Endothelial cells and renal epithelial cells do not express the Wegener''s autoantigen, proteinase 3.

In vitro and in vivo T cell responses were determined during the course of bronchopulmonary infection with mucoid Pseudomonas aeruginosa. T cell responses were compared in two inbred mouse strains, namely BALB/c mice, which are resistant to the establishment of chronic bronchopulmonary Ps. aeruginosa infection, and C57Bl/6 mice, which have high numbers of bacteria in the lungs through 14 days post-infection. Unseparated lung cells and lung T cells from BALB/c mice exhibited significantly higher in vitro proliferative responses to both heat-killed Ps. aeruginosa and concanavalin A (Con A) than cells from C57Bl/6 mice through 20 days post-intratracheal infection with 10(4) colony-forming units (CFU) Ps. aeruginosa. Proliferation of unseparated lung cells but not lung T cells from BALB/c mice infected 6 days previously with 10(5) CFU Ps. aeruginosa was suppressed in response to Con A; these cells were unresponsive to specific antigen. Suppression of lymphocyte proliferation in the lungs of C57Bl/6 mice infected with 10(4) CFU Ps. aeruginosa and in BALB/c mice infected with 10(5) CFU was found to be mediated by adherent lung cells via the production of nitric oxide and prostaglandins. Determination of in vivo T cell-mediated responses in infected mice demonstrated that resistant BALB/c mice had high DTH and low Pseudomonas-specific antibody responses, while C57Bl/6 mice had low DTH and high antibody levels, in particular, IgG2b and IgM.     

Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia

Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P. aeruginosa pneumonia in mice that exhibit different immunologic phenotypes. C57BL/6 mice with conditional knockout of the arginase-1 (Arg1) gene from myeloid cells (Arg1^ΔM) or BALB/c mice treated with small molecule inhibitors of arginase were infected intratracheally with P. aeruginosa. Weight loss, mortality, bacterial clearance, and lung injury were assessed and compared, as were the characterization of immune cell populations over time post-infection. Myeloid arginase-1 deletion resulted in greater morbidity along with more severe inflammatory responses compared to littermate control mice. Arg1^ΔM mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1^ΔM mice recovered from inflammatory lung injury at a significantly slower rate. Conversely, treatment of BALB/c mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine hydrochloride (BEC) did not change morbidity as defined by weight loss, but mice at day 10 post-infection treated with BEC had gained significantly more weight back than controls. Neutrophil and macrophage infiltration were similar between groups in the lung parenchyma, and neutrophil migration into the airways was reduced by BEC treatment. Differences seem to lie in the impact on T cell subset disposition. Arg1^ΔM mice had increased total CD4+ T cell expansion in the lymph nodes, and increased T cell activation, IFNγ production, and IL-17 production in the lymph nodes, lung interstitium, and airways, while treatment with BEC had no impact on T cell activation or IL-17 production, but reduced the number of T cells producing IFNγ in the lungs. Lung injury scores were increased in the Arg1^ΔM mice, but no differences were observed in the mice treated with pharmacologic arginase inhibitors. Overall, myeloid arginase production was demonstrated to be essential for control of damaging inflammatory responses associated with P. aeruginosa pneumonia in C57BL/6 mice, in contrast to a protective effect in the Th2-dominant BALB/c mice when arginase activity is globally inhibited.     

Susceptibility to Yersinia pseudotuberculosis Infection is Linked to the Pattern of Macrophage Activation

