This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spahn, T. W. Articles by Kucharzik, T. Search for Related Content PubMed PubMed Citation Articles by Spahn, T. W. Articles by Kucharzik, T.

Next Article 

Infection and Immunity, November 2005, p. 7077-7088, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7077-7088.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

Role of Lymphotoxin in Experimental Models of Infectious Diseases: Potential Benefits and Risks of a Therapeutic Inhibition of the Lymphotoxin-ß Receptor Pathway

Department of Medicine B, Münster University Hospital, Münster, Germany,¹ Section of Clinical Immunology, University Hospital Zürich, Zurich, Switzerland²

	INTRODUCTION

Top Introduction References

 
The immune system provides different mechanisms to protect organisms against pathogens, most of which are infectious agents. Simultaneously, immune activation secondary to genetic factors and/or environmental signals can induce detrimental autoimmunity. The effector pathways in host defense and autoimmunity use similar cytokines and chemokines. Accordingly, tumor necrosis factor alpha (TNF-), for instance, is similarly important in the control of various infections and in the induction of autoimmunity.

Hallmarks of the adaptive immune system are antigen-specific cellular and humoral immune responses. Secondary lymphoid organs serve as sites of contact between antigen-presenting cells (APCs) and immune effector T and B lymphocytes. Chemokines and cytokines serve as messengers determining the type of immune response to a given antigen. The TNF family cytokine lymphotoxin (LT) plays a pivotal role in the development of secondary lymphoid organs.

The chronic and relapsing course of many autoimmune diseases calls for new biological agents capable of suppressing the underlying inflammatory disorders. Recent studies indicate that inhibition of LTß receptor (LTßR)-mediated signaling in adult animals suppresses autoimmunity by modulating the cellular structure of secondary lymphoid organs (reviewed in reference 22). Because of the wide range of autoimmune diseases positively influenced by this treatment, blockade of the LTßR might serve as a new treatment principle for human autoimmune diseases. However, immune responses to infectious pathogens are also altered in mice with disrupted LTßR signaling. While the course of virus- and lipopolysaccharide (LPS)-induced shock, experimental Trypanosoma brucei infection, cerebral malaria, and experimental prion disease are less severe, inhibition of the LTßR is also associated with exacerbation of mycobacterial infection and infectious colitis. This review summarizes the findings of studies using mice with disrupted LTßR signaling in models of infectious diseases and discusses the relevance of these observations in considering LTßR blockade as a potential treatment for human autoimmune diseases.

	THE LYMPHOTOXIN AND LIGHT LIGAND/RECEPTOR SYSTEM AND ITS ROLE IN LYMPHOID ORGAN ARCHITECTURE AND AUTOIMMUNE DISEASES

 
Expression and regulation of ligands and receptors. Lymphotoxin is a TNF family cytokine. The seminal discovery of impaired secondary lymphoid organ formation in LT gene-deficient (–/–) mice (11) has shed new light on the biological functions of LT, which was long considered to be a redundant cytokine for TNF-. Figure 1, top left, describes the LT/LIGHT ligands and receptors. Soluble LT₃ is a secreted protein that interacts with the TNF receptors I (55 kDa) and II (75 kDa) (TNFR-I and -II) (reviewed in reference 68). LT is coexpressed with the membrane protein LTß as LTß heterodimers, which are tethered to the cell membrane. LT₁ß₂ binds to a TNF family receptor known as LTßR. LIGHT is a second ligand interacting with the LTßR. LIGHT also binds to the TNF family receptors herpesvirus entry mediator (HVEM) and decoy receptor 3. Activated lymphocytes and a subset of resting B cells express LT. The LTßR is expressed mainly on nonhematopoietic and myeloid lineage cells (reviewed in reference 22). The expression of LTß and LIGHT is induced by activation of lymphoid cells and certain cytokines and chemokines, including interleukin 4 (IL-4), IL-7, CXC chemokine ligand 13 (CXCL13), and CCL19/CCL21 (22). While regulation of LTßR expression remains to be defined, HVEM expression is induced during T-cell activation (22). Figure 1, top right, depicts the factors, chemokines, and cytokines involved in LTß regulation and regulated by LTßR activation. Expression of LT on lymphocytes provides signals necessary for stromal cells to secrete CXCL13. CXC chemokine receptor 5⁺ (CXCR5⁺) B cells are attracted to such stromal cells. CCL21 attracts T cells and dendritic cells, which together with B cells and stromal cells form lymphoid follicles with separated T- and B-cell zones, high endothelial venules, and follicular dendritic cell (FDC) networks.

View larger version (71K): [in this window] [in a new window]   FIG. 1. (Top left) Lymphotoxin/LIGHT ligands and receptors. Soluble LT3 interacts with the TNF receptors I (55 kDa) and II (75 kDa), while membrane-bound LT1ß2 heterodimers interact with the membrane molecule LTßR. LIGHT is a second ligand of the LTßR that also binds to the soluble decoy receptor 3 (DCR3) and the HVEM. (Top right) The expression of LTß is induced by activation of the lymphoid cell and the cytokines IL-4 and IL-7, CXCL13, and CCL19/CCL21. CXCR5+ B cells are attracted to such stromal cells. CCL21 attracts T cells and dendritic cells, which together with B cells and stromal cells form lymphoid follicles with separated T- and B-cell zones. (Bottom) Role of LTß-LTßR interaction in the formation and maintenance of FDC networks. On top is shown the interaction between LT1ß2 expressed on follicular B cells and LTßR expressed on FDCs, resulting in secretion of CXCL13, which attracts B cells to the follicle. A CXCL13 gradient is required to maintain the differentiation status of the FDCs. LTßR engagement is necessary for continued expression of VCAM1 on FDC networks. On the bottom, blocking of LTßR results in a loss of differentiation of FDCs and presumably cell death and the loss of the CXCL13 chemokine gradient. Thus, the follicle disintegrates.

Gestational and postgestational inhibition of LTßR-mediated signaling. Treatment with soluble LTßR-immunoglobulin G (IgG) fusion protein (LTßRIgG) similarly blocks the interaction of LTß and LIGHT with the LTßR. Therefore, the effects observed in LTßRIgG-treated animals are a result of the inhibition of both ligands. Gestational treatment with LTßRIgG prevents the formation of PPs and LNs (56). Postgestational LTßR signaling during the first 6 weeks after birth is critical for the development of intestinal lamina propria B cells, IgA secretion, and isolated lymphoid follicles of the intestine (38, 48).

