RESUMEN
Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.
Asunto(s)
Coinfección/inmunología , Interferones/inmunología , Infecciones por Orthomyxoviridae/inmunología , Neumonía Neumocócica/inmunología , Sobreinfección/inmunología , Animales , Susceptibilidad a Enfermedades , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
Infection of mice with the bacterium Ehrlichia muris elicits a protective T cell-independent (TI) IgM response mediated primarily by a population of CD11c-expressing plasmablasts in the spleen. Although splenic marginal zone (MZ) B cells are considered to be important for TI responses to blood-borne pathogens, MZ B cells were not responsible for generating plasmablasts in response to Ehrlichia muris. Moreover, antigen-specific serum IgM was decreased only modestly in splenectomized mice and in mice that lacked spleen, lymph nodes, and Peyer's patches (SLP mice). Both splenectomized and SLP mice were protected against lethal ehrlichial challenge infection. Moreover, we found a high frequency of Ehrlichia-specific plasmablasts in the omentum of both conventional and SLP mice. Omental plasmablasts elicited during Ehrlichia infection lacked expression of CD138 but expressed CD11c in a manner similar to that of their splenic counterparts. Selective ablation of CD11c-expressing B cells nearly eliminated the omental Ehrlichia-specific plasmablasts and reduced antigen-specific serum IgM, identifying the omental B cells as a source of IgM production in the SLP mice. Generation of the omental plasmablasts was route dependent, as they were detected following peritoneal infection but not following intravenous infection. Our data identify the omentum as an important auxiliary site of IgM production during intracellular bacterial infection.
Asunto(s)
Anticuerpos Antibacterianos/metabolismo , Ehrlichiosis/inmunología , Inmunoglobulina M/metabolismo , Epiplón/inmunología , Células Plasmáticas/inmunología , Animales , Antígeno CD11c/análisis , Ehrlichia/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Epiplón/patología , Sindecano-1/análisisRESUMEN
UNLABELLED: Asthma was the most common comorbidity observed among patients hospitalized with influenza A virus during the 2009 pandemic. However, little remains known about how the asthmatic phenotype influences protective immune responses against respiratory viral pathogens. Using the ovalbumin-induced allergic lung inflammation model, we found that asthmatic mice, unlike nonasthmatic mice, were highly susceptible to secondary heterologous virus challenge. While primary virus infection generated protective memory immune responses against homologous secondary virus challenge in both asthmatic and nonasthmatic mice, full protection against heterologous A/California/04/2009 (CA04) viral infection was observed only in nonasthmatic mice. Significant reductions in CA04-specific IgA, IgG, and IgM levels and in CA04-neutralizing activity of bronchoalveolar lavage fluid (BALF) was observed following secondary CA04 challenge of PR8-immunized asthmatic mice. Furthermore, transfer of immune BALF obtained from nonasthmatic, but not asthmatic, donors following secondary viral infection generated protection against CA04 in naive recipients. Nonspecific B-cell activation by CpG inoculation restored protection in PR8-immunized, CA04-challenged asthmatic mice. These results demonstrate a causal link between defective mucosal antibody responses and the heightened susceptibility of asthmatic mice to influenza infection and provide a mechanistic explanation for the observation that asthma was a major risk factor during the 2009 influenza pandemic. IMPORTANCE: The prevalence of asthma worldwide is increasing each year. Unfortunately, there is no cure for asthma. Asthmatic individuals not only suffer from consistent wheezing and coughing but are also believed to be more prone to serious lung infections that result in bronchitis and pneumonia. However, little is known about the influence of asthma on host mucosal immunity. Here we show that antibody responses during secondary heterologous influenza infections are suboptimal and that this is responsible for the increased mortality in asthmatic mice from viral infections. Understanding the mechanism of increased susceptibility will aid in developing new antiviral therapies for asthmatic patients.
