Published online before print July 14, 2006
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* Department of Dermatology and Allergic Diseases, University of Ulm, Germany;
Institute of Pathology and Departments of
Medical Hematology and Oncology and
¶ Dermatology and Center for Molecular Medicine (ZMMK), University of Cologne, Germany;
Department for Molecular and Cellular Sports Medicine, Institute of Circulation Research and Sports Medicine, Cologne, Germany; and
|| Department of Experimental Immunology, Society for Biotechnological Research (GBF), Braunschweig, Germany
1 Correspondence: Department of Dermatology and Allergic Diseases, University of Ulm, Maienweg 12, 89081 Ulm, Germany. E-mail: karin.scharffetter-kochanek{at}medizin.uni-ulm.de
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Key Words: hypergammaglobulinemia • proinflammatory cytokines • Mott cells • animal models
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subunits L, M, X, and D, ß2 integrins form distinctive, functional complexes termed lymphocyte function-associated antigen-1 (CD11a/CD18), membrane-activated complex-1 (CD11b/CD18), gp150,95 (CD11c/CD18), or CD11d/CD18, which are expressed exclusively on hematopoietic cells [2
3
4
]. Absence of the common ß chain (CD18) simultaneously affects all heterodimeric ß2 integrins and leads to leukocyte-adhesion deficiency type-1 (LAD1), a rare, autosomal-recessive syndrome caused by heterogeneous mutations in the CD18 gene [5 6 7 ]. Expression of less than 1% of CD18 causes the severe form of the disease with recurrent life-threatening bacterial or fungal infections, resulting in death of patients early in childhood [8 , 9 ]. Such fatal courses of the disease are a result of the severe primary immunodeficiency in these patients, which is characterized by poor cellular [7 , 9 ] and humoral [7 , 10 ] effector functions. Depressed or absent specific antibody titers, reduced class switch, and ineffective memory generation are the consequences in LAD1 patients [7 , 10 , 11 ].
We have previously reported on a murine model for LAD1 with a CD18 null mutation, which shares all major features with the human syndrome [12 , 13 ]. Earlier findings suggested that the B cell phenotype was skewed by secondarily elevated interleukin (IL)-6 serum levels [12 ]. IL-6 is a proinflammatory cytokine, which supports acute-phase reactions during infections [14 ] and among other properties, enhances plasma cell differentiation as well as immunoglobulin G (IgG) production [15 , 16 ]. In fact, deregulated gene expression of IL-6 is involved in the pathogenesis of polyclonal and monoclonal plasma cell abnormalities and hypergammaglobulinemia [14 , 17 ]. In addition, IL-6 is cause for hypergammaglobulinemia induced by microorganisms and microbe-derived products such as lipopolysaccharide (LPS) but not for the secretion of specific antibodies, suggesting that specific versus polyclonal B lymphocyte activations are differentially regulated by this cytokine [18 ].
Recently, we could demonstrate that IgG-producing plasma cells, which were newly generated upon immunization with a T-dependent antigen, accumulated in the lymph nodes of CD18–/– mice as a result of a deficiency in leaving the medullary cords of the lymph nodes [19 ]. A hampered homing of IgG+ plasma cells to the bone marrow was the consequence. In that context, we had hypothesized that accumulation of plasma cells in lymph nodes of CD18–/– mice may favor a micro-milieu in which IL-6 may be secreted by the plasma cells in a paracrine manner, supporting further plasma growth, Ig production, and potentially, even abnormal differentiation, as also reported previously for other plasma cell-associated diseases [15 , 17 , 20 21 22 ].
We herein studied a CD18–/– IL-6–/– double mutant, which abrogated a potential influence of a biased IL-6 secretion on the B cellular system. Subsequently, we revisited functional and morphologic features of terminal B cell differentiation to define the effect of CD18 deficiency in this respect.
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LPS injection
CD18–/– and wild-type (WT) mice kept under SPF conditions were injected intraperitoneally (i.p.) with 50 µg LPS (Escherichia coli, Serotype 055:B5, Sigma, Deisenhofen, Germany) in 200 µl phosphate-buffered saline (PBS) per animal, and animals were bled from the tail vein at the indicated time-points after LPS injection, and subsequently, serum was separated from full blood. IL-6 levels were determined from sera by enzyme-linked immunosorbent assay (ELISA).
Determination of serum Ig and cytokine levels
Serum Ig isotypes were determined by sandwich ELISA as described previously [24
]. IL-6 serum levels were assessed using a commercially available murine IL-6 ELISA kit (R&D Systems, Abingdon, Oxon, UK) according to the distributed protocols.
