An Update on the Role and Potential Molecules in Relation to Ruminococcus gnavus in Inflammatory Bowel Disease, Obesity and Diabetes Mellitus.

Ruminococcus gnavus (R. gnavus) is a gram-positive anaerobe commonly resides in the human gut microbiota. The advent of metagenomics has linked R. gnavus with various diseases, including inflammatory bowel disease (IBD), obesity, and diabetes mellitus (DM), which has become a growing area of investigation. The initial focus of research primarily centered on assessing the abundance of R. gnavus and its potential association with disease presentation, taking into account variations in sample size, sequencing and analysis methods. However, recent investigations have shifted towards elucidating the underlying mechanistic pathways through which R. gnavus may contribute to disease manifestation. In this comprehensive review, we aim to provide an updated synthesis of the current literature on R. gnavus in the context of IBD, obesity, and DM. We critically analyze relevant studies and summarize the potential molecular mediators implicated in the association between R. gnavus and these diseases. Across numerous studies, various molecules such as methylation-controlled J (MCJ), glucopolysaccharides, ursodeoxycholic acid (UDCA), interleukin(IL)-10, IL-17, and capric acid have been proposed as potential contributors to the link between R. gnavus and IBD. Similarly, in the realm of obesity, molecules such as hydrogen peroxide, butyrate, and UDCA have been suggested as potential mediators, while glycine ursodeoxycholic acid (GUDCA) has been implicated in the connection between R. gnavus and DM. Furthermore, it is imperative to emphasize the necessity for additional studies to evaluate the potential efficacy of targeting pathways associated with R. gnavus as a viable strategy for managing these diseases. These findings have significantly expanded our understanding of the functional role of R. gnavus in the context of IBD, obesity, and DM. This review aims to offer updated insights into the role and potential mechanisms of R. gnavus, as well as potential strategies for the treatment of these diseases.

Specific Alternation of Gut Microbiota and the Role of Ruminococcus gnavus in the Development of Diabetic Nephropathy.

In this study, we aim to investigate the precise alterations in the gut microbiota during the onset and advancement of diabetic nephropathy (DN) and examine the impact of Ruminococcus gnavus (R. gnavus) on DN. Eight-week-old male KK-Ay mice were administered antibiotic cocktails for a duration of two weeks, followed by oral administration of R. gnavus for an additional eight weeks. Our study revealed significant changes in the gut microbiota during both the initiation and progression of DN. Specifically, we observed a notable increase in the abundance of Clostridia at the class level, higher levels of Lachnospirales and Oscillospirales at the order level, and a marked decrease in Clostridia_UCG-014 in DN group. Additionally, there was a significant increase in the abundance of Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae at the family level. Moreover, oral administration of R. gnavus effectively aggravated kidney pathology in DN mice, accompanied by elevated levels of urea nitrogen (UN), creatinine (Cr), and urine protein. Furthermore, R. gnavus administration resulted in down-regulation of tight junction proteins such as Claudin-1, Occludin, and ZO-1, as well as increased levels of uremic toxins in urine and serum samples. Additionally, our study demonstrated that orally administered R. gnavus up-regulated the expression of inflammatory factors, including nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) and Interleukin (IL)-6. These changes indicated the involvement of the gut-kidney axis in DN, and R. gnavus may worsen diabetic nephropathy by affecting uremic toxin levels and promoting inflammation in DN.

Jiangtang Decoction Ameliorates Diabetic Kidney Disease Through the Modulation of the Gut Microbiota.