Asunto(s)
Asma/inmunología , Asma/virología , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/virología , Infecciones por Orthomyxoviridae/inmunología , Animales , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Asma/complicaciones , Linfocitos B/inmunología , Linfocitos B/virología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/virología , Susceptibilidad a Enfermedades/etiología , Femenino , Inmunidad Mucosa/inmunología , Inmunoglobulinas/inmunología , Inflamación/inmunología , Inflamación/virología , Virus de la Influenza A/inmunología , Pulmón/inmunología , Pulmón/virología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/etiología , Infecciones por Orthomyxoviridae/virologíaRESUMEN
Immunological memory has long considered to be harbored in B cells that express high-affinity class-switched IgG. IgM-positive memory B cells can also be generated following immunization, although their physiological role has been unclear. In this study, we show that bacterial infection elicited a relatively large population of IgM memory B cells that were uniquely identified by their surface expression of CD11c, CD73, and programmed death-ligand 2. The cells lacked expression of cell surface markers typically expressed by germinal center B cells, were CD138 negative, and did not secrete Ab ex vivo. The population was also largely quiescent and accumulated somatic mutations. The IgM memory B cells were located in the region of the splenic marginal zone and were not detected in blood or other secondary lymphoid organs. Generation of the memory cells was CD4 T cell dependent and required IL-21R signaling. In vivo depletion of the IgM memory B cells abrogated the IgG recall responses to specific Ag challenge, demonstrating that the cell population was required for humoral memory, and underwent class-switch recombination following Ag encounter. Our findings demonstrate that T cell-dependent IgM memory B cells can be elicited at high frequency and can play an important role in maintaining long-term immunity during bacterial infection.
Asunto(s)
Linfocitos B/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Memoria Inmunológica , 5'-Nucleotidasa/metabolismo , Animales , Proteínas de la Membrana Bacteriana Externa/administración & dosificación , Proteínas de la Membrana Bacteriana Externa/inmunología , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/inmunología , Ehrlichia/inmunología , Ehrlichiosis/inmunología , Centro Germinal/inmunología , Inmunización , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptores de Interleucina-21/metabolismo , Sindecano-1/metabolismoRESUMEN
B cell activating factor of the tumor necrosis factor family (BAFF) is an essential survival factor for B cells and has been shown to regulate T cell-independent (TI) IgM production. During Ehrlichia muris infection, TI IgM secretion in the spleen was BAFF dependent, and antibody-mediated BAFF neutralization led to an impairment of IgM-mediated host defense. The failure of TI plasmablasts to secrete IgM was not a consequence of alterations in their generation, survival, or early differentiation, since all occurred normally in infected mice following BAFF neutralization. Gene expression characteristic of plasma cell differentiation was also unaffected by BAFF neutralization in vivo, and except for CD138, plasmablast cell surface marker expression was unaffected. IgM was produced, since it was detected intracellularly, and impaired secretion was not due to a failure to express the IgM secretory exon. Addition of BAFF to plasmablasts in vitro rescued IgM secretion, suggesting that BAFF signaling can directly regulate secretory processes. Our findings indicate that BAFF signaling can modulate TI host defense by acting at a late stage in B cell differentiation, via its regulation of terminal plasmablast differentiation and/or IgM secretion.
Asunto(s)
Factor Activador de Células B/inmunología , Linfocitos B/inmunología , Ehrlichia/inmunología , Ehrlichiosis/inmunología , Inmunoglobulina M/inmunología , Animales , Factor Activador de Células B/antagonistas & inhibidores , Factor Activador de Células B/metabolismo , Diferenciación Celular , Inmunoglobulina M/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Transducción de Señal/inmunología , Sindecano-1/inmunología , Linfocitos T/inmunologíaRESUMEN
IgM responses are well known to occur early postinfection and tend to be short-lived, which has suggested that this Ig does not significantly contribute to long-term immunity. In this study, we demonstrate that chronic infection with the intracellular bacterium Ehrlichia muris elicits a protective, long-term IgM response. Moreover, we identified a population of CD138(high)IgM(high) B cells responsible for Ag-specific IgM production in the bone marrow. The IgM-secreting cells, which exhibited characteristics of both plasmablasts and plasma cells, contributed to protection against fatal ehrlichial challenge. Mice deficient in activation-induced cytidine deaminase, which produce only IgM, were protected against fatal ehrlichial challenge infection. The IgM-secreting cells that we have identified were maintained in the bone marrow in the absence of chronic infection, as antibiotic-treated mice remained protected against challenge infection. Our studies identify a cell population that is responsible for the IgM production in the bone marrow, and they highlight a novel role for IgM in the maintenance of long-term immunity during intracellular bacterial infection.
