Immune Mechanisms
Against Extracellular
Pathogens
Ingo B Autenrieth, Ludwig Maximilians University, Munich, Germany
Joachim Hein, Ludwig Maximilians University, Munich, Germany
Ralf Schulte, Ludwig Maximilians University, Munich, Germany
Extracellular pathogens replicate and/or persist on mucosal surfaces or in host tissues
outside host cells and may rapidly spread or establish an infection. In this habitat, however,
they have to fight against several humoral (e.g. defensins, lactoferrin, antibodies) and
cellular (phagocytes, T cells) immune defence mechanisms.
Introduction
Microorganisms should be classified as extracellular if
their habitat, the space in which they multiply and persist in
the host, is primarily outside host cells. The advantage of
this habitat is that these microorganisms can take their
nutrients directly from the body fluids. Moreover, extra-
cellular microorganisms have the ability to spread rapidly
through extracellular fluids or to move rapidly within
tissues or on surfaces such as the mucosa. This strategy
may allow widespread infections to become established in a
short period of time. The disadvantage of the extracellular
habitat, however, is that these microorganisms are
continuously exposed to components of the host defence
such as complement or phagocytic cells as well as
antibodies. Extracellular microorganisms include mucosal
pathogens such as Helicobacter pylori, Vibrio cholerae,
Escherichia coli, and Yersinia enterocolitica, and purulent
bacteria such as Staphylococcus spp., Streptococcus spp.
and Bacteroides spp. Furthermore, eukaryotic pathogens
such as Candida spp. and macroparasites including
Schistosoma spp. or Onchocerca spp. are located extra-
cellularly. As infections with some of the latter organisms
may have a very individual pathogenesis, the mechanisms
described herein are related to bacterial infections if not
otherwise mentioned.
Until recently, it was generally believed that host
responses to extracellular pathogens were trivial and
restricted to the nonspecific components mentioned above.
However, recent work on extracellular pathogens such as
Yersinia enterocolitica, Bacteroides fragilis and Candida
albicans has demonstrated that some of these extracellular
microorganisms may express virulence factors by which
the pathogens subvert or evade innate host defence
mechanisms. Therefore, certain host defence components
such as CD4 T-helper 1 (TH1) cells that are normally
required for elimination of intracellular pathogens are also
ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net
Secondary article
. Introduction
Article Contents
. Innate Immunity Against Extracellular Pathogens
. Humoral and Cellular Immunity Against Extracellular
Pathogens
. Cytokine Regulation of Protective Immune Responses
Against Extracellular Pathogens
. Tissue Reactions Induced by Extracellular Pathogens
. Immune Evasion by Extracellular Pathogens
. Adverse Effects of the Immune Response
involved in and essentially required for resolution of
infections with some of the extracellular pathogens.
Innate Immunity Against Extracellular
Pathogens
The skin and mucosal surfaces have inherent nonimmune
defence mechanisms to modulate bacterial growth and
minimize the risk of bacterial infections. Healthy skin is
keratinized and, therefore, an effective physical barrier to
infection by most extracellular pathogens. The combina-
tion of lysozyme, toxic lipids and hydrogen ions secreted by
cutaneous glands exerts bacteriostatic protection for
cutaneous pores and hair follicles (Salyers and Whitt,
1994). Unlike the skin, mucosal surfaces such as the
gastrointestinal tract, the nasopharynx, the upper airway,
and the urogenital tract are not keratinized and are
colonized by a normal, indigenous bacterial microflora
with up to 1011 –1012 bacteria per g mucosal tissue.
The proliferation of bacteria in these mucosal compart-
ments is controlled by various mechanisms. In the
gastrointestinal tract, peristaltic motility, the secretion of
mucus, the stomach acid and the detergent action of bile
limit the number of bacteria. In addition, the mucosal fluid
contains many antibacterial products such as mucin,
lysozyme, lactoferrin and defensins.
