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Immune Paralysis in Sepsis: Recent Insights and Future Development

Authors:
  • Tarumanagara University - Faculty of Medicine
1
Immune paralysis in sepsis: recent insights and future development
Benjamin M Tang,1,2 Velma Herwanto,1 Anthony S McLean1
Affiliation:
1Department of Intensive Care Medicine, Level 2, North Block, Nepean Hospital,
Derby Street, Kingswood NSW 274, Australia
2Centre for Immunology and Allergy Research, Westmead Institute for Medical
Research, Westmead NSW 2145, Australia
Corresponding author:
Professor Anthony McLean, Department of Intensive Care Medicine, Nepean
Hospital, Australia. Email: Anthony.McLean@health.nsw.gov.au
Word count: 2348
Tables/Figures: 1
2
Introduction
Immune paralysis, or the inability of the immune response to recover despite clearance
of pathogens by antimicrobials, is a major cause of death in sepsis patients. Persistent
immune paralysis leads to a failure to eradicate the primary infection and an increased
susceptibility to secondary infection.[1, 2] The clinical relevance of this
immunosuppressed state in sepsis patients is evidenced by the frequent occurrence of
infection with opportunistic and multidrug-resistant bacterial pathogens and the
reactivation of latent viruses (cytomegalovirus, Epstein-Barr virus and herpes simplex
virus-1).[3-8] Here, we review recent insights related to the cellular mechanisms of
sepsis-induced immune paralysis and the development of novel therapies for treating
immune paralysis.
How does immune paralysis occur?
We begin with a brief review of the established literature on the mechanisms of immune
paralysis. These mechanisms have been well studied in both animal models and human
studies. They fall into in three main categories as follows;
Death of immune cells
Sepsis causes progressive, apoptosis-induced loss of cells of the immune system.
Apoptosis is prominent in CD4 T+-cells, CD8+ T-cells, B-cells, natural killer (NK) cells
and follicular dendritic cells in septic patients. Two pathways for apoptosis have been
identified, (1) the death-receptor pathway and (2) mitochondrial-mediated pathway.[9]
3
The detrimental effects of apoptosis are not only related to the severe loss of immune
cells but also to the impact that apoptotic cell uptake has on the surviving immune cells.
Uptake of apoptotic cells by monocytes, macrophages and dendritic cells either lead to
increased anti-inflammatory cytokine production (e.g. interleukin-10) or results in an
anergy state (see below) that further exacerbates the immune suppressive state.[10, 11]
Immune cell exhaustion or “anergy”
A robust cytokine response, after stimulation by pathogens or bacterial antigens (e.g.
lipopolysaccharide), is a common characteristic of healthy, well-functioning immune
cells. The progressive loss of such a response is a well-recognised condition in sepsis.
This condition has been alternatively named as “immune cell exhaustion”, “anergy” or
“endotoxin tolerance”.[12] T cell anergy, or an impaired response to an antigen with
decreased release of cytokines in the T cells, can lead to immune dysfunction in sepsis
patients. Immune cell anergy also occurs in macrophages and monocytes. Loss of their
expression of surface receptor, major histocompatibility complex class II, contributes
to macrophage and monocyte dysfunction.[13] Furthermore, the decrease in monocytes
CD14/human leukocyte antigen (HLA)-DR co-expression correlates with the degree of
immune dysfunction and results in a poorer outcome in severe sepsis.[14]
Anti-inflammatory state
During sepsis, the anti-inflammatory cytokine IL-10 is produced by T regulatory (Treg)
and T helper (TH)2 cells and suppresses the TH1 response. This suppressive
environment results in a marked decrease in monocyte production of pro-inflammatory
cytokines TNF-α, IL-1β, and IL-6.[13, 14]
4
What are the new insights from recent studies?
The above three processes, although well supported by many studies, are unlikely to be
the only mechanisms that underpin sepsis-induced immune paralysis. Additional
mechanisms have been discovered in more recent studies.
Immune-metabolic dysfunctions
Immune cells rely on oxidative phosphorylation as their main energy source. However,
during sepsis, immune cells shift their metabolism towards aerobic glycolysis.[15, 16]
This shift is an important adaptive mechanism that helps maintain host defence. The
failure of this shift may explain immune paralysis during sepsis. In a recent landmark
study, investigators found that in immune cells during sepsis both oxidative
phosphorylation and aerobic glycolysis were greatly diminished. The investigators also
observed that the expected metabolic shift did not occur.[12, 17] The cellular
consequence of this metabolic failure is significant, as immune cells require an
adequate supply of adenosine triphosphate and other metabolic intermediates (e.g.