Purpose: This study aimed to elucidate the impact of Jiangtang decoction (JTD) on diabetic kidney disease (DKD) and its association with alterations in the gut microbiota. Methods: Using a diabetic mouse model (KK-Ay mice), daily administration of JTD for eight weeks was undertaken. Weekly measurements of body weight and blood glucose were performed, while kidney function, uremic toxins, inflammation factors, and fecal microbiota composition were assessed upon sacrifice. Ultra-structural analysis of kidney tissue was conducted to observe the pathological changes. Results: The study findings demonstrated that JTD improve metabolism, kidney function, uremic toxins and inflammation, while also exerting a modulatory effect on the gut microbiota. Specifically, the genera Rikenella, Lachnoclostridium, and unclassified_c_Bacilli exhibited significantly increased abundance following JTD treatment, accompanied by reduced abundance of norank_f_Lachnospiraceae compared to the model group. Importantly, Rikenella and unclassified_c_Bacilli demonstrated negative correlations with urine protein levels. Lachnoclostridium and norank_f_Lachnospiraceae were positively associated with creatinine (Cr), indoxyl sulfate (IS) and interleukin (IL)-6. Moreover, norank_f_Lachnospiraceae exhibited positive associations with various indicators of DKD severity, including weight, blood glucose, urea nitrogen (UN), kidney injury molecule-1 (KIM-1) levels, trimethylamine-N-oxide (TMAO), p-cresyl sulfate (pCS), nucleotide-binding oligomerization domain (Nod)-like receptor family pyrin domain-containing 3 (NLRP3) and IL-17A production. Conclusion: These findings suggested that JTD possess the ability to modulate the abundance of Rikenella, Lachnoclostridium, unclassified_c_Bacilli and norank_f_Lachnospiraceae within the gut microbiota. This modulation, in turn, influenced metabolic processes, kidney function, uremic toxin accumulation, and inflammation, ultimately contributing to the amelioration of DKD.

Non-small Cell Lung Cancer Cells Modulate the Development of Human CD1c+ Conventional Dendritic Cell Subsets Mediated by CD103 and CD205.

Advanced non-small cell lung cancer (NSCLC) leads to a high death rate in patients and is a major threat to human health. NSCLC induces an immune suppressive microenvironment and escapes from immune surveillance in vivo. At present, the molecular mechanisms of NSCLC immunopathogenesis and the immune suppressive microenvironment induced by NSCLC have not been fully elucidated. Here, we focus on the effect of NSCLC cells on the development and differentiation of human CD1c+ conventional dendritic cell (DC) subsets mediated by CD205 and CD103. The peripheral blood mononuclear cells (PBMCs) were isolated from NSCLC patients and healthy donors. DCs were induced and cocultured with primary NSCLC cells or tumor cell line H1299. DCs without incubation with tumor cells are control. The protein expression of costimulatory molecules such as CD80 and CD86, HLA-DR, pro-/anti-inflammatory cytokines such as IL-10 and IL-12, and CD205 and CD103 on CD1c+ DCs was detected by flow cytometry. Our data revealed two new subpopulations of human CD1c+ DCs (CD1c+CD205+CD103+ and CD1c+CD205+CD103- DC) in healthy donors and NSCLC patients. NSCLC cells modulate the development of the CD1c+CD205+CD103+ DC and CD1c+CD205+CD103- DC subpopulations in vitro and ex vivo. NSCLC cells also suppress the expression of signal molecules such as CD40, CD80, CD86, and HLA-DR on CD1c+ DCs. In addition, the production of pro-inflammatory cytokines, including IL-12 and IL-23, is downregulated by NSCLC cells; however, the secretion of anti-inflammatory cytokines, such as IL-10 and IL-27, by CD1c+ DCs is upregulated by NSCLC cells. Our results suggest that NSCLC cells may induce immune tolerogenic DCs, which block DC-mediated anti-tumor immunity in NSCLC patients. Our data may be helpful in revealing new cellular mechanisms related to the induction of tolerogenic CD1c+ DCs by NSCLCs and the development of an immune suppressive microenvironment that causes tumor cells to escape immune surveillance. Our results indicate a potential role for CD1c+ DC subsets mediated by CD205 and CD103 in DC-mediated immunotherapy to target NSCLC in the future.

Moxibustion with Chinese herbal has good effect on allergic rhinitis.