T helper 1 cells play a crucial role in the clearance of Yersinia pseudotuberculosis infection. By producing cytokines and presenting antigens to T cells, activated macrophages can orientate the adaptive immune response. The pathway used by macrophages to metabolize arginine has been employed as an important parameter to discriminate their activation state. In this study, the pattern of macrophage activation in Y. pseudotuberculosis- infected BALB/ c ( Yersinia -susceptible) and C57BL/6 ( Yersinia -resistant) mice and their immunostimulatory capacity were analysed. In the early phase of infection, macrophages obtained from C57BL/6 mice produced higher levels of NO, lower arginase activity, and larger amounts of IL-12 and TNF-α than macrophages from BALB/ c mice. On the other hand, macrophages derived from BALB/ c mice produced higher levels of IL-10 and TGF-β than C57BL/6 mice. The Y. pseudotuberculosis infection leads to a fall in the macrophage immunostimulatory capacity of both strains of mice, with T-cell proliferation significantly reduced 12 h after infection. Moreover, we observed in the supernatant of co-culture of macrophages from infected mice with T lymphocytes from heat-killed Yersinia -immunized mice lower IFN-γ production by cells from BALB/ c mice than by C57BL/6 mice, and IL-4 was produced only by BALB/ c mice on the first- and third-day post-infection. These results suggest that the pattern of macrophage activation is associated with susceptibility and resistance to Y. pseudotuberculosis infection in BALB/ c and C57BL/6 mice.     

Differences in migration inhibitory factor production by C57Bl/6 and BALB/c mice in allergic and irritant contact dermatitis

Two strains of mice, BALB/c and C57Bl/6, which are known to differ in their inflammatory responsiveness to allergens, were analyzed regarding their expression of macrophage migration inhibitory factor (MIF). Allergic contact dermatitis to 2,4-dinitro-1-fluorobenzene and irritant contact dermatitis to croton oil were studied immunohistologically at designated time intervals after elicitation. BALB/c mice presented a significantly more intense ear swelling response than C57Bl/6 mice and showed a strong endothelial MIF expression in the early phase of inflammation in both allergic and irritant contact dermatitis. Endothelial MIF expression was much weaker in C57Bl/6 mice. Furthermore, the infiltration rate of inflammatory cells (MIF+ and BM8+ macrophages, Lyt2+ and L3T4+ T cells) was significantly higher in BALB/c than in C57Bl/6 mice. We conclude that genetically determined differences of susceptibility to allergens and irritants in BALB/c and C57Bl/6 mice are reflected by the intensity of MIF expression in the microvascular endothelium and immigrating inflammatory cells. MIF seems to appear as first molecular equivalent of developing inflammation and probably determines the degree of cellular infiltration.     

Differential expression of interleukin-5 mRNA+ cells and eosinophils in Nippostrongylus brasiliensis infection in resistant and susceptible strains of mice

Interleukin (IL)-5 is produced by both T cells and eosinophils and has been implicated in lymphocyte and eosinophil differentiation and maturation. The extent to which differences in IL-5 expression contribute to genetic variability in parasite immunity was investigated by comparing eosinophilia, IgE production, mastocytosis and IL-5 mRNA⁺ cells following Nippostrongylus brasiliensis infection of resistant (BALB/c) and susceptible (C57BL/6) mice. In uninfected mice, IL-5 mRNA⁺ cells detected by in situ hybridization were distributed throughout the lamina propria and crypt regions of the small intestine in both strains, but were 1.5-fold higher in BALB/c than in C57BL/6 mice. Following N. brasiliensis infection, the numbers of IL-5 mRNA⁺ cells in BALB/c mice continued to increase until day 11 post-infection at which time they were more than 4-fold more numerous than in uninfected control mice of the same strain. In C57BL/6 mice, IL-5 mRNA⁺ cells reached peak numbers on day 7 post-infection, only 1.5-fold higher than uninfected controls, but the numbers began to decline thereafter. At all time points after day 5, the numbers of IL-5 mRNA⁺ cells in the gut of C57BL/6 mice were significantly lower than BALB/c mice. The differences in numbers of IL-5 mRNA⁺ cells induced by infection in each strain of mice correlated with changes in blood and intestinal eosinophilia, mastocytosis and IgE production and was reflected in differences in worm expulsion and egg counts. Although numbers of intestinal IgA-containing cells increased in both strains after infection, there was no difference between strains except at day 11 when there were significantly higher numbers in BALB/c mice than in C57BL/6 mice. These results suggest that IL-5 is an important regulatory factor determining host immunity to parasite infection and that differential regulation of IL-5 expression explains in part the observed strain differences with respect to parasite resistance.     

