144 Bratisl Lek Listy 2007; 108 (3): 144 148

REVIEW

The Effect of Head Injury Upon the Immune System

Smrcka M1, Mrlian A1, Karlsson-Valik J1, Klabusay M2

Department of Neurosurgery, University Hospital Brno, Czech Republic. msmrcka@fnbrno.cz

Abstract

Severe head injuries are characterized by high mortality and morbidity. In spite of guidelines based
therapy the treatment is frequently unsuccessful. Extracranial infectious complications are considered
to be an important problem during the course of recovery, and possibly immunological changes could
explain their occurrence. Head injuries cause an imbalance within the helper cell community, resulting
in a TH2 dominance. This development is influenced by the soluable agents of the sympathic nervous
system and the hypothalamic-pituitary-adrenal axis. The crucial research of damaged cellular immu-
nity concluded Quattrocchi in 1991. Both the activation of microglial cells and the accumulation of T-
cells after crossing the BBB indicate production of pro-inflammatory mediators in the CNS after in-
jury. The leaking of pro-inflammatory mediators to the circulation develops to a systemic inflamma-
tory response syndrome (SIRS). On the contrary, an overwhelming of anti-inflammatory substances
leads to an anti-inflammatory response syndrome (CARS). It is suggested that an imbalance between
these two immune responses is responsible for organ dysfunction and increased susceptibility to infec-
tions in polytrauma victims. Concerning mediators, IL-6 draws attention because of its high marker
ability. Finally, post-traumatic infections have also been correlated with an altered function of antigen-
presenting cells (APC). Concerning the quantity, the humoral part of immune system seems to be
stimulated, but its function and phagocyte activity shows several defects. Finally, TH2 dominance in-
duces IgE levels accumulation. All these changes are strongly under effect of stress based release of
endogenous glucocorticoids and catecholamine, which influence the complex network of cytokines and
cell mediators (Fig. 3, Ref. 18). Full Text (Free, PDF) www.bmj.sk.
Key words: severe head injuries, immune system, stress reaction, TH2 dominance.

Head injuries are the third most common pathology in the
central nervous system and it counts for a main cause of mortal-
ity and disability among people between the age of 20 and 40.
This group has a major representation of male victims. Head
injuries can be divided by many points of view. In compliance
with our research it is apposite to divide them into two groups
primary and secondary lesions. Studying polytrauma mortality
generally, it is shown that deaths occurring immediately or early
after the trauma is determined by primary brain injuries or hem-
orrhagic shock. Deaths occurring later after hospitalization are
due to secondary brain injuries or host defense failure (revers-
ible systemic inflammation) (1). These indications further high-
light the clinical importance of head trauma.
Brain injury serves as one of the most challenging problems
facing clinicians. A quick pre- and in-hospital management is of
great importance for the outcome of the patient and has during
recent decades been brought to light. This has improved the
chances of a positive outcome and thus lowered the mortality
rate significantly (2, 3). Still, understanding of the pathophysi-
ology behind the brain injury and its consequences becomes the
theoretical basis that enhances the possibility of a better and more
effective therapeutic treatment.
The goal of the successful therapy is to protect the brain from
secondary insults keeping CPP level above 60. In spite of guide-
lines based therapy the mortality of brain injuries is high. How-
1
Department of Neurosurgery, University Hospital Brno, Czech Repub-
lic, and 2Department of Haematooncology, University Hospital Brno,
Czech Republic
Address for correspondence: M. Smrcka, MD, Dept of Neurosurgery,
Jihlavska 20, CZ-625 00 Brno, Czech Republic.
Phone: +420.5.32233746
Acknowledgement: This article is supported from IGA MZ R NR
7999-3.
 Smrcka M et al. The Effect of Head Injury Upon the Immune System 145

Ischemia / Shear injury

EEA release

Ion channels open

Na+ Influx Ca2+ Influx Second

messenger K+
damage K+
K+
Cell damage Inactivation of
free radical
protective enzymes
K+ Efflux

Cytotoxic edema Free radicals Na+

Local Cytokines (except IL-1)

Astrocytes inflammation SIRS
swelling
Raised ICP K+ K+ Na+ -Leukocyte -Complement cascade
K+ Swollen perivascular adherence -Kallikrein-kinin-system
processes -Coagulation system
-Acute phase reaction
1. Endothelial damage
(Impaired BBB)
Reduced CBF Vasogenic edema 2. Parenchymal cell damage

Fig. 1. Primary shear injury and secondary ischemic lesion causes a cascade of cellular events, finally resulting in
tissue damage and the development of cerebral inflammation. (Picture redrawn and modified from Keel M et al, 2005,
and Reilly P et al, 1997.)