Mucin traps the microbes and facilitates their transpor-
tation. Lysozyme reduces bacterial load by cleaving 1–4
linkage of N-acetylmuramic acid in the bacterial peptido-
glycan. Iron (Fe3 1 ) is essential to all microorganisms. As a
simple defence mechanism, humans and animals have
developed mechanisms to withhold iron from microorgan-
isms, using iron-binding proteins such as lactoferrin to
decrease the iron availability for microorganisms. The
antimicrobial activity of lactoferrin arises from both
1
 Immune Mechanisms Against Extracellular Pathogens
sequestration of environmental iron and membrane
disruption of Gram-negative bacteria (e.g. enterohaemor-
rhagic E. coli) by its cleavage products (Ellison, 1994).
Lactoferrin is found in human mucosal secretions as well as
in granules of polymorphonuclear leucocytes.
Paneth cells in the crypts of the small intestine can
participate in the mucosal defence by producing enteric
defensins, or cryptidins. These are homologues of myeloid
defensins, a family of antimicrobial peptide components of
phagocytic leucocytes. Defensins bind to bacterial mem-
branes electrostatically and subsequently form multimeric
pores, thereby killing microbes (Ganz and Weiss, 1997).
If the above inherent nonspecific defence mechanisms
fail to prevent colonization, pathogens might invade and
gain access to host tissue. In this situation, various
additional immune mechanisms are required for and
involved in eradication of the pathogens. Some of these
mechanisms were mentioned above as part of the mucosal
defence line. Others include pattern recognition molecules
or receptors such as complement, collectins and various
antibacterial peptides. All of them recognize patterns
shared among groups of pathogens (Hoffmann et al.,
1999).
One systemic response to infection is to lower the serum
concentration of iron by an increase in the transferrin
concentration in serum. Iron at the site of inflammation
may be reduced by neutrophil-secreted lactoferrin. More-
over, lactoferrin promotes the phagocytic activity of
human polymorphonuclear leucocytes. In addition, neu-
trophils deliver a complex antibiotic arsenal to sites of
infection. Among these cytotoxic systems, an array of
antimicrobial peptides (defensins) are directed against
microorganisms before and after sequestration into a
phagocytic vacuole.
Another line of defence is the complement system which
serves as an auxillary system in immunity, both on its own
and by interaction with humoral immunity. The comple-
ment system comprises more than 30 plasma or membrane
proteins. Its activation relies on a cascade of proteolytic
steps performed by serine protease domains in the
components involved. Three different pathways of activa-
tion exist. The complement system is either activated by
target-bound antibodies (the classical pathway), by poly-
saccharide structures of microbes (the mannose-binding
lectin pathway), or by recognition of foreign surface
structures by complement itself (the alternative pathway).
All three merge into the activation of the complement
factors C3 and C5, and finally the assembly of a pore-
forming, lytic membrane attack complex (MAC).
In addition to direct killing by the MAC, coating of
microbes with C3 fragments leads to their uptake into
phagocytic cells via the complement receptor. The
solubility and immunogenicity of antigens are improved
by attachment to C3 fragments. Furthermore, cells of the
unspecific defence system (neutrophils, macrophages and
mast cells) become stimulated by anaphylatoxins, small
2
peptides generated in the course of proteolytic complement
activation.
However, some pathogenic microorganisms have so-
phisticated mechanisms to evade recognition or constrain
suitable attack and destruction. Thus, Yersinia enteroco-
litica and certain strains of E. coli and Streptococcus
pyogenes have evolved mechanisms to resist C3 deposition,
opsonophagocytosis or complement-mediated cytolytic
damage (Moffitt and Frank, 1994).
Collectins are a group of lectins that also play a role in
the first-line host defence. They recognize specific carbo-
hydrate residues on the surface of microorganisms and
promote the killing of microbes either by acting directly as
an opsonin or by activating the mannose-binding lectin
complement pathway.
Phagocytosis by polymorphonuclear leucocytes and
monocytes or macrophages is the mechanism by which
most pathogens are ultimately destroyed. Bacterial inter-
nalization is initiated by the interaction of specific
receptors on the surface of the phagocytes with ligands
on the surface of bacteria. There are receptors for
nonopsonic recognition and for recognition of bacteria
opsonized with complement or antibodies.
