RESUMEN
Marginal zone B (MZB) cells are a B-cell subset that produces T-cell-independent antibodies to blood-borne antigens. In this study, we examined the effects of MZB cell depletion on the immune response to the Lyme disease spirochete Borrelia burgdorferi, an extracellular pathogen for which T-cell-independent antibody is an important host defense. MZB cell depletion of C3H/HeJ mice using monoclonal antibody to LFA-1 and alpha(4)beta(1) integrins reduced B. burgdorferi-specific immunoglobulin M (IgM) titers, enhanced pathogen burden, and led to more severe arthritis assessed within the first 2 weeks of infection. In addition, MZB cell-depleted mice had reduced levels of B. burgdorferi-specific IgG, which correlated with diminished splenic CD4+ T-cell-activation, proliferation, and cytokine production. Passive transfer of immune mouse serum from infected control mice into infected MZB cell-depleted mice reduced pathogen burden but did not alter the expression of T-cell activation markers on splenic CD4+ T cells. These findings demonstrate that MZB cells not only are a source of pathogen-specific IgM important for limiting spirochete burden and pathology but also play a prominent role in the priming of splenic T-cell responses to a blood-borne pathogen.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Borrelia burgdorferi/patogenicidad , Enfermedad de Lyme/inmunología , Depleción Linfocítica , Animales , Linfocitos B/inmunología , Borrelia burgdorferi/genética , Borrelia burgdorferi/inmunología , Linfocitos T CD4-Positivos/inmunología , Centro Germinal , Inmunidad Innata , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Interferón gamma/sangre , Enfermedad de Lyme/microbiología , Enfermedad de Lyme/fisiopatología , Activación de Linfocitos , Depleción Linfocítica/métodos , Ratones , Ratones Endogámicos C3HRESUMEN
Iron deficiency is associated with alterations in dopamine and serotonin transporters as well as changes in dopamine receptor (DR) density, monoamine concentrations, and in vivo extracellular contents of monoamines in terminal fields. Human infants with iron deficiency have both delayed maturation as well as lengthened central conduction times in auditory evoked potential studies. The current study utilizes the magnitude of the acoustic startle response (ASR), prepulse inhibition (PPI), and mean latency to maximum startle response (T(max)), to examine the functional integrity of response to environmental cues. Male and female rats consumed iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. ID rats of both sexes had 20-60% reductions in ASR when compared to CN rats but there was no effect on PPI. T(max) was significantly longer by 10-20% in females, but not males. Dopamine transporter density was significantly lower in putamen, nucleus accumbens, and olfactory tubercle in males, but not female rats while the serotonin transporter was significantly different from control animal density in five of 14 brain regions. Norepinephrine transporter density was lower in the locus ceruleus of ID male rats but was unaffected in ID female rats. Regression modeling of ASR with brain monoamine transporters and receptors showed hematocrit, norepinephrine transporter (NET) in dentate gyrus, and D1R in the nucleus accumbens account for nearly 49% of the variance in ASR. T(max) was not significantly associated with any of the independent variables. We conclude that iron deficiency affects the startle response, but not the inhibitory circuits involved in prepulse inhibition. Importantly, sex also strongly influenced these behavioral responses. Future studies, perhaps pharmacologic in nature, are necessary to ascertain whether iron deficiency modifies the contribution of monoaminergic systems to responses to environmental stimuli.
Asunto(s)
Inhibición Psicológica , Deficiencias de Hierro , Tiempo de Reacción/fisiología , Reflejo Acústico/fisiología , Reflejo de Sobresalto/fisiología , Estimulación Acústica/métodos , Animales , Animales Recién Nacidos , Conducta Animal , Benzazepinas/farmacocinética , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Encefálica/fisiología , Cocaína/análogos & derivados , Cocaína/farmacocinética , Antagonistas de Dopamina/farmacocinética , Relación Dosis-Respuesta en la Radiación , Femenino , Fluoxetina/análogos & derivados , Fluoxetina/farmacocinética , Hierro/sangre , Modelos Lineales , Hígado/metabolismo , Masculino , Unión Proteica/efectos de los fármacos , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
In this study, we extend previous work on iron deficiency and dopamine (DA) transporters to include an examination of central serotonin (5-HT) and noradrenergic (NE) transporters. Rats were fed either iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. In males, an additional group of iron deficient animals (IR) were given iron supplementation. DA, 5-HT, and NE transporter binding was done in situ on thin sections. ID males, but not females, decreased DA transporter binding in the nucleus accumbens, caudate putamen and substantia nigra by 20-40%. ID males also had a 20-30% reduction in 5-HT transporter binding in several areas (nucleus accumbens, olfactory tubercle, colliculus) while in ID females there was 15-25% increased serotonin transporter binding in the olfactory tubercle, zona incerta, anteroventral thalamic nucleus and vestibular nucleus. Iron deficiency reduced 3H-nisoxetine binding to the NE transporter in locus ceruleus and anteroventral thalamic nucleus in males but not females. Only some of the changes observed in DA, serotonin and NE transporter binding were reversible by iron supplementation. These findings show that iron deficiency affects monoamine systems related to homeostasis and in most cases males appear to be more vulnerable than females.
Asunto(s)
Encéfalo/metabolismo , Fluoxetina/análogos & derivados , Deficiencias de Hierro , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Simportadores/metabolismo , Animales , Núcleo Caudado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Fluoxetina/metabolismo , Hierro/administración & dosificación , Masculino , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Núcleo Accumbens/metabolismo , Vías Olfatorias/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Caracteres Sexuales , Sustancia Negra/metabolismo , TritioRESUMEN
Ab that arise in the absence of T cell help are a critical host defense against infection with the spirochetes Borrelia burgdorferi and Borrelia hermsii. We have previously shown that CD1d-deficient (CD1d(-/-)) mice have impaired resistance to infection with B. burgdorferi. In mice, CD1d expression is highest on marginal zone B (MZB) cells, which produce Ab to blood-borne Ag. In this study we examined MZB cell activation and Ab production in mice infected with B. hermsii, which achieve high levels of bacteremia. We show by flow cytometry that MZB cells associate with B. hermsii and up-regulate the activation markers syndecan I and B7.1 within 16 h of infection. By 24 h, MZB cells secrete B. hermsii-specific IgM, coinciding with the loss of activation marker expression and the reduction in spirochete burden. In contrast, MZB cells from CD1d(-/-) mice remain activated for at least 96 h of infection, but produce only minimal B. hermsii-specific IgM in vivo and ex vivo; pathogen burden in the blood also remains elevated. Wild-type mice depleted of MZB cells using mAb to LFA-1 and alpha(4)beta(1) integrin have reduced serum levels of B. hermsii-specific IgM and increased pathogen burden, similar to B. hermsii-infected CD1d(-/-) mice. Passive transfer of immune mouse serum, but not naive mouse serum, into infected CD1d(-/-) mice leads to down-regulation of activation markers and clearance of B. hermsii from the MZB cells. These results demonstrate that blood-borne spirochetes activate MZB cells to produce pathogen-specific IgM and reveal a role for CD1d in this process.