Genetic background affects the expansion of macrophage subsets in the lungs of Mycobacterium tuberculosis‐infected hosts

M1 macrophages are more effective in the induction of the inflammatory response and clearance of Mycobacterium tuberculosis than M2 macrophages. Infected C57BL/6 mice generate a stronger cellular immune response compared with BALB/c mice. We hypothesized that infected C57BL/6 mice would exhibit a higher frequency and function of M1 macrophages than infected BALB/c mice. Our findings show a higher ratio of macrophages to M2 macrophages in the lungs of chronically infected C57BL/6 mice compared with BALB/c mice. However, there was no difference in the functional ability of M1 and M2 macrophages for the two strains in vitro. In vivo, a deleterious role for M2 macrophages was confirmed by M2 cell transfer, which rendered the infected C57BL/6, but not the BALB/c mice, more susceptible and resulted in mild lung inflammation compared with C57BL/6 mice that did not undergo cell transfer. M1 cell transfer induced a higher inflammatory response, although not protective, in infected BALB/c mice compared with their counterparts that did not undergo cell transfer. These findings demonstrate that an inflammation mediated by M1 macrophages may not induce bacterial tolerance because protection depends on the host genetic background, which drives the magnitude of the inflammatory response against M. tuberculosis in the pulmonary microenvironment. The contribution of our findings is that although M1 macrophage is an effector leucocyte with microbicidal machinery, its dominant role depends on the balance of M1 and M2 subsets, which is driven by the host genetic background.     

Differences in innate immune responses correlate with differences in murine susceptibility to Chlamydia muridarum pulmonary infection

We investigated the phenotypic basis for genetically determined differences in susceptibility and resistance to Chlamydia muridarum pulmonary infection using BALB/c and C57BL/6 mice. Following C. muridarum intranasal inoculation, the intensity of infection was very different between BALB/c and C57BL/6 beginning as early as 3 days post‐infection. Intrapulmonary cytokine patterns also differed at early time‐points (days 2 and 4) between these two strains of mice. The early recruitment of neutrophils to lung tissue was greater in BALB/c than in C57BL/6 mice and correlated with a higher number of inclusion forming units (IFU) of C. muridarum. At day 12 post‐infection, BALB/c mice continued to demonstrate a greater burden of infection, significantly higher lung cytokine levels for tumour necrosis factor‐α and interleukin‐17 (IL‐17) and a significantly lower level for interferon‐γ than did C57BL/6 mice. In vitro, bone‐marrow‐derived dendritic cells (BMDCs) from BALB/c mice underwent less functional maturation in response to C. muridarum infection than did BMDCs from C57BL/6 mice. The BMDCs of BALB/c mice expressed lower levels of activation markers (CD80, CD86, CD40 and major histocompatibility complex class II) and secreted less IL‐12 and more IL‐23 than BMDCs from C57BL/6 mice. Overall, the data demonstrate that the differences exhibited by BALB/c and C57BL/6 mice following C. muridarum pulmonary infection are associated with differences in early innate cytokine and cellular responses that are correlated with late differences in T helper type 17 versus type 1 adaptive immune responses.     

Differences in the modulation of reactive species,lipid bodies,cyclooxygenase-2, 5-lipoxygenase and PPAR-γ in cerebral malaria-susceptible and resistant mice

Proinflammatory responses are associated with the severity of cerebral malaria. NO, H₂O₂, eicosanoid and PPAR-γ are involved in proinflammatory responses, but regulation of these factors is unclear in malaria. This work aimed to compare the expression of eicosanoid-forming-enzymes in cerebral malaria-susceptible CBA and C57BL/6 and −resistant BALB/c mice. Mice were infected with Plasmodium berghei ANKA, and the survival rates and parasitemia curves were assessed. On the sixth day post-infection, cyclooxygenase-2 and 5-lipoxygenase in brain sections were assessed by immunohistochemistry, and, NO, H₂O₂, lipid bodies, and PPAR-γ expression were assessed in peritoneal macrophages. The C57BL/6 had more severe disease with a lower survival time, higher parasitemia and lower production of plasmodicidal NO and H₂O₂ molecules than BALB/c. Enhanced COX-2 and 5-LOX expression were observed in brain tissue cells and vessels from C57BL/6 mice, and these mice expressed higher constitutive PPAR-γ levels. There was no translocation of PPAR-γ from cytoplasm to nucleus in macrophages from these mice. CBA mice had enhanced COX-2 expression in brain tissue cells and vessels and also lacked PPAR-γ cytoplasm-to-nucleus translocation. The resistant BALB/c mice presented higher survival time, lower parasitemia and higher NO and H₂O₂ production on the sixth day post-infection. These mice did not express either COX-2 or 5-LOX in brain tissue cells and vessels. Our data showed that besides the high parasite burden and lack of microbicidal molecules, an imbalance with high COX-2 and 5-LOX eicosanoid expression and a lack of regulatory PPAR-γ cytoplasm-to-nucleus translocation in macrophages were observed in mice that develop cerebral malaria.     

