CHIKV, in particular, re-emerged in 2004 to cause massive outbreaks of disease affecting millions. Īrthritogenic alphaviruses, including chikungunya virus (CHIKV), Mayaro virus, and Ross River virus, are emerging public health concerns. In humans, HIV infection of CD4 + T cells results in loss of follicular T helper cell responses and impaired Ab production. Vaccinia virus disrupts the dLN SCS macrophage layer, preventing antigen acquisition and subsequent B cell responses. Lymphocytic choriomeningitis virus (LCMV), a prototypical mouse pathogen, impairs Ab responses in the dLN via a number of mechanisms, including the recruitment of inflammatory monocytes that promote B cell apoptosis.
Some viruses have evolved strategies to subvert humoral immune responses in the dLN.
Some of these activated, proliferating B cells go on to form plasmablasts, while others persist in tight clusters in the follicle, forming germinal centers (GCs). After activation, B cells migrate to the borders of the B cell follicle and to the interfollicular region of the dLN to encounter CD4 + T cells. B cells acquire viral antigen through interactions with SCS macrophages which readily acquire viral antigens borne by the afferent lymphatics. Naïve B cells enter the dLN through high endothelial venules (HEVs) and then migrate to defined follicles subjacent to the dLN subcapsular sinus (SCS).
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The antiviral Ab response is initiated in the draining lymph node (dLN) through a series of molecular interactions and cellular movements that require intact lymphoid tissue architecture and function. B cells and virus-specific antibodies (Abs) are important arms of the adaptive immune response for limiting viral dissemination and controlling viral infections. Together, our data suggest that pathogenic CHIKV triggers the influx and activation of monocytes and neutrophils in the dLN that impairs virus-specific B cell responses.ĭraining lymphoid organs have a critical role in the initiation of effective adaptive immune responses to vaccines and pathogens. Infiltrating monocytes expressed iNOS through a local IRF5- and IFNAR1-dependent pathway that was partially TLR7-dependent. Both inducible nitric oxide synthase (iNOS) and the phagocyte NADPH oxidase (Nox2) contributed to impaired dLN organization and function. Blocking this influx improved lymphocyte accumulation, dLN organization, and CHIKV-specific B cell responses. Infection of WT mice with pathogenic, but not acutely cleared CHIKV, induced MyD88-dependent recruitment of monocytes and neutrophils to the dLN. Here, we define mechanisms whereby chikungunya virus (CHIKV), a mosquito-transmitted RNA virus that causes outbreaks of acute and chronic arthritis in humans, hinders dLN antiviral B cell responses. Some viruses subvert LN B cell activation however, our knowledge of viral hindrance of B cell responses of important human pathogens is lacking. Humoral immune responses initiate in the lymph node draining the site of viral infection (dLN). Statistical significance was determined by Student’s t-test. Data are derived from 2 independent experiments. ( J) Representative flow cytometry plots of CD138 +IgD - plasma cells (gated on CD19 +), ( K) percentage and ( L) total number of plasma cells in the spleen at 14 dpi. ( G) Representative flow cytometry plots of GL7 +CD95 + GC B cells (gated on CD19 +B220 + cells), ( H) percentage and ( I) total number of GC B cells in the spleen at 14 dpi. ( D) Representative flow cytometry plots of CD138 +IgD - plasma cells (gated on CD19 +), ( E) percentage and ( F) total number of plasma cells in the left inguinal LN at 14 dpi. ( A) Representative flow cytometry plots of GL7 +CD95 + GC B cells (gated on CD19 +B220 + cells), ( B) percentage and ( C) total number of GC B cells in the left inguinal LN at 14 dpi.
one day prior to inoculation with 10 3 PFU of CHIKV AF15561 in the left footpad. C57BL/6 mice were treated with 300–500 μg IgG2b isotype control mAb or anti-Gr-1 mAb i.p. S4 Fig: The effects of anti-Gr-1 mAb treatment are largely confined to the dLN.
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