A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult

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Treatment of mice with the anticoccidial drug Toltrazuril does not interfere with the development of a specific cellular intestinal immune response to Eimeria falciformis

Immunity against Eimeria-infections is highly specific and it depends on cell-mediated effector mechanisms. Infections of BALB/c mice with 1000 sporulated oocysts of Eimeria falciformis led to protection against challenge infections. Treatment with the anticoccidium Toltrazuril, during primary infection, terminated the ongoing disease and did not interfere with the establishment of protective immunity against challenge infections. Mesenteric lymph node cells of infected, treated as well as non-treated and challenged BALB/c mice, showed a similar proliferation upon stimulation with parasite antigen. In contrast, neither cells of the Peyers patches, intraepithelial lymphocytes, nor spleen cells responded to stimulation with parasite antigens. Cells from all compartments and of all investigated groups proliferated and released the cytokines IFN- and IL-4 in response to the mitogen Concanavalin A. The number of cells releasing IFN- or IL-4 was not dependent on the status of infection or previous treatment with Toltrazuril. The serum IgG response against total sporozoite antigens of individual mice showed that in addition, a systemic humoral response developed in infected mice, independent of a previous drug treatment, although the specific IgG antibody concentration was higher in non-treated mice. Thus, Toltrazuril does not impair the parasite specific intestinal cellular and systemic antibody response and does not prevent the development of protection against challenge infection.     

Direct and indirect role of Toll-like receptors in T cell mediated immunity

Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that playan important role in protective immunity against infection and inflammation.They act as central integrators ofa wide variety of signals,responding to diverse agonists of microbial products.Stimulation of Toll-like receptorsby microbial products leads to signaling pathways that activate not only innate,but also adaptive immunity byAPC dependent or independent mechanisms.Recent evidence revealed that TLR signals played a determiningrole in the skewing of na(?)ve T cells towards either Th1 or Th2 responses.Activation of Toll-like receptors alsodirectly or indirectly influences regulatory T cell functions.Therefore,TLRs are required in both immuneactivation and immune regulation.Study of TLRs has significantly enhanced our understanding of innate andadaptive immune responses and provides novel therapeutic approaches against infectious and inflammatorydiseases.Cellular & Molecular Immunology.2004;1(4):239-246.     

Toll-like receptor 3 gene polymorphisms in South African Blacks with type 1 diabetes

Type 1 diabetes is the consequence of exposure of genetically susceptible individuals to specific environmental precipitants. The innate immune system provides the initial response to exogenous antigen and links with the adaptive immune system. The aim of this study was to assess the role of polymorphisms occurring in the cytoplasmic region of toll-like receptor (TLR) 3 gene and immediate 5' sequence, in subjects of Zulu descent with type 1 diabetes in KwaZulu-Natal, South Africa. Seventy-nine subjects with type 1 diabetes and 74 healthy normal glucose tolerant gender-matched control subjects were studied. Parts of exon 4 and exon 3/intron 3 of the TLR3 gene were studied by polymerase chain reaction, direct sequencing and restriction enzyme digestion with Bts 1. Of the nine polymorphisms studied, a significant association with type 1 diabetes was found for the major allele in the 2593 C/T polymorphism and for the minor alleles in the 2642 C/A and 2690 A/G polymorphisms, which were found to be in complete linkage disequilibrium. Correction of the P-values for the number of alleles studied, however, rendered the results no longer significant. These results suggest that polymorphisms in the TLR3 gene, which is part of the innate immune system, may be associated with type 1 diabetes in this population.     

Effects of non-MHC background genes on the induction of CD4+ T cells that prevent rejection of a highly immunogenic tumor, FBL-3

This study showed that non-MHC genes common to (DBA/2 H-2^d)and (DBA/1 H-2^q) gave rise to suppressor T (T_a) cells in thehybrid F₁ mice between C57BL/6 (B6) strain in the antl-FBL-3tumor responses. FBL-3, a Friend virus-induced tumor cell lineof B6 mouse origin, is highly immunogenic as shown by findingsthat syngenelc and hybrid F₁ mice with several other inbredstrains rejected up to 3 x 10⁷ tumor cells inoculated s.c. andgenerated potent CTL responses after mixed lymphocyte tumorcell culture. In contrast to these mice, (B6 x DBA/2) and (B6x DBA/1)F1 mice did not reject the tumor as the tumor dosesincreased. Progressive tumor growth in these F₁ mice was blockedby an I.p. Injection of cyclophosphamlde (250 mg/kg) on day10, but not on day 5, after tumor cell inoculation. Antl-CD4(GK1.5) mAb exerted similar therapeutic effects against tumorwhen given twice, between day 0 and 10, whereas the additionalinjection of antl-CD8 mAb enhanced the tumor growth in micethat otherwise rejected the tumor. Thus, In the response of(B6 x DBA/2)F, mice to FBL-3 tumor cells, CD4⁺ T₈ seemed todown-regulate the immunologically mediated regression of thetumor produced by CD8⁺ CTL. This was evidenced by limiting dilutionculture analyses, which showed that the frequency of an FBL-3-speclflcCTL precursor in the (B6 x DBA/2)F1 mice that rejected the tumorwith antl-CD4 mAb was 7- to 9-fold higher than that in micein which the tumor regressed spontaneously. That more than onegene was involved in suppressor T cell induction was shown bythe tumor growth pattern in (B6 x DBA/2)F₁ x B6 backcross andB6D2F2 mice.     