Nonopsonic recognition occurs by the phagocyte
receptors CD14, associated with Toll-like receptors or
CD11b/CD18 which bind lipopolysaccharide (LPS) of
Gram-negative bacteria, the scavenger receptor type I
recognizing peptidoglycan of Gram-positive bacteria, or
the mannose receptor binding to carbohydrate moieties on
the bacterial surface.
Recognition of microbes as possible pathogens and
efficient destruction is enhanced by opsonization of
bacteria with complement or antibodies. Thus, phagocytes
express the complement receptors CR1, CR3, CR4 and
C1qR and the Fc immunoglobulin G receptor. After
recognition, bacteria are ingested into a phagosome via an
actin-dependent mechanism. Subsequently, the phago-
some matures by a series of fusion and fission events
involving components of the endocytic pathway, culmi-
nating in the mature phagolysosome. In the phagolyso-
some bacteria are exposed to an array of killing
mechanisms.
One mechanism involves the reduction of oxygen (O2) to
superoxide anion (O2 2 ), a reactive oxygen intermediate
(ROI), which in turn generates other ROI toxic to bacteria.
Furthermore, in macrophages the formation of reactive
nitrogen intermediates, in particular the formation of nitric
oxide (NO) can be induced. The latter enables macro-
phages to kill pathogens such as E. coli, Staphylococcus
aureus, C. albicans or Schistosoma mansoni. Other anti-
microbial mechanisms involve defensins that can kill
organisms including Pseudomonas aeruginosa, E. coli and
S. aureus. Moreover, acidification, lysosomal enzymes and
lactoferrin are involved in bacterial elimination by
phagocytes (Hampton et al., 1998).

Although natural killer cells have been implicated in
direct bactericidal interaction with bacteria the molecular
basis of this putative interaction remains to be established.
It is currently believed that NK cells participate in control
of bacterial infection rather indirectly by cytokine produc-
tion which activates macrophages to degrade the patho-
gens.
Humoral and Cellular Immunity Against
Extracellular Pathogens
The humoral immune response is mediated by antibodies.
Antibodies are secreted by B cell-derived plasma cells and
found in the plasma, in extracellular fluids, secretions and
on mucosal surfaces. Antibody-mediated immune re-
sponses may lead to the destruction of microorganisms,
and are thus highly effective weapons against pathogens
which multiply in the extracellular spaces of the body.
Basically, there are three major mechanisms by which
antibodies contribute to immunity against extracellular
pathogens. First, antibodies may bind to pathogens or
products such as toxins produced by pathogens. In turn,
antibodies may prevent bacterial colonization, adherence
to or invasion of mucosal surfaces or tissues, or protect the
host from the detrimental effects of toxic bacterial
products. Antibodies that disclose these effects are
designated as neutralizing antibodies.
Second, antibodies may enable phagocytic cells to ingest
and kill pathogens, a process called opsonization. Phago-
cytes are activated by antibodies which bind to specific Fc
receptors on their surface. It is essential that the Fc
receptors are able to distinguish antibodies bound to a
pathogen from the majority of free unbound antibodies.
This can be achieved by multimerization of antibodies
bound to extracellular bacteria.
Third, antibodies can also activate the complement
cascade (classical activation pathway). Complement in
turn may strongly enhance opsonization or directly lyse
bacteria. Bacterial killing by complement activation
comprises a sequence of polymerization reactions resulting
in the formation of a membrane attack complex, which
introduces pores into membranes of extracellular patho-
gens. Which of the aforementioned effector mechanisms is
actually recruited in a particular immune response to a
given pathogen is determined by the isotype or class of
antibodies produced, e.g. immunoglobulin M (IgM), IgG,
IgA or IgE.