Mode of action of LTßR inhibition in adult mice. The lymphoid microenvironment is defined as the local interplay between mobile lymphocytes and the fixed reticular/stromal cells and includes cell adhesion, trafficking, chemokine function, and cellular positioning (22). Secondary lymphoid organs are structures with a high degree of plasticity. Inhibition of LTßR signaling in adult mice alters the lymphoid microenvironment. As shown in Fig. 1, bottom, FDC networks and GCs disintegrate and B-cell follicles disappear in the absence of LTßR signaling. Figure 2 depicts the lymphoid microarchitecture of a murine wild-type (wt) spleen and describes the changes observed in mice with blocked LTßR signaling. Table 2 and Fig. 3 summarize the changes to the lymphoid microenvironment observed in mice with disrupted LT₁ß₂-LTßR signaling. FDC networks consist of a scaffold of specialized reticular fibroblasts that retain and present intact antigen to B cells. Memory B cells develop during the GC reaction. Permanent LT₁ß₂-LTßR interaction is required to maintain a CXCL13 chemokine gradient, which attracts CXCR5⁺ B cells to the follicle and is also required to maintain the differentiation status of the recruited B cells and the FDCs in the network. Similarly, LTßR engagement is required for continued expression of the vascular-cell adhesion molecule 1 (VCAM1) by the FDC network (23, 25).

View larger version (53K): [in this window] [in a new window]   FIG. 2. Splenic lymphoid architecture and effects of inhibition of LTßR-mediated signaling. The spleen consists of a red and a white pulp, which are segregated by marginal zones that contain macrophages. Marginal zones are not detectable in LT–/– and LTßR–/– mice. Within the white pulp (inset with magnification), T and B cell areas are clearly separated in mice with physiological LTßR-mediated signaling. The borders between T- and B-cell zones are ill defined in LT–/–, LTßR–/–, and LTß–/– mice. B-cell follicles are absent in these gene-deficient mice. FDCs can be detected within B-cell follicles of wild-type mice. Within days after inhibition of LTßR-mediated signaling, FDCs disappear in adult mice. Similarly, a proportion of CD11c+ dendritic cells disappear in the spleens of mice with blocked LTßR-mediated signal transduction.

View larger version (35K): [in this window] [in a new window]   FIG. 3. Biological effects of inhibition of LT1ß2/LIGHT-LTßR interaction in autoimmune and infectious diseases. Soluble LTßRIgG fusion protein blocks LTßR-mediated signaling. Three biological mechanisms (circles) have been described: loss of CXCL13 gradient in follicular dendritic cell networks, loss of adhesion molecule expression, and loss of proper and timely positioning of T cells in lymphoid organs. These mechanisms contribute to changes in secondary lymphoid organ formation and microarchitecture, as indicated by the four boxes. The altered lymphoid organs are associated with changes in the courses of autoimmune and infectious inflammatory diseases. Animal models in which LTßRIgG has been used in adult mice, a situation comparable to potential human treatment, are indicated by italic font and underlining. Disease models which are not altered in mice with blocked LTßR have not been depicted. ind., induced.

Inhibition of the LTßR also blocks the migration or maturation of the cysteine-rich domain of the mannose receptor (CR-Fc)-positive DCs (42, 71) Figure 3 describes three potential mechanisms by which inhibition of the LTßR alters autoimmunity and host defense.

PPs, isolated lymphoid follicles, cryptopatches, and colonic patches are organized lymphoid aggregates of the intestine. The number and cellular contents of these aggregates are reduced in adult mice undergoing anti-LTßR treatment (13).

The potential mode of action in anti-LTßR treatment is to impair immune function by preventing proper placement of T cells, B cells, and APCs in secondary lymphoid organs, thus preventing the induction of appropriate antigen-specific immune responses. In contrast, selective inhibition of LIGHT signaling results in a loss of LIGHT-mediated costimulatory stimuli. Soluble HVEM-Fc fusion protein selectively blocks LIGHT-HVEM interactions, inhibits CD3-induced T-cell proliferation, and reduces the frequency of spontaneous diabetes in nonobese diabetic mice (67).

Ectopic "tertiary" lymphoid organs and inflammatory diseases. A number of human inflammatory and autoimmune disorders are associated with the formation of ectopic lymphoid structures at the site of the inflamed organ which resemble secondary lymphoid organs (69; reviewed in reference 60). It is likely that immune responses to self antigens expand in these de novo lymphoid organs, as they allow colocalization of antigen-specific T and B cells with APCs. In mice, ectopic lymphoid structures can be induced by transgenic overexpression of LT (31), and they are called tertiary lymphoid tissues. Data from animal models of autoimmune diseases associated with the formation of ectopic lymphoid tissue indicate that autoimmunity is less severe, cured, or prevented if the LTßR is blocked in these conditions (reviewed in reference 22). A potential role for microbial pathogens in the pathogenesis of inflammatory disorders, such as rheumatoid arthritis or inflammatory bowel disease, has been discussed (18). Granulomas are common histological hallmark of Crohn's disease and mycobacterial infections and serve as sites where T cells, APCs, and antigens collocate (44). Granulomas resemble tertiary lymphoid tissues. The recruitment of T cells to granulomas was impaired in LT^–/– (donor) (transfer) wt (recipient) bone marrow chimeras infected with Mycobacterium tuberculosis (58). It is therefore possible that anti-LTßR targeted therapy might also shut down common pathways of host defense and inflammatory responses that might lead to autoimmunity in genetically predisposed persons.

Lymphotoxin and LIGHT contribute to central immune tolerance in mice. While a stimulatory role for LTßR signaling in the induction of peripheral autoimmune disease has been demonstrated by effective treatment of such conditions by anti-LTßR therapy, the thymic expression of LTßR and LTßR ligands contributes to central tolerance. Lymphotoxin signaling is required for the expression of Aire, which is a key mediator of central tolerance for peripherally restricted antigens. Similarly, LTßR ligand expression on thymic epithelial cells is required for proper differentiation of thymic medullary epithelial cells. LT^–/– and LTßR^–/– mice show infiltration of liver, lung, pancreatic islands, and kidney with activated lymphocytes, and autoantibodies can be detected in these mice (7, 10). Thus, LTßR signaling plays different roles in the peripheral and central control of immune tolerance.

	THE ROLE OF LTßR-MEDIATED SIGNALING IN INFECTIOUS DISEASES

 
Bacterial infections. Both types of animal models predominantly requiring cellular immunity and T-cell-mediated humoral immunity for clearance of bacteria have been investigated. Host defense against intracellular bacteria eliminated by cellular immune mechanisms in mice with disrupted LTßR-mediated signaling was severely impaired in most studies. The immune response against bacterial pathogens inducing combined T- and B-cell immunity varied in mice with blocked LTßR activation with the different models tested, suggesting that certain bacterial antigens (Citrobacter rodentium) required LTßR-mediated signaling while others (Salmonella enterica) were cleared in an LTßR-independent fashion.