LPS stimulation of bone marrow-derived macrophages
Bone marrow-derived macrophages were obtained from femurs of CD18–/– and WT mice as described previously [25
]. Briefly, bone marrow was flushed through with Dulbecco’s modified Eagle’s medium (DMEM; Biochrom, Berlin, Germany). After osmotic shock, 3 x 106 cells/10 ml medium were grown in DMEM supplemented with 10% heat-inactivated fetal calf serum (PAA Laboratories, Pasching, Austria), 10% conditioned supernatant from L929 cells, 2% L-glutamine, penicillin/streptomycin, 100 U/100 µg/ml, and 1% nonessential amino acids (Biochrom) in Teflon-coated bags (Heraeus, Hanau, Germany) in a 7% CO2 atmosphere at 37°C. After 6 days, cells were removed from Teflon bags and seeded into 24-well cell-culture plates (NUNC, Roskilde, Denmark) at a concentration of 2 x 105/well. Mature bone marrow-derived macrophages from CD18–/– and WT mice were then incubated in the presence of 20 ng LPS (purified from E. coli, Sigma)/ml DMEM for 24 h at 37°C and 5% CO2. Supernatants were harvested and subjected to ELISA for murine IL-1, IL-1ß, and IL-6, according to the manufacturer’s protocols (all R&D Systems).
Immunohistochemistry
Spleens, lymph nodes, Peyer’s patches, and tonsils were removed at indicated time intervals after immunization and were fixed in 4% paraformaldehyde prior to paraffin embedding. Immunohistochemistry was performed on paraffin sections (5–10 µm) using antibodies against murine Ki-67 (Dianova, Hamburg, Germany). After treatment with normal goat serum, sections were incubated with the second antibody (Dako, Glostrup, Denmark). All sections were then developed with an extravidin-coupled horseradish peroxidase complex (2-amino-4-phosphonobutyrate) and a nickel-enhanced 3'-diaminobenzidine tetrahydrochloride (Sigma).
Preparation of thin and ultrathin sections
Tissues fixed in 4% paraformaldehyde were treated subsequently with 2% osmium tetroxide in 0.1 M PBS for 2 h at 4°C, washed in 0.1 M PBS, dehydrated in a graded ethanol series, and embedded in araldite. Thin slices (0.5 µM) were stained with methylen blue and investigated using a Zeiss Axiophot (Carl Zeiss, Oberkochem, Germany). Ultrathin, 60 nm sections were examined using an electron microscope (902A, Carl Zeiss) after further contrasting with uranyl acetate-lead citrate.
Statistical analysis
Quantitative results are presented as mean values ± SD. Mean values were tested by means of a two-tailed heteroscedastic Student’s t-test, or in cases of a non-Gaussian distribution, Mann-Whitney U test was used. Differences were considered to be statistically significant at values of P < 0.05. In column charts, P < 0.05 is indicated by an asterisk (*) and P < 0.005, by a double asterisk (**).
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Secretion of IL-6 is stimulated by environmental stress and by challenge with microbial agents such as bacterial wall components. To further study the role and underlying mechanisms of an increased IL-6 production, we first analyzed mice maintained under different mouse facility conditions for their IL-6 serum concentrations. Using an ELISA specific for murine IL-6, an up to 20-fold increase in serum concentrations of IL-6 was detected in CD18–/– mice as compared with the analogously housed WT cohorts when mice were kept under conventional or barrier facility conditions (P<0.005), respectively (Fig. 1 ). IL-6 levels from WT and CD18–/– mice kept in the conventional facility were significantly higher when compared with corresponding groups in the barrier facility (P<0.05). It is interesting that under SPF conditions, no significant differences between CD18–/– and WT mice were found. In both groups, IL-6 was only detectable in serum of few mice.
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Figure 1. Deregulated IL-6 secretion in CD18–/– mice. IL-6 serum levels of CD18–/– ( ) and WT ( ) mice kept under a conventional or barrier facility or SPF conditions were subjected to ELISA. IL-6 content in pg/ml was calculated from standard curves. Bars represent the medians of the respective cohorts. *, P < 0.05; **, P < 0.005.
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Highly increased IL-6 serum levels in CD18–/– mice after injection of LPS
To further address the hypothesis that pathogens or their inert products may be responsible for the observed increase in serum IL-6 in CD18–/– mice, we used LPS from E. coli as a model antigen for bacterial wall components allowing a standardized exposure of all mice. CD18–/– and WT control mice were injected i.p. with 50 µg LPS per animal. Subsequently, IL-6 serum levels were determined by ELISA at the indicated time-points after LPS injection (Fig. 2
).