ever, recent decades of research has illuminated other indepen- History

dent factors, which indeed influence the outcome. Particularly
extra cranial infectious complications are considered an impor-
tant problem during the course of recovery, and it has been sug-
gested that immunological changes could explain their occur-
rence. Immune system and its changes are well regulated by com-
plex network of neuro immune cross talk, issuing highly spe-
cific regulatory control. Changes in different parts of the host
defense mechanisms could supposedly influence the outcome
by making way for extra cranial complications. Many studies
have evaluated these effects of head injury, and especially the
cellular arm reports significant differences in comparison with
the non injured person. It is indicated that patients surviving their
trauma will have a full recovery and normalisation of their im-
mune system (4).
On the other hand, the more detailed nature of the immuno-
logical changes has not yet been sufficiently investigated. Al-
though, many speculators agree on the theory that head injury
causes most likely an imbalance within the TH (helper) cell com-
munity, resulting in a TH2 dominance. This development is clearly
influenced by the soluable agents of the sympathic nervous sys-
tem and the hypothalamic-pituitary-adrenal axis.
A TH2 dependent response suppresses the cellular immunity
and instead stimulates the humoral parts. Probably this has
evolved to protect the host from an overwhelming of potentially
harmful inflammatory mediators. However, it seems as if these
events also increase the patients susceptibility for developing
an infection.
In 1991 Quattrocchi et al (5) reported suppression of mul-
tiple parameters of cellular immune function along with a higher
incidence of infection. In vivo observations of delayed type hy-
persensitivity (DTH) skin anergy were noticed, but even more
interesting in vitro changes occurred. When stimulated with lym-
phocyte mitogen, phytohaemagglutinin (PHA), the peripheral
blood lymphocytes obtained within 24 hour after injury showed
impaired phenotypic expression of CD2+ (T-cell), CD4+ (T-
helper-cell) and CD25+ (alpha subunit of the interleukin-2 re-
ceptor). Also a decreased blastogenesis was observed. This highly
suggests head injury to alternate the helper T-cells ability to an-
swer to mitogen stimulation and thus suppress their activity.
Quattrocchi et al (5) discuss this to be due to presence of sup-
pressor cells, soluable mediators or intrinsic T-cell dysfunction.
These hypothesis became the subject of their next publica-
tion, Quattrocchi et al (6). In addition to their early material they
now presented data from other studies showing suppression of
IL-2 and INF-gamma production (without changes in IL-1 pro-
duction) and also suppression of LAK (lymphokine-activated
killer) cytotoxity (CD8+ T-cells). This indicates a general de-
creased function of both CD8+ and CD4+ effectors T-cells. In
their own experiments they could confirm the influence of sup-
pressor lymphocytes and also postulated the rapidity of immune
suppression to be due to significant effects of soluable serum
factors. Since these studies many more have followed showing
more or less the same results. Meert et al (7) repeated the similar
146 Bratisl Lek Listy 2007; 108 (3): 144 148

TH-2

IL-10
Traumatic IL-4 CARS
injury IL-13
TGF-

APC Immune-
suppression

MHC II - Depressed expression Post-traumatic

infection

Fig. 2. Traumatic injury results in a TH2 type response and a depressed expression of MHC class II. These events will
suppress several aspects of the immune responsiveness, further increasing the susceptibility of post-traumatic infec-
tious complication. (Picture redrawn and modified from Keel M et al, 2005.)