Allergic rhinitis (AR) is a chronic inflammatory disease of rhino-ocular mucosa, affecting up to 40% of population worldwide. Chinese herbal medicines and Acupuncture, adopted thousands of years in China, has good effect on allergic rhinitis. This study evaluates the effects of Moxibustion with Chinese herbal in treating patients with allergic rhinitis over a 1-year follow-up. A randomized controlled trial was conducted in a sample of 355 participants recruited from Guangdong general hospital of China. After baseline measurements, participants were randomly assigned to treatment-group or control group. Treatment group received Moxibustion with Chinese herbal. Control group received Loratadine. The main outcomes, including symptom severity and quality of life were measured using the Allergic Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Both moxibustion with Chinese herbal and Loratadine improve nose symptoms such as stuffy/blocked, sneezing, runny nose, itchy nose, sore nose and post-nasal drip in patients with AR. Symptoms fatigue, loss of taste, afraid of cold/wind and cold limb were improved significantly in moxibustion with Chinese herbal group. The mean quality of life scores decreased in both groups after treatment. Compare to control group, moxibustion with Chinese herbal is more effective than Loratadine in improving the quality of life in patients with AR. The results show moxibustion with Chinese herbal was effective to reduce symptoms and enhance quality of life in patients with allergic rhinitis. It is a simple, convenient and economic therapy for patients with AR. Further controlled trials of its effects in patients with allergic rhinitis are recommended.

Cloning and gene expression of signal transducers and activators of transcription (STAT) homologue provide new insights into the immune response and nucleus graft of the pearl oyster Pinctada fucata.

The signal transducers and activators of the transcription (STAT) family play an important role in regulatory and cellular functions by regulating the expression of a variety of genes, including cytokines and growth factors. In the present study, a Pinctada fucata STAT protein, termed PfSTAT, was described. The deduced amino acid sequence of PfSTAT contains the conserved STAT_bind domain and the SH2 domain, and the additional Bin/Amphiphysin/Rvs (BAR) domain, but does not have STAT_alpha and STAT_int domains. Multiple sequence alignments revealed that PfSTAT showed relatively low identity with vertebrate and other invertebrate STATs, and phylogenetic analysis indicated that the evolution of STAT may have been more complex and ancient. Gene expression analysis revealed that PfSTAT is involved in the immune response to polyinosinic-polycytidylic acid (poly I:C) stimulation and in the nucleus insertion operation. This study contributes to a better understanding of PfSTAT in protecting the pearl oyster from disease or injury caused by grafting.

Nuclear factor of activated T cells (NFAT) in pearl oyster Pinctada fucata: molecular cloning and functional characterization.

Nuclear factor of activated T cells (NFAT) plays an important role in nonimmune cells and also in T cells and many other cells of the immune system, by regulating the expression of a variety of genes involved in the immune response, organ development, developmental apoptosis and angiogenesis. In the present study, the NFAT homology gene, PfNFAT, from the pearl oyster Pinctada fucata was cloned and its genomic structure and promoter were analyzed. PfNFAT encodes a putative protein of 1226 amino acids, and contains a highly conserved Rel homology region (RHR) with DNA-binding specificity, and a regulatory domain (NFAT homology region, NHR) containing a potent transactivation domain (TAD). The PfNFAT gene consists of 12 exons and 11 introns, and its promoter contains potential binding sites for transcription factors such as NF-κB (Nuclear factor κB), STATx (signal transducer and activator of transcription), AP-1 (activator protein-1) and Sox-5/9 (SRY type HMG box-5/9), MyoD (Myogenic Differentiation Antigen) and IRF (Interferon regulatory factor). Comparison and phylogenetic analysis revealed that PfNFAT shows high identity with other invertebrate NFAT, and clusters with the NFAT5 subgroup. Furthermore, gene expression analysis revealed that PfNFAT is involved in the immune response to lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (poly I:C) stimulation and in the nucleus inserting operation. The study of PfNFAT may increase understanding of molluscan innate immunity.

Curative effect of Dingqi analgesic patch on cancer pain: a single-blind randomized controlled trail.