The first antibodies to be produced in a humoral immune
response are IgM. IgM is the dominant class of secreted
antibodies in the primary immune response and, interest-
ingly, is also produced in secondary responses. The early
IgM antibodies are generated before B cells have under-
gone somatic hypermutation and therefore tend to be of
low affinity. However, IgM antibodies can compensate for
Immune Mechanisms Against Extracellular Pathogens
their relatively low affinity by forming pentamers which
allow simultaneous binding to multivalent antigens such as
bacterial cell wall polysaccharides, resulting in high
avidity. The pentameric structure makes IgM antibodies
especially potent in activating the complement system, a
mechanism which is important in controlling the spread of
extracellular pathogens into the bloodstream.
Other immunoglobulin isotypes, such as IgG, IgA and
IgE, are smaller in size, diffuse easily out of the blood into
the tissues and are increased in secondary immune
responses. Immunoglobulin G (IgG) is the predominant
immunoglobulin in the blood and extracellular fluids and
comprises more than 75% of serum immunoglobulin. The
presence of high-affinity IgG is the hallmark of secondary
humoral immune responses. IgG efficiently opsonizes
pathogens for engulfment by phagocytes and activates
the complement system. Moreover, IgG antibodies are
transported across the placenta to the fetus during the late
phase of gestation. The maternal antibodies provide
significant protection to the neonates from many extra-
cellular bacterial infections such as E. coli or group B
streptococci.
Immunoglobulin A (IgA) is the major immunoglobulin
in secretions, on mucosal surfaces and in colostral milk.
IgA antibodies are synthesized by plasma cells in the
lamina propria. Upon binding of polymeric IgA to the
poly-immunoglobulin receptor expressed on the basolat-
eral side of epithelial cells, IgA is internalized, transcytosed
and secreted with a part of the poly-IgR (secretory
component) as secretory IgA. The secretory component
may protect the secretory IgA (S-IgA) molecule from
proteolytic cleavage. S-IgA antibodies function mainly as
neutralizing antibodies, whereas they mediate poor opso-
nization or activation of complement. In fact, in a mouse
back-pack tumour model it has been demonstrated that S-
IgA may prevent infection by, for example, Vibrio cholerae.
In vitro experiments demonstrated that S-IgA may prevent
binding of bacteria to epithelial cells. As complexes of S-
IgA with bound pathogens are transported and excreted,
S-IgA is believed to mediate ‘immune exclusion’. On the
other hand, however, S-IgA–pathogen complexes can be
taken up by M cells and transported into Peyer’s patches.
Finally, immunoglobulin E (IgE) antibodies are bound
by receptors on basophils and mast cells. Microbial
antigens bound to IgE may trigger the cells to release
mediators, including histamine that immediately gives rise
to allergic reactions including mucus secretion, coughing
and sneezing, vomiting, diarrhoea and inflammation.
Although pathogens may be expelled by these reactions it
is not yet clear as to whether these antibodies are important
for defence against extracellular bacteria. However, IgE
antibodies may confer protection against extracellular
parasitic infections.
The cellular immunity is mediated by T cells. Three
major types of effector T cells can be distinguished: CD8 1
abT-cell receptor (TCR) cytotoxic T cells that recognize
3
 Immune Mechanisms Against Extracellular Pathogens
peptides bound to major histocompatibility complex
(MHC) class I molecules, CD4 1 abTCR 1 helper T cells
that respond to peptides presented by MHC class II
molecules, and gdTCR 1 T cells. Moreover, microbial
nonpeptide glycolipid antigens may be presented by CD1
molecules to abTCR 1 CD4 2 CD8 2 or CD8 1 T cells
(Jullien et al., 1997).
CD8 1 T cells kill infected targeted cells and thus
prevent the spread of intracellular pathogens from cell to
cell. However, they play only a minor, if any, role in the
control of extracellular pathogens.