Macrophages and protective immunity in Mycobacterium lepraemurium infections in a ''resistant'' (C57Bl) and a ''susceptible'' (BALB/c) mouse strain

The progressive low resistance form of M. lepraemurium infection in BALB/c mice and the more benign form of infection in C57Bl mice provided appropriate models for analysing the role of macrophages in the spectrum of leprosy in man. Although C57Bl mice were more resistant to both primary and challenge infections than BALB/c mice, peritoneal macrophages from infected mice of both strains were bacteriostatic in vitro. However, a diffusion chamber technique demonstrated that macrophages of BALB/c mice were usually less effective in controlling mycobacterial multiplication in vivo than those of C57Bl mice. This technique also revealed two diffusible factors in infected mice of both strains: one able to activate, the other able to suppress macrophage anti-mycobacterial activity. In C57Bl mice, the macrophage activating factor was apparently dominant; in BALB/c mice, the macrophage suppressor factor seemed to play the major role.     

Effect of dioxydine and cyclophosphane on lipid peroxidation and superoxide dismutase and catalase activities in C57Bl/6 and BALB/c mice

Twenty-four hours after intraperitoneal injection of cyclophosphane (40 mg/kg) and dioxydine (300 mg/kg) to C57Bl/6 mice, liver catalase activity dropped by 29 and 23%, respectively. In BALB/c mice, dioxydine (but not cyclophosphane) reduced catalase activity by 24%. Superoxide dismutase activity was lowered by cyclophosphane (but not dioxydine) in BALB/c mice, and by both dioxydine and cyclophosphane in C57Bl/6 mice (by 24 and 86%, respectively). The level of 2-thiobarbituric acid (TBA)-reactive lipid peroxidation (LPO) products in the liver of BALB/c mice treated with cyclophosphane and dioxydine increased 1.4- and 2.1-fold, respectively, while in C57Bl/6 mice it did not differ from the control. The initial rate ofin vitro-induced LPO in BALB/c mice receiving cyclophosphane and dioxydine increased 1.5- and 4-fold, respectively. In C57Bl/6 mice both cyclophosphane and dioxydine inhibited the accumulation of TBA-reactive LPO products. On the whole, animals of the C57Bl/6 strain are more resistant to the LPO-inducing action of mutagens than BALB/c mice, despite the fact that the latter are characterized by a higher activity of antioxidant enzymes. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 5, pp. 528–532, May, 1996     

Immunity Parameters in Mice of Different Strains

Quantitative composition and functional activity of immunocompetent cells differ in mice of different strains. The counts of T cells in the bone marrow and spleen, proliferative activity of T cells in the spleen, levels of IL-2 and IL-10 production by splenic T cells, number of antigen-specific T cells and their functional activity are low in C57Bl/6, BALB/c, and CC57W mice and high in CBA/CaLac, DBA/2, and C3H animals. Low phagocytic activity of peritoneal macrophages was detected in BALB/c and CC57W mice and high activity in C3H animals. The content of antibody-producing cells in the spleens of C57Bl/6, BALB/c, and CC57W mice is higher than in CBA/CaLac, DBA/2, C3H, A/SN, and AKR/JY mice. Functional activity of B cells is lower in BALB/c and CC57W compared to CBA/CaLac and DBA/2 mice. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 8, pp. 189–191, August, 2005     

BALB/c and C57Bl/6 mice infected with virulentBurkholderia pseudomalleiprovide contrasting animal models for the acute and chronic forms of human melioidosis

