Autoimmune Theories of Chronic Spontaneous Urticaria

Urticaria (hives) is a highly prevalent skin disorder that can occur with or without associated angioedema. Chronic spontaneous urticaria (CSU) is a condition which persists for more than 6 weeks in duration and occurs in the absence of an identifiable provoking factor. CSU results from pathogenic activation of mast cells and basophils, which gives rise to the release of proinflammatory mediators that support the generation of urticaria. Several theories have been put forth regarding the pathogenesis of CSU with much evidence pointing toward a potential autoimmune etiology in up to 50% of patients with this condition. In this review, we highlight the evidence surrounding the autoimmune pathogenesis of chronic urticaria including recent data which suggests that CSU may involve contributions from both immunoglobin G (IgG)-specific and immunoglobulin E (IgE)-specific autoantibodies against a vast array of antigens that can span beyond those found on the surface of mast cells and basophils

Development of Immunologic Tolerance in a Murine Model of House Dust Mite-Induced Asthma

Archival abstract submitte

Regulation of IgE activity in inhalational tolerance via formation of IgG anti-IgE/IgE immune complexes

Abstract Background Allergic asthma is an inflammatory disorder of the airways that results from inappropriate production of IgE against harmless, environmental antigens. Sequestration of free IgE using humanized IgG anti-IgE is an effective therapy for asthma and other atopic disorders. However, the status of free IgE in subjects who have naturally developed immune tolerance to inhaled antigens has not been well studied. Methods C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) for 7 days to induce allergic airway disease (AAD) or 6 weeks to induce a state of local inhalational tolerance (LIT). Serum from AAD or LIT mice, diluted to achieve equivalent levels of total OVA-specific IgE, was used to sensitize rat basophil leukemia cells for allergen-mediated degranulation. Levels of degranulation were measured in relation to serum concentrations of free IgE and IgG anti-IgE/IgE immune complexes. Results Serum from AAD animals induced a greater degree of basophil degranulation than serum from LIT animals. These results correlated with higher levels of free IgE in AAD animals, whereas LIT mice demonstrated a significant increase in IgG anti-IgE/IgE immune complexes relative to their diseased counterparts. Conclusions Sequestration of free IgE by naturally occurring IgG anti-IgE may aid in the development of immune tolerance against inhaled allergens. The decrease in bioavailability of free IgE may, in turn, contribute to the overall reduction of asthma symptoms via a mechanism that mimics the therapeutic effects of humanized IgG anti-IgE

Poor Long-Term Efficacy of Prevnar-13 in Sickle Cell Disease Mice Is Associated with an Inability to Sustain Pneumococcal-Specific Antibody Titers.

One of the most common causes of morbidity and mortality in children with sickle cell disease (SCD) is infection with the pneumococcal bacterium (Streptococcus pneumoniae). Unfortunately, the polysaccharide-conjugate vaccine appears to be less effective in individuals with SCD when compared to the general population. We sought to better understand the relative efficacy of pneumococcal vaccination in a SCD mouse challenge model.Transgenic control and SCD mice were monitored for mortality after intranasal pneumococcal infection or pneumococcal vaccination with Prevnar-13 and type-matched challenge. Anti-pneumococcal antibody titers were measured by ELISA and opsonophagocytosis was measured in vitro.Mortality after pneumococcal infection was similar between control and SCD mice. However, after three intramuscular polysaccharide-conjugate vaccinations, all control mice were protected following high-dose intranasal infection, whereas 60% of SCD mice died. Anti-pneumococcal antibody titers showed initial IgG and IgM responses in both groups, but waning titers were observed in the SCD group, even after boosting. When functionally assayed in vitro, serum from SCD mice 13 weeks after a second booster shot maintained little to no ability to opsonize pneumococci, while serum from control mice sustained a significantly higher capacity opsonization. Thus, it appears that SCD mice do not maintain antibody responses to pneumococcal polysaccharides after Prevnar-13 vaccination, thereby leaving them susceptible to mortality after type-matched infection.Our results emphasize the need to better understand the correlates of immune protection in SCD so that pneumococcal vaccines can be improved and mortality reduced in this susceptible population

Prevnar-13 vaccination does not protect SCD mice from pneumococcal infection.

<p>Mice were vaccinated and challenged according to the schedule outlined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149261#pone.0149261.g001" target="_blank">Fig 1</a>. Mice were intranasally challenged with 1X10⁶ CFU of A66.1 and mortality was assessed measured. <i>p</i> = 0.01, as determined by the log-rank/Mantel-Cox test. White boxes = SCD, black boxes = controls.</p

Pneumococcal-specific antibody titers after vaccination.

<p>PPS3-specific total IgG (A), IgG3 (B), and IgM (C) antibody titers were measured by ELISA in Prevnar-13 vaccinated 2–3 month old control and SCD mice at weeks 0 (before vaccination), 4, 9, and 14. * = <i>p</i> < 0.05 and ** = <i>p</i> <0.01 for between groups comparisons at the same time point (as determined using a two-tailed Student’s T-test) and † = <i>p</i> < 0.05 for within group comparisons across time points (as determined using a One-way ANOVA). For IgM comparisons between groups, <i>p</i> = 0.07 and <i>p</i> = 0.08 at weeks 4 and 9, respectively. For IgM comparisons within the control group, <i>p</i> = 0.08. White boxes = SCD, black boxes = controls.</p

Mouse model of pneumococcal vaccination and infectious challenge.

<p>2–3 month old mice were bled, and serum was collected prior to initial priming with Prevnar-13 on week 0. Mice were boosted on weeks 3 and 5 with the same vaccine. Mice were again bled on weeks 4, 9, and 14. Mice were then challenged with the virulent A66.1 strain of <i>S</i>. <i>pneumoniae</i> on week 18 and mortality was assessed for 16 days after challenge.</p

Histopathology and Gram staining of lung tissues in mice that succumb to intranasal pneumococcal infection.

<p>H+E staining of lung tissue from control (A) and SCD (B) mice after they succumbed to pneumococcal infection. Gram stain of the same lung tissue in control (C) and SCD (D) mice. Wide arrows point to pneumococci in blood vessels and narrow arrows point to pneumococci colonizing the surface of the lung tissue.</p

Transgenic Sickle Cell Disease Mice Have High Mortality and Dysregulated Immune Responses After Vaccination

Background Children with sickle cell disease (SCD) are susceptible to recurrent infections, which are often life threatening and necessitate frequent vaccinations. Given the altered baseline immunity and proinflammatory state associated with SCD, we sought to determine the relative safety and efficacy of vaccination in transgenic SCD mice. Methods Eight week-old SCD mice were vaccinated with ovalbumin (OVA) and aluminum hydroxide weekly for three weeks by the intraperitoneal (IP) or intramuscular (IM) route. One week after the third vaccination, serum cytokines/chemokines, immunoglobulins, and bronchoalveolar lavage (BAL) fluid cytokines were measured. Results Only SCD mice were prone to mortality associated with vaccination as 40% of the animals died after the IP vaccinations and 50% died after the IM vaccinations. Serum IgG2b and IgM were significantly lower in SCD than C57Bl/6 mice after vaccination, but OVA-specific IgE was significantly higher. Serum interleukin 1 alpha (IL-1α), IL-2, IL-5, macrophage inflammatory protein 1 alpha (MIP-1α), and granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly lower in SCD mice than C57Bl/6 mice after vaccination, whereas BAL fluid IL-1β and IL-6 were elevated. Conclusions Mice with SCD appear to have a dysregulated immune response to vaccination. Thus, the relative safety and immunogenicity of vaccination should be studied in greater detail in the context of SCD