OBJECTIVE: To observe the curative effect of an acupoint application with a Dingqi analgesic patch on moderate to severe pain caused by liver cancer. METHODS: Forty patients with moderate to severe pain caused by liver cancer were randomly divided into a treatment group (TG) and a control group (CG). Patients with moderate pain were given 100 mg qd of a sustainably released tablet of tramadol hydrochloride; patients with severe pain were given 4.2 mg q3d of the fentanyl transdermal system. The ashi points Ganshu (BL 18), Danshu (BL 19) and Qimen (LR 14) were chosen for the acupoint application intervention. CG patients were given a sham patch and TG patients were given a Dingqi analgesic patch. A visual analogue scale (VAS) was used before treatment and after 1, 3, 6, 9 and 12 days of treatment. The Karnofsky score was measured before treatment and after 12 days of treatment. Any main adverse reactions (e.g. nausea, constipation, dizziness and headache) were recorded after 6 and 12 days of treatment. Any skin side effects (i.e. skin irritation and allergic reactions) were recorded. RESULTS: The VAS in TG was significantly lower than that in CG after 3, 6, 9 and 12 days of treatment (P < 0.05). There was no significant difference in the Karnofsky score before treatment and after 12 days of treatment between CG and TG. There were also no significant differences in the main adverse reactions or skin side effects after 6 and 12 days of treatment between CG and TG (P > 0.05). CONCLUSION: The Dingqi analgesic patch can enhance the analgesic effect of tramadol and fentanyl.

Trypanosoma congolense Infections: Induced Nitric Oxide Inhibits Parasite Growth In Vivo.

Wild-type (WT) C57BL/6 mice infected intraperitoneally with 5 × 10(6) Trypanosoma congolense survive for more than 30 days. C57BL/6 mice deficient in inducible nitric oxide synthase (iNOS(-/-)) and infected with 10(3) or 5 × 10(6) parasites do not control the parasitemia and survive for only 14 ± 7 or 6.8 ± 0.1 days, respectively. Bloodstream trypanosomes of iNOS(-/-) mice infected with 5 × 10(6)T. congolense had a significantly higher ratio of organisms in the S+G2+M phases of the cell cycle than trypanosomes in WT mice. We have reported that IgM anti-VSG-mediated phagocytosis of T. congolense by macrophages inhibits nitric oxide (NO) synthesis via CR3 (CD11b/CD18). Here, we show that during the first parasitemia, but not at later stages of infection, T. congolense-infected CD11b(-/-) mice produce more NO and have a significantly lower parasitemia than infected WT mice. We conclude that induced NO contributes to the control of parasitemia by inhibiting the growth of the trypanosomes.

Intradermal infections of mice by low numbers of african trypanosomes are controlled by innate resistance but enhance susceptibility to reinfection.

Antibodies are required to control blood-stage forms of African trypanosomes in humans and animals. Here, we report that intradermal infections by low numbers of African trypanosomes are controlled by innate resistance but prime the adaptive immune response to increase susceptibility to a subsequent challenge. Mice were found 100 times more resistant to intradermal infections by Trypanosoma congolense or Trypanosoma brucei than to intraperitoneal infections. B cell-deficient and RAG2(-/-) mice are as resistant as wild-type mice to intradermal infections, whereas inducible nitric oxide synthase (iNOS)(-/-) mice and wild-type mice treated with antibody to tumor necrosis factor (TNF) α are more susceptible. We conclude that primary intradermal infections with low numbers of parasites are controlled by innate defense mediated by induced nitric oxide (NO). CD1d(-/-) and major histocompatibility complex (MHC) class II(-/-) mice are more resistant than wild-type mice to primary intradermal infections. Trypanosome-specific spleen cells, as shown by cytokine production, are primed as early as 24 h after intradermal infection. Infecting mice intradermally with low numbers of parasites, or injecting them intradermally with a trypanosomal lysate, makes mice more susceptible to an intradermal challenge. We suggest that intradermal infections with low numbers of trypanosomes or injections with trypanosomal lysates prime the adaptive immune system to suppress protective immunity to an intradermal challenge.

Serum biochemistry, serology, and parasitology of boreal caribou (Rangifer tarandus caribou) in the Northwest Territories, Canada.

