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ABSTRACT: Spinal cord injury (SCI) results in immune depression. To better understand how injury inhibits humoral immunity, the effects of chronic thoracic SCI on B cell development and immune responses to thymus-independent type 2 and thymus-dependent Ags were determined. Mice received complete crush injury or control laminectomy at either thoracic level 3, which disrupts descending autonomic control of the spleen, or at thoracic level 9, which conserves most splenic sympathetic activity. Although mature B cell numbers were only mildly reduced, bone marrow B cell production was transiently but profoundly depressed immediately after injury. Despite the return of normal B cell production 4 wk after SCI, mice receiving thoracic level 3 injury showed a significant reduction in their ability to mount primary thymus-independent type 2 or thymus-dependent immune responses. The latter were marked by decreases in germinal center B cells as well as class-switched high-affinity Ab-secreting cells. Importantly, injury did not affect affinity maturation per se, pre-existing B cell memory, or secondary humoral immune responses. Taken together, these findings show that chronic high thoracic SCI impairs the ability to mount optimal Ab responses to new antigenic challenges, but spares previously established humoral immunity.
The Journal of Immunology 04/2012; 188(11):5257-66. · 5.79 Impact Factor
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ABSTRACT: Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un-injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4(+) T lymphocyte proliferation and IFN-γ production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses.
Experimental Neurology 11/2010; 226(1):242-53. · 4.70 Impact Factor
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Katherine S Held,
William G Glass,
Yevgeniya I Orlovsky,
Kimberly A Shamberger,
Ted D Petley,
Patrick J Branigan,
Jill M Carton,
Heena S Beck,
Mark R Cunningham,
Jacqueline M Benson,
Thomas E Lane
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ABSTRACT: The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell-mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.
Viral Immunology 07/2008; 21(2):173-88. · 1.97 Impact Factor
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ABSTRACT: Viral infection of the central nervous system (CNS) results in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences. One of the principal factors that directs the outcome of infection is the localized innate immune response, which is proceeded by the adaptive immune response against the invading viral pathogen. The role of the immune system is to contain and control the spread of virus within the CNS, and paradoxically, this response may also be pathological. Studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV) have provided important insights into how the immune system combats neuroinvasive viruses, and have identified molecular and cellular mechanisms contributing to chronic disease in persistently infected mice.
Frontiers in Bioscience 02/2008; 13:4393-406. · 3.52 Impact Factor
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ABSTRACT: The role of CC chemokine receptor 1 (CCR1) in host defense and disease development was determined in a model of viral-induced neurologic disease. Intracerebral (IC) infection of mice with mouse hepatitis virus (MHV) results in an acute encephalitis followed by a chronic demyelinating disease similar in pathology to the disease multiple sclerosis (MS). No increase in mortality was observed during the acute phase of disease following MHV infection of mice lacking CCR1 (CCR1-/-) as compared to wild-type (CCR1+/+) mice. However, by 21 d post-infection, 74% of CCR1-/- mice had succumbed to death compared to only 32% mortality of CCR1+/+ mice, indicating that chemokine signaling through CCR1 significantly (p <or= 0.04) enhanced survival following IC infection with MHV. Increased mortality in CCR1-/- mice was not associated with increased viral recovery from the CNS, although CCR1 deficiency correlated with reduced T-cell accumulation within the CNS during acute, but not chronic, disease. Despite the reduction in T-cell trafficking into the CNS of CCR1-/- mice during acute disease, components of host defense remained unaltered; T-cell effector functions including cytolytic activity and proliferation and the expression of IFN-gamma within the CNS were not significantly different between CCR1+/+ and CCR1-/- infected mice. In addition, macrophage infiltration into the CNS was unaffected in MHV-infected CCR1-/- mice when compared to CCR1+/+ mice. Furthermore, assessment of neuropathology revealed no difference in the severity of demyelination between CCR1-deficient and wild-type mice. Together, these findings reveal that T-cell and macrophage trafficking are not dependent on CCR1 and highlight an important role for CCR1 signaling in promoting survival during chronic MHV infection.
Viral Immunology 01/2008; 20(4):599-608. · 1.97 Impact Factor
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ABSTRACT: Herpes simplex virus type 1 (HSV-1) uses multicomponent mechanisms for binding, penetration, and cell-to-cell passage. These processes are affected by polysulfonated compounds. In this paper we have addressed the question of whether the same or different interactions of HSV-1 with polysulfonated compounds are involved in binding, penetration, and passage. For this, we have compared the inhibitory dose-response for a series of polysulfonated and cationic compounds known to block HSV-1 infections. These comparisons were done at the level of binding, penetration, and cell-to-cell passage. Variations in the parameters of the dose-response curves - IC(50) and Hill coefficients (n (H)) - are consistent with HSV-1 having multiple interactions with sulfonated cellular components in all these processes. Some of the interactions seem to be common to the three processes, while others are particular for each one.
Virus Genes 07/2007; 34(3):241-8. · 1.85 Impact Factor
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ABSTRACT: The CC chemokine ligand 2 (CCL2, monocyte chemoattractant protein-1) is important in coordinating the immune response following microbial infection by regulating T cell polarization as well as leukocyte migration and accumulation within infected tissues. The present study examines the consequences of mouse hepatitis virus (MHV) infection in mice lacking CCL2 (CCL2(-/-)) in order to determine if signaling by this chemokine is relevant in host defense. Intracerebral infection of CCL2(-/-) mice with MHV did not result in increased morbidity or mortality as compared to either wild type or CCR2(-/-) mice and CCL2(-/-) mice cleared replicating virus from the brain. In contrast, CCR2(-/-) mice displayed an impaired ability to clear virus from the brain that was accompanied by a reduction in the numbers of antigen-specific T cells as compared to both CCL2(-/-) and wild-type mice. The paucity in T cell accumulation within the central nervous system (CNS) of MHV-infected CCR2(-/-) mice was not the result of either a deficiency in antigen-presenting cell (APC) accumulation within draining cervical lymph nodes (CLN) or the generation of virus-specific T cells within this compartment. A similar reduction in macrophage infiltration into the CNS was observed in both CCL2(-/-) and CCR2(-/-) mice when compared to wild-type mice, indicating that both CCL2 and CC chemokine receptor 2 (CCR2) contribute to macrophage migration and accumulation within the CNS following MHV infection. Together, these data demonstrate that CCR2, but not CCL2, is important in host defense following viral infection of the CNS, and CCR2 ligand(s), other than CCL2, participates in generating a protective response.
Virology 12/2004; 329(2):251-60. · 3.35 Impact Factor