(i) Intracellular mycobacterial infections: BCG and M. tuberculosis. While a central role for TNF- in immunity against mycobacterial infections has been well characterized (1, 20, 27, 64), the contribution of soluble LT₃ as the second TNFR-I ligand in antimycobacterial host defense was unknown. Therefore LT^–/– mice and TNF- and LT double-gene-deficient (TNF/LT^–/–) mice were infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) (8, 26, 51) or Mycobacterium tuberculosis (14). Studies investigating the role of LT in experimental mycobacterial disease are of clinical relevance considering the reactivation of tuberculosis observed in patients treated with TNF- antagonists (21). Table 3 summarizes studies investigating bacterial infections in mice with blocked LTßR signaling. The course of mycobacterial infection was lethal in TNF/LT^–/– and LT^–/– mice. Survival was longer in BCG-infected LT^–/– mice (182 days) and in TNF-^–/– mice (56 days) than in TNF/LT^–/– mice (35 days), indicating that the absence of TNF- in this infection leads to broader immunodeficiency than the absence of LT. The impaired antimycobacterial immune response in mice without TNF- was aggravated by the simultaneous lack of LT (8). Similarly, the bacterial loads of the lung on day 28 of the infection were 1,000-, 40-, and 1.4-fold higher in TNF/LT^–/–, TNF-^–/–, and LT^–/– mice than in the respective wt mice. Introduction of an LT transgene in TNF/LT^–/– mice delayed disease onset but failed to restore resistance to BCG infection, suggesting a transient protective effect exerted by LT in this disease model. Roach et al. generated LT^–/– wt bone marrow chimeras in order to investigate the role of soluble LT₃ in antimycobacterial immunity (58). There was lethal disease in wt mice with lymph nodes and LT^–/– bone marrow, indicating a critical role for soluble LT in antimycobacterial immunity.

Causes for the impaired antimycobacterial immunity in LT and TNF/LT gene-deficient mice varied in the different models studied. The granulomatous responses to BCG infection were similarly delayed and impaired in TNF/LT^–/– and TNF-^–/– mice (8, 26). There were fewer macrophages with reduced inducible nitrite oxide synthase (iNOS) and acid phosphatase expression. Fewer T cells could be detected in these lesions. These observations indicate a central role for TNF in the recruitment of T cells and macrophages to granulomatous lesions, which cannot be compensated for by the presence of LT. Conversely, transgenic expression of noncleavable membrane TNF- in TNF/LT^–/– mice resulted in a two- to fourfold increase in the number of hepatic granulomas, which were of smaller size and predominantly consisted of macrophages (51).

In LT^–/– wt bone marrow chimeras infected with M. tuberculosis, there was normal recruitment of T cells to the lungs (58). However, pulmonary T cells remained in the perivascular and peribronchial areas and failed to collocate with the macrophages in granulomas.

There are controversial findings generated in different systems regarding the role of LT₁ß₂-LTßR interaction in the control of mycobacterial infections (14, 39, 58). Wild-type mice infected with BCG and undergoing LTßRIgG treatment and LTßR^–/– mice infected with M. tuberculosis suffered a more severe course of disease (14, 39). Similarly, the bacterial loads in livers and lungs of LTß^–/– mice infected with M. tuberculosis were elevated (14). LTßR^–/– wt bone marrow chimeras failed to control M. tuberculosis infection (14). The impaired immune response against mycobacteria in mice with disrupted LTßR was associated with decreased iNOS activity in the lung and spleen (14, 39). In contrast, Roach reported normal clearance of mycobacterial infections in LTß^–/– wt bone marrow chimeras. The reasons for these discrepant observations are unknown and might be related to a different lymphoid microenvironment in LTß^–/– wt and LTßR^–/– wt bone marrow chimeras. LIGHT, a second ligand of the LTßR, is not involved in the control of disease, as LIGHT^–/– mice cleared M. tuberculosis infections at the same rate as wt mice did (14).

The course of experimental murine listeriosis was more severe in TNF/LT^–/– and LTßR^–/– mice, suggesting that in addition to TNF-, LT and engagement of the LTßR are critical for control of this intracellular pathogen (27, 53, 59).

Most studies indicate that interaction of LT₃-TNFR and of LTß with the LTßR is required for control of infections with the intracellular pathogens Mycobacterium and Listeria. The elimination of these pathogens depends strongly on cellular immunity. Only one study utilized LTßRIgG in adult mice (39), a situation comparable to human treatment of autoimmune diseases. This study showed a significant but moderate increase in the number of acid-fast bacilli (three- to fourfold) in LTßRIgG-treated mice compared to 10- to 1,000-fold increases observed in the studies utilizing gene-deficient mice. However, the biological relevance of this observation in terms of disease-related mortality was not investigated in this study, as all mice were sacrificed for in vitro analysis 4 weeks after infection, while most gene-deficient mice used in other studies died after day 30 following mycobacterial infection.

Experimental infectious colitis. (i) Salmonella enterica serovar Typhimurium and Salmonella enterica. Infection of LT family gene-deficient mice with Salmonella enterica serovar Typhimurium has been utilized to investigate the roles of LT and TNF- in the regulation of anti-Salmonella immunity.

Oral infection of TNF/LT^–/– mice with S. enterica serovar Typhimurium results in a lethal course of infection compared to mild disease in wt mice. This difference was most likely due to reduced recruitment of neutrophils to the site of infection, as well as reduced intracellular killing of S. enterica serovar Typhimurium by granulocytes (12).

Mice undergoing oral pretreatment with streptomycin develop infectious colitis, which closely resembles human S. enterica-induced colitis, following oral infection with S. enterica serovar Typhimurium. The development of S. enterica-induced colitis was not affected by the presence of PP, MLN, or the LTßR, as the courses of the infection in wt and LTßR^–/– mice without PP and MLN were similar. Infection of mice with S. enterica without antibiotic treatment induced a typhoid type of disease with bacterial expansion in PP and MLN. Interestingly, the typhoid type of S. enterica infection was also similar in wt and LTßR^–/– mice, indicating that while S. enterica might home to intestinal lymphoid organs, PP, MLN, and LTßR are not required for antibacterial immunity against this invasive pathogen (4).