CD4 1 T cells can be divided into two major subsets
based on the pattern of their cytokine production
(O’Garra, 1998). TH1 cells produce interferon g (IFNg),
interleukin 2 (IL-2), and tumour necrosis factor (TNF),
thereby activating macrophages and stimulating cell-
mediated immunity. In contrast, TH2 cells produce IL-4,
IL-5, IL-6, IL-10 and IL-13, and mediate antibody-
mediated immune responses and allergic reactions. Ac-
cording to the TH1/TH2 dogma, TH1 responses are
involved and required for resolution of infections by
intracellular pathogens, whereas TH2 responses may be
involved in elimination of extracellular pathogens (Ro-
magnani, 1996). However, there are multiple overlapping
immune defence mechanisms against pathogens on the one
hand and highly sophisticated means of immune subver-
sion by pathogens on the other hand. Therefore, the TH1/
TH2 paradigm is somewhat oversimplified (Allen and
Maizels, 1997). For example, it is well established that TH1
immune responses are essentially required for overcoming
infections caused by extracellularly located pathogens such
as Y. enterocolitica, C. albicans or Bacteroides spp. It has
been shown that athymic T cell-deficient nude mice are
highly susceptible to infection with Y. enterocolitica and
adoptive transfer of Yersinia-specific CD4 1 TH1 cell
clones protects against lethal challenge with yersiniae
(Autenrieth et al., 1992). Furthermore, neutralization of
cytokines such as tumour necrosis factor a (TNFa), IFNg,
IL-12 and IL-18, which are involved in TH1-mediated
immune responses, abrogates resistance against Yersinia
infection. There is evidence that antigen-presenting cells
activated by extracellular bacterial stimuli start releasing
IL-12 and IL-18, which synergize in inducing IFNg
production in natural killer (NK) cells and CD4 1 TH1
cells. One of the most important consequences of IFNg
secretion is the activation of macrophages which is
essential for clearance of certain extracellular pathogens
such as Y. enterocolitica. In certain parasitic infections,
however, TH2 cells appear to mediate protective immunity.
The vast majority of T cells carry the abTCR, whereas
only about 5% of circulating T cells express the gdTCR.
However, in certain epithelial tissues such as the intestinal
mucosa gd T cells represent up to 50% of the lymphocytes.
A role for gd T cells in immune defence has been claimed by
their in vivo expansion in response to certain bacterial,
parasitic and viral pathogens (Fairhurst et al., 1998). In
4
addition, experiments with the TCR gene knockout mice
indicate that gd T cells are important in the early immune
response against intracellular bacteria. Recently, it has
been shown that gd T cells respond to two MHC-related
surface molecules, MICA and MICB, that are expressed by
epithelial cells in response to infections (Groh et al., 1998).
Nevertheless, the role of gd T cells in immunity to
extracellular pathogens as well as their precise function
remains unclear.
Cytokine Regulation of Protective
Immune Responses Against
Extracellular Pathogens
During the initial phase of inflammation after bacterial
invasion, many cell types residing in the mucosa or skin
produce molecules important in controlling infections.
Epithelial cells play an important role during the initial
phase by signalling the presence of infectious microorgan-
isms to lymphocytes and phagocytes. Infection of epithelia
of the respiratory, the gastrointestinal or the urogenital
tract leads to the production and secretion of a number of
proinflammatory cytokines (e.g. TNFa, IL-1a, IL-1b,
granulocyte–macrophage colony-stimulating factor (GM-
CSF)) and chemokines (e.g. IL-8, membrane cofactor
protein 1 (MCP-1)) by epithelial cells. These products
modulate or induce the expression of E-selectin, intracel-
lular adhesion molecule 1 (ICAM-1), and vascular adhe-
sion molecule 1 (VCAM-1) on endothelial cells and
selectins and integrins in leucocytes. These molecular
changes increase the migration of neutrophils but also
macrophages to sites of inflammation. Macrophages
further increase systemic activation of phagocytes by
releasing TNFa and IL-1. Natural killer (NK) cells if
stimulated by both bacterial products and cytokines
release IFNg which in turn activates macrophages.
Bacterial products released to the systemic circulation
trigger many systemic changes, i.e. fever. Cytokines like
IL-6 and IL-1 and glucocorticoids induce the acute-phase
response by stimulating hepatocytes to produce and
secrete a variety of molecules (C-reactive protein, collec-
tins).
Tissue Reactions Induced by
Extracellular Pathogens
Tissue reactions upon infection with bacteria can be
divided into two forms: purulent and granulomatous.
