinical scenarios of ACLF. For ACLF patients not undergoing LT, functional immune monitoring could help stratify risk, guide immunomodulatory therapies, and predict spontaneous recovery. In patients awaiting LT, dynamic assessment of immune competence – rather than lymphocyte counts alone – may refine prioritization criteria and identify those most likely to benefit from early transplantation. Furthermore, in the posttransplant setting, profiling functional immune restoration (e.g., cytokine responsiveness, T-cell repertoire diversity) may inform immunosuppression tapering and predict graft tolerance. Thus, while Peng et al’s data[1] stem from a transplant cohort, the conceptual shift from quantitative to functional immune metrics holds broader implications: It urges the field to develop validated functional assays that can guide management across the entire ACLF continuum, both before and after transplantation.

The case for dynamic monitoring

The study by Peng et al[1] successfully demonstrated the dynamic reconstruction process of PBLSs following LT, which in itself indicates that the immune state evolves over time. Therefore, it is plausible that the immune state of ACLF patients prior to transplantation may also undergo a period of rapid changes. A single point-in-time measurement may not reflect the dynamic trajectory of a disease. For example, a patient with a persistently declining lymphocyte count may exhibit a significantly worse prognosis than one with a count that remains stable at a low level. The authors also prospectively highlighted the necessity of dynamic monitoring at the conclusion of the discussion section, and our findings provide compelling support for this perspective. Therefore, continuous longitudinal monitoring of PBLS function in a cohort of ACLF patients who have not undergone transplantation may reveal strong correlations between its changing trends and both disease progression and prognosis. This approach could identify more valuable immunobiological markers and ultimately provide a precise time window for immune intervention.

CONCLUSION

In conclusion, the study by Peng et al[1] provides valuable data that inadvertently highlights a critical knowledge gap in ACLF immunology: The disconnect between immune cell quantity and function. We propose that their “negative” correlation should serve as a catalyst to shift the focus from static counts to dynamic, functional immune profiling. Embracing this paradigm – through assays measuring cytokine production, exhaustion markers, mitochondrial fitness, and cytotoxic capacity – will not only deepen our understanding of ACLF pathogenesis but also pave the way for more precise risk stratification, personalized therapeutic interventions, and optimized transplant management. Ultimately, unlocking the functional dimension of immune dysregulation is key to improving outcomes across the entire spectrum of ACLF.