(ii) Citrobacter rodentium. We have recently investigated the role of LT ₁ß₂-LTßR interactions in the course of infectious colitis induced by Citrobacter rodentium (65). Infection of mice with the gram-negative bacterium C. rodentium serves as an animal model of human infection with enteropathogenic and enterohemorrhagic Escherichia coli (36). In adult and immune-competent mice, there is only mild transient colitis with hyperplasia of infected colonic epithelial cells. The course of C. rodentium-induced colitis was more severe in LTßRIgG-treated mice, with increased disease-related mortality (65). Similarly, there was nearly 100% disease-related mortality in C. rodentium-infected LT^–/–, LTß^–/–, and LTßR^–/– mice, suggesting a critical role for LT₁ß₂-LTßR interactions in anti-Citrobacter immunity. In mice with disrupted LTßR signaling, there were fewer splenic CD11c⁺ dendritic cells following oral infection. FDCs were absent in the spleens of LTßRIgG-treated mice. Similarly, there were fewer colonic lymphoid follicles in LTßRIgG-treated mice and in the gene-deficient mice used. In LTßR^–/– mice, anti-Citrobacter IgG2a antibody titers were reduced while IgG1 titers were increased. Similarly, there was increased Citrobacter-induced secretion of IL-4 in LTßR^–/– mice. These observations indicate that the loss of local intestinal lymphoid organs and changes to antigen-presenting functions of the spleen are associated with impaired immunity against this noninvasive pathogen.

(iii) LPS-induced systemic shock. A number of studies showed resistance of TNF/LT^–/– mice against lethal endotoxemia induced by intravenous LPS injection (12, 17), depending on the bacterial origin of the LPS. Eugster described resistance to shock induced by coadministration of D-galactosamine and E. coli-derived LPS (17). Netea et al. demonstrated increased resistance of TNF/LT^–/– mice to lethal endotoxemia induced by E. coli and K. pneumoniae LPS compared to S. enterica serovar Typhimurium LPS (46). These differences were associated with increased IL-1 and gamma interferon secretion following injection of the lethal S. enterica serovar Typhimurium LPS. BCG-sensitized TNF/LT^–/– and TNF-^–/– mice were completely resistant to E. coli LPS-induced shock, whereas LT^–/– mice showed prolonged survival compared to wt mice (8). Thus, LT contributes to septic shock, although TNF- appears to be more potent in the induction of LPS shock than LT.

Viral infections. A number of studies have investigated the role of LT in viral infections, most of them studying influenza virus, herpesvirus, and lymphocytic choriomeningitis virus infections in gene-deficient mice with anatomical defects. Table 4 summarizes studies of experimental viral infections in mice. Except for two studies (37, 55), all of them utilized mice with genetic defects of the LT ligands. Similar to LPS-induced shock models, virus-induced systemic shock was less severe in mice with impaired LTßR, most likely due to a depletion of virus-specific CD8⁺ T cells following LTßRIgG treatment. Overall antiviral cytotoxic-T-cell immune responses were more or less impaired, and the clearance of the virus was slowed down or inhibited, leading to a lethal course in influenza A virus (40), murine cytomegalovirus (MCMV) (5), and Theiler's virus (37) infections. In the extensively studied lymphocytic choriomeningitis virus infection model, the defective antiviral immune response was secondary to the loss of the marginal zone in the spleen (6, 45) but not due to the absence of LTß itself. Similarly, treatment of adult wt mice with LTßRIgG did not affect immunity against Theiler's virus infection, while LT^–/– and LTßR^–/– mice failed to mount appropriate antiviral cytotoxic-T-cell responses (37), suggesting that changes to splenic and lymph node architecture, but not the presence of LTß, were critical for clearing of the infection.

All gene-deficient mice tested in this study failed to control intracerebral T. gondii and succumbed to acute necrotizing Toxoplasma encephalitis. The lethal course of disease was associated with reduced intracerebral expression of iNOS and lower splenic NO levels. Experiments with bone marrow reconstitution chimeras demonstrated an exclusive role of TNF-- and LT-producing hematopoietic cells for surviving toxoplasmosis.

(ii) Leishmania. Infection of LTß^–/– mice with Leishmania major was associated with a fatal course of disease with visceral spread of parasites despite the resistant genetic background of the C57BL/6 mice used in this study (70). The impaired and delayed cellular and humoral anti-L. major immune response in LTß^–/– mice was secondary to changes in the lymphoid architecture. Reconstitution of LTß^–/– mice with wt bone marrow failed to restore effective antiparasite immunity, whereas wt mice receiving LTß^–/– bone marrow were not immunocompromised.

Murine Leishmania donovani infection induces visceral leishmaniasis and is more severe in both TNF-^–/– and LT^–/– mice (15). Experiments with bone marrow radiation chimeras indicated a critical role for liver-generated LT in the migration of leukocytes from periportal to sinusoidal areas, while T-cell-generated TNF- and LT were required for the control of parasite growth.

(iii) Trypanosoma brucei. Infection of LT^–/– and TNF/LT^–/– double-gene-deficient mice with the extracellular parasite Trypanosoma brucei was associated with control of disease and slightly prolonged survival of LT^–/– mice following infection (43). Trypanosoma-specific IgM and IgG2a serum antibody titers were increased in LT^–/– mice, indicating that germinal centers and FDC networks were not required for this antiparasite humoral immune response.

(iv) Cerebral malaria. Infection of mice with Plasmodium berghei serves as an animal model for human cerebral malaria. LT^–/– mice were protected against cerebral malaria, as they did not develop perivascular cerebral hemorrhage. Bone marrow chimera experiments indicated that a radioresistant cerebral cell population is the source of the LT required for extravasation of malaria-infected erythrocytes (16).

Prion disease/scrapie. Transmissible spongiform encephalopathies (TSEs), or "prion diseases," are chronic neurodegenerative diseases that affect humans and animals. Most TSEs, including human variant Creutzfeldt-Jakob disease and experimental prion disease in mice, are transmitted by peripheral exposure. TSE infection results in conversion of normal prion protein (PrP^c) to the disease-associated form, PrP^sc. Intracerebral or peripheral administration of prions to mice induces a rise of infectivity in the spleen and in other lymphoid organs long before the development of neuropathological changes. PrP^sc migrates from the lymphoid compartments to the central nervous system by neuronal transport. FDCs in the germinal centers of lymphoid organs have been implicated as initial sites of accumulation of PrP^sc. FDCs trap antigen-antibody complexes. Studies using intraperitoneal (i.p.) (41, 54) and oral (50) routes of scrapie infection provided different results regarding the role of FDCs and LT ligands/receptors in this infection. LT^–/–, LTß^–/–, TNF/LT^–/–, and LTßR^–/– mice with disrupted LT₁ß₂-LTßR signaling undergoing i.p. inoculation resisted infection and contained no infectivity in spleens and lymph nodes (54). Similarly, pretreatment of wt mice with LTßRIgG prior to i.p. scrapie infection blocked early PrP^sc accumulation in the spleen and reduced disease susceptibility. In contrast, LT^–/– mice orally infected with scrapie were susceptible to disease while LTß^–/– mice were resistant (50). However, pretreatment of wt mice with LTßRIgG prior to oral infection with scrapie blocked PrP^sc in PP and MLN and prevented neuroinvasion (41).