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Figure 2. LPS injection results in excessive IL-6 serum concentrations in CD18–/– mice. CD18–/– () and WT () mice housed under SPF conditions were injected i.p. with 50 µg LPS per animal. Subsequently, IL-6 serum levels were determined by ELISA at the indicated time-points after LPS injection, as done before. Bars represent the medians of the respective cohorts.
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Increased release of IL-6 by CD18–/– macrophages in vitro
IL-6 is produced by a variety of hematopoietic and nonhematopoietic cells, among them T and B lymphocytes, fibroblasts, endothelial cells, keratinocytes, hepatocytes, and other cells. However, mononuclear phagocytic cells and antigen-presenting cells are the most prominent sources of IL-6 [26
27
28
]. To test whether mononuclear phagocytes could function as a source of the deregulated IL-6 production found in CD18–/– mice, we exposed bone marrow-derived macrophages of CD18–/– and WT mice to LPS in an in vitro assay. As shown by Figure 3
, supernatants of CD18–/– macrophages contained significantly more IL-6 (up to 14 ng/ml) than supernatants harvested from WT macrophages at 24 h after LPS stimulation (P<0.05). As a control for LPS-inducible cytokines, IL-1 and IL-1ß were also determined and revealed a strong increase in supernatants of CD18–/– macrophages compared with the WT (P<0.005). Although CD18–/– macrophages showed a marked alteration of cytokine secretion, we could mostly rule out that this was a result of a major impact of CD18 deficiency, leading to an impaired maturation and differentiation of bone marrow-derived macrophages in vitro. This was evidenced by fluorescein-activated cell sorter phenotyping of bone marrow-derived macrophages isolated from CD18–/– and WT mice using staining for the macrophage differentiation markers F4/80, MOMA-2, intercellular adhesion molecule-1, and scavenger receptor class B (CD36). These markers showed a highly similar expression pattern on CD18–/– and WT bone marrow-derived macrophages (data not shown). Collectively, these data demonstrate that CD18–/– bone marrow-derived macrophages can contribute to a deregulated IL-6 secretion in CD18–/– mice.
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Figure 3. LPS injection results in a higher release of proinflammatory cytokines from macrophages of CD18–/– compared with WT mice. Mature bone marrow-derived macrophages from CD18–/– and WT mice were incubated in the presence of 20 ng LPS (purified from E. coli, Sigma)/ml DMEM for 24 h at 37°C and 5% CO2. Supernatants were harvested and subjected to ELISA for murine IL-1, IL-1ß, and IL-6, according to the manufacturer’s protocols (all R&D Systems). Data are depicted as the mean ± SD. *, P < 0.05; **, P < 0.005.
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To test this hypothesis, we set out to differentiate between effects primarily caused by the genetic deficiency for CD18 and putative secondary effects underlying the deregulated IL-6 production on the humoral immune response. We therefore generated a CD18–/– IL-6–/– double-mutant mouse model by crossing CD18–/– mice with an IL-6–/– mutant [23 ] to abolish a potentially biasing influence of IL-6 in CD18–/– mice. IL-6 mutants were identified by Southern blotting, and lack of IL-6 was confirmed by standard murine IL-6 ELISA (data not shown), as described previously [23 ]. Subsequently, mouse Ig ELISAs were performed from sera of CD18–/–, CD18–/– IL-6–/–, and control mice kept under SPF conditions to detect the different antibody classes and isotypes/allotypes (Fig. 4 ). With exception of IgG3, all IgG isotypes were highly elevated in CD18–/– mice over WT controls, ranging from a sixfold increase of IgG1 (P<0.05) to a more than tenfold increase of IgG2a (P<0.005). Compared with CD18–/– mice, CD18–/– IL-6–/– double-mutant mice showed a marked reduction of all IgG isotypes, which were increased previously, corresponding to those of the CD18+/+ IL-6–/– controls (P=0.41). Thus, in CD18–/– mice, elevated IgG levels could be causally related to a deregulated IL-6 production and were not directly a result of the absence of CD18.