While bacteria that cause granulomatous reactions are
typically intracellularly located, bacteria that cause puru-
lent infections are usually extracellularly located. These
 Immune Mechanisms Against Extracellular Pathogens

bacteria include Gram-positive cocci (e.g. streptococci,
staphylococci) or Gram-negative rods (e.g. E. coli, and
coliforms such as Klebsiella spp., Enterobacter spp., as well
as Bacteroides spp.). Infections with ‘purulent’ bacteria are
characterized by an acute onset and course, short duration
and by accumulation of polymorphonuclear leucocytes at
sites of bacterial replication. As pointed out above,
opsonizing antibodies may be protective in these events,
and diseases usually subside after phagocytes have ingested
and killed the pathogens. Moreover, in order to avoid
unwanted host tissue destruction the defence mechanisms
such as complement that are involved in these events are
rapidly degraded by cell-bound and serum proteases.
It may well be that different phases of abscess formation
(Figure 1) can be observed simultaneously by histology. For
example, it may be possible to visualize (1) small
nonpyogenic foci consisting predominantly of mono-
nuclear cells in the liver; (2) microabscesses composed of
polymorphonuclear leucocytes lacking a particular outline
towards the normal tissue; (3) large abscesses with or
without a central necrosis and a distinct border made up of
mononuclear cells, fibroblasts and lymphocytes. The
typical, stereotypic tissue reaction to extracellular patho-
gens is believed to be the result of the nonspecific tissue
mechanisms upon stimulation with bacterial products such
as lipopolysaccharides produced by Gram-negative bac-
teria or by teichoic acid from Gram-positive bacteria and

Figure 1 Pyogenic infections caused by an extracellular bacterial pathogen in mice. (a) Granuloma-like lesion (arrows) composed of mononuclear cells in
the liver 3 days after bacterial infection. Such lesions typically occur in the early phase of infection in the liver, and may also occur upon infection with
intracellular bacteria. (b) Microabscess (arrows) composed of polymorphonuclear leucocytes in the liver 5 days postinfection with a bacterial
pathogen. (c) Abscess (necrotic centre indicated by an asterisk) in the spleen 7 days postinfection. The abscess is demarcated by a border (arrows),
exterior to which is normal spleen tissue (right). (d) Necrotic lesion (indicated by an asterisk) rather than classical abscess in the liver of a T cell-deficient
mouse upon infection with an extracellular bacterial pathogen, suggesting that T cells are required for formation of abscesses.

5
 Immune Mechanisms Against Extracellular Pathogens
yeast, or by small peptides containing formyl methionine
as their N-terminal amino acids. These products give rise to
a stereotypic cytokine and chemokine response that leads
to recruitment of polymorphonuclear leucocytes and other
inflammatory cells. However, it should be stressed that the
pattern of tissue alterations depends on the host immune
system. Thus, in immunocompromised hosts, the tissue
response to extracellular bacteria may be unusual. In the
case of T cell-deficient mice, the lesions induced by
extracellular pathogens are less demarcated, histiocytes
may be present, and extended tissue necrosis may occur
(Figure 1). Moreover, extracellular eukaryotic pathogens
such as parasites usually cause specific tissue alterations
(e.g. granulomatous reactions) different from pyogenic
lesions.
Immune Evasion by Extracellular
Pathogens
Most pathogenic bacteria produce virulence factors such
as adhesins, invasins, aggressins, impedins, modulines that
enable them to subvert or evade the host defence
mechanisms (Marack and Kappler, 1994; Finlay and
Falkow, 1997). The genes that encode these factors may
be located on plasmids, phages, or on pathogenicity islands
within the chromosome. While some of these factors exert a
nonspecific toxic effect to many cells and tissues (e.g.
aggressins such as proteases, hyaluronidases, etc.), others
are highly specific, acting via distinct receptors of host cells
(e.g. superantigens, type III protein secretion machinery).
