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1
Departments of
* Surgery,
Molecular Biology and Biochemistry, Mayo Clinic, Rochester, Minnesota, USA;
Department of Surgery, University of Washington Seattle, Washington, USA; and
Transplantation Biology and Departments of Immunology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA
1Correspondence: Departments of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. E-mail: Platt.jeffrey{at}mayo.edu
ABSTRACT
Although immune responses are generally considered to be systemic, local events such as interaction of complement products with blood vessels and with inflammatory cells play a pivotal role in determining the nature and manifestations of immune responses. This paper will discuss how blood vessel physiology and immunity influence one another to reach homeostasis upon exposure to an infectious agent. We review new insights into the mechanisms by which the microenvironment of tissues protects against microbial invasion yet facilitates migration of leukocytes and ‘decides’ whether immunity or tolerance ensues and whether, in the face of immunity, protective responses or tissue injury ensues. These ‘decisions’ are made based on interaction of components of normal tissues such as proteoglycans and injured tissues such as cell-associated cytokines with receptors on immune cells and blood vessels.—Saadi, S., Wrenshall, L. E., Platt, J. L. Regional manifestations and control of the immune system.
Key Words: immunity • vascular endothelium • heparan sulfate proteoglycan • complement • antigen-presenting cells
THE INTRODUCTION OF antigen in one location triggers ‘systemic’ changes that lead to delivery of cytokines, effector cells, and subsequent memory responses to diverse locations in the body. If the manifestations of immunity are systemic, functions such as confining infectious agents, their products to sites of entry, and limiting tissue injury are not. To the extent that infectious agents are so confined, the generation and regulation of immune responses must be subject to local rather than systemic controls.
Primitive organisms control infection by sequestering invading organisms in a proteinaceous clot (1)
. Plants with no circulatory system rapidly limit infection by a response that leads to rapid death of the infected cell. The dying cells sequester the infection by producing signal molecules like reactive oxygen intermediates that induce defense-related genes (2)
. The evolution of a circulatory system allows the advent of systemic immunity but increases the need to prevent the spread of infectious organisms to distant sites. Because pathogens proliferate rapidly and acquire virulence traits through recombination and conjugative plasmids, they may evade the systemic immune responses of the host. Regional containment and eradication of microorganisms by nonspecific defenses prevent the emergence of pathogens.
This paper will discuss the means by which infectious agents and tissue injury are localized and contained in tissues and yet are able to stimulate systemic immune responses. We refer to the events at sites of injury as regional responses and discuss how regional blood flow and complement in the circulation and heparan sulfate in tissues generate and govern regional responses.
THE REGIONAL INITIATION OF IMMUNITY
Early events
Early events occur within minutes of entry of infectious agents to limit the spread of infection and preserve the tissue. The initial barrier against the spread of infectious agents is provided by complement. This task involves contradictory needs. On the one hand, complement must prevent access of infectious agent to the circulation, yet it prompts entry of protective elements such as phagocytes and leukocytes to the site of infection.
Walling off
The first facet of early response is containment of infection. Once infectious agents have invaded a tissue where concentration of complement is low and neutrophils are scarce, they must be sequestered or walled off. Complement, platelets, and fragments of heparan sulfate proteoglycans contribute to the ‘walling off’ of the infection (Fig. 1
).
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The most potent and rapid mediator of walling off is the small amount of complement. In tissues, complement initiates the walling off of infected sites by interrupting the blood–tissue barrier of endothelium. Within minutes of complement activation, terminal complement complexes increase small blood vessel permeability by disrupting endothelium integrity (3)
. Terminal complement complexes such as C5b67 and the membrane attack complex cause endothelial cells to round up, exposing tissue factor and von Willebrand factor in the underlying matrix. The interaction of tissue factor (present on smooth muscle cells; ref 4
) with plasma coagulation factor VIIa, forms the tissue factor-VIIa complex that activates factor X and/or IX (5)
, resulting in generation of thrombin and formation of fibrin clots. Fibrin clots isolate the infectious agent. Von Willebrand factor contributes to sequestration of infectious agents as described below.
Another important mediator of walling off are the platelet aggregates. Platelets contribute to the containment of infectious agents by forming platelet plugs. Important factors leading to formation of platelet aggregates are the exposure of platelets in blood vessel to von Willebrand factor and to thrombin. Von Willebrand factor facilitates adhesion of platelets to collagen (6)
, and binds to and stimulates platelet glycoprotein Ib (7
, 8)
. Thrombin, causes platelet aggregation via two pathways (9
, 10)
. In the first pathway, thrombin binds to platelet protease-activated receptor 1, causing activation of glycoprotein IIb/IIIa, which rapidly cross-links to fibrinogen dimers and leads to platelet aggregation. In the second pathway, thrombin induces rapid binding of platelet glycoprotein Ib to the polymerizing fibrin, causing platelet aggregation.