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Figure 4. IL-6 is mainly but not exclusively responsible for the hypergammaglobulinemia in CD18–/– mice. Serum was collected from naïve CD18+/+ IL-6+/+ (), CD18–/– IL-6+/+ (), CD18+/+ IL-6–/– (•), and CD18–/– IL-6–/– ( ) mice at an age of 10–12 weeks. Mouse Ig ELISAs were performed to detect IgM, IgA, and IgE class antibodies as well as the different IgG isotypes/allotypes. Obtained curves were related to curves of corresponding Ig standards, and absolute amount of antibody was calculated in microgram per milliliter; bars represent the medians of each cohort. *, P < 0.05; **, P < 0.005; #, P > 0.1 (not significant).
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Elevated IL-6 levels lead to the formation of abnormal plasma cells in CD18–/– mice
Our results indicate that IL-6 largely contributes to hypergammaglobulinemia with a pronounced increase of most IgG isotypes, suggesting that polyclonal B cell activation is differentially regulated by this cytokine in CD18–/– mice. Indeed, IL-6 is a key cytokine inducing terminal differentiation of B cells into plasma cells and supporting class switch from IgM to IgG. We thus envisioned that phenotypic changes of terminal B cell differentiation may also occur in CD18–/– mice. In fact, initial light microscopic analysis had revealed pronounced changes in hematoxylin and eosin stainings of secondary lymphoid tissues of the spleen and lymph nodes of CD18–/– mice [12
, 33
].
To detect a potential morphologic correlate of an elevated IL-6 secretion on lymphoid cell expansion and B cell differentiation, we performed methylen-blue staining, immunohistochemistry, and electron microscopy of CD18–/– and WT spleens. Thin sections of WT spleens (Fig. 5A ) showed the typical red-pulp and white-pulp architecture; central arteries and marginal zones could be identified as parts of the white pulp. In contrast, CD18–/– mice (Fig. 5B) presented with a resolved splenic structure characterized by a loss of demarcation between red and white pulp. We assessed the pattern and quantity of proliferating cells, as we envisioned a potential IL-6-induced increase in B cell proliferation, particularly in the germinal centers of the B cell follicles [34 ]. It is surprising that immunohistochemistry for the proliferation-associated antigen Ki-67 did not indicate an increased focal proliferation of cells, as would be the case in an enhanced germinal center reaction, but revealed a scattered distribution of proliferating cells in spleens of CD18–/– mutants (Fig. 5D) . By contrast, regular and typical size Ki-67+ cell clusters could be detected within the white pulp of WT spleens (Fig. 5C) , reflecting the focal proliferation of B cells within the germinal centers [35 ]. Analyses of lymphoid tissues from CD18–/–IL-6–/– double-mutant mice were carried out analogously and revealed an identical, scattered distribution of proliferating cells, indicating that the observed effect resulted from the absence of CD18 and was not related to an overproduction of IL-6 (data not shown).
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Figure 5. CD18–/– mice reveal a disrupted splenic lymphoid architecture. Spleens from 6-month-old, naïve WT (A, C) and CD18–/– (B, D) mice kept under barrier facility conditions were prepared for histological analysis. (A, B) Thin sections of 0.5 µm were stained with methylen blue, and splenic red pulp and white pulp structures were examined by light microscopy. (C, D) Immunohistochemistry for the proliferation-associated antigen Ki-67 was performed at paraffin sections (brown staining). Secondary lymphoid follicles were identified as focally proliferating cell clusters in WT mice (C) and were absent in CD18–/– mutants (D). Representative pictures out of n = 6 spleens are shown. Original scale bar, 400 µm (A, B); 1 mm (C, D). RP, Red pulp; WP, white pulp; MZ, marginal zone; GC, germinal center; arrowheads, central artery.
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Figure 6. The occurrence of abnormal plasma cells in CD18–/– mice is abrogated in CD18–/– IL-6–/– double-mutant mice. (A, B) In CD18–/– mice, transmission electron microscopy of all major secondary lymphoid tissues (spleen, lymph nodes, Peyer’s patches) revealed an abundance of abnormal plasmacytoid cells (Mott cells, "M") characterized by Russel’s inclusion bodies (arrows) with widened (arrowheads) ER at various stages. (C) In CD18–/– IL-6–/– double-mutant mice, the appearance of abnormal plasma cells and Mott cells was almost abolished. Typical plasma cells were detected, although in low numbers. These findings correlated with observations made in WT mice (D). In CD18–/– IL-6–/– and WT mice, widening of the ER or Russel’s bodies could be detected occasionally but were much less marked than in CD18–/– mice. Representative high-power fields out of n = 6 spleens are depicted. Original scale bar, 3 µm (A, C, D); 4.5 µm (B).