Asunto(s)
Células de la Médula Ósea/inmunología , Células de la Médula Ósea/microbiología , Ehrlichiosis/inmunología , Ehrlichiosis/prevención & control , Inmunoglobulina M/biosíntesis , Líquido Intracelular/inmunología , Células Plasmáticas/inmunología , Células Plasmáticas/microbiología , Animales , Células de la Médula Ósea/metabolismo , Enfermedad Crónica , Ehrlichia/inmunología , Ehrlichiosis/microbiología , Inmunoglobulina M/fisiología , Líquido Intracelular/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Plasmáticas/metabolismo , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismo , Células Precursoras de Linfocitos B/microbiología , Bazo/inmunología , Bazo/metabolismo , Bazo/microbiología , Factores de TiempoRESUMEN
Germinal centers (GCs) are specialized microenvironments in secondary lymphoid organs that facilitate the development of high-affinity, isotype-switched Abs, and immunological memory; consequently, many infections require GC-derived IgG for pathogen clearance. Although Ehrlichia muris infection elicits a robust expansion of splenic, IgM-secreting plasmablasts, we detected only very low frequencies of isotype-switched IgG-secreting cells in mouse spleens, until at least 3 wk postinfection. Instead, Ag-specific IgG was produced in lymph nodes, where it required CD4 T cell help. Consistent with these findings, organized GCs and phenotypically defined splenic GC B cells were found in lymph nodes, but not spleens. Ehrlichial infection also inhibited spleen IgG responses against a coadministered T cell-dependent Ag, hapten 4-hydroxy-3-nitrophenyl acetyl (NP)-conjugated chicken gamma globulin in alum. NP-specific B cells failed to undergo expansion and differentiation into GC B cells in the spleen, Ab titers were reduced, and splenic IgG production was inhibited nearly 10-fold when the Ag was administered during infection. Our data provide a mechanism whereby an intracellular bacterial infection can compromise local immunity to coinfecting pathogens or antigenic challenge.
Asunto(s)
Anticuerpos Antibacterianos/metabolismo , Ehrlichia/inmunología , Ehrlichiosis/inmunología , Centro Germinal/inmunología , Inmunoglobulina G/metabolismo , Terapia de Inmunosupresión , Líquido Intracelular/inmunología , Líquido Intracelular/microbiología , Animales , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/patología , Ehrlichiosis/microbiología , Ehrlichiosis/patología , Epítopos de Linfocito T/inmunología , Centro Germinal/microbiología , Centro Germinal/patología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Inmunoglobulina M/biosíntesis , Líquido Intracelular/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Bazo/inmunología , Bazo/microbiología , Bazo/patologíaRESUMEN
Although T-independent immunity is known to be generated against bacterial capsular and cell wall polysaccharides expressed by a number of bacterial pathogens, it has not been studied in depth during intracellular bacterial infections. Our previous study demonstrated that Ehrlichia muris, an obligate intracellular tick-borne pathogen, generates protective classical TI responses in CD4 T cell-deficient C57BL/6 mice. We found that E. muris T-independent immunity is accompanied by the expansion of a very large extrafollicular spleen population of CD11c(low)-expressing plasmablasts that exhibit characteristics of both B-1 and marginal zone B cells. The plasmablasts comprised up to 15% of the total spleen lymphocytes and approximately 70% of total spleen IgM(high)IgD(low) cells during peak infection in both wild-type and MHC class II-deficient mice. The CD11c(low) cells exhibited low surface expression of B220, CD19, and CD1d, high expression of CD11b, CD43, but did not express CD5. Approximately 50% of the CD11c(low) cells also expressed CD138. In addition to CD11b and CD11c, the plasmablasts expressed the beta(1) (CD29) and alpha4 (CD49d) integrins, as well as the chemokine receptor CXCR4, molecules which may play roles in localizing the B cells extrafollicular region of the spleen. During peak infection, the CD11c(low) cells accounted for the majority of the IgM-producing splenic B cells and nearly all of the E. muris outer membrane protein-specific IgM-secreting cells. Thus, during this intracellular bacterial infection, CD11c expression identifies a population of Ag-specific spleen plasmablasts responsible for T-independent Ab production.
Asunto(s)
Anticuerpos Antibacterianos/biosíntesis , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/inmunología , Ehrlichia/inmunología , Ehrlichiosis/inmunología , Células Plasmáticas/inmunología , Bazo/inmunología , Animales , Antígenos T-Independientes/inmunología , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígeno CD11c/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ehrlichiosis/microbiología , Inmunoglobulina M/biosíntesis , Ratones , Ratones Mutantes , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Bazo/citología , Bazo/metabolismo , Sindecano-1/inmunología , Sindecano-1/metabolismoRESUMEN
Human monocytic ehrlichiosis (HME) is a tick-borne disease caused by Ehrlichia chaffeensis. Patients exhibit diagnostically important hematological changes, including anemia and thrombocytopenia, although the basis of the abnormalities is unknown. To begin to understand these changes, we used a mouse model of ehrlichiosis to determine whether the observed hematological changes induced by infection are associated with altered hematopoietic activity. Infection with Ehrlichia muris, a pathogen closely related to E. chaffeensis, resulted in anemia, thrombocytopenia, and a marked reduction in bone marrow cellularity. CFU assays, conducted on days 10 and 15 postinfection, revealed a striking decrease in multipotential myeloid and erythroid progenitors. These changes were accompanied by an increase in the frequency of immature granulocytes in the bone marrow and a decrease in the frequency of B lymphocytes. Equally striking changes were observed in spleen cellularity and architecture, and infected mice exhibited extensive extramedullary hematopoiesis. Splenomegaly, a characteristic feature of E. muris infection, was associated with an expanded and disorganized marginal zone and a nearly 66-fold increase in the level of Ter119(+) erythroid cells, indicative of splenic erythropoiesis. We hypothesize that inflammation associated with ehrlichia infection suppresses bone marrow function, induces the emigration of B cells, and establishes hematopoietic activity in the spleen. We propose that these changes, which may be essential for providing the innate and acquired immune cells to fight infection, are also responsible in part for blood cytopenias and other clinical features of HME.