Also contributing to the walling off of infectious agent is the metabolism of heparan sulfate. Heparan sulfate is a ubiquitous complex polysaccharide covalently linked to a core protein (proteoglycans). Heparan sulfate proteoglycans are present on cell surfaces and in extracellular matrices, where they play an important role in regulation of vascular functions such as maintaining the barrier and anticoagulant functions of endothelium (see ref 11
for a review). Activation of complement on endothelial cells causes expression of ectoproteases that cleave the protein core of heparan sulfate proteoglycans (12)
. Activation of platelets leads to release of heparanase, an endoglycosidase that cleaves heparan sulfate chains (13)
, resulting in focal loss of heparan sulfate from endothelium (14
, 15)
. The loss of heparan sulfate from endothelium disrupts the endothelial barrier and promotes coagulation, mirroring the effects of complement on endothelial cells.
Inflammation
A second facet of early response is the generation of inflammation. Inflammation promotes migration of circulating neutrophils to the site of infection for rapid elimination of the pathogen by phagocytosis. Complement is intimately involved in initiation of inflammation.
Activation of complement by infectious agents generates inflammatory mediators such as iC3b, anaphylotoxins (C3a and C5a), and the membrane attack complex. Anaphylotoxins activate phagocytes. C5a triggers neutrophils to elaborate chemotactic activity (16)
, release proteases (17)
, and generate oxidants (18
, 19)
. C5a and membrane attack complex induce rapid cell surface expression of P-selectin on endothelial cells, augmenting neutrophil-endothelial cell adhesion (20
, 21)
. iC3b deposition on pathogens and endothelial cells provides a ligand for adherence of neutrophils and other phagocytes, which express CD11b/CD18 (CR3) (22)
. Recruitment and local migration of leukocytes to the region of infection and injury are facilitated by the formation of gaps between adjacent endothelial cells induced by terminal complement complexes (3)
.
Although usually portrayed as a system activated by infectious organisms, the complement system is activated by damaged cells and blood vessels in the vicinity of such cells (23)
. For example, loss of sialic acid from the surface of cells and disruption of cell membranes, exposing components of the cytoplasm, activate the classical and alternative complement pathways (24)
Likewise, a sluggish blood flow caused by fibrin clots, platelet thrombi, and interstitial pressure creates a nidus for one or both pathways of complement (25
26
27)
. There is also a growing body of evidence suggesting that acidic pH, which predominates at sites of immune activity, facilitates complement activation (28)
.
In vivo models for early events
The ways complement contributes to regional immune responses can be deduced from several experimental systems. Activation of complement is believed to be the pivotal event in the course of ischemia reperfusion injury, where complement activation triggers the earliest tissue changes. For example, in a model of lung ischemia-reperfusion injury in which rats undergo left lung ischemia, followed by reperfusion, Eppinger et al. showed that complement activity in blood decreases precipitously after reperfusion, and this decrease is associated with damage to the normal vascular barrier (29)
. Administration of complement inhibitors such as cobra venom factor decreases vascular injury and restores the normal vascular barrier after lung ischemia-reperfusion. Complement inhibition by soluble complement receptor 1 also inhibits intestinal ischemia reperfusion injury (26)
and C6 deficiency reduces renal ischemia reperfusion injury (27)
.
Complement plays a pivotal role in development of hyperacute rejection of xenograft. When organs are transplanted between disparate species, complement activation on endothelium of the graft leads to rejection of the graft within minutes or hours. This rejection is triggered by terminal complement complexes (30)
and is caused at least in part by disruption of endothelial integrity and platelet aggregation, as discussed above. Hyperacute rejection demonstrates how rapidly and completely the regional circulation is disrupted by complement.
The involvement of heparan sulfate metabolism early in the course of regional immune responses can be seen in animal studies. Cardiac xenografts lose 
30% of labeled heparan sulfate within 5 min of reperfusion of the xenograft, and inhibition of heparan sulfate release by administration of non-anticoagulant heparin prevents the dramatic manifestation of hyperacute rejection without inhibiting complement activation (31)
. The latter demonstrates how the metabolism of heparan sulfate, together with or independent of complement, can contribute to the regionalization of immune responses.