Adhesins mediate the close contact to host cells which
may allow colonization, the targeted deposition of toxins,
or induction of host cell apoptosis. Factors such as
capsules of pneumococci or Haemophilus influenzae, the
streptococcal M protein or the adhesin YadA of Yersinia
efficiently inhibit phagocytosis of bacteria by professional
phagocytes.
Siderophores are low-molecular weight iron-chelating
compounds produced by pathogens in order to maintain
their supply of iron in iron-restricted environments (such
as the host). Recently, however, it has been demonstrated
that siderophores may have a dual role: growth promotion
of the pathogen by iron delivery and immunosuppression
of the host (e.g. inhibition of T- and B-cell proliferation,
inhibition of cytokine production by macrophages, mod-
ulation of the oxidative burst in polymorphonuclear
leucocytes).
More recently, an increasing body of evidence suggests
that many microorganisms possess highly efficient protein
secretion machineries such as the type III secretion system
of Yersinia or Pseudomonas. By means of these systems,
bacteria can secrete and translocate proteins into host cell
membranes or the cytosol in order to modulate host cell
functions. Yersinia outer proteins are translocated into
6
macrophages and may inhibit activation of nuclear factor
kB (NFkB), a central transcription factor for production
of, for example, proinflammatory cytokines.
Impedins and modulines are factors involved in the
subversion of specific immunity. Streptococcal M protein,
the capsules of E. coli or group B meningococci induce
weak antibody responses due to molecular mimicry. By
antigen variation of pili and outer membrane proteins
Neisseria gonorrhoeae evades specific antibody responses.
Superantigens produced by streptococci and staphylococ-
ci, for example, may stimulate T cells and/or antigen-
presenting cells by binding to distinct regions of MHC class
II molecules. Although bacterial superantigens may cause
lethal shock in mice, their role in the pathogenesis of
bacterial infections in humans, except for toxic shock
syndrome, is not yet clear.
Aggressins are usually (exo-)toxins, such as diphtheria
toxin, shiga toxins and haemolysins, that cause damage to
host cells and tissues. Moreover, a number of enzymes such
as proteases, hyaluronidases, DNAases, IgA proteases are
produced and secreted by microorganisms and may
damage host cells or tissue and destroy host defence
components such as antibodies. The latter factors are
particularly important in the pathogenesis of purulent
infections with staphylococci, streptococci, Bacteroides
spp. and Clostridium spp.
Some factors, such as short-chain fatty acids (SCFAs),
which are produced by anaerobic bacteria in the intestine
may have a dual ambiguous role: on the one hand SCFAs
contribute to the metabolism of intestinal epithelial cells,
on the other hand they may paralyse polymorphonuclear
leucocytes by protone-shuttling, leading to intracellular
acidification.
Adverse Effects of the Immune
Response
Beside elimination of the pathogen, the host defence
mechanisms activated upon microbial infections may
damage the host by nonspecific and specific pathomechan-
isms. Extracellular microorganisms or their products/
toxins such as lipopolysaccharide (or endotoxin), teichoic
acid or bacterial DNA may trigger stimulation of
production of proinflammatory cytokines including IL-1
and TNFa in a variety of host cells. In turn, these events
may promote endothelial cell–leucocyte adhesion, release
of proteases, activation of clotting and arachidonate
metabolites as well as many other proinflammatory factors
and cytokines. These events may subsequently lead to a
syndrome designated as systemic inflammatory response
syndrome. Upon progression of this syndrome, sepsis and
septic shock may occur. In these cases, the host response to
the infection is overwhelming and may promote immune
paralysis and a fatal course. Moreover, superantigens

produced by streptococci and staphylococci may promote
a T cell-mediated lethal shock.
Upon cellular stress, both prokaryotic and eukaryotic
cells produce heat-shock proteins (HSPs) in order to
maintain their homeostasis. As HSPs are evolutionary
highly conserved and microbial HSPs are immunodomi-
nant antigens, it was originally assumed that immune
responses to shared epitopes of microbial and host HSPs
might cause a breakdown of tolerance, and subsequent
autoimmune diseases. While for infections with intracel-
lular pathogens such as chlamydia or mycobacteria there is
some evidence that T-cell responses to HSPs might play a
pathological role, this is not yet established for extra-
cellular pathogens. In fact, anti-HSP60 T-cell responses are
protective in infections with extracellular yersiniae in mice.