As FDCs were similarly absent in TNF-^–/–, TNFR-I^–/–, and LT, LTß^–/– mice but only LT gene-deficient mice were protected against experimental scrapie, FDCs are not required for the replication of scrapie in lymphoid tissue following i.p. infection. More likely, some other yet-undefined effect of impaired LTßR-mediated signaling is critical for control of the expansion of scrapie protein in lymphoid tissues. The susceptibility of LT^–/– mice to oral scrapie and the resistance of LTß^–/– mice and LTßRIgG-pretreated mice to oral infection are two controversial observations which require further investigation.

	SUMMARY AND CONCLUSIONS

 
The studies of experimental infectious diseases summarized in this review reveal the complex biological functions of the LTß/LIGHT-LTßR pathway in immunity to infectious agents. As the courses of the respective infections were attenuated, unchanged, or even more severe, the role of LTßR signaling in host defense depends on the respective pathogens. Animal models predominantly requiring cellular immunity or T helper cell-mediated humoral immunity for clearance of the respective infectious agent have been investigated. Overall, the contribution of the LTßR pathway to host defense against the respective pathogen depended on the antigenic properties of the pathogen, but not on the type of immune response induced by it.

Host defense against bacterial intracellular pathogens such as mycobacteria and Listeria mediated by cellular immune mechanisms in mice with disrupted LTßR-mediated signaling was severely impaired in most studies. Similarly, in most models of viral infections, cytotoxic-T-cell responses were diminished, although the defect in host defense observed was secondary to changes in lymphoid microarchitecture and not caused by the absence of LT. The elimination of the obligate intracellular parasite Toxoplasma gondii depends on T-cell responses and on the presence of LT. Conversely, the clearance of the intracellular parasite Leishmania major depends on T helper 1-mediated cellular immunity and is independent of LTßR-mediated signaling, while the extracellular parasite Trypanosoma brucei is similarly cleared in LT^–/– mice and in wild-type mice (43), indicating that there is no common pattern for LTßR signaling in the host defense against intracellular or extracellular parasites. The immune responses against bacterial pathogens inducing combined T- and B-cell immunity varied in mice with blocked LTßR activation with the different models tested, suggesting that certain bacterial antigens (Citrobacter rodentium) required LTßR mediation while others (Salmonella enterica) were cleared in an LTßR-independent fashion.

The beneficial effects of anti-LTßR therapy observed in experimental virus- and LPS-induced shock, cerebral malaria, and prion disease call for further studies of the role of LTßR signaling in the pathogeneses of similar human disease conditions and suggest that anti-LTßR therapy might also be a future treatment for these diseases.

Few studies using bone marrow chimeras and soluble antagonist LTßRIgG fusion protein in wt mice have demonstrated differential roles of secondary lymphoid organs and the cytokines LT₃ and its membrane-bound heterodimers. Thus, soluble LT₃ and the LTßR play pivotal roles in immunity against mycobacterial infections and C. rodentium-induced colitis. The presence of the LTßR on bone marrow-derived cells is required to clear these infections in mice. In contrast, LT₁ß₂/LIGHT-LTßR interactions are not required to clear experimental L. major infection, while a normal splenic, PP, and LN microenvironment is required to overcome experimental leishmaniasis (70). Similarly, an intact splenic microenvironment is required for the induction of appropriate antiviral immune responses in the lymphocytic choriomeningitis virus model (6, 45).

Inhibition of the LTßR is a future therapeutic concept in treatment of autoimmune diseases (22). The effects of such treatment are secondary to changes to the lymphoid microenvironment and have also been demonstrated in the spleens of nonhuman primates (23). Compared to the effects observed in LT gene-deficient mice, changes following short-term LTßRIgG treatment are moderate (Table 1). However, long-term treatment with LTßRIgG in mice also deletes PPs and colonic patches and reduces the number of intestinal DCs (13).

The treatment of adult mice with anti-LTßR agents is, considering the substantial differences between human and murine immune systems, a situation comparable to the treatment of humans with anti-LTßR therapy. Impaired host defense following LTßRIgG treatment has been observed in the BCG and C. rodentium models, while Theiler's virus infection was not affected by LTßRIgG treatment (37, 39, 65). Thus, bearing in mind the different modes of action in experimental murine infections and spontaneous infections of humans, immunity against mycobacterial infections and infectious colitis induced by enteropathogenic and enterohemorrhagic E. coli might be impaired in humans undergoing anti-LTßR treatment. The immunosuppressive and thus host defense-suppressive effect of anti-LTßR therapy will probably depend on the dose and duration of such treatments.

Gestational treatment of mice with LTßRIgG results in permanent changes to the development of lymphoid organs (56). Similar to other potent immune-modulating therapies, the treatment of pregnant women should be strictly prohibited, and preventive measures, such as the use as of oral contraceptives, should be mandatory in sexually active women undergoing such treatment.

Considering the need for new and effective treatment modalities of human inflammatory and autoimmune diseases, LTßR blockade might be a potent biological tool which has to be carefully tested in clinical trials, considering the delicate balance between sufficient host defense and the suppression of autoimmunity.

	FOOTNOTES

 
* Corresponding author. Present address: Department of General Internal Medicine and Gastroenterology, Marienhospital Osnabrück, Johannisfreiheit 2-4, 49074 Osnabrück, Germany. Phone: 49-541-326-4102. Fax: 49-541-326-4656. E-mail: spahn{at}uni-muenster.de.