Intermediate events: activation of endothelial cells
The next series of events in the regional response to infection and tissue injury occurs within hours and involves elaboration of new proteins by endothelial cells and cells of the vessel wall. In normal tissues, endothelial cells inhibit coagulation and inflammation and promote the relaxation of vascular smooth muscle. After exposure to noxious agents, endothelial cells undergo a profound series of changes known collectively as activation. Activated endothelial are 1) procoagulant owing to expression of tissue factor and plasminogen activator inhibitor type 1 (PAI-1) and to the loss of thrombomodulin; 2) vasoconstrictive owing to the production of endothelin-1 and thromboxane A2; and 3) proinflammatory owing to the expression of adhesion molecules and chemokines.
Because the walling off and inflammatory responses in the early stages of regional responses are transient (due to the short-lived nature of mediators and their effects), activation of endothelial cells, which lasts longer and leads to sequestration of microorganisms in fibrin clots and influx of phagocytes and macrophages into wounds, may provide a more continuous response. Activation of endothelial cells is believed to be caused by extrinsic factors such as endotoxin or intrinsic factors such as interleukin 1 (IL-1) and tumor necrosis factor 
(TNF-). However, in some wounds or at sites of viral infection where these factors are limiting or absent, complement and platelets activated in the early phase of regional response mediate endothelial cell activation.
Complement mediates activation of endothelial cells by different pathways. Complement C1q interaction with endothelial cell receptors up-regulates mRNA for adhesion molecules like E-selectin, ICAM-1 and VCAM-1, increasing endothelial adhesiveness for leukocytes (32)
. Insertion of the membrane attack complex in endothelial cells induces expression of IL-1 (33)
. IL-1 in turn acts in an autocrine manner, up-regulating E-selectin, ICAM-1, and VCAM-1 on endothelial cells (34
, 35)
. Membrane attack complex stimulates endothelial cells to produce chemokines such as IL-8, MCP-1, RANTES, and perhaps other chemokines in an IL-1 dependent or -independent manner (36
, 37)
. Expression of adhesion molecules and chemokines promotes local activation and influx of leukocytes to the site of injury. Membrane attack complex-mediated IL-1 up-regulation in endothelial cells leads to coagulation by inducing tissue factor (33
, 34)
and PAI-1 (38)
and causes vasoconstriction by inducing endothelin 1 and thromboxane A2 (39
, 40)
in endothelial cells.
Activated platelets trigger activation of endothelial cells by interacting with vascular endothelium. Activation of platelets by thrombin may cause platelet-associated IL-1 to up-regulate tissue factor and E-selectin on endothelial cells, heightening the coagulant and inflammatory properties of blood vessels (41)
.
Endothelial cell activation by membrane attack complex and activated platelets causing coagulation and vasoconstriction may lead to slowing of blood and pathophysiologic conditions associated with it. Likewise, activation of endothelial cells promotes local activation and influx of leukocytes and contributes (as discussed below) the late events in regional immune responses.
In vivo models of intermediate events
Whole animal studies support, albeit in a preliminary way, the idea that IL-1 plays a central role during intermediate phase of regional immune responses especially in complement-mediated activation of endothelium. The role of IL-1 in intermediate events of regional immune responses has been suggested from in vivo studies in which IL-1 signaling has been blocked the use of either IL-1 receptor type I-deficient mice (IL-1R-/-) or the IL-1 receptor antagonist (IL1-ra).
Blockade of IL-1 receptor has been used to explore the role of IL-1 in ischemia reperfusion injury and acute vascular rejection of xenografts, where activation of complement and of endothelial cells plays an important role in regional immune responses. IL-1 is detectable in endothelial cells of reperfused cardiac grafts (42)
and expression of IL-1 in endothelial cells coincides with an increase in serum level of IL-1. IL-1 in turn appears to drive the cascade of inflammation seen in ischemia reperfusion injury (43)
. Administration of IL-1 receptor antagonist blocks ischemia reperfusion-mediated neutrophil infiltration and autoinduction of IL-1 and improves the survival of cardiac allografts (42)
. IL-1 is important in renal ischemia reperfusion injury. IL-1 receptor knockout mice develop fewer infiltrating PMN in postischemic renal tissues and recovery of renal functions is accelerated significantly compared with controls (44)
. An association between complement and IL-1 in immunity is dramatically apparent in acute vascular rejection of xenografts. Acute vascular rejection of vascularized xenografts is believed to be mediated by anti-donor antibodies and small amounts of complement that induce activation of endothelial cells (35)
. We recently tested whether IL-1 plays a central role in activation of endothelial cells in acute vascular rejection. In guinea pig hearts transplanted into rats receiving IL-1 receptor antagonist and under conditions where acute vascular rejection always occurs, intervascular coagulation was diminished, survival was extended, and xenograft structural integrity was drastically improved (Fig. 2
).