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We demonstrate directly that IL-6 is increased significantly in serum of CD18–/– mice, and the extent of IL-6 production depended on the degree of exposure to microorganisms or microbial products such as LPS used as a bacterial wall model antigen. Apart from inoculation of LPS, infection of mice by microorganisms including viruses, parasites, and bacteria induces, in addition to formation of specific antibodies, a strong B lymphocyte polyclonal activation [29 , 30 ]. The enhanced production of natural antibodies resulting from such B cell polyclonal activation may play an important role in the defense against infections, especially at the early times after invasion of the host by viruses or bacteria, when specific responses have not yet matured [50 ]. Often, a T-independent proliferation of B cells [29 ] probably results from a direct interaction of a microbial product with receptors expressed on B cells [51 ] or is indirectly supported by key receptors such as CD14, Toll-like receptor 2 (TLR2), and TLR4 on accessory cells [52 , 53 ].
Among the cytokines capable to stimulate B cells, IL-6, in synergy with IL-1, induces B cell proliferation and secretion of large amounts of Ig [31
]. Furthermore, the production of IgG by B cells, already committed to its secretion, is enhanced by IL-6 [16
, 31
, 32
]. We here demonstrated a significantly increased IL-6 secretion in vivo and in vitro in the absence of CD18. Also, IL-1 and IL-1ß were detected at highly elevated concentrations in LPS-stimulated bone marrow-derived macrophages isolated from CD18–/– mice. It is interesting that IL-1 could not be detected in serum of CD18–/– mice at significantly higher levels than in WT mice (data not shown). This does not preclude a localized increase of IL-1 in tissues of CD18–/– mice exposed to microbes or their products, as our in vitro data clearly indicate. IL-1 may thus contribute additionally to propelling terminal B cell differentiation and Ig production in CD18–/– mice [31
]. Considering our in vitro data about a modest increase in IL-6 production by CD18–/– bone marrow-derived macrophages in comparison with the marked increase of IL-6 found in the serum of CD18–/– mice, it is possible that macrophages may not alone be responsible for the observed increase in serum IL-6 levels in CD18–/– mice.
The definite proof for a pathophysiologic role of the elevated IL-6 production in CD18–/– mice eventually comes from the CD18–/– IL-6–/– double-mutant generated to abrogate the biasing influence of a deregulated IL-6 secretion in CD18–/– mice on B cellular differentiation. Our former data revealed a severe hypergammaglobulinemia in CD18–/– mice with an up to 20-fold increase in most IgG isotypes [12 ]. These preliminary findings were herein corroborated and extended. In the underlying studies, the data about the elevated IgG serum levels were derived from mice housed under SPF conditions, where no significant increase in serum IL-6 could be detected, in contrast to high IL-6 levels detected under conventional housing, which was analyzed in the earlier study quoted [12 ]. Only in a CD18–/– IL-6–/– double-mutant, high-serum IgG levels were abrogated, whereas hypergammaglobulinemia could not be abolished by mere maintenance under SPF conditions. This strongly argues for an ongoing deregulation of IL-6 secretion in CD18–/– mice, which was undetectable in serum but must have been prevailing in the secondary lymphoid tissues analyzed even when mice were kept SPF.
Furthermore, this is supported by the morphological correlate of an ongoing IL-6 overproduction in secondary lymphoid tissues of CD18–/– mice. In addition to stimulating Ig secretion, IL-6 functions as a potent in vitro and in vivo growth factor for murine plasma cells [16 , 28 , 31 ]. Although gross disturbances of lymphoid architecture, such as of the splenic white pulp in CD18–/– mice, were independent of IL-6, also occurring in CD18–/– IL-6–/– double-mutants, an altered terminal B cell differentiation with plasmacytosis [12 ] and a high frequency of Mott cells were directly dependent on IL-6 secretion. A permanent stimulation by proinflammatory cytokines, especially by IL-6, leading to an overproduction and eventually, to an intracellular accumulation of Ig, together with a defective, unfolded protein response [54 , 55 ], has been made responsible as a central pathomechanism for the generation of abnormal plasma cells previously [38 ]. In addition, egress of newly generated IgG+ plasma cells from lymph nodes is disrupted in the absence of CD18, thus preventing their homing to bone marrow. This represents a pathomechanism, which is primary and intrinsic to ß2 integrin deficiency itself, occurring independently of IL-6 [19 ]. As plasma cell differentiation and function are influenced distinctively by the respective micro-milieu composed of stromal cells, extracellular matrix, and soluble factors, it may be postulated that the abnormal retention of plasma cells within the lymph node medullary cords of CD18–/– mice also contributes to the observed, abnormal plasma cell phenotype and deregulated Ig production. Indeed, deregulated serum levels could not be reduced completely to WT levels for all Ig classes/IgG isotypes by ablation of IL-6 in CD18–/– IL-6–/– mice (Fig. 4) . One explanation for this may be the intrinsic effect of CD18 deficiency, directly affecting cellular signaling pathways for plasma cell differentiation and Ig production or causing mispositioning of plasma cells in the lymph nodes instead of the bone marrow. However, further investigations are required to elucidate the underlying mechanism.