NAD+) to maintain critical cellular functions during host defence, including activation,
differentiation and proliferation.[18]
Transcriptomics changes
Changes in cellular function are controlled, in part, at a gene-expression level.
Therefore, studies on gene-expression changes (i.e. transcriptomics) have revealed
considerable insight into the host response in sepsis. The findings from these studies
demonstrated increased gene-expressions in pro-inflammatory, anti-inflammatory, and
mitochondrial dysfunction and decreased gene-expression in translational initiation,
mTOR signaling, adaptive immunity and antigen presentation.[19-21] A recent
5
landmark gene-expression study explored the correlation between gene-expression
changes and patient level outcomes (e.g. mortality). The authors discovered a subgroup
of sepsis patients who displayed gene-expression changes that corresponded to an
immunosuppressive phenotype and termed these gene-expression changes the ‘sepsis
response signature’ 1. Genes included in this gene-expression signature indicate
changes in T cell exhaustion, endotoxin tolerance, and down regulation of HLA class
II. The authors showed that the presence of this immunosuppressive signature predicted
poor prognosis.[22]
Epigenetic modifications
Gene-expression can be modulated at an epigenetic level. Epigenetic modification
could retain unfavourable changes in gene-expression and maintain these changes
beyond the acute phase of infection. This “imprinting” process may contribute to the
persistence of the immune suppressive state during the post resuscitation period of
sepsis. For example, epigenetic imprinting might occur in progenitor cells in the bone
marrow and in other immune tissues, such as spleen and thymus. This may explain why
the immune system is not completely recovered by the generation of new immune cells
from the bone marrow. Similarly, epigenetic reprogramming may be retained in the
progenitor cells of patients who survive sepsis, allowing them to perpetuate the
epigenetic marks into well differentiated cells, which further compromises the immune
response.[23] Together, these findings suggest that epigenetic changes in immune cells
may be important factors in contributing to the prolonged effect of post-septic
complications.[24]
6
How do leukocytes contribute to immune paralysis?
Monocytes and macrophages
Monocytes and macrophages play important roles in sepsis-induced immune paralysis.
In sepsis, the capacity of monocytes to release pro-inflammatory cytokines in response
to endotoxin (e.g. LPS) or other toll-like receptor (TLR) agonists is diminished. This
phenomenon is known as endotoxin tolerance.[25] Two major consequences of
endotoxin tolerance on monocytes and macrophages are (1) an increase in the release
of immunosuppressive mediators (mainly IL-10) and (2) a decrease in antigen
presentation as a result of reduced expression of HLA-DR. Both consequences are
associated with augmented susceptibility to secondary microbial infection and a worse
outcome in sepsis.[26, 27]
Neutrophils and myeloid-derived suppressor cell (MDSC)s
Neutrophils contribute to immune paralysis in three ways. First, neutrophils produce
large amounts of immunosuppressive cytokine IL-10 during sepsis. These alterations
are assumed to be due to abnormalities in toll-like receptor (TLR) signalling, which is
analogous to endotoxin tolerance in monocytes. Second, suppressive neutrophil-like
cells (i.e. MDSCs), a subtype of differentiated neutrophils that accumulate in the
lymphoid organ after infection, could also contribute to immune paralysis by blocking
T cell function and promoting T regulatory cells. Third, neutrophils release nuclear
extracellular traps (NETs) that may be immunosuppressive. NETs are normal parts of
host defence; however, an excessive release of NETs can lead to extensive tissue
damage. Sepsis patients have been observed having increased NETs in their circulation,
which correlates with organ dysfunction.[24, 28]
7
Dendritic cells
Dendritic cells (DC) are central components for linking the innate and adaptive
immunity. Sepsis causes loss of DC in various lymphoid and non-lymphoid tissues.
Both plasmacytoid and myeloid DCs are particularly vulnerable to sepsis-induced
apoptosis. DC loss was more apparent in patients with sepsis who died than in those
who survived, and it was also more marked in patients who subsequently developed
nosocomial infections than in those patients who did not. Monocyte-derived DCs from
patients with sepsis were unable to induce a robust effector T cell response but instead
induced T cell anergy. These anergic T cells, in turn, may disrupt DC function.