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Late events: regional initiation of adaptive immune responses
Generation of immune response to the pathogen is pivotal to clearance of intracellular microorganisms and establishes protective immunity via antibodies against some extracellular organisms. Events that mediate sequestration of infectious agents and regional inflammation help to generate adaptive immune responses. Because adaptive immunity is generated at sites remote from the infection, such as lymph nodes, products of infectious agents must be delivered to these remote sites at the same time that microorganisms are regionally sequestered. Antigen-presenting cells, especially dendritic cells, capture and deliver antigens to the lymphoid organs. Complement and heparan sulfate are important stimuli for activation of antigen-presenting cells.
Complement is a powerful stimulus for initiation of adaptive immune responses. C3d and C3dg, which are fragments of C3b bound to pathogens and are generated by the action of factor I, provide potent stimulation for lymphocyte responses (45)
. C5a activates antigen-presenting cells and triggers secretion of cytokines (46)
. C5a directly elicit migration of antigen-presenting cells, especially dendritic cells (46
, 47)
. Membrane attack complex inserted on endothelial cells induces production of IL-1 (35)
, which plays a role in maturation and migration of dendritic cells from tissue into lymph nodes (48)
. Endothelial cells stimulated by membrane attack complex elaborate the chemotactic chemokine RANTES (36
, 37)
, which elicits migration of dendritic cells (47)
.
As discussed, the early period after tissue injury and invasion of microorganisms is characterized by cleavage of heparan sulfate proteoglycans. Heparan sulfate fragments may be powerful stimuli for initiation of primary immune responses by mediating maturation and activation of antigen-presenting cells (49
, 50)
(Fig. 3
). The antigen-presenting cells of normal tissues are functionally immature because costimulatory molecules are not expressed and MHC class II molecules are not recycled. After stimulation with endotoxin and cytokines, these cells undergo a maturation process, including expression of CD80 and CD86 (B71 and B72), and present antigenic peptides as stable complexes with MHC class II. Heparan sulfate is of particular import in the absence of exogenous stimulus such as endotoxin and cytokines. Heparan sulfate fragments activate macrophages, leading to enhanced expression of MHC class II, CD54, CD86, and release of IL-1, IL-6, IL-12, and TNF- (51
, 52)
and to phenotypic and functional maturation of dendritic cells (53)
. These changes profoundly increase the ability of macrophages and dendritic cells to stimulate immunity.
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In vivo models of late events
A variety of experiments has suggested that complement activation may help initiate adaptive immune responses. Allografts transplanted into complement C6-deficient animals (54)
or in animals treated with complement inhibitors (55)
, survive significantly longer and have less cellular infiltration than controls. Inactivation of complement reduced vascular injury in the renal allograft. In addition, complement promotes adaptive immunity by increasing metabolism of heparan sulfate proteoglycans. Consistent with this idea are experiments showing that delayed-type hypersensitivity and allograft rejection are inhibited by low doses of heparin that inhibits degradation of heparan sulfate proteoglycans by inhibiting heparanase (56)
.
IL-1 appears to have an important role in adaptive immune responses. It protects against infection with intracellular microorganisms such as Listeria monocytogenes and Mycobacterium tuberculosis. For example, IL-1R-/- mice are highly susceptible to infection by Listeria monocytogene (57)
. By day 5 after infection, IL-1R-/- mice have 100- and 1000-fold greater bacterial loads in spleen and liver, respectively, than their wild-type littermates. As another example, overexpression of IL-1 receptor antagonist inhibits primary immune responses to Listeria infection, reduces survival, and increases bacterial loads in the target organs (58)
. When infected with Mycobacterium tuberculosis, IL-1R-/- mice are more susceptible to pulmonary tuberculosis, as shown by increased mortality and enhanced mycobacterial outgrowth in lungs associated with defective migration of macrophages and lymphocytes into inflamed tissues (59)
.
THE REGIONAL CONTROL OF IMMUNITY
If there is a compelling need for regional containment of microorganisms and activation of immunity, there is also a need for the regional regulation of responses and extinction of immunity. How local elements of tissues such as complement and heparan sulfate proteoglycans might mediate such putative properties has not been studied formally, but some speculation can be offered.