Boreal caribou (Rangifer tarandus caribou) are an ecologically and culturally important wildlife species and now range almost exclusively in the boreal forests of Canada, including the Northwest Territories, northern Alberta, and British Columbia. Boreal caribou are threatened throughout their Canadian range because of direct and indirect natural and anthropogenic factors. In the Northwest Territories, however, they have a continuous range that overall has not yet been subjected to the same degree of anthropogenic habitat fragmentation and degradation that has occurred elsewhere in Canada. To monitor the health of boreal caribou populations and individuals, we collected blood from 104 adult, female boreal caribou captured between March 2003 and February 2006 and measured serum biochemical parameters. Serum creatinine was higher in pregnant than in nonpregnant caribou. Several biochemical parameters differed among years, but they tended to be similar to those reported for reindeer. Serum antibodies were found to an alphaherpesvirus, Toxoplasma gondii, and to the Mycobacterium avium subspecies paratuberculosis in 37.5, 2.9, and 1.3% of boreal caribou, respectively. Fecal samples were collected from 149 boreal caribou, and Cryptosporidium sp. oocysts, Giardia sp. cysts, trichostrongyle ova, dorsal-spined nematode larvae, cestode ova, and Eimeria sp. were found. Trypanosoma sp. was detected in the blood of 72.1% of boreal caribou. Eimeria sp., Cryptosporidium sp., and Giardia sp. have not been previously reported in boreal caribou.

Immunization of newborn and adult mice with low numbers of BCG leads to Th1 responses, Th1 imprints and enhanced protection upon BCG challenge.

Neonatal bacille Calmette-Guerin (BCG) vaccination is widely employed to protect against tuberculosis. Predominant Th1 but not mixed Th1/Th2 responses are thought to be protective. If so, effective vaccination must cause Th1 imprints. The immune system of infants differs from that of adults and such differences could critically affect neonatal vaccination. We demonstrate that BCG infection of infant and adult mice produces similar responses. Infection with low and high numbers of BCG, respectively, leads to sustained Th1 and mixed Th1/Th2 responses. Low-dose but not high-dose infection also results in Th1 imprints, guaranteeing a Th1 response upon high-dose challenge, and resulting in optimal bacterial clearance. Our observations on low-dose Th1 imprinting are intriguing in the context of the well-known madras trial. In this trial, the highest dose of BCG, which had insignificant side effects, was administered to over 250,000 human subjects. This high-dose vaccination resulted in insignificant protection against tuberculosis.

Characterization of major surface protease homologues of Trypanosoma congolense.

Trypanosomes encode a family of proteins known as Major Surface Metalloproteases (MSPs). We have identified six putative MSPs encoded within the partially sequenced T. congolense genome. Phylogenic analysis indicates that T. congolense MSPs belong to five subfamilies that are conserved among African trypanosome species. Molecular modeling, based on the known structure of Leishmania Major GP63, reveals subfamily-specific structural variations around the putative active site despite conservation of overall structure, suggesting that each MSP subfamily has evolved to recognize distinct substrates. We have cloned and purified a protein encoding the amino-terminal domain of the T. congolense homologue TcoMSP-D (most closely related to Leishmania GP63). We detect TcoMSP-D in the serum of T. congolense-infected mice. Mice immunized with the amino-terminal domain of TcoMSP-D generate a persisting IgG1 antibody response. Surprisingly, a low-dose challenge of immunized mice with T. congolense significantly increases susceptibility to infection, indicating that immunity to TcoMSP-D is a factor affecting virulence.

T cells and immunopathogenesis of experimental African trypanosomiasis.

