Divergent adaptive and innate immunological responses are observed in humans following blunt trauma
Kevin R Kasten
0
Holly S Goetzman
0
Maria R Reid
0
Alison M Rasper
0
Samuel G Adediran
0
Chad T Robinson
0
Cindy M Cave
0
Joseph S Solomkin
0
Alex B Lentsch
0
Jay A Johannigman
0
Charles C Caldwell
0
0
Division of Research, Department of Surgery, University of Cincinnati College of Medicine
,
Cincinnati, Ohio 45267-0558
,
USA
Background: The immune response to trauma has traditionally been modeled to consist of the systemic inflammatory response syndrome (SIRS) followed by the compensatory anti-inflammatory response syndrome (CARS). We investigated these responses in a homogenous cohort of male, severe blunt trauma patients admitted to a University Hospital surgical intensive care unit (SICU). After obtaining consent, peripheral blood was drawn up to 96 hours following injury. The enumeration and functionality of both myeloid and lymphocyte cell populations were determined. Results: Neutrophil numbers were observed to be elevated in trauma patients as compared to healthy controls. Further, neutrophils isolated from trauma patients had increased raft formation and phospho-Akt. Consistent with this, the neutrophils had increased oxidative burst compared to healthy controls. In direct contrast, blood from trauma patients contained decreased nave T cell numbers. Upon activation with a T cell specific mitogen, trauma patient T cells produced less IFN-gamma as compared to those from healthy controls. Consistent with these results, upon activation, trauma patient T cells were observed to have decreased T cell receptor mediated signaling. Conclusions: These results suggest that following trauma, there are concurrent and divergent immunological responses. These consist of a hyper-inflammatory response by the innate arm of the immune system concurrent with a hypo-inflammatory response by the adaptive arm.
-
Background
Inflammation can be detected following trauma, even in
the absence of infection, due to a global
ischemia/reperfusion injury resulting in the systemic inflammatory
response syndrome (SIRS). SIRS is diagnosed clinically
when patients have more than one of the following
clinical findings: significant changes in body temperature,
tachycardia, tachypnea, or white blood cell count of
>12,000 cells L-1 or <4,000 L-1[1]. This
hyper-inflammatory response can be further characterized by
increased expression of inflammatory mediators such as
pro-inflammatory cytokines, acute phase proteins, and
complement that result in leukocyte activation and
extravasation from the vascular compartment into
surrounding tissues (reviewed in [2]). Additionally,
numbers of neutrophils in the periphery increase, as does the
priming of these cells [3,4]. Increased neutrophil
numbers and activation can lead to bystander tissue damage
with increased complications upon subsequent infection
[5]. Recently, key structural elements of priming have
been identified. Priming results in the formation of
supramolecular complexes, which can include an array
of receptors, structural proteins, and components of the
nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase. These form on detergent-resistant membrane
fragments called rafts, which are specialized membrane
elements enriched in glycosphingolipids, cholesterol, and
anti-apoptotic active Akt [6]. This proximity allows for
close coupling of receptor mediated signaling, effector
function, and crosstalk between surface receptors and
downstream signaling systems [7].
The compensatory anti-inflammatory response
syndrome (CARS) is proposed to follow SIRS in trauma
patients. In the innate arm of the immune system,
CARS can be characterized in patients exhibiting
reductions in monocyte HLA-DR expression or ex vivo tumor
necrosis factor alpha production [8]. In the adaptive arm
of the immune system, CARS is characterized by a
blunted response to infections due to decreased T cell
numbers as well as mitogen unresponsiveness [9,10]. T
cell apoptosis is responsible for declining T cell
numbers following trauma [10,11]. Mitogen
unresponsiveness after injury results in both reduced T cell cytokine
production and decreased protein phosphorylation
following T cell receptor-mediated stimulation [12,13].
Altogether, decreases in T cell numbers and
responsiveness are thought to predispose trauma patients to
nosocomial infections, sepsis, and multiple organ dysfunction
[14,15].
These studies strongly suggest that trauma-induced
changes to the immune system can predispose the
patient to subsequent adverse clinical events, especially
in the event of an infection. Currently, there are
multiple therapies known to up or down regulate
inflammation and the immune system [16]. Ideally, therapies
should protect all cellular host defense compartments
from hyper-inflammation, as well as from anergy.
However, the response to trauma is dynamic and there exists
a need to effectively monitor the immune status of
patients in order to properly modulate inflammation.
In recent years there has been recognition that (...truncated)