Regional blood flow
Regional blood flow may control regional immune responses by regulating IL-1 and heparan sulfate proteoglycan metabolism (Fig. 4
). In an active physiological blood flow, IL-1 is carried away and activation of endothelium is less efficient whereas in a sluggish blood flow, IL-1-IL-1R interaction is more effective, leading to efficient endothelial cell activation. The cleavage of heparan sulfate is controlled by blood flow. If the blood flow is slow, acidosis predominates and heparanase, which is tightly regulated by pH, becomes quite active. If, on the other hand, the flow of blood is physiological, enzyme activity is rapidly lost (60)
. Sluggish blood flow may return to a physiological state by healing of interrupted sites on the endothelium. For example, membrane attack complex-mediated gaps that are formed between endothelial cells and lead to formation of thrombi, rapidly disappear owing to the secretion of a product from endothelial cells that heals disrupted cell junctions (3)
. Another way to return to physiological blood flow is by dissolving fibrin clots. Under acidic conditions, which predominate at inflammatory loci, fibrinolytic system is activated. Perfusion with acidic solutions causes an increase in plasminogen activator release (61)
, and in many cases systemic acidosis is associated with abnormalities in the coagulation and fibrinolytic systems and bleeding (62)
.
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Complement
Although complement induces immune responses, it contributes to regulation of immune responses and induction of tolerance. Complement activation is necessary for the negative selection of self-reactive B cell. Mice with a targeted disruption of CR2 or C4 produce autoantibodies, suggesting that the interaction of C4d with CR2 (CD21/CD35) is needed to regulate immunity or maintain tolerance (63)
. Activated C3 is required for induction of immunosuppression and antigenic tolerance. For example, C3 deficiency or blockade of C3 cleavage to C3b prevents UV-mediated immunosuppression to a contact sensitizer (64)
, suggesting that ligation of iC3b with CD11b+ actively induces antigenic tolerance. Complement may suppress immunity by promoting activation of phospholipase A2 (65)
and synthesis of COX-2 (40
, 66)
, which together lead to production of PGE2, a potent suppressor of immunity (67)
. PGE2 is necessary for induction of tolerance (68
, 49
, 29)
.
Role of IL-1
Regional responses may be regulated in part by IL-1. Although under the acute conditions described above, IL-1 induces coagulation and inflammation, over longer periods it may help resolve injury. IL-1 induces protective factors in vascular endothelial cells or surrounding tissues. For example, IL-1 stimulates the expression of inducible form of nitric oxide synthase (69)
, which inhibits adhesion of leukocytes to vascular endothelium (70)
. IL-1 stimulates production of heme oxygenase 1, which is protective against vascular constriction, proliferation (71)
, and oxidant injury (72)
. IL-1 up-regulates I
B, which inhibits NFB and thus turns off the activated state of endothelial cells (35)
.
Although heparan sulfate proteoglycans initiate immune responses, they contribute to regulation of immune responses. As an example, heparan sulfate proteoglycans inhibit complement activation by inhibiting Clq (73)
or enhancing C1 inhibitor-mediated inactivation of C1 (74)
. Heparan sulfate chains signal macrophages to produce PGE2 (51
, 75)
. Heparan sulfate tethers IL-2 in the spleen and peripheral tissues, in this way priming T cells for activation induced cell death (76)
.
At sites of inflammation and immunity, acidosis predominates due to local lactic acid production. Local acidosis causes inhibition of macrophage chemotaxis, impairment of lymphocyte cytotoxicity, and proliferation leading to suppression of immunity (28)
.
PROSPECTS AND PREDICTIONS
Recent years have brought an increasingly detailed picture of the molecular mechanisms underlying the activation of lymphocytes. This picture, which might be construed as a molecular model of immunology, works very well at a single-cell level but may fail to fully represent the nature of immune responses seen in whole tissues and organs. The liver, for example, is thought to exert peculiar suppressive effects on immune responses that cannot be recapitulated in vitro. On the other hand, attempts to characterize immune responses based on whole organ study (77)
may fail to account for the mixture of responses commonly seen because one part of an organ may initiate immune responses whereas another part may give rise to suppression or to anergy. To fully understand how immune responses arise, it is necessary to consider such regional factors as the state of activation of nearby blood vessels and platelets and the release of biologically active molecules from adjacent cells. It is in such a microenvironment that the system of adaptive immunity evolved and exerts its real functions.
ACKNOWLEDGMENTS
Work by the authors is supported by grants from the National Institutes of Health.
Received for publication October 31, 2001. Revision received January 28, 2002. REFERENCES
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) and stimulate maturation and migration of dendritic cells (DC) to lymph nodes. 4) Control of immunity by heparan sulfate chains. Heparan sulfate chains promote the synthesis and elaboration of PGE2, suppressing immunity. The metabolism of heparan sulfate proteoglycans thus may be an early step in the control of immune responses in tissues.