Burkholderia pseudomalleiis the aetiological agent of melioidosis, a life-threatening bacterial disease occurring in many species of animals, including man. Infection in humans commonly manifests as one of three clinical presentations: acute, subacute or chronic disease. Investigations were undertaken to assess the suitability of BALB/c and C57Bl/6 mice as animal models for the different forms of human melioidosis. The course of infection in BALB/c mice was similar to that which occurs in acute human infection. By contrast, infection of C57Bl/6 mice appeared to mimic chronic human melioidosis. While BALB/c mice suffered a rapidly-progressive bacteraemia which resulted in host death by 96 h, C57Bl/6 mice were able to prevent this, and typically remained asymptomatic for up to 6 weeks. LD₅₀values of 4 cells and 2.5×10⁴cells for BALB/c and C57Bl/6 mice, respectively, reflect these observations. The heightened level of resistance toB. pseudomalleiobserved in C57Bl/6 mice was suggested to have a genetic basis, when the susceptibilities of first filial and reciprocal backcross generations were examined. Growth kinetics ofB. pseudomalleiwithin BALB/c and C57Bl/6 peritoneal exudate cell (PEC) cultures were examined to investigate PEC microbicidal efficiency as a determinant of host susceptibility. C57Bl/6 PEC cultures exhibited greater microbicidal efficiency towardsB. pseudomalleiwhen compared to BALB/c cells, indicating that susceptibility may be determined by non-specific, cellular mechanisms. Collectively, these results suggest that the BALB/c and C57Bl/6 strains of mice may provide excellent models for acute and chronic human melioidosis, respectively.     

Nitric oxide production by BCG-infected pleural macrophages from C57Bl/6 and DBA-2 mice

We studied the kinetics of in vivo nitrite production in the inflammatory reaction induced by M. bovis BCG into the pleural space. Pleural macrophages harvested from C57Bl/6 mice after acute BCG infection produced high levels of nitric oxide (NO). Enhanced production was obtained upon stimulation with LPS plus IFN-gamma. In sharp contrast, macrophages from DBA-2 mice produced low levels of NO, as nitrite, at the same time interval (24 h after BCG infection), being completely refractory to further stimulation. After the third day, NO production was similar in both strains. There was a close relationship between nitrite levels in the pleural exudate in vivo and those produced by harvested macrophages in vitro. In this in vivo system, the pattern of NO production by pleural macrophages one day after BCG infection was discrepant and unexpected in the response of C57Bl/6 and DBA-2 mice. However, this early response did not affect the late progressive NO production in both mice strains, that may be responsible to the late control of the mycobacteria growth.     

Experimental African trypanosomiasis: differences in cytokine and nitric oxide production by macrophages from resistant and susceptible mice.

Immunosuppression in experimental infections with Trypanosoma congolense is mediated by the synergistic action of macrophages and a novel lymphocyte(s), which involves the activity of IFN-gamma as well as IL-10. BALB/c mice are highly susceptible while C57Bl/6 mice are relatively resistant to T. congolense infections. Plasma and/or supernatants of spleen cell cultures of infected susceptible BALB/c mice have more IL-10 but less IL-12 than those of infected relatively resistant C57Bl/6 mice. Cells of a BALB/c macrophage cell line, when pulsed with T. congolense, produce more IL-10 and IL-6, but have less TNF-alpha mRNA, than equally treated cells of a C57Bl/6 cell line. Peritoneal and/or bone marrow-derived macrophages obtained from BALB/c mice, pulsed with T. congolense in culture, produce less nitric oxide, TNF-alpha and IL-12, but more IL-6 and IL-10 than equally treated macrophages isolated from C57Bl/6 mice. We suggest that genetic resistance to African trypanosomiasis is expressed at the level of the macrophage.     

Cytomegalovirus hepatitis: characterization of the inflammatory infiltrate in resistant and susceptible mice.