Editor: J. B. Kaper

	REFERENCES

Top Introduction References

 

1.	Adams, L. B., C. M. Mason, J. K. Kolls, D. Scollard, J. L. Krahenbuhl, and S. Nelson. 1995. Exacerbation of acute and chronic murine tuberculosis by administration of a tumor necrosis factor receptor-expressing adenovirus. J. Infect. Dis. 171:400-405.[Medline]
2.	Alimzhanov, M. B., D. V. Kuprash, M. H. Kosco-Vilbois, A. Luz, R. L. Turetskaya, A. Tarakhovsky, K. Rajewsky, S. A. Nedospasov, and K. Pfeffer. 1997. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc. Natl. Acad. Sci. USA 94:9302-9307.[Abstract/Free Full Text]
3.	Banks, T. A., B. T. Rouse, M. K. Kerley, P. J. Blair, V. L. Godfrey, N. A. Kuklin, D. M. Bouley, J. Thomas, S. Kanangat, and M. L. Mucenski. 1995. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155:1685-1693.[Abstract]
4.	Barthel, M., S. Hapfelmeier, L. Quintanilla-Martinez, M. Kremer, M. Rohde, M. Hogardt, K. Pfeffer, H. Russmann, and W.-D. Hardt. 2003. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71:2839-2858.[Abstract/Free Full Text]
5.	Benedict, C. A., T. A. Banks, L. Senderowicz, M. Ko, W. J. Britt, A. Angulo, P. Ghazal, and C. F. Ware. 2001. Lymphotoxins and cytomegalovirus cooperatively induce interferon-beta, establishing host-virus detente. Immunity 15:617-626.[CrossRef][Medline]
6.	Berger, D. P., D. Naniche, M. T. Crowley, P. A. Koni, R. A. Flavell, and M. B. Oldstone. 1999. Lymphotoxin-beta-deficient mice show defective antiviral immunity. Virology 260:136-147.[CrossRef][Medline]
7.	Boehm, T., S. Scheu, K. Pfeffer, and C. C. Bleul. 2003. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTßR. J. Exp. Med. 198:757-769.[Abstract/Free Full Text]
8.	Bopst, M., I. Garcia, R. Guler, M. L. Olleros, T. Rulicke, M. Muller, S. Wyss, K. Frei, M. Le Hir, and H. P. Eugster. 2001. Differential effects of TNF and LT in the host defense against M. bovis BCG. Eur. J. Immunol. 31:1935-1943.[CrossRef][Medline]
9.	Chao, C. C., S. Hu, G. Gekker, W. J. Novick, Jr., J. S. Remington, and P. K. Peterson. 1993. Effects of cytokines on multiplication of Toxoplasma gondii in microglial cells. J. Immunol. 150:3404-3410.[Abstract]
10.	Chin, R. K., J. C. Lo, O. Kim, S. E. Blink, P. A. Christiansen, P. Peterson, Y. Wang, C. Ware, and Y. X. Fu. 2003. Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4:1121-1127.[CrossRef][Medline]
11.	De Togni, P., J. Goellner, N. H. Ruddle, P. R. Streeter, A. Fick, S. Mariathasan, S. C. Smith, R. Carlson, L. P. Shornick, J. Strauss-Schoenberger, et al. 1994. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264:703-707.[Abstract/Free Full Text]
12.	Dharmana, E., M. Keuter, M. G. Netea, I. C. Verschueren, and B. J. Kullberg. 2002. Divergent effects of tumor necrosis factor-alpha and lymphotoxin-alpha on lethal endotoxemia and infection with live Salmonella typhimurium in mice. Eur. Cytokine Netw. 13:104-109.[Medline]
13.	Dohi, T., P. D. Rennert, K. Fujihashi, H. Kiyono, Y. Shirai, Y. I. Kawamura, J. L. Browning, and J. R. McGhee. 2001. Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167:2781-2790.[Abstract/Free Full Text]
14.	Ehlers, S., C. Holscher, S. Scheu, C. Tertilt, T. Hehlgans, J. Suwinski, R. Endres, and K. Pfeffer. 2003. The lymphotoxin beta receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J. Immunol. 170:5210-5218.[Abstract/Free Full Text]
15.	Engwerda, C. R., M. Ato, S. Stager, C. E. Alexander, A. C. Stanley, and P. M. Kaye. 2004. Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of Leishmania donovani infection. Am. J. Pathol. 165:2123-2133.[Abstract/Free Full Text]
16.	Engwerda, C. R., T. L. Mynott, S. Sawhney, J. B. De Souza, Q. D. Bickle, and P. M. Kaye. 2002. Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principal mediator of murine cerebral malaria. J. Exp. Med. 195:1371-1377.[Abstract/Free Full Text]
17.	Eugster, H. P., M. Muller, U. Karrer, B. D. Car, B. Schnyder, V. M. Eng, G. Woerly, M. Le Hir, F. di Padova, M. Aguet, R. Zinkernagel, H. Bluethmann, and B. Ryffel. 1996. Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice. Int. Immunol. 8:23-36.[Abstract/Free Full Text]
18.	Fourneau, J. M., J. M. Bach, P. M. van Endert, and J. F. Bach. 2004. The elusive case for a role of mimicry in autoimmune diseases. Mol. Immunol. 40:1095-1102.[CrossRef][Medline]
19.	Futterer, A., K. Mink, A. Luz, M. H. Kosco-Vilbois, and K. Pfeffer. 1998. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59-70.[CrossRef][Medline]
20.	Garcia, I., Y. Miyazaki, G. Marchal, W. Lesslauer, and P. Vassalli. 1997. High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: synergistic action of TNF and IFN-gamma in the differentiation of protective granulomas. Eur. J. Immunol. 27:3182-3190.[Medline]
21.	Gardam, M. A., E. C. Keystone, R. Menzies, S. Manners, E. Skamene, R. Long, and D. C. Vinh. 2003. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect. Dis. 3:148-155.[CrossRef][Medline]
22.	Gommerman, J., and J. L. Browning. 2003. Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3:642-655.[CrossRef][Medline]
23.	Gommerman, J. L., F. Mackay, E. Donskoy, W. Meier, P. Martin, and J. L. Browning. 2002. Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway. J. Clin. Investig. 110:1359-1369.[CrossRef][Medline]
24.	Guinamard, R., M. Okigaki, J. Schlessinger, and J. V. Ravetch. 2000. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 1:31-36.[CrossRef][Medline]
25.	Husson, H., S. M. Lugli, P. Ghia, A. Cardoso, A. Roth, K. Brohmi, E. G. Carideo, Y. S. Choi, J. Browning, and A. S. Freedman. 2000. Functional effects of TNF and lymphotoxin 1ß2 on FDC-like cells. Cell Immunol. 203:134-143.[CrossRef][Medline]
26.	Jacobs, M., N. Brown, N. Allie, and B. Ryffel. 2000. Fatal Mycobacterium bovis BCG infection in TNF-LT-alpha-deficient mice. Clin. Immunol. 94:192-199.[CrossRef][Medline]
27.	Kindler, V., A. P. Sappino, G. E. Grau, P. F. Piguet, and P. Vassalli. 1989. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56:731-740.[CrossRef][Medline]
28.	Koni, P. A., and R. A. Flavell. 1999. Lymph node germinal centers form in the absence of follicular dendritic cell networks. J. Exp. Med. 189:855-864.[Abstract/Free Full Text]
29.	Koni, P. A., R. Sacca, P. Lawton, J. L. Browning, N. H. Ruddle, and R. A. Flavell. 1997. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6:491-500.[CrossRef][Medline]
30.	Korner, H., M. Cook, D. S. Riminton, F. A. Lemckert, R. M. Hoek, B. Ledermann, F. Kontgen, B. Fazekas de St Groth, and J. D. Sedgwick. 1997. Distinct roles for lymphotoxin-alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur. J. Immunol. 27:2600-2609.[Medline]
31.	Kratz, A., A. Campos-Neto, M. S. Hanson, and N. H. Ruddle. 1996. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183:1461-1472.[Abstract/Free Full Text]
32.	Kumaraguru, U., I. A. Davis, S. Deshpande, S. S. Tevethia, and B. T. Rouse. 2001. Lymphotoxin alpha–/– mice develop functionally impaired CD8+ T cell responses and fail to contain virus infection of the central nervous system. J. Immunol. 166:1066-1074.[Abstract/Free Full Text]
33.	Kuprash, D. V., M. B. Alimzhanov, A. V. Tumanov, A. O. Anderson, K. Pfeffer, and S. A. Nedospasov. 1999. TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes. J. Immunol. 163:6575-6580.[Abstract/Free Full Text]
34.	Langermans, J. A., M. E. Van der Hulst, P. H. Nibbering, P. S. Hiemstra, L. Fransen, and R. Van Furth. 1992. IFN-gamma-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha. J. Immunol. 148:568-574.[Abstract]
35.	Lee, B. J., S. Santee, S. Von Gesjen, C. F. Ware, and S. R. Sarawar. 2000. Lymphotoxin-alpha-deficient mice can clear a productive infection with murine gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J. Virol. 74:2786-2792.[Abstract/Free Full Text]
36.	Levine, M. M. 1987. Escherichia coli that cause diarrhea: enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic, and enteroadherent. J. Infect. Dis. 155:377-389.[Medline]
