Transgenic sickle cell disease mice have high mortality and dysregulated immune responses after vaccination

Szczepanek, Steven M.; Secor, Eric R.; Bracken, Sonali; Guernsey, Linda; Rafti, Ektor; Matson, Adam; Thrall, Roger S.; Andemariam, Biree

doi:10.1038/pr.2013.85

Cited by 16 publications

(19 citation statements)

References 28 publications

(36 reference statements)

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“…Histopathology and immunophenotyping suggests that naïve SCD mice exist in a pro-inflammatory immune state, in agreement with previous reports from our laboratory 25,26 and that of other groups in both mouse models 37,38 and in humans with SCD 39 . The immune system in SCD may be primed to respond aggressively to inhaled allergen by virtue of this pro-inflammatory state, providing one explanation for the high morbidity and mortality seen in SCD patients with asthma.…”

Section: Discussionsupporting

confidence: 92%

“…Our group has previously reported an altered baseline immunophenotype in the serum, gut, and spleen of SCD mice 25 , raising speculation that disruption in SCD splenic lymphofollicular morphology results in impaired systemic immunity. Furthermore, we have shown sensitization with systemically administered ovalbumin (OVA)/alum leads to increased mortality, antigen-specific serum IgE, and BAL fluid IL-6, and IL-1β 26 . Additionally, Nandekar et al demonstrated histopathological evidence of enhanced pulmonary inflammation in SCD mice under an experimental asthma protocol 27 .…”

Section: Introductionmentioning

confidence: 99%

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The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

Andemariam

Adami

Singh

et al. 2015

Translational Research

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Co-morbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We utilized a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal (IP) route followed by daily, nose-only OVA-aerosol challenge to induce AAD. The lungs of naive SCD mice showed signs of inflammatory and immune processes: (1) histologic and cytochemical evidence of airway inflammation as compared to naïve wildtype mice; (2) bronchoalveolar lavage fluid (BAL) contained increased total lymphocytes, %CD8+ T cells, G-CSF, IL-5, IL-7, and CXCL1, and (3) lung tissue and hilar lymph node (HLN) had increased CD4+, CD8+, and regulatory T cells (Tregs). Further, SCD mice at AAD demonstrated significant changes compared to the naïve state: (1) BAL with increased %CD4+ T cells and Tregs, lower %CD8+ T cells, and decreased IFNγ, CXCL10, CCL2, and IL-17, (2) serum with increased OVA-specific IgE, IL-6, and IL-13, and decreased IL-1α and CXCL10, (3) no increase in Tregs in the lung tissue or HLN, and (4) hypo-responsiveness to methacholine challenge. In conclusion, SCD mice have an altered immunologic pulmonary milieu and physiologic responsiveness. These findings suggest that the clinical phenotype of AAD in SCD mice differs from that of wildtype mice and suggests that individuals with SCD may also have a unique, divergent phenotype perhaps amenable to a different therapeutic approach.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

Andemariam

Adami

Singh

et al. 2015

Translational Research

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“…Indeed, several reports [9, 10, 11, 15] by different groups have shown increased mortality, lung histopathology, and eosinophilia in SCD mice when compared to WT mice in the OVA model. Neither a high nor a low dose of HDM resulted in a difference between the genotypes in terms of these inflammatory outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…These mice also exhibit greater airway hyperreactivity (increased airway resistance after methacholine challenge) than WT mice with AAD, as measured by plethysmography [11]. Other consistent findings between humans and mice with SCD and asthma include high levels of allergen-induced immunoglobulin E (IgE) and Th2 cytokines in both the blood and respiratory mucosa [10-15]. …”

Section: Introductionmentioning

confidence: 99%

House Dust Mite-Induced Allergic Lung Inflammation Is Not Exacerbated in Sickle Cell Disease Mice