SUMMARY: African trypanosomes are pathogens for humans and livestock. They are single-cell, extra-cellular parasites that cause persistent infections of the blood and induce profound immunosuppression. Here, we review recent work on experimental African trypanosomiasis, especially infections with Trypanosoma congolense, in mice with regard to mechanisms of immunosuppression and immunopathology. The center of the immunopathology is the T-cell-independent production of antibodies to the variant surface glycoprotein (VSG) of trypanosomes, the anti-VSG antibody-mediated phagocytosis of trypanosomes by macrophages, and the subsequent profound dysregulation of the macrophage system. Depending on the genetics of the host and the parasite load, the malfunction of the macrophage system is enhanced by interferon-gamma produced by parasite-specific, major histocompatibility complex class II-restricted, matrix-adherent CD4(+) T cells or downregulated by interleuin-10 produced by parasite-specific, CD4(+)CD25(high) Forkhead box protein 3(+) regulatory T cells. There is a physiological conflict of the two relevant cytokines interleukin-10 and interferon-gamma in regulating the immunopathology versus regulating the induction and effect of protective immune responses. On the basis of very recent work in our laboratory, we propose a hypothetical model suggesting a cross-regulation of natural killer T cells and CD4(+)CD25(high) Forkhead box protein 3(+) regulatory T cells in experimental infections with T. congolense.

[The summary of the clinic study of Zhi-Xin-Fang treating the heart failure resulting from cardiomyopathy].

OBJECTIVE: To observe the therapeutic and prognostic effects and to evaluate the safety of Zhi-Xin-Fang on heart failure resulting from cardiomyopathy. METHODS: 62 patients with cardiomyopathy combined with heart failure were treated with standard western medical therapy as treatment group. The other 60 patients with the same diseases were administered with both Zhi-Xin-Fang and standard western medicines as control. Several parameters were observed to evaluate the effect of Zhi-Xin-Fang on the heart failure, containing the therapeutic effect of clinical symptom and physical signs, the improvement of heart function and the ultrasonic caridogram. We also observed the effect of Zhi-Xin-Fang to relieve the clinical symptom and improve the heart function and quality of life and prognosis. RESULTS: As the NYHA classify for heart failure, the effective rate for the treatment group was 95% , more effective than the control group (effective rate: 80.65%) (P<0.05). There was significant improvement for LVEF and LVDS for both groups. However, the treatment group was better than the control group (P<0.05). The clinical symptom was significantly improved compared to the untreatment in both groups. The treatment group was better than the control group for effective rate (P<0.05) but not for the total effective rate. There was no significant difference for the function of liver and kidney, blood routine method, electrolyte compared to before for the two groups. CONCLUSION: The standard western medicines combined with Zhi-Xin-Fang is a good therapy for treating heart failure resulting from cardiomyopathy. The combined therapy can relieve the cinical symptom of heart failure, improve the heart function and quality of life. It is also safer for the patients. However, its long-term prognosis should be further studied in the future.

Regulatory T cells prevent control of experimental African trypanosomiasis.

African trypanosomes are single-cell, extra-cellular blood parasites causing profound immunosuppression. Susceptible BALB/c mice infected s.c. into a footpad with 10(4) Trypanosoma congolense die with fulminating parasitemia within 10 days. We injected BALB/c mice 2 days before such an infection with different doses of a depleting mAb specific for CD25, a surface marker of regulatory T cells (Tregs). Pretreatment with a low, optimal dose of anti-CD25 resulted in a dramatic effect, in that the infected mice did not develop parasitemia, as well as eliminated all parasites and showed no signs of disease. Their spleens showed a 100% reduction of CD4(+)CD25(high) T cells and overall a 70% reduction of CD4(+)CD25(+)Foxp3(+) T cells 7 days postinfection. The protective effect of treatment with an optimal dose of anti-CD25 could be reversed by administration of l-N6-(1-imminoethyl) lysine, a specific inhibitor of inducible NO synthase or administration of anti-CD8 Ab. Analysis of the cytokine patterns and cell surface marker in infected mice pretreated with anti-CD25 Abs pointed to a potential NKT cell response. We then conducted infections in CD1d(-/-) mice. From our observations, we conclude that CD4(+)CD25(high)Foxp3(+) Tregs prevent, in normal infected susceptible mice, an early protective response mediated by CD8(+) NKT cell-dependent activation of macrophages to kill parasites by production of NO. Our results also indicate that different populations of NKT cells have protective or suppressive effects. Our observations lead us to propose a hypothesis of cross-regulation of NKT cells and Tregs in trypanosome infections.

