Germinal center B cells are dispensable in prion transport and neuroinvasion

Heikenwälder, Mathias; Federau, Christian; Boehmer, Lotta von; Schwarz, Petra; Wagner, Mareike; Zeller, Nicolas; Haybaeck, Johannes; Prinz, Marco; Aguzzi, Adriano

doi:10.1016/j.jneuroim.2007.09.022

Cited by 18 publications

(19 citation statements)

References 52 publications

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“…CD40 −/− mice fail to develop germinal centers and memory B-cell responses, yet CD40L −/− mice show unaltered incubation times upon i.p. prion challenge [54]. Similarly to the other immunocompromised mouse models investigated, CD40 −/− mice developed terminal scrapie upon infection with prion aerosols with an attack rate of 100% (n = 3, 276±50 dpi).…”

Section: Resultsmentioning

confidence: 95%

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

et al. 2011

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Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.

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Section: Resultsmentioning

confidence: 95%

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

et al. 2011

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“…Elimination of GCs had no effect on peripheral prion replication and disease progression in mice infected i.p. with RML5 (50), supporting this interpretation. However, GC-deficient mice infected intracranially with 139A mouse adapted scrapie prions exhibited a significant delay to terminal disease (51).…”

Section: Discussionsupporting

confidence: 64%

Genetic Depletion of Complement Receptors CD21/35 Prevents Terminal Prion Disease in a Mouse Model of Chronic Wasting Disease

Michel

Ferguson

Johnson

et al. 2012

The Journal of Immunology

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The Complement System has been shown to facilitate peripheral prion pathogenesis. Mice lacking Complement receptors CD21/35 partially resist terminal prion disease when infected intraperitoneally with mouse-adapted scrapie prions. Chronic wasting disease (CWD) is an emerging prion disease of captive and free-ranging cervid populations that, like scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. Here we show that mice overexpressing the cervid prion protein and susceptible to CWD (Tg(cerPrP)5037 mice) but lack CD21/35 expression completely resist clinical CWD upon peripheral infection. CD21/35 deficient Tg5037 mice exhibit greatly impaired splenic prion accumulation and replication throughout disease, similar to CD21/35 deficient murine PrP mice infected with mouse scrapie. TgA5037;CD21/35-/- mice exhibited little or no neuropathology and deposition of misfolded, protease-resistant PrP associated with CWD. CD21/35 translocates to lipid rafts and mediates a strong germinal center response to prion infection that we propose provides the optimal environment for prion accumulation and replication. We further propose a potential role for CD21/35 in selecting prion quasi-species present in prion strains that may exhibit differential zoonotic potential compared to the parental strains.

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“…In contrast, treatment with LTβR-Ig led to strong decrease of inflammation and also ablated AIP in Tg mice. We also depleted germinal center B-cells using anti-CD40L antibody [45]. Although IgG levels were reduced, the load of pancreatic inflammation and progression to AIP remained unchanged in …”

Section: Discussionmentioning

confidence: 99%

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Seleznik¹,

Reding²,

Romrig

et al. 2012

Gastroenterology

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BACKGROUND AIMS:: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to development of AIP and new therapeutic strategies. METHODS:: We used quantitative PCR, immunohistochemical and ELISA analyses to measure expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing LT and specifically in acinar cells ( Ela1-LTab mice). RESULTS:: mRNA levels of lymphotoxin (LT) and were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines ( CXCL13, CCL19, CCL21, CCL1 and BAFF) was increased in pancreatic and serum samples from patients. Upregulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LT (Ela1-LT) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LT did not cause autoimmunity in mice without lymphocytes(Ela1-LTab/Rag1(-/-)); moreover lack of pro-inflammatory monocytes (Ela1-LTab/Ccr2-/-) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as anti-pancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS:: Overexpression of LT specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LT R ligands might be used to treat patients with AIP.

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Germinal center B cells are dispensable in prion transport and neuroinvasion

Cited by 18 publications

References 52 publications

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Genetic Depletion of Complement Receptors CD21/35 Prevents Terminal Prion Disease in a Mouse Model of Chronic Wasting Disease

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

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