Molecular characterization of a novel pattern recognition protein from nonspecific cytotoxic cells: sequence analysis, phylogenetic comparisons and anti-microbial activity of a recombinant homologue

Nonspecific cytotoxic cells (NCC) are the first identified and most extensively studied killer cell population in teleosts. NCC kill a wide variety of target cells including tumor cells, virally transformed cells and protozoan parasites. The present study identified a novel evolutionarily conserved oligodeoxynucleotide (ODN) binding membrane protein expressed by channel catfish (Ictalurus punctatus) NCC. Peptide fingerprinting analysis of the ODN binding protein (referred to as NCC cationic anti-microbial protein-1/ncamp-1) identified a peptide that was used to design degenerate primers. A catfish NCC cDNA library was used as template with these primers and the PCR-amplified product was sequenced. The translated sequence contained 203 amino acids (molecular mass of 22,064.63 Da) with characteristic lysine rich regions and a pI=pH 10.75. Sequence comparisons of this protein indicated similarity to zebrafish (51.2%) histone family member 1-X and (to a lesser extent) to trout H1. A search of EST databases confirmed that ncamp-1 is also expressed in various tissues of channel catfish as well as zebrafish. Inspection for signature repeats in ncamp-1 and comparisons with histone-like peptides from different species indicated the presence of multiple lysine based motifs composed of AKKA or PKK repeats. The novel protein was cloned, expressed in E. coli and the recombinant was used to generate rabbit anti-serum. The recombinant ncamp-1 bound GpC and CpG ODNs and was detected with homologous anti-ncamp-1 polyclonal antibodies. Western blots of NCC membranes using anti-ncamp-1 serum detected a 29 kDa protein. Binding competition experiments demonstrated that anti-ncamp-1 antibodies and GpC bound to the same protein on NCC. Two different truncated forms of ncamp-1 as well as the full-length recombinant protein exhibited anti-microbial activity. The present study demonstrated the expression by NCC of a new membrane protein that may participate in the recognition of bacterial DNA and as such participate in innate anti-microbial immune responses in teleosts.     

Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1

Lipoproteins or lipopeptides (LP) are bacterial cell wall components detected by the innate immune system. For LP, it has been shown that TLR2 is the essential receptor in cellular activation. However, molecular mechanisms of LP recognition are not yet clear. We used a FLAG-labeled derivative of the synthetic lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine (Pam(3)CSK(4)) to study the roles of CD14, TLR2 and TLR1 in binding and signaling of LP and their molecular interactions in human cells. The activity of Pam(3)CSK(4)-FLAG was TLR2 dependent, whereas the binding was enabled by CD14, as evaluated by flow cytometry and confocal microscopy. Using FRET and FRAP imaging techniques to study molecular associations, we could show that after Pam(3)CSK(4)-FLAG binding, CD14 and Pam(3)CSK(4)-FLAG associate with TLR2 and TLR1, and TLR2 is targeted to a low-mobility complex. Thus, LP binding to CD14 is the first step in the LP recognition, inducing physical proximity of CD14 and LP with TLR2/TLR1 and formation of the TLR2 signaling complex.     

Antitumor action of glycopeptides from the cell wall of Lactobacillus bulgaricus

The antitumor action of the substance blastolysin, the main components of which are glycopeptide fragments from the cell wall ofLactobacillus bulgaricus, was studied. Blastolysin exhibits a specific antitumor effect against sarcoma S-180, leukemia P-388, plasmacytoma MOPC-315, adenocarcinoma AKATOL, melanosarcoma B-16, carcinoma LLC, and spontaneous tumors of mice. It has low toxicity, does not depress hematopoiesis, and in the character of its action on tumor tissue it differs essentially from known chemotherapeutic preparations.M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the USSR, Moscow. Scientific-Production Laboratory of Biologically Active Substances, Sofia, Bulgaria. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 12, pp. 709–712, December, 1977.     

NKG2D ligands: unconventional MHC class I-like molecules exploited by viruses and cancer

Our best teachers in revealing the importance of immune pathways are viruses and cancers that have subverted the most prominent pathways to escape from immune recognition. Viruses and cancer impair antigen presentation by classical MHC class I to escape adaptive immunity. The activating receptor NKG2D and its MHC class I-like ligands are other recently defined innate and adaptive immune pathways exploited by viruses and cancer. This review discusses recent advances in the understanding of how NKG2D, expressed on innate immune cells including natural killer cells, gammadelta+ T cells and macrophages, and adaptive immune cells such as CD8+ T cells, recognize stress-induced, MHC class I-like, self-ligands. Moreover, we describe how viruses and cancer have developed strategies to evade this recognition pathway.     

小儿喉乳头状瘤HPV-DNA及体液免疫检测

目的：探讨小儿喉乳头状瘤（ＪＬＰ）人乳头瘤病毒（ＨＰＶ）感染途径及发病机理。方法：采用ＰＣＲ及ＰＣＲ产物斑点杂交技术检测ＪＬＰ组织ＨＰＶ－ＤＮＡ;散射免疫比浊法测定血清Ｉｇ及补体Ｃ３。结果：ＪＬＰ组织ＨＰＶ总感染率为９５％（１９／２０）,其中ＨＰＶ。型为５５％（１１／２０）,ＨＰＶ１１为３０％（６／２０）,ＨＰＶ６＋１１型为１０％（２／２０）;ＪＬＰ患者血清ＩｇＧ、ＩｇＡ、ＩｇＭ、Ｃ３值正常,对照