Collectively, these data suggest that DC death/dysfunction is an important determinant
of sepsis-induced immunosuppression and mortality.[11]
CD4+ TH cell subsets
Mature CD4+ TH cells have been characterized into TH1, TH2 and TH17 cell subsets
based on the type of cytokines that they produce in response to stimulation. Both TH1
and TH2 cell-associated cytokine production are decreased during the initial immune
response to sepsis. This could be related to the significant reductions in the expression
of T-bet and GATA-binding protein 3 (GATA3), which are transcription factors that
modulate the TH1 and TH2 cell response. The TH17 cell response is also reduced in
sepsis, possibly as a result of decreased expression of the retinoic acid receptor-related
orphan receptor-γt (RORγt), which is the transcription factor that is specific for TH17
cells. This defect in the TH17 cell phenotype in sepsis is likely to be a contributing
factor to the increased susceptibility of these patients to secondary fungal
infections.[29]
8
T regulatory cells
The number of T regulatory (Treg) cells increase during sepsis. One reason for this
could be that they are more resistant to sepsis-induced apoptosis, presumably because
of an increase expression of the anti-apoptotic protein BCL-2. Another reason is the
increase of alarmins, including heat shock proteins and histones, which are strong
inducers of Treg cells. In addition, Treg cells inhibit both monocyte and neutrophil
function. Furthermore, Treg cells precipitate an NK cell-dependent endotoxin tolerance-
like phenomenon that is characterized by decreased production of interferon (IFN)-γ
and granulocyte-macrophage colony-stimulating factor. Based on these observations,
it is clear that Treg cells play a critical role in sepsis-induced immune paralysis.[10]
γδ T cells
The γδ T cells are a distinct subset of lymphocytes that reside mainly in the intestinal
mucosa. They recognize invading pathogens and mount a prompt, innate-like immune
response by releasing IFN-γ, IL-17 and various chemokines. The number of circulating
γδ T cells is significantly decreased in patients with sepsis and the depletion is parallel
to the sepsis severity. The loss of their number in the intestinal mucosa might be
detrimental because it allows invasion of intestinal pathogens into the circulation or the
peritoneal cavity, thereby causing secondary infections.[30]
Natural killer cells
In patients with sepsis, the number of circulating natural killer (NK) cells are markedly
decreased, often for weeks, and the low numbers of NK cells are associated with an
increased mortality. Their cytotoxic function and cytokines productions are also
reduced. In addition, decreased IFN-γ production by NK cells was identified as a
9
possible contributing factor to increased secondary infection in sepsis and reactivation
of latent infection.[31]
B lymphocytes
B cells or B-lymphocytes have a relevant immunoregulatory role in that they present
antigens to T lymphocytes and differentiate into antibody producing cells. B cell
exhaustion is a hallmark of sepsis; it compromises the ability of B cells to produce
antibodies and the efficient eradication of pathogens.[32, 33]
Future approach in immunotherapeutics new ways to treat sepsis?
The above review suggests that there are many potential targets for immune modulation
therapy, which might help reverse or reduce the effect of sepsis-induced immune
paralysis. Such therapy may include agents that inhibit apoptosis, block negative
costimulatory molecules, decrease the level of anti-inflammatory cytokines, increase
HLA-DR expression, and reactivate “exhausted” or anergic T cells.[34] These agents
(currently investigated in pre-clinical studies) are summarized in Table 1.
10
Immune cells
Mechanisms implicated in sepsis
Immunotherapy
Monocytes and
macrophages
Endotoxin tolerance
Increase immunosuppressive
mediators, esp. IL-10
Reduced expression of HLA-DR
Reprogramming to M2
phenotype
IFN-γ, G-CSF, GM-CSF, anti-PD-
L1-antibody, IL-15
Neutrophil and
MDSC
Decrease apoptosis
Increase IL-10
Increase immature cells with
decrease antimicrobial function
Block T cell function and
promote Treg
Release NET
IL-15, recombinant human IL-7,
G-CSF, GM-CSF
DC
Increase apoptosis
Induce T cell anergy
Induce Treg proliferation
Reduce antigen presentation to T
cell and B cell
IL-15
CD4+ TH cell subset
Increase apoptosis
Exhaustion
TH2 cell polarization
Recombinant human IL-7, anti-
PD-1-antibody, anti-PD-L1-
antibody, IL-15, anti-IL-10, anti-
TGF-ß
Treg cell
Resistance to apoptosis
Inhibit monocyte and neutrophil
function
Precipitate NK cell-dependent
endotoxin tolerance-like
phenomenon
Recombinant human IL-7, anti-IL-
10, anti-TGF-ß
γδ T cell
Decrease number, esp. in
intestinal mucosa
Recombinant human IL-7
NK cell
Increase apoptosis
Reduce cytotoxic function
Decrease IFN-γ production
IL-15
B lymphocyte
Increase apoptosis
Exhaustion compromise