Mice susceptible and resistant to murine cytomegalovirus (MCMV) were infected with this virus and livers were harvested after 2-231 days. Cryostat sections were stained to visualize cells bearing CD4, CD8 or Mac-1 antigens. Mac-1+ cells were prevalent in inflammatory foci after 2 days. These cells persisted in susceptible BALB/c and A/J mice, but disappeared from livers of resistant C57Bl/6 and CBA/CaH mice by day 28. T cell inflammation peaked on days 7-11. This declined by day 56 in C57Bl/6 and CBA/CaH mice, but persisted in BALB/c and A/J mice for at least 231 days. Persistent CD8+ cells were dispersed throughout the parenchyma. More CD8+ cells were observed 7-14 days after infection in the livers of bg/bg (natural killer (NK) cell-deficient) C57Bl/6 and CBA mice, and in C57Bl/6 mice depleted of NK1.1 cells by MoAb. Thus, mice of strains susceptible to MCMV exhibit hepatitis characterized by persistence of dispersed CD8+ cells. This phenomenon may be limited by NK cells in resistant strains.     

Cytokine responses in mice infected with<Emphasis Type="Italic"> Clonorchis sinensis</Emphasis>

FVB and BALB/c mice show different morbidity, development of Clonorchis sinensis, and pathological changes following C. sinensis infection. FVB mice are susceptible and BALB/c mice are relatively more resistant to C. sinensis infection. To investigate the relationship between cytokine reaction and susceptibility to C. sinensis infection in FVB and BALB/c mice, we described both the patterns and kinetics of Th1 cytokines and Th2 cytokines in spleen cell culture. Interleukin (IL)-4 and IL-10 cytokine production in the culture supernatants of the concanavalin-A-stimulated spleen cells increased at 2–3 weeks post-infection in both strains. IL-5 production increased between 2 and 5 weeks post-infection in both strains, and reached a peak level at 2 weeks post-infection in BALB/c mice and 4 weeks post-infection in FVB mice. In contrast, gamma interferon (IFN-) production decreased between 2 and 4 weeks in both strains. IL-2 production increased slightly in BALB/c mice following infection, but was unchanged in FVB mice. IL-4 production over preinfection levels was significantly higher in FVB mice, whereas IFN-, IL-2, and IL-10 production were significantly higher in BALB/c mice. The levels of serum immunoglobulin E (IgE) and blood eosinophils in both mouse strains significantly increased between 3 and 6 weeks postinfection. Serum IgE levels were significantly higher in FVB mice than in BALB/c mice. The results of this study suggest that susceptibility to C. sinensis infection is associated with Th2 cytokine production, especially IL-4 which is predominant in relatively susceptible FVB mice.     

Morphofunctional changes of BALB/c and C57BL/6 mice's immune system under chronic bacterial gram-negative endotoxicosis

Chronic endotoxicosis was modeled by subcutaneous injection of the sepharose in complex with LPS. In these conditions we have studied morphofunctional changes of the immune system of BALB/c and C57Bl/6 mice, which are characterized by the different types of the immune response (Th2 type is predominant in BALB/c, Th1--in C57Bl/6). In the 1st-7th day t in the serum of BALB/c mice the endotoxin level increased in 21.3 times, in C57Bl/6--in 20.6 times. The endotoxin antibodies significantly decreased in 1th-7th days, on the 14th day it increased in the serum of both mice's strains. Morphofunctional changes of the immune system after chronic endotoxicosis were different in BALB/c and C57BI/6 mice. On the 1th day after injection of LPS and sepharose, in the thymus of C57Bl/6 mice the cortex layer was exhausted because of cell death, in the thymus of BALB/c mice II-III stages of accidental involution were developed. On the 7-14th day after injection of LPS and sepharose in the spleen of C57Bl/6 mice T- and B-zones were hyperplastic, however in spleen of BALB/c mice only T-zone were enlarged. After LPS and sepharose injection changes of cytokine production synthesized by KonA activated splenic cells were found out. In both strains the level of proinflammatory cytokines--TNFalpha and IL-1beta decreased, as well the Th1-cytokine IL-2. The production o fTh2-cytokine - IL-4, significantly decreased only in C57BI/6 mice. We suggest that damaging effect of LPS injection is determined by predominant Th2 or Th2 types of the immune response.     

Expression of the calcium-binding proteins MRP8 and MRP14 by early infiltrating cells in experimental contact dermatitis.