Moreover, microbial antigens such as the polysacchar-
ide capsule of Neisseria meningitidis group B or the LPS of
Campylobacter jejuni (particularly Lior 11) or Helicobacter
pylori may elicit humoral or cellular immune responses
that are directed against shared epitopes expressed in the
central nervous system (e.g. neural cell adhesion molecule,
NCAM) and/or human blood group antigens (e.g. Lewis
X), respectively. In fact, Campylobacter jejuni infections
have been implicated in the pathogenesis of Guillain–
Barré syndrome, for example. Moreover, M protein from
class I Streptococcus pyogenes is not only an important
virulence factor that mediates resistance against phagocy-
tosis and complement, but expresses also cross-reactive
epitopes of, for example, cardiac myosin, and gives rise to
pathological antibody and T-cell responses.
Finally, immune complexes composed of specific anti-
microbial antibodies and microbial antigens may be
produced during microbial infections (e.g. Haemophilus
spp., Streptococcus spp., Yersinia spp.) and may account
for complications such as nephropathy, vasculopathy or
reactive arthritis.
References
Allen JE and Maizels RM (1997) Th1–Th2: reliable paradigm or
dangerous dogma? Immunology Today 18: 387–392.
Immune Mechanisms Against Extracellular Pathogens
Autenrieth IB, Tingle A, Reske-Kunz A and Heesemann J (1992) T
lymphocytes mediate protection against Yersinia enterocolitica in
mice: characterization of murine T cell clones specific for Y.
enterocolitica. Infection and Immunity 60: 1140–1149.
Ellison RT (1994) The effects of lactoferrin on gram-negative bacteria.
Advances in Experimental Medicine and Biology 357: 71–90.
Fairhurst RM, Wang CX, Sieling PA, Modlin RL and Braun J (1998)
CD1-restricted T cells and resistance to polysaccharide-encapsulated
bacteria. Immunology Today 19: 257–259.
Finlay BB and Falkow S (1997) Common themes in microbial
pathogenicity revisited. Microbiology and Molecular Biology Reviews
61: 136–169.
Ganz T and Weiss J (1997) Antimicrobial peptides of phagocytes and
epithelia. Seminars in Hematology 34: 343–345.
Groh V, Steinle A, Bauer S and Spies T (1998) Recognition of stress-
induced MHC molecules by intestinal epithelial gd cells. Science 279:
1737–1740.
Hampton MB, Kettle AJ and Winterbourn CC (1998) Inside the
neutrophil phagosome: oxidants, myeloperoxidase, and bacterial
killing. Blood 92: 3007–3017.
Hoffmann JA, Kafatos FC, Janeway Jr. CA and Ezekowitz RAB (1999)
Phylogenetic perspectives in innate immunity. Science 284: 1313–
1318.
Jullien D, Stenger S, Ernst WA and Modlin RL (1997) CD1 presentation
of microbial nonpeptide antigens to T cells. Journal of Clinical
Investigation 99: 2071–2074.
Marack P and Kappler J (1994) Subversion of the immune system by
pathogens. Cell 76: 323–332.
Moffitt MC and Frank MM (1994) Complement resistance in microbes.
Springer Seminars in Immunopathology 15: 327–344.
O’Garra A (1998) Cytokines induce the development of functionally
heterogenous T helper cell subsets. Immunity 8: 275–283.
Romagnani S (1996) Understanding the role of Th1/Th2 cells in
infection. Trends in Microbiology 4: 470–473.
Salyers AA and Whitt DD (1994) Bacterial Pathogenesis, A Molecular
Approach. Washington DC: ASM Press.
Further Reading
Nahm MH, Apicella MA and Briles DE (1999) Immunity to
extracellular bacteria. In: Paul WE (ed.) Fundamental Immunology,
4th edn, pp. 1373–1386. Philadelphia: Lippincott-Raven.