Asunto(s)
Ehrlichia chaffeensis , Ehrlichiosis/inmunología , Granulocitos/patología , Hematopoyesis , Adaptación Fisiológica , Animales , Antígenos CD/análisis , Antígenos de Grupos Sanguíneos/análisis , Células de la Médula Ósea/patología , Quimiocina CXCL12/análisis , Quimiocina CXCL12/genética , Modelos Animales de Enfermedad , Ehrlichiosis/sangre , Ehrlichiosis/patología , Eritropoyesis , Femenino , Humanos , Inmunidad Innata , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Transferrina/análisis , Bazo/patología , Esplenomegalia/etiologíaRESUMEN
How spatial and temporal changes in major histocompatibility complex/peptide antigen presentation to CD4 T cells regulate CD4 T-cell responses during intracellular bacterial infections is relatively unexplored. We have shown that immunization with an ehrlichial outer membrane protein, OMP-19, protects mice against fatal ehrlichial challenge infection, and we identified a CD4 T-cell epitope (IA(b)/OMP-19(107-122)) that elicited CD4 T cells following either immunization or infection. Here, we have used an IA(b)/OMP-19(107-122)-specific T-cell line to monitor antigen display ex vivo during acute and chronic infection with Ehrlichia muris, a bacterium that establishes persistent infection in C57BL/6 mice. The display of IA(b)/OMP-19(107-122) by host antigen-presenting cells was detected by measuring intracellular gamma interferon (IFN-gamma) production by the T-cell line. After intravenous infection, antigen presentation was detected in the spleen, peritoneal exudate cells, and lymph nodes, although the kinetics of antigen display differed among the tissues. Antigen presentation and bacterial colonization were closely linked in each anatomical location, and there was a direct relationship between antigen display and CD4 T-cell effector function. Spleen and lymph node dendritic cells (DCs) were efficient presenters of IA(b)/OMP-19(107-122), demonstrating that DCs play an important role in ehrlichial infection and immunity. Chronic infection and antigen presentation occurred within the peritoneal cavity, even in the presence of highly activated CD4 T cells. These data indicated that the ehrlichiae maintain chronic infection not by inhibiting antigen presentation or T-cell activation but, in part, by avoiding signals mediated by activated T cells.
Asunto(s)
Presentación de Antígeno , Antígenos Bacterianos/inmunología , Ehrlichia/inmunología , Ehrlichiosis/inmunología , Activación de Linfocitos , Linfocitos T/inmunología , Animales , Líquido Ascítico/inmunología , Células Dendríticas/inmunología , Epítopos de Linfocito T/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Bazo/inmunologíaRESUMEN
We report that IgA-/- mice exhibit specific defects in IgG antibody responses to various polysaccharide vaccines (Francisella tularensis LPS and Pneumovax), but not protein vaccines such as Fluzone. This defect further included responses to polysaccharide-protein conjugate vaccines (Prevnar and Haemophilus influenzae type b-tetanus toxoid vaccine). In agreement with these findings, IgA-/- mice were protected from pathogen challenge with protein- but not polysaccharide-based vaccines. Interestingly, after immunization with live bacteria, IgA+/+ and IgA-/- mice were both resistant to lethal challenge and their IgG anti-polysaccharide antibody responses were comparable. Immunization with live bacteria, but not purified polysaccharide, induced production of serum B cell-activating factor (BAFF), a cytokine important for IgG class switching; supplementing IgA-/- cell cultures with BAFF enhanced in vitro polyclonal IgG production. Taken together, these findings show that IgA deficiency impairs IgG class switching following vaccination with polysaccharide antigens and that live bacterial immunization can overcome this defect. Since IgA deficient patients also often show defects in antibody responses following immunization with polysaccharide vaccines, our findings could have relevance to the clinical management of this population.