CR3 (CD11b/CD18) is the major macrophage receptor for IgM antibody-mediated phagocytosis of African trypanosomes: diverse effect on subsequent synthesis of tumor necrosis factor alpha and nitric oxide.

Immunoglobulin M (IgM) antibodies to the variant surface glycoproteins (VSG) of African trypanosomes are the first and predominant class of anti-trypanosomal antibodies in the infected host. They are a major factor in controlling waves of parasitemia, but not in long-term survival. The macrophage receptor(s) that enables phagocytosis of IgM anti-VSG-coated African trypanosomes is unknown. We assessed whether complement receptor CR3 (CD11b/CD18) might be involved in mediating phagocytosis of Trypanosoma congolense. We show that murine complement C3 fragments are deposited onto T. congolense when the trypanosomes are incubated with IgM anti-VSG and fresh mouse serum. In the presence of fresh mouse serum, there is significantly and markedly less phagocytosis of IgM-opsonized T. congolense by CD11b-deficient macrophages compared to phagocytosis by wild-type macrophages (78% fewer T. congolense are ingested per macrophage). Significantly less tumor necrosis factor (TNF)-alpha (38% less), but significantly more nitric oxide (NO) (63% more) are released by CD11b-deficient macrophages that have engulfed trypanosomes than by equally treated wild-type macrophages. We conclude that CR3 is the major, but not the only, receptor involved in IgM anti-VSG-mediated phagocytosis of T. congolense by macrophages. We further conclude that IgM anti-VSG-mediated phagocytosis of T. congolense enhances synthesis of disease-producing TNF-alpha and inhibits synthesis of parasite-controlling NO. We suggest that signaling of inhibition of NO synthesis is mediated via CR3.

Experimental African trypanosomiasis: a subset of pathogenic, IFN-gamma-producing, MHC class II-restricted CD4+ T cells mediates early mortality in highly susceptible mice.

Infections of highly susceptible BALB/c mice with virulent strains of Trypanosoma congolense or Trypanosoma brucei result in rapid death (8 days). We have previously shown that this mortality is IFN-gamma dependent. In this study we show that IFN-gamma is produced predominantly by CD3+Thy1.2+TCRbeta+CD4+ T cells shortly before the death of infected mice. Mortality may therefore be dependent on IFN-gamma-producing CD4+ T cells. Surprisingly, infected CD4+/+ and CD4-/- BALB/c mice have similar parasitemia and survival time. In infected CD4-/- mice, the production of both IFN-gamma and IL-10 is very low, suggesting that both cytokines are predominantly produced by CD4+ T cells and that the outcome of the disease might depend on the balance of their effects. Infected BALB/c mice partially depleted of CD4+ T cells or MHC class II function have lower parasitemia and survive significantly longer than infected normal BALB/c mice or infected BALB/c mice whose CD4+ T cells are fully depleted. Partial depletion of CD4+ T cells markedly reduces IFN-gamma secretion without a major effect on the production of IL-10 and parasite-specific IgG2a Abs. Based on our previous and current data, we conclude that a subset of a pathogenic, MHC class II-restricted CD4+ T cells (Tp cells), activated during the course of T. congolense infection, mediates early mortality in infected BALB/c mice via excessive synthesis of IFN-gamma. IFN-gamma, in turn, exerts its pathological effect by enhancing the cytokine release syndrome of the macrophage system activated by the phagocytosis of parasites. We speculate that IL-10-producing CD4+ T cells might counteract this effect.

Impaired Kupffer cells in highly susceptible mice infected with Trypanosoma congolense.

In highly susceptible BALB/c mice infected with Trypanosoma congolense, the total number of Kupffer cells in the liver remains constant; however, their mean size increases fivefold towards the terminal stage. About 25% of Kupffer cells undergo apoptosis. We suggest that development of an impairment of the macrophage system might be a major mechanism for inefficient elimination of trypanosomes.