investigations as Quattrocchi et al had preformed some years
earlier, but this time in children between the ages of 17 to 18
suffering from severe head injury. The results showed to be com-
parable, with marked suppression in T-lymphocyte circulating
numbers, activation and mitogenesis, within the first two weeks
after trauma. Wolach et al (4), showed significant deficiencies
of all lymphocyte phenotypes of the cellular arm (CD4+, CD8+
and circulating T-cells) and also NK-cells, in comatose patients
after severe brain injury.
Systemic consequences of trauma
Both the activation of microglial cells and the accumulation
of T-cells after crossing the BBB indicate production of pro-
inflammatory mediators in the CNS after injury. The leaking of
pro-inflammatory mediators to the circulation develops to type
of hyperinflammation referred to as systemic inflammatory re-
sponse syndrome (SIRS) (Fig. 1). On the contrary, an overwhelm-
ing of anti-inflammatory substances leads to a systemic hypo-
inflammation known as compensatory anti-inflammatory re-
sponse syndrome (CARS) (Fig. 2). It is suggested that an imbal-
ance between these two immune responses is responsible for
organ dysfunction and increased susceptibility to infections ob-
served in polytrauma victims. Keel et al (1) present neurons, glial
cells and astrocytes as producers of both pro- and anti-inflam-
matory substances and their receptors, resulting in local inflam-
mation and leakage to the circulation with a following SIRS.
The local inflammation in the CNS does not differ much from
other tissue inflammatory responses after injury, and the same
both protective and harming effects are observed (8). Studying
the cytokines after brain injury confirms this suggestion. Lau et
al (9) found in vitro that astrocytes produce and release interleukin
1, interleukin 6, tumor necrosis factor alpha and interferon gamma
1 hour after shear stress. Further research confirms these results
and especially IL-6 draws attention, because it seems to be a
good marker for the severity of brain injury. Indeed, IL-6 is well
known to induce release and production of acute phase proteins
in hepatocytes. This would explain the existents of an acute phase
response in close head injured patient, observed by Young et al
(10). Woiciechowsky et al (11) confirmed this raise in IL-6 lev-
els, but could also correlate the plasma concentrations of IL-6
with the severity of brain injury and pneumonia, thus proposing
an influence of head injury on the occurring of post-trauma in-
fections. This mediator is produced by many cells and acts on
most cells, but only stimulating effects have been observed. For
example, IL-6 can together with IL-1 function as a co-stimulatory
signal in T-cell activation, but its most important effect has showed
to be stimulating B-cells to differentiate into plasma cells (1).
Decreased resistance to infection is observed in patients with
serious traumatic injury and major burns. Suppression of cell-
mediated immunity is known to occur in these patients and sev-
eral detailed investigations have explored its regulatory nature.
Concerning T-helper cells (TH), OSullivan et al (12) found
the impaired adaptive immunity not only to be a generalized sup-
pression, but rather a conversion of the naive TH cells towards
the TH2 phenotype. Thus, although the mean T-lymphocyte lev-
els may be decreased, the TH1/TH2 ratio is changed leading to a
raised concentration TH2, compared with the non traumatic pa-
tient (Fig. 3). This is supported by reduced serum concentrations
of IL-2 and IL-12, along with a major increase in IL-4 and IL-
10. Several recent studies show similar results and also report
elevated serum levels of IL-13 and transforming growth factor-
(TGF-), produced by both TH2 cells and monocytes/macroph-
ages (13). Although the anti-inflammatory effect of IL-4 is of
great interest considering the aspects of suppressed immunity in
head injured patients, we must not forget to mention the pro-
inflammatory properties. In naive B-cells, IL-4 is well known to
induce heavy chain isotype switching, proliferation and differ-
entiation into plasma-cells, leading to an increased production
of immunoglobulin E (14). Summarizing these events, it seems
as if severe traumatic injury and burns is followed by an increased
production of IL-10, IL-13 and IL-4 by TH2 cells and mono-
 Smrcka M et al. The Effect of Head Injury Upon the Immune System
? IL-5
IL-4 from other
IL-2 cellular sources
IL-4
Autocrine
activation
Antigen
recognition
Naive CD4+ Activated
T-cell T-cells
IL-12 from activated
macrophages and
other APCs
Fig. 3. The picture illustrates the naive CD4+ T-cell activation, proliferation and differentiation into a specific TH phenotype.
Different cytokines issues the regulatory changes, as well as the effectors mechanisms, resulting in either a TH1 or TH2 type re-
sponse. (Picture redrawn and modified from Abbas et al, 2004.)
cytes/macrophages, leading to a decreased resistance to infec-
tion correlating with subsequent septic events (Fig. 2). If closed
head injury affects the immunological events similarly is yet to
be proved. Finally, post-traumatic infections have also been corre-
lated with an altered function of antigen-presenting cells (APC).
These, mainly monocytes/macrophages, show reduced expression
of co-stimulators and the MHC (major histocompatibility com-
plex) class II molecule HLA-DR (human leukocyte antigen) (13).
Aspects of humoral and phagocyte functions after severe iso-
lated head injury
Humoral and phagocyte functions involve immunoglobu-
lines, complement components, monocytes/macrophages and
polymorph nuclear leucocytes (PMNL).
There are not many studies available focusing on these pa-
rameters after severe head injury, mainly because no major ef-
fects have been noticed to occur. However, Wolach et al (4, 14)
included major investigations of the phagocyte and humoral func-
tions in their observations of immunological defects in coma-
tose patients after severe head injury. All investigations were
made in peripheral blood.
Starting with the phagocyte arm, they observed a reduced gen-
eration of superoxide by neutrophils when in vitro stimulated with