Asunto(s)
Inmunoglobulina A/genética , Vacunas Neumococicas/inmunología , Vacunas Conjugadas/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Cápsulas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/uso terapéutico , Células Cultivadas , Femenino , Citometría de Flujo , Vacunas contra Haemophilus/inmunología , Vacunas contra Haemophilus/uso terapéutico , Vacuna Neumocócica Conjugada Heptavalente/inmunología , Vacuna Neumocócica Conjugada Heptavalente/uso terapéutico , Inmunoglobulina A/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Vacunas Neumococicas/uso terapéutico , Vacunas Conjugadas/uso terapéuticoRESUMEN
BACKGROUND: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression. CONCLUSIONS/SIGNIFICANCE: In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.
Asunto(s)
Granulocitos/patología , Pulmón/patología , Neumonía/patología , Tuberculosis/patología , Animales , Antígenos Ly/metabolismo , Recuento de Colonia Microbiana , Cruzamientos Genéticos , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Granulocitos/metabolismo , Mediadores de Inflamación/metabolismo , Pulmón/microbiología , Masculino , Ratones , Mycobacterium tuberculosis/crecimiento & desarrollo , Fagocitos/metabolismo , Fagocitos/patología , Neumonía/complicaciones , Neumonía/microbiología , Sitios de Carácter Cuantitativo/genética , Tuberculosis/complicaciones , Tuberculosis/genética , Tuberculosis/microbiología , Pérdida de PesoRESUMEN
Much has been learned about the structure, function, and production of IgM, since the antibody's initial characterization. It is widely accepted that IgM provides a first line of defense during microbial infections, prior to the generation of adaptive, high-affinity IgG responses that are important for long-lived immunity and immunological memory. Although IgM responses are commonly used as a measure of exposure to infectious diseases, it is perhaps surprising that the role of and requirement for IgM in many microbial infections has not been well explored in vivo. This is in part due to the lack of capabilities, until relatively recently, to evaluate the requirement for IgM in the absence of coincident IgG responses. Such evaluations are now possible, using gene-targeted mouse strains that produce only IgM, or isotype-switched IgG. A number of studies have revealed that IgM, produced either innately, or in response to antigen challenge, plays an important and perhaps under appreciated role in many microbial infections. Moreover, the characterization of the roles of various B cell subsets, in the production of IgM, and in host defense, has revealed important and divergent roles for B-1a and B-1b cells. This review will highlight studies in which IgM, in its own right, has been found to play an important role, not only in early immunity, but also in long-term protection, against a variety of microbial pathogens. Observations that long-lived IgM responses can be generated in vivo suggest that it may be feasible to target IgM production as part of vaccination strategies.
Asunto(s)
Infecciones Bacterianas/inmunología , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismo , Virosis/inmunología , Animales , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Citidina Desaminasa/deficiencia , Humanos , Inmunoglobulina M/química , Inmunoglobulina M/genética , Memoria Inmunológica , Inmunoterapia , Ratones , Ratones Noqueados , Virosis/terapiaRESUMEN
Although humoral immunity has been shown to contribute to host defense during intracellular bacterial infections, its role has generally been ancillary. Instead, CD4 T cells are often considered to play the dominant role in protective immunity via their production of type I cytokines. Our studies of highly pathogenic Ehrlichia bacteria isolated from Ixodes ovatus (IOE) reveal, however, that this paradigm is not always correct. Immunity to IOE infection can be induced by infection with a closely related weakly pathogenic ehrlichia, Ehrlichia muris. Type I cytokines (i.e., gamma interferon, tumor necrosis factor alpha, and interleukin-12) were not necessary for E. muris-induced immunity. In contrast, humoral immunity was essential, as shown by the fact that E. muris-infected B-cell-deficient mice were not protected from IOE challenge and because E. muris immunization was effective in CD4-, CD8-, and major histocompatibility complex (MHC) class II-deficient mice. Immunity was unlikely due to nonspecific inflammation, as prior infection with Listeria monocytogenes did not induce immunity to IOE. Antisera from both wild-type and MHC-II-deficient mice provided at least partial resistance to challenge infection, and protection could also be achieved following transfer of total, but not B-cell-depleted, splenocytes obtained from E. muris-immunized mice. The titers of class-switched antibodies in immunized CD4 T-cell- and MHC class II-deficient mice, although lower than those observed in immunized wild-type mice, were significant, indicating that E. muris can induce class switch recombination in the absence of classical T-cell-mediated help. These studies highlight a major protective role for classical T-cell-independent humoral immunity during an intracellular bacterial infection.