ROLE OF CELLULAR EVENTS

IN PATHOPHYSIOLOGY OF
SEPSIS
UNDER THE SUPERVISION OF DR. PRANITA SARANGI
BY:
AGRAJ SHARMA
12111005
B TECH.
BIOTECHNOLOGY

WHAT IS SEPSIS

Sepsis is systemic inflammatory response to an infection. Sepsis

develops due to a dysfunctional host immune response to an
uncontrolled infection. In North America, approximately 750,000
cases of sepsis occur each year, with mortality ranging from 30% to
50%

STAGES IN SEPSIS

PRO-INFLAMMATORY STAGE

The initial pro-inflammatory, or the cytokine storm stage,

is responsible for the recruitment of innate immune cells
such as macrophages and neutrophils in response to an
ongoing infection.

At this stage, recruited macrophages/monocytes secrete

pro-inflammatory cytokines, chemokines, reactive
oxygen species (ROS) via activation of toll-like receptors
(TLRs) and NFB pathway, which are very critical for the
killing of bacteria.

This stage is primarily responsible for conveying

appropriate signals to the cells of the adaptive immunity
to intensify the immune responses and facilitate
pathogen clearance.

IMMUNOSUPPRESIVE STAGE

It has been demonstrated that leukocytes isolated from

the septic patients at this stage show an altered
immunological status such as increased IL-10 secretion,
anergy in T cells with a shift to Th2 phenotype, reduced
MHC-II expression by antigen presenting cells.

In such patients, development of multi-organ failure and

sepsis are seen as a frequent complication.

HOMEOSTATIS

ROLE OF INNATE IMMUNE CELLS

IN SEPSIS

NEUTROPHILS:

At initial stages, phagocytic role of neutrophils assist in cleaning up the

bacterial load and reducing sepsis induced damage. In addition to
antimicrobial components, during sepsis, following activation with
PAMPs and pro-inflammatory cytokines, neutrophils express surface
molecules such as CD64 (Receptor for IgG),CD14 which increases
circulation.

One of the primary causes of intensified hyper-inflammatory stage is

due to the suppression of apoptosis of circulating neutrophils, which is
responsible for causing major tissue damages.

The possible causes of apoptosis suppression are attributed to

sustained mitochondrial membrane potential and reduced caspase-9
activity andcaspase-8 phosphorylation.

MACROPHAGES:

This cellular activation process leads to release of a large pool of proinflammatory cytokines such as TNF-, IL-6, IL-1, IL-8, IL-12, platelet
activating factor (PAF), ROS and microbicidal components (lysozyme,
cationic proteins, acid hydrolases, and lactoferrin) that act against the
microbes.

Recently, programmed cell death receptor (PD-1) was shown to be involved

in the macrophage immune dysfunction. Research showed that deletion of
PD1 inhibited migration of macrophages isolated from septic mice.

Endotoxins like LPS, macrophages enter into an unresponsive state and

cannot respond to further challenge of endotoxin with a reduced proinflammatory cytokine and chemokine production and is termed as
endotoxin tolerance in macrophages. As a result of endotoxin tolerance,
there is a cellular reprogramming which up-regulates the expression of
immunosuppressive mediators.

DENDRITIC CELLS:

Dendritic Cells(DCs)function as the major antigen presenting cells for

T cell activation, secrete IL-12 and IL-10 and express MHCII and costimulatory molecules on their surfaces, thus acting as the
connecting bridge between innate and acquired immune systems.

According to a post-mortem study of patients with sepsis, both the

number and area occupied by splenic DCs was highly reduced in
trauma and sepsis patients as compared to healthy individuals.

Interaction of TLR2 and TLR4 on DCs with their respective ligands

could induce depletion of DCs but the mechanisms behind apoptosis
and deletion of DCs during sepsis remain unknown and requires
further exploration.

ROLE OF ADAPTIVE IMMUNE

CELLS IN SEPSIS

T LYMPHOCYTES:

The development and progression of sepsis is associated with a

dysfunction of innate and adaptive immune systems, (e.g. enhanced T and
B cell apoptosis, inhibition of Th1 cell function, reduction in T cell receptor
(TCR) function, and increased presence of T-regulatory cells in tissues.

The CD4+ T cells in sample tissues showed suppressed production of IFN-

and TNF-, decreased expression of CD127 (the IL-7R -chain), but
increased expression of PD1, which is another phenotypic feature of
exhausted T cells.

The study showed increased its ligand, PDL1 expression in capillary

endothelial cells and bronchial epithelial cells of septic patients potentially
altering the function of T cells that have migrated to the site of infection.
animal studies that showed inhibition of PD1PDL1 interaction could
improve survival in sepsis by reducing T cell exhaustion.

B CELLS:

The role of B lymphocytes in the pathogenesis of sepsis has to be

explored.

There is a reduction in the peripheral blood B lymphocytes, which

could be due to an increase in CD95 expression on the B cells as
seen in septic shock patient.

Co-stimulatory molecules CD80 and CD86 which are critical

molecules in the B-cell antigen presentation function, are also highly
up-regulated in septic shock patients admitted to ICUs.

TREATMENT AVAILABLE

To date, except recombinant activated protein C, FDA

has not approved any other drug for treating severe
sepsis.

Recombinant human activated protein C which was the

only FDA approved drug for treating sepsis was also
shown to improve sepsis survival via inhibition of
neutrophil chemotaxis via binding to neutrophils
integrins.

Integrin 31 was up-regulated on a subset of

neutrophils that showed hyper inflammatory phenotype
during sepsis and deletion of this integrin from
neutrophils improved survival of septic animals.

CONCLUSION

THANK YOU