Jiang

Gavitt

Szczepanek

2019

Int Arch Allergy Immunol

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Aim: Asthma appears to be a common comorbid condition in children with sickle cell disease (SCD), and such individuals may be at a higher risk for increased morbidity and mortality. However, several reports have indicated that asthma severity is not particularly high in those with SCD, and airway hyperreactivity and wheeze may be independently associated with SCD. In SCD mice, exacerbated allergic airway disease (AAD) has been observed in response to the model antigen ovalbumin (OVA). We sought to determine if allergic lung inflammation is also exacerbated in SCD mice when they are exposed to the human allergen, house dust mite (HDM). Methods and Results: Eosinophil counts in bronchoalveolar lavage fluid were determined by cytocentrifugation and increased in both wild-type (WT) and SCD mice after acute exposure to a high dose (25 µg) of HDM, which then decreased in chronically exposed mice. WT mice exposed to a low dose of HDM (1 µg) followed the same pattern of eosinophil flux, but SCD mice did not induce much eosinophilia after acute exposure to HDM. As was observed in previous studies, lung lesions similarly increased in severity in both WT and SCD mice after acute exposure to HDM, which remained elevated after chronic exposure. Furthermore, serum HDM-specific IgE titers similarly increased and selected serum cytokines were similar in both WT and SCD mice. Conclusion: These results contrast with previous reports of exacerbated AAD in SCD mice exposed to OVA and support the alternative hypothesis that asthmatic responses are normal in those with SCD.

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“…Following the identification of a heightened systemic inflammatory state in SCD mice and humans, studies evaluated organ‐specific profiles for injury, with a particular focus on inflammatory and oxidative stress markers in SCD mice models . Although the lungs are a well‐known target of injury in SCD, there is limited knowledge of the airway inflammatory markers in sickle cell lung disease and are largely based on murine studies (Table ) and vary based on the antigen used to study immune responses . While low dose LPS challenge was associated with elevated levels of TNFα, IL‐1β, and soluble VCAM in serum and broncho‐alveolar lavage (BAL) fluid in transgenic sickle cell mice, systemic OVA challenge (intraperitoneal or intramuscular injections) was associated with increased serum IgE, increased IL‐6, and IL‐1β, in BAL and airway tone, in the absence of histological changes in transgenic SCD mice .…”

Section: Sickle Cell Disease Acute Chest Syndrome and Asthmamentioning

confidence: 99%

Airway inflammation in sickle cell disease—A translational perspective

Manwani

Rastogi

2018

Pediatric Pulmonology

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Asthma and sickle cell disease (SCD) are common chronic conditions in children of African ancestry that are characterized by cough, wheeze, and obstructive patterns on pulmonary function. Pulmonary function testing in children with SCD has estimated a prevalence of obstructive lung disease ranging from 13% to 57%, and airway hyper-responsiveness of up to 77%, independent of a diagnosis of asthma. Asthma co-existing with SCD is associated with increased risk of acute chest syndrome (ACS), respiratory symptoms, pain episodes, and death. However, there are inherent differences in the pathophysiology of SCD and asthma. While classic allergic asthma in the general population is associated with a T-helper 2 cell (Th-2 cells) pattern of cell inflammation, increased IgE levels and often positive allergy testing, inflammation in SCD is associated with different inflammatory pathways, involving neutrophilic and monocytic pathways, which have been explored to a limited extent in mouse models and with a dearth of human studies. The current review summarizes the existent literature on sickle cell related airway inflammation and its cross roads with allergic asthma-related inflammation, and discusses the importance of further elucidating and understanding these common and divergent inflammatory pathways in human studies to facilitate development of targeted therapy for children with SCD and pulmonary morbidity.

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Transgenic sickle cell disease mice have high mortality and dysregulated immune responses after vaccination

Cited by 16 publications

References 28 publications

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

House Dust Mite-Induced Allergic Lung Inflammation Is Not Exacerbated in Sickle Cell Disease Mice

Airway inflammation in sickle cell disease—A translational perspective

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