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1.
PLoS One ; 8(11): e81299, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24250831

RESUMO

IgM antibodies specific for a certain antigen can enhance antibody responses when administered together with this antigen, a process believed to require complement activation by IgM. However, recent data show that a knock-in mouse strain, Cµ13, which only produces IgM unable to activate complement, has normal antibody responses. Moreover, the recently discovered murine IgM Fc receptor (FcµR or TOSO/FAIM3) was shown to affect antibody responses. This prompted the re-investigation of whether complement activation by specific IgM is indeed required for enhancement of antibody responses and whether the mutation in Cµ13 IgM also caused impaired binding to FcµR. The results show that IgM from Cµ13 and wildtype mice bound equally well to the murine FcµR. In spite of this, specific Cµ13 IgM administered together with sheep red blood cells or keyhole limpet hemocyanine was a very poor enhancer of the antibody and germinal center responses as compared with wildtype IgM. Within seconds after immunization, wildtype IgM induced deposition of C3 on sheep red blood cells in the blood. IgM which efficiently enhanced the T-dependent humoral immune response had no effect on activation of specific CD4(+) T cells as measured by cell numbers, cell division, blast transformation, or expression of the activation markers LFA-1 and CD44 in vivo. These observations confirm the importance of complement for the ability of specific IgM to enhance antibody responses and suggest that there is a divergence between the regulation of T- and B-cell responses by IgM.


Assuntos
Ativação do Complemento/imunologia , Imunidade Humoral , Imunoglobulina M/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Proteínas do Sistema Complemento/imunologia , Técnicas de Introdução de Genes , Imunoglobulina M/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Receptores Fc/imunologia , Receptores Fc/metabolismo , Linfócitos T/metabolismo
2.
PLoS One ; 7(7): e41968, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848677

RESUMO

Early complement components are important for normal antibody responses. In this process, complement receptors 1 and 2 (CR1/2), expressed on B cells and follicular dendritic cells (FDCs) in mice, play a central role. Complement-activating IgM administered with the antigen it is specific for, enhances the antibody response to this antigen. Here, bone marrow chimeras between Cr2(-/-) and wildtype mice were used to analyze whether FDCs or B cells must express CR1/2 for antibody responses to sheep erythrocytes (SRBC), either administered alone or together with specific IgM. For robust IgG anti-SRBC responses, CR1/2 must be expressed on FDCs. Occasionally, weak antibody responses were seen when only B cells expressed CR1/2, probably reflecting extrafollicular antibody production enabled by co-crosslinking of CR2/CD19/CD81 and the BCR. When SRBC alone was administered to mice with CR1/2(+) FDCs, B cells from wildtype and Cr2(-/-) mice produced equal amounts of antibodies. Most likely antigen is then deposited on FDCs in a way that optimizes engagement of the B cell receptor, making CR2-facilitated signaling to the B cell superfluous. SRBC bound to IgM will have more C3 fragments, the ligands for CR1/2, on their surface than SRBC administered alone. Specific IgM, forming a complex with SRBC, enhances antibody responses in two ways when FDCs express CR1/2. One is dependent on CR1/2(+) B cells and probably acts via increased transport of IgM-SRBC-complement complexes bound to CR1/2 on marginal zone B cells. The other is independent on CR1/2(+) B cells and the likely mechanism is that IgM-SRBC-complement complexes bind better to FDCs than SRBC administered alone. These observations suggest that the immune system uses three different CR1/2-mediated effector functions to generate optimal antibody responses: capture by FDCs (playing a dominant role), transport by marginal zone B cells and enhanced B cell signaling.


Assuntos
Eritrócitos/imunologia , Imunoglobulina M/imunologia , Receptores de Complemento 3d/imunologia , Ovinos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Dendríticas Foliculares/imunologia , Feminino , Imunização , Camundongos , Receptores de Complemento 3d/deficiência
3.
Proc Natl Acad Sci U S A ; 108(43): E934-42, 2011 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-21987785

RESUMO

Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen-Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cµ13, with a point mutation in the gene encoding the third constant domain of the µ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cµ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.


Assuntos
Formação de Anticorpos/imunologia , Via Clássica do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Cadeias mu de Imunoglobulina/imunologia , Animais , Anticorpos Monoclonais/imunologia , Proteína C-Reativa/imunologia , Cromatografia em Agarose , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , ELISPOT , Citometria de Fluxo , Técnicas de Introdução de Genes , Cadeias mu de Imunoglobulina/genética , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Mutação de Sentido Incorreto/genética , Reação em Cadeia da Polimerase , Componente Amiloide P Sérico/imunologia
4.
J Clin Microbiol ; 45(5): 1410-4, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17329456

RESUMO

Genotyping of Chlamydia trachomatis is limited by the low sequence variation in the genome, and no adequate method is available for analysis of the spread of chlamydial infections in the community. We have developed a multilocus sequence typing (MLST) system based on five target regions and compared it with analysis of ompA, the single gene most extensively used for genotyping. Sequence determination of 16 reference strains, comprising all major serotypes, serotypes A to L3, showed that the number of genetic variants in the five separate target regions ranged from 8 to 16. The genetic variation in 47 clinical C. trachomatis isolates of representative serotypes (14 serotype D, 12 serotype E, 11 serotype G, and 10 serotype K strains) was analyzed; and the MLST system detected 32 variants, whereas 12 variants were detected by using ompA analysis. Specimens of the predominant serotype, serotype E, were differentiated into seven genotypes by MLST but into only two by ompA analysis. The MLST system was applied to C. trachomatis specimens from a population of men who have sex with men and was able to differentiate 10 specimens of one predominant ompA genotype G variant into four distinct MLST variants. To conclude, our MLST system can be used to discriminate C. trachomatis strains and can be applied to high-resolution molecular epidemiology.


Assuntos
Chlamydia trachomatis/classificação , Chlamydia trachomatis/genética , Reação em Cadeia da Polimerase/métodos , Variação Genética , Genótipo
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