ability of antibody production
and pathogen eradication
Recombinant human IL-3
Table 1. The proposed therapies targeting immune cell implicated in sepsis-induced
immune paralysis
11
Recombinant human IL-7. IL-7 is essential for T cell development and
function. It upregulates the expression of anti-apoptotic molecule BCL-2,
induces the proliferation of peripheral T cells and sustains increased numbers
of circulating blood CD4+ and CD8+ T cells. In addition, IL-7 administration
causes reduction in the proportion of Treg cells in the circulation, rejuvenates
exhausted T cells by decreasing programmed death 1 (PD1) expression and
increases the expression of cell adhesion molecules, thereby facilitating the
trafficking of T cells to sites of infection.[10, 13]
IL-15. IL-15 has been targeted to reverse apoptosis and improve immune
suppression in sepsis and its administration reduces apoptosis of NK cell, DC,
CD8+ T cell, and gut epithelial cells. It also raises IFN-γ levels and percentage
of NK cells.[35]
IFN-γ. A key immunological defect in sepsis is the decreased production of
IFN-γ. Treatment with recombinant IFN-γ has been observed to reverse
monocyte dysfunction in sepsis patients whose monocytes had decreased HLA-
DR expression and reduced amounts of TNF in response to LPS.[36] Thus, IFN-
γ might be effective in sepsis patients who have entered the immunosuppressive
phase.
Granulocyte colony stimulating factor (G-CSF) and granulocyte-
macrophage colony stimulating factor (GM-CSF). Administration of these
agents has resulted in the restoration of HLA-DR expression, fewer days on the
ventilator and in the ICU, restored TNF production, and reduced the acquisition
of nosocomial infection; however, there was no clear benefit in terms of
mortality.[37]
12
Blockade of PD-1 and PD-L1 signaling with PD-1 and PD-L1-specific
antibodies have showed improved survival in clinically relevant animal models
of bacterial sepsis. These agents work by reversing several effects of PD-1 and
PD-L1 proteins (apoptosis, T cell suppression and anti-inflammatory cytokines
production).[34]
Administration of allogenic mesenchymal stem cells is a relatively new
approach. The administration demonstrates lower organ dysfunction and
mortality in animal models via anti-microbial, anti-apoptotic,
immunomodulatory and barrier-preserving effects.[38]
Should we use a biomarker-guided approach?
A prerequisite for the application of immunotherapy in sepsis-induced immune
paralysis is the proper selection of patients. Therefore, we advocate a precision
medicine approach where biomarkers are used to select patients with abnormalities in
specific immune pathways. Potential biomarkers include decreased monocyte HLA-
DR expression and increased circulating IL-10 concentrations, both of which assess
innate immune function and therefore can be utilized to stratify patients for IFN-γ or
GM-CSF treatment. Other parameters include decreased absolute CD4+ T cell number
and increased percentage of Treg cells, which can be used to stratify patients for IL-7
therapy. Additional parameters include PD-1 expression on CD4+ and CD8+ cells or
PD-L1 expression on monocytes, which could help selecting candidates for PD-1 and
PD-L1-specific antibodies therapy. IFN-γ production by T cells, and the IL-10/ TNF
ratio are some other options of biomarkers that can be utilized to guide immunotherapy
in sepsis.[10, 39, 40]
13
Conclusion
This review summarized recent advances and new insights relating to the mechanisms
of immune paralysis in sepsis. Current evidence clearly indicates that no single
therapeutic agent can adequately treat such a broad range of immunological
abnormalities present in sepsis. In this regard, clinical trials recruiting a heterogeneous
patient population are unlikely to succeed due to their poor discrimination in
recognizing subsets of patients with specific immunological deficits. Future clinical
trials should therefore adopt a precision medicine approach in which clinicians use
“omics” technology to select the right patients (i.e. those with biomarker-proven
abnormalities in immune pathways) and treat these patients with the right therapeutic
agents (i.e. drugs that target these pathways).
14
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... Our results should support the inclusion of leptospirosis groups in clinical trials for drugs targeted to treat sepsis, such as antibiotics. Table 1 was compiled based on three current references, describing the main components of the immune system associated with sepsis that were studied here and the molecular markers that identify them (16)(17)(18). The discussion about other mediators involved in the pathophysiology of sepsis, such as neutrophils, Treg, chemokines, IL-33, and IL-15 are beyond the scope of this work. ...
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The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.