It is remarkable that our finding of plasmacytosis, occurrence of abnormal plasmacytoid cells, and a highly increased serum IgG level are reminiscent of reports about IL-6 transgenic mice [16
]. Kishimoto and coworkers [56
] demonstrated that activated B cells expressing IL-6 receptors can respond to IL-6 even in vitro, differentiating into plasma cells. These authors reach the conclusion that IL-6 induced plasmacytosis directly in these transgenic mice by stimulating cell division and maturation of B cells, whereas other cytokines such as IL-1 were induced by IL-6 and could expand the plasma cell population further [16
]. Agents inducing or supporting initial B cell activation as a prerequisite to further expansion may be derived from microorganisms such as LPS [18
, 30
]. It is most interesting that abnormal plasmacytoid cells and Mott cells are found in states of chronic inflammation [39
, 40
] and in IL-6 hypersecretion disorders such as Castleman’s disease [20
, 22
] or cardiac myxoma [57
] and have been reported to also coincide with hypergammaglobulinemia [40
]. Apart from the polyclonal expansion of B cells, myeloma/plasmacytoma was also shown to be dependent on as well as responsible for a continuous production of IL-6 in several cases [31
, 58
, 59
]. In our studies, we did not find any evidence for a monoclonal growth of plasma cells in CD18–/– mice. Serum IgG titers showed similar increases of all 
-heavy chain isotypes and also a typical distribution of 
- and 
-light chains (data not shown) in all mice analyzed.
The essential role of a deregulated production of IL-6 for the observed plasma cell phenotype in CD18–/– mice was proven directly, as by genetically eliminating the exaggerated IL-6 expression (IL-6–/–), we could abolish the abnormal plasma cell phenotype in CD18–/– mice along with the hypergammaglobulinemia. This was confirmed by comparative ultrastructural analyses of lymphoid tissues from CD18–/– single- and CD18–/– IL-6–/– double-mutants. Whereas the latter mutants were largely void of abnormal plasmacytoid cells with dilated cisternae of the ER and terminal Mott cells with Russel’s bodies resembling WT, our data, vice versa, strongly support the results obtained from IL-6 transgenic mice.
Finally, by eliminating the influence of IL-6 on Ig production, the adaptive immune response was also reduced but still functional in CD18–/– IL-6–/– mutants combining the immunodeficiencies of both single gene knockouts (Supplemental data). We thus show that although hypergammaglobulinemia was abrogated, production of antigen-specific IgG was still possible in CD18–/– IL-6–/– mutants.
We demonstrate that in CD18–/– mice, IL-6 may play a pivotal role in microorganism-triggered IgG production, subsequent to B lymphocyte polyclonal activation causing hypergammaglobulinemia and an abnormal plasma cell phenotype. The herein-generated CD18–/– IL-6–/– double-deficient mouse model directly indicates that the deregulated IL-6 secretion is responsible for parts of the phenotype seen in the CD18–/– mouse mutant and thus represents a suitable tool to further investigate CD18-dependent pathomechanisms distinct from a biasing influence of a secondarily increased IL-6 production. Understanding the pathogenic mechanisms induced by soluble mediators in CD18–/– mice may not only give new insight into immunodeficiency syndromes such as LAD1 but also may improve the conception of diseases accompanied and influenced by hypersecretion of proinflammatory cytokines, such as IL-6 overproduction in Castleman’s disease or chronic inflammation. Those patients might benefit from IL-6 antagonizing therapy [59 60 61 ].
Received December 17, 2005; revised March 29, 2006; accepted April 13, 2006.
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d ß 2, binds preferentially to ICAM-3 Immunity 3,683-690[CrossRef][Medline] and IL-6 act antagonistically in the induction of human IgG1 but additively in the induction of IgG2 J. Immunol. 153,4948-4958[Abstract]This article has been cited by other articles:
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