The immune response to an allergen is not only dependent on the inflammatory stimulus, but also on the genetic disposition of the individual. Important effector cells in the immune response are myelomonocytic cells in their various differentiation stages. We recently described the expression of MRP8 and MRP14, two calcium-binding proteins of the S-100 family, by these cells during inflammatory activation. Here, we investigated whether their expression in murine contact dermatitis is dependent on the stimulus by which dermatitis is elicited, and if it is related to the genetic constitution of different inbred strains of mice. Therefore we performed immunohistochemical studies on the distribution of MRP8- and MRP14-positive cells during experimentally induced allergic (ACD) and irritant contact dermatitis (ICD). Both forms of dermatitis were elicited in BALB/c and C57B1/6 mice. BALB/c mice were found to react with a more intense inflammatory response in both ACD and ICD (high responders) than C57Bl/6 mice (low responders). The expression of MRP8 and MRP14 in both forms of dermatitis correlated with the early influx of macrophages and with the cell density of the infiltrate. Also the percentage of MRP8- and MRP14-positive cells in the infiltrate during ACD or ICD was higher in the more intense inflammatory reaction of BALB/c mice compared to C57Bl/6 mice. We conclude that MRP8 and MRP14 define a differentiation stage of inflammatory macrophages and that their expression correlates with the activity of inflammatory processes.     

Genetically determined disparate innate and adaptive cell-mediated immune responses to pulmonary Mycobacterium bovis BCG infection in C57BL/6 and BALB/c mice

The current study was designed to investigate the impact of genetic heterogeneity on host immune responses to pulmonary intracellular infection by using two mouse strains of distinct genetic background, C57BL/6 and BALB/c mice, and a model intracellular pathogen, Mycobacterium bovis BCG. Upon infection, compared to C57BL/6 mice, BALB/c mice developed an earlier response of interleukin 12 (IL-12), gamma interferon (IFN-gamma), tumor necrosis factor alpha, and macrophage chemoattractive protein 1, and greater neutrophilic influx to the lung by days 7 and 14. However, the level of these cytokines at days 27, 43, and 71 was much lower in BALB/c mice than in C57BL/6 mice. The magnitude of cellular responses was also much lower in the lung of BALB/c mice around day 27. Histologically, while C57BL/6 mice developed lymphocytic granulomas, BALB/c mice displayed atypical granulomas in the lung. Of importance, the level of type 2 cytokines IL-4 and IL-10 remained low and similar in the lung of both C57BL/6 and BALB/c mice throughout. Furthermore, lymphocytes isolated from systemic and local lymphoid tissues of infected BALB/c mice demonstrated a markedly lower antigen-specific IFN-gamma recall response. While the number of mycobacterial bacilli recovered from both the lung and spleen of BALB/c mice was similar to that in C57BL/6 mice at day 14, it was higher than that in C57BL/6 mice at day 43. However, it was eventually leveled off to that in C57BL/6 counterparts later. These results suggest the following: (i) genetic heterogeneity can lead to differential innate and adaptive cell-mediated immune responses to primary pulmonary mycobacterial infection; (ii) it is the level of adaptive, but not innate, immune response that is critical to host resistance; and (iii) a lower type 1 immune response in BALB/c mice is not accompanied by a heightened type 2 response during pulmonary mycobacterial infection.     

Morphofunctional characteristic of the immune system in BALB/c and C57BL/6 mice

Inbred animals serve as an adequate model to study the role of genetic factors in adaptive, disadaptive, and pathological processes. Morphofunctional study of the immune system was performed on intact BALB/c and C57Bl/6 mice. The structural and functional parameters of the immune system in BALB/c and C57Bl/6 mice differ under physiological conditions. In BALB/c mice, volume density of T zone in the spleen and production of IL-2, IL-3, IL-4, IL-10, and TNF-α were much higher than in C57Bl/6 mice. However, IL-12 production in BALB/c mice was lower than in C57Bl/6 mice. C57Bl/6 mice were characterized by higher cytostatic activity of splenic NK cells. The observed interstrain differences are genetically determined and contribute to the type of adaptive processes and different sensitivity of these mice to pathogenic agents.