RESUMO
Antibody responses induced at mucosal and nonmucosal sites demonstrate a significant level of autonomy. Here, we demonstrate a key role for mucosal interferon regulatory factor-4 (IRF4)-dependent CD103+CD11b+ (DP), classical dendritic cells (cDCs) in the induction of T-dependent immunoglobulin G (IgG) and immunoglobulin A (IgA) responses in the mesenteric lymph node (MLN) following systemic immunization with soluble flagellin (sFliC). In contrast, IRF8-dependent CD103+CD11b- (SP) are not required for these responses. The lack of this response correlated with a complete absence of sFliC-specific plasma cells in the MLN, small intestinal lamina propria, and surprisingly also the bone marrow (BM). Many sFliC-specific plasma cells accumulating in the BM of immunized wild-type mice expressed α4ß7+, suggesting a mucosal origin. Collectively, these results suggest that mucosal DP cDC contribute to the generation of the sFliC-specific plasma cell pool in the BM and thus serve as a bridge linking the mucosal and systemic immune system.
Assuntos
Células Dendríticas/imunologia , Fatores Reguladores de Interferon/metabolismo , Linfonodos/imunologia , Mucosa/imunologia , Plasmócitos/imunologia , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Células Cultivadas , Flagelina/imunologia , Imunidade Humoral , Imunoglobulina A/metabolismo , Switching de Imunoglobulina , Imunoglobulina G/metabolismo , Cadeias alfa de Integrinas/metabolismo , Integrina alfa4/metabolismo , Cadeias beta de Integrinas/metabolismo , Fatores Reguladores de Interferon/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The identification of intestinal macrophages (mφs) and dendritic cells (DCs) is a matter of intense debate. Although CD103(+) mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103(-) MPs remain controversial. We show here that intestinal CD103(-)CD11b(+) MPs can be separated clearly into DCs and mφs based on phenotype, gene profile, and kinetics. CD64(-)CD103(-)CD11b(+) MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6C(hi) monocytes. Surprisingly, a significant proportion of these CD103(-)CD11b(+) DCs express CCR2 and there is a selective decrease in CD103(-)CD11b(+) DCs in mice lacking this chemokine receptor. CCR2(+)CD103(-) DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by T cells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2(+) DCs that is involved in priming mucosal T helper type 17 (Th17) responses.
Assuntos
Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/metabolismo , Animais , Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Humanos , Imunofenotipagem , Cadeias alfa de Integrinas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Interleucina-12/metabolismo , Interleucina-17/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Fenótipo , Receptores CCR2/metabolismo , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologiaRESUMO
Small intestinal lamina propria (SI-LP) CD103(+) dendritic cells (DCs) are imprinted with an ability to metabolize vitamin A (retinol), a property underlying their enhanced capacity to induce the gut-homing receptors CC chemokine receptor-9 and α4ß7 on responding T cells. In this study, we demonstrate that imprinting of CD103(+) DCs is itself critically dependent on vitamin A and occurs locally within the small intestine (SI). The major vitamin A metabolite retinoic acid (RA) induced retinol-metabolizing activity in DCs both in vitro and in vivo, suggesting a direct role for RA in this process. Consistent with this, SI-LP CD103(+) DCs constitutively received RA signals in vivo at significantly higher levels than did colonic CD103(+) DCs. Remarkably, SI CD103(+) DCs remained imprinted in mice depleted of dietary but not of systemic retinol. We found that bile contained high levels of retinol, induced RA receptor-dependent retinol-metabolizing activity in bone marrow-derived DCs, and imprinted these cells with the ability to generate gut-tropic T cells. Taken together, these results suggest a novel and unexpected role for bile in SI-LP CD103(+) DC imprinting.
Assuntos
Bile/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Retinoides/metabolismo , Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Bile/química , Bile/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Células Dendríticas/citologia , Dieta , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR/metabolismo , Retinoides/imunologia , Transdução de Sinais/imunologia , Linfócitos T/citologia , Vitamina A/análiseRESUMO
BACKGROUND: Children with hydrocephalus represent a heterogeneous group with various aetiologies and disability profiles. Over the years, continuous changes in medical care have occurred and updated information is important. AIM: To study disability profiles in aetiological and gestational age subgroups of children with hydrocephalus in the 1990s. METHOD: A population-based series of 114 children, 70 with infantile hydrocephalus and 44 with hydrocephalus associated with MMC. All the children were examined clinically and interviewed. RESULTS: Learning disabilities were present in 47 % of children with infantile hydrocephalus compared with 16 % of those with MMC, cerebral palsy in 27 % vs. zero and epilepsy in 34 vs. 11 %. Even after excluding children with cerebral palsy, the majority had abnormal tendon reflexes and scored below the 5th centile on a motor test. Hydrocephalus overt at birth, low gestational age, a perinatal origin, enlarged ventricles at follow-up and several shunt revisions all indicated risk factors for a poor outcome. CONCLUSIONS: In spite of major advances in management, hydrocephalus in children still has a considerable impact on outcome. Being born very preterm and with a hydrocephalus that is already overt at birth involve the highest risk of a poor outcome. Apart from major impairments, the children frequently have definite motor problems.