37.	Lin, X., X. Ma, M. Rodriguez, X. Feng, L. Zoecklein, Y. X. Fu, and R. P. Roos. 2003. Membrane lymphotoxin is required for resistance to Theiler's virus infection. Int. Immunol. 15:955-962.[Abstract/Free Full Text]
38.	Lorenz, R. G., D. D. Chaplin, K. G. McDonald, J. S. McDonough, and R. D. Newberry. 2003. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J. Immunol. 170:5475-5482.[Abstract/Free Full Text]
39.	Lucas, R., F. Tacchini-Cottier, R. Guler, D. Vesin, S. Jemelin, M. L. Olleros, G. Marchal, J. L. Browning, P. Vassalli, and I. Garcia. 1999. A role for lymphotoxin beta receptor in host defense against Mycobacterium bovis BCG infection. Eur. J. Immunol. 29:4002-4010.[CrossRef][Medline]
40.	Lund, F. E., S. Partida-Sanchez, B. O. Lee, K. L. Kusser, L. Hartson, R. J. Hogan, D. L. Woodland, and T. D. Randall. 2002. Lymphotoxin-alpha-deficient mice make delayed, but effective, T and B cell responses to influenza. J. Immunol. 169:5236-5243.[Abstract/Free Full Text]
41.	Mabbott, N. A., J. Young, I. McConnell, and M. E. Bruce. 2003. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J. Virol. 77:6845-6854.[Abstract/Free Full Text]
42.	Mackay, F., G. R. Majeau, P. Lawton, P. S. Hochman, and J. L. Browning. 1997. Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur. J. Immunol. 27:2033-2042.[Medline]
43.	Magez, S., B. Stijlemans, G. Caljon, H. P. Eugster, and P. De Baetselier. 2002. Control of experimental Trypanosoma brucei infections occurs independently of lymphotoxin-alpha induction. Infect. Immun. 70:1342-1351.[Abstract/Free Full Text]
43.	Mebius, R. E. 2003. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3:292-303.[CrossRef][Medline]
44.	Mielke, M. E., C. Peters, and H. Hahn. 1997. Cytokines in the induction and expression of T-cell-mediated granuloma formation and protection in the murine model of listeriosis. Immunol. Rev. 158:79-93.[CrossRef][Medline]
45.	Muller, S., L. Hunziker, S. Enzler, M. Buhler-Jungo, J. P. Di Santo, R. M. Zinkernagel, and C. Mueller. 2002. Role of an intact splenic microarchitecture in early lymphocytic choriomeningitis virus production. J. Virol. 76:2375-2383.[Abstract/Free Full Text]
46.	Netea, M. G., L. J. van Tits, J. H. Curfs, F. Amiot, J. F. Meis, J. W. van der Meer, and B. J. Kullberg. 1999. Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans. J. Immunol. 163:1498-1505.[Abstract/Free Full Text]
47.	Neumann, B., A. Luz, K. Pfeffer, and B. Holzmann. 1996. Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. J. Exp. Med. 184:259-264.[Abstract/Free Full Text]
48.	Newberry, R. D., J. S. McDonough, K. G. McDonald, and R. G. Lorenz. 2002. Postgestational lymphotoxin/lymphotoxin beta receptor interactions are essential for the presence of intestinal B lymphocytes. J. Immunol. 168:4988-4997.[Abstract/Free Full Text]
49.	Ngo, V. N., H. Korner, M. D. Gunn, K. N. Schmidt, D. S. Riminton, M. D. Cooper, J. L. Browning, J. D. Sedgwick, and J. G. Cyster. 1999. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189:403-412.[Abstract/Free Full Text]
50.	Oldstone, M. B., R. Race, D. Thomas, H. Lewicki, D. Homann, S. Smelt, A. Holz, P. Koni, D. Lo, B. Chesebro, and R. Flavell. 2002. Lymphotoxin-alpha- and lymphotoxin-beta-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion. J. Virol. 76:4357-4363.[Abstract/Free Full Text]
51.	Olleros, M. L., R. Guler, N. Corazza, D. Vesin, H. P. Eugster, G. Marchal, P. Chavarot, C. Mueller, and I. Garcia. 2002. Transmembrane TNF induces an efficient cell-mediated immunity and resistance to Mycobacterium bovis bacillus Calmette-Guerin infection in the absence of secreted TNF and lymphotoxin-alpha. J. Immunol. 168:3394-3401.[Abstract/Free Full Text]
52.	Pasparakis, M., L. Alexopoulou, M. Grell, K. Pfizenmaier, H. Bluethmann, and G. Kollias. 1997. Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor. Proc. Natl. Acad. Sci. USA 94:6319-6323.[Abstract/Free Full Text]
53.	Pfeffer, K., T. Matsuyama, T. M. Kundig, A. Wakeham, K. Kishihara, A. Shahinian, K. Wiegmann, P. S. Ohashi, M. Kronke, and T. W. Mak. 1993. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73:457-467.[CrossRef][Medline]
54.	Prinz, M., F. Montrasio, M. A. Klein, P. Schwarz, J. Priller, B. Odermatt, K. Pfeffer, and A. Aguzzi. 2002. Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc. Natl. Acad. Sci. USA 99:919-924.[Abstract/Free Full Text]
55.	Puglielli, M. T., J. L. Browning, A. W. Brewer, R. D. Schreiber, W. J. Shieh, J. D. Altman, M. B. Oldstone, S. R. Zaki, and R. Ahmed. 1999. Reversal of virus-induced systemic shock and respiratory failure by blockade of the lymphotoxin pathway. Nat. Med. 5:1370-1374.[CrossRef][Medline]
56.	Rennert, P. D., J. L. Browning, R. Mebius, F. Mackay, and P. S. Hochman. 1996. Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184:1999-2006.[Abstract/Free Full Text]
57.	Rennert, P. D., D. James, F. Mackay, J. L. Browning, and P. S. Hochman. 1998. Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity 9:71-79.[CrossRef][Medline]
58.	Roach, D. R., H. Briscoe, B. Saunders, M. P. France, S. Riminton, and W. J. Britton. 2001. Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J. Exp. Med. 193:239-246.[Abstract/Free Full Text]
59.	Rothe, J., W. Lesslauer, H. Lotscher, Y. Lang, P. Koebel, F. Kontgen, A. Althage, R. Zinkernagel, M. Steinmetz, and H. Bluethmann. 1993. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364:798-802.[CrossRef][Medline]
60.	Ruddle, N. H. 1999. Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development. Immunol. Res. 19:119-125.[Medline]
61.	Scheu, S., J. Alferink, T. Potzel, W. Barchet, U. Kalinke, and K. Pfeffer. 2002. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J. Exp. Med. 195:1613-1624.[Abstract/Free Full Text]
62.	Schlüter, D., L. Y. Kwok, S. Lutjen, S. Soltek, S. Hoffmann, H. Korner, and M. Deckert. 2003. Both lymphotoxin-alpha and TNF are crucial for control of Toxoplasma gondii in the central nervous system. J. Immunol. 170:6172-6182.[Abstract/Free Full Text]
63.	Sedger, L. M., S. Hou, S. R. Osvath, M. B. Glaccum, J. J. Peschon, N. van Rooijen, and L. Hyland. 2002. Bone marrow B cell apoptosis during in vivo influenza virus infection requires TNF-alpha and lymphotoxin-alpha. J. Immunol. 169:6193-6201.[Abstract/Free Full Text]
64.	Senaldi, G., S. Yin, C. L. Shaklee, P. F. Piguet, T. W. Mak, and T. R. Ulich. 1996. Corynebacterium parvum- and Mycobacterium bovis bacillus Calmette-Guerin-induced granuloma formation is inhibited in TNF receptor I (TNF-RI) knockout mice and by treatment with soluble TNF-RI. J. Immunol. 157:5022-5026.[Abstract]
65.	Spahn, T. W., C. Maaser, L. Eckmann, J. Heidemann, A. Lugering, R. Newberry, W. Domschke, H. Herbst, and T. Kucharzik. 2004. The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 127:1463-1473.[CrossRef][Medline]
66.	Wang, J., A. Foster, R. Chin, P. Yu, Y. Sun, Y. Wang, K. Pfeffer, and Y. X. Fu. 2002. The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function. Eur. J. Immunol. 32:1969-1979.[CrossRef][Medline]
67.	Wang, J., J. C. Lo, A. Foster, P. Yu, H. M. Chen, Y. Wang, K. Tamada, L. Chen, and Y. X. Fu. 2001. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J. Clin. Investig. 108:1771-1780.[CrossRef][Medline]
68.	Ware, C. F. 2005. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23:787-819.[CrossRef][Medline]
69.	Weyand, C. M., P. J. Kurtin, and J. J. Goronzy. 2001. Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am. J. Pathol. 159:787-793.[Free Full Text]
70.	Wilhelm, P., D. S. Riminton, U. Ritter, F. A. Lemckert, C. Scheidig, R. Hoek, J. D. Sedgwick, and H. Korner. 2002. Membrane lymphotoxin contributes to anti-leishmanial immunity by controlling structural integrity of lymphoid organs. Eur. J. Immunol. 32:1993-2003.[CrossRef][Medline]
71.	Yu, P., Y. Wang, R. K. Chin, L. Martinez-Pomares, S. Gordon, M. H. Kosco-Vilbois, J. Cyster, and Y. X. Fu. 2002. B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion. J. Immunol. 168:5117-5123.[Abstract/Free Full Text]