formyl-methyonyl-leucyl-proline (fMLP) and phorbolmyristate
acetate (PMA). The authors referred to former studies showing
that PMNLs become hyperactive during the first 12 hours of the
post-traumatic period, thereafter, entering a late phase where they
reduce in number and function up till 72 hours after trauma. The
effects are believed to be caused by changes in concentrations of
pro-inflammatory mediators. Wolach et al showed similar results
in head injured patients, both in their study 1993 (14) and 2001 (4).
Abnormal humoral function could explain the defective bac-
tericidal activity of the PMNLs. Adding homologous serum in
vitro corrected the PMNL impairment, indicating deficient opso-
147
Eosinophil
activation
IL-4
IL-10
IL-13
IL-6+
TH-2 cells Stimulation of
Inhibits B-cell differentiation
macrophage into IgE producing
activation plasma cell
INF- Macrophage Inhibition of TH-1
TNF + activation type immune
response
TH-1 cells
nisation, an essential precondition for phagocytosis. As shown
in the paper from 1993 (14), neither superoxide anion release nor
random migration or chemotactic capability was defective in the
neutrophils, confirming the theory of a defect humoral function.
Early reduction in complement components C1q, C1r and
C4, along with deficiencies of IgG2 and IgG4 seems to be the
reason. These levels increase quickly after head injury and stay
normal during the vegetative period. Since the number of B-cells
show post-traumatic changes, the decrease is supposed to be
caused by increased consumption of the mediators. The time
courses of all these events well correlates with the changes ob-
served in PMNL function, thus confirming the early and late
period hypothesis, also known as the two-hit model. Observa-
tions of high IgE levels after trauma and cerebral infarction are
mentioned in a few studies, suggesting a post-traumatic conver-
sion of the TH-cells towards the TH2 phenotype (15).
The changes in cytokine concentrations after trauma are in
most aspects quite well studied, but still the mechanisms behind
the observed alterations are not very clear. Elenkov et al (16, 17,
18) have during the last ten years published data suggesting that
the stress-induced glucocorticoids and catecholamine strongly
affect the balance between TH1 and TH2. If true, this would add
valuable facts to the understanding of immune alterations after
head injury.
In 1996 (16), they reported alterations to occur in the cytokine
panorama produced by cells in response to bacterial lipo-
polysaccaride (LPS) in human whole blood, when exposed to
the known mediators of stress. Glucocorticoids showed to
strongly decrease the serum levels of IL-12, the well known in-
ducer of TH1 phenotypic differentiation. Catecholamines showed
the same results; however, they also increased the serum con-
centrations of IL-10. The effects are mediated through both APC
and the lymphocytes themselves. These observations suggest a
highly selective suppression of TH1 function and a shift toward
TH2 cytokine pattern in response to stressful stimulation. Hence,
148 Bratisl Lek Listy 2007; 108 (3): 144 148
this could explain some very important CNS regulatory path-
ways of immune function, and also influence the susceptibility
of an individual to certain infectious diseases after trauma.
Similar observations were made in 2000 (17), but now se-
rum levels of histamine and adenosine seemed to have similar
effects as glucocorticoids and catecholamine. Except IL-12, other
TH-1 stimulating signal molecules, such as TNF-, INF- and
INF-gamma, showed to suffer the same suppression. Summariz-
ing all their observations in the review from 2004 (18), Elenkov
et al reported the last evidence for an up-regulation of IL-4, IL-6
and IL-13 levels after stress reaction, once again confirming their
hypothesis. It is important to note that all these effects are seen
in vivo after endogenous changes in different mediator concen-
trations, everything within the physiological range.
Conclusions
The effects of severe closed head injury upon the immune
system are mainly issued through impairment of the cellular as-
pects. Trauma is directly followed by a decreased number of cir-
culating T-lymphocytes, helper cells imbalance and impaired T-
lymphocyte activation and proliferation. Also decreased num-
bers of NK-cells are described. The most presumptive reason
could be an early reduction in complement components C1q,
C1r and C4, along with deficiencies of IgG2 and IgG4. Finally
TH2 dominance induces IgE levels accumulation reaching the
values typical for atopic reaction or parasitic disease..
Phagocyte impairment of the PMNL ability to kill bacteria
is correlated with defective opsonisation, probably due to in-
creased consumption of humoral mediators early after trauma.
After initial deficiency, the humoral immunity shows a quick
recovery in most patients, except from increased concentrations
of IgE. All these changes are strongly under effect of stress based
release of endogenous glucocorticoids and catecholamine, which
influence the complex network of cytokines and cell mediators.
Whether head injuries affect the immune system or not, seems
quite obvious. That this modulation increases the risk for develo-
ping extracranial infectious complications, has also found strong
evidence. However, the detailed nature of the host defense mecha-
nism and its regulation, during the posttraumatic period is still to
be revealed. So far, we can only speculate, but several indications
suggest a highly controlled cross talk of events, rather than just
mere accidental suppression. Learning more about these connec-
tions will bring us closer to the full understanding of their purpo-
ses, and might even create modern approaches for future therapies.
Although many of the concerns in the concept of neuro-im-
mune cross talk, and particularly its alterations after head injury,
is suggested, there are still many problems to be solved and hy-
pothesis to be proved. However, it is still clear that a connection
exists and that modulated change of the immune system does
appear after head trauma.
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Received September 20, 2006.
Accepted November 3, 2006.