This article has been cited by other articles:

• Cadman, E. T., Abdallah, A. Y., Voisine, C., Sponaas, A.-M., Corran, P., Lamb, T., Brown, D., Ndungu, F., Langhorne, J. (2008). Alterations of Splenic Architecture in Malaria Are Induced Independently of Toll-Like Receptors 2, 4, and 9 or MyD88 and May Affect Antibody Affinity. Infect. Immun. 76: 3924-3931 [Abstract] [Full Text]  
• Ehrchen, J. M., Roth, J., Roebrock, K., Varga, G., Domschke, W., Newberry, R., Sorg, C., Muller-Tidow, C., Sunderkotter, C., Kucharzik, T., Spahn, T. W. (2008). The Absence of Cutaneous Lymph Nodes Results in a Th2 Response and Increased Susceptibility to Leishmania major Infection in Mice. Infect. Immun. 76: 4241-4250 [Abstract] [Full Text]  
• Westphal, S., Lugering, A., von Wedel, J., von Eiff, C., Maaser, C., Spahn, T., Heusipp, G., Schmidt, M. A., Herbst, H., Williams, I. R., Domschke, W., Kucharzik, T. (2008). Resistance of Chemokine Receptor 6-Deficient Mice to Yersinia Enterocolitica Infection: Evidence of Defective M-Cell Formation in Vivo. Am. J. Pathol. 172: 671-680 [Abstract] [Full Text]  
• Kang, W., Kudsk, K. A., Sano, Y., Lan, J., Yang-Xin, F., Gomez, F. E., Maeshima, Y. (2007). Effects of Lymphotoxin {beta} Receptor Blockade on Intestinal Mucosal Immunity. JPEN J Parenter Enteral Nutr 31: 358-365 [Abstract] [Full Text]  
• Xu, Y., Flies, A. S., Flies, D. B., Zhu, G., Anand, S., Flies, S. J., Xu, H., Anders, R. A., Hancock, W. W., Chen, L., Tamada, K. (2007). Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 109: 4097-4104 [Abstract] [Full Text]  

This Article Full Text (PDF)