Increased sensitivity to IL‐4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis

  title={Increased sensitivity to IL‐4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis},
  author={Alan P. Knutsen and Procter S. Hutchinson and Gary M. Albers and Judy D Consolino and J. Smick and Viswanath P. Kurup},
Background:  Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ T‐cell response to Aspergillus fumigatus allergens and a hyper‐immunoglobulin (Ig)E state compared with cystic fibrosis patients without ABPA. We hypothesize that one reason for this response is increased sensitivity to interleukin (IL)‐4 in ABPA resulting in increased expression of CD23 and CD86 and leading to a positive amplification mechanism that increases Th2 CD4+ T cell responses. 

Lymphocytes in allergic bronchopulmonary aspergillosis.

  • A. Knutsen
  • Medicine, Biology
    Frontiers in bioscience : a journal and virtual library
  • 2003
It is demonstrated that ABPA patients have increased sensitivity to IL-4 stimulation and skewing of Th2 responses to Aspergillus allergens in ABPA subjects and a Th1 response in non-ABPA subjects.

Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti‐IgE antibody (omalizumab)

A CF patient with her third exacerbation of ABPA who was treated with monoclonal anti‐IgE (omalizumab) antibody resulted in improvement of pulmonary symptoms and lung function not achieved with antibiotics or prednisone alone.

Immunopathology and Immunogenetics of Allergic Bronchopulmonary Aspergillosis

The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses to A. fumigatus antigens and suggest that immune modulation with medications such as anti-IgE, anti-IL-4, and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA.

Genetic and respiratory tract risk factors for aspergillosis: ABPA and asthma with fungal sensitization.

It is proposed that increased sensitivity of IL-4 mediated activities secondary to polymorphisms IL- 4R in conjunction of other polymorphisms such as IL-13 and IL-10 in conjunction with HLA-DR2/DR5 restriction to Aspergillus antigens in ABPA patients result in increased B-cell activity, monocyte/dendritic cell phenotype that skews Th2 responses, and skewing of As pergillus-specific Th2 cells.

Chapter 7 Allergic bronchopulmonary aspergillosis and other fungal diseases

Treatment of ABPA consists of a two tiered approach, glucocorticoids to control immunological activity and antifungal agents to suppress fungal load.

Retracted: Immunopathology and Immunogenetics of Allergic Bronchopulmonary Aspergillosis

The paper titled “Immunopathology and Immunogenetics of Allergic Bronchopulmonary Aspergillosis” has been retracted as it was found to contain a substantial amount of material from the following published article.

Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches

An update on ABPA in children with CF, where Corticosteroids, itraconazole and voriconazole continue to be the bedrock of ABPA therapy, but other molecules, such as posaconazoles, vitamin D, recombinant INF-γ and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, have been showing positive results.

Enhanced IgE allergic response to Aspergillus fumigatus in CFTR−/− mice

Cytokine mRNA levels of IL-5 and GM-CSF in the bronchoalveolar lavage (BAL) fluid, and BAL cell differentials indicated that CFTR mutation caused a shift from anIL-5-predominant to an IL-4-predominated cytokine profile.

A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection.

A role for Th17 and Th2 T cells in chronic inflammation in lungs of patients with CF is proposed, as high concentrations of these cytokines/chemokines in CF airways precede infection with P. aeruginosa.

Allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis: diagnostic criteria when the IgE level is less than 500 IU/mL.



Increased Sensitivity to IL-4 in Patients with Allergic Bronchopulmonary Aspergillosis

This is the first study to demonstrate that ABPA patients have increased sensitivity to IL-4 stimulation compared to other atopic individuals, such as ABPA > atopic >> nonatopic patients.


Asp f I CD4+ TH2-like T-cell lines in allergic bronchopulmonary aspergillosis.

Asp f I-specific T-cell lines established from patients with ABPA were characterized as being CD4+ TH2-like in their cytokine synthesis pattern, and secreted IL-4 behaved in an autocrine fashion, stimulating proliferation.

The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis.

The limited number of T cell clones isolated from three ABPA patients and their role in Ag presentation emphasizes the possibility that the six identified HLA-DR subtypes are important in the pathophysiology of ABPA.

Anti-CD86 (B7.2) treatment abolishes allergic airway hyperresponsiveness in mice.

It is suggested that the CD86 costimulatory ligand plays a major role in the development of allergic inflammation and AHR in allergen-challenged mice and that selective blockade of accessory signals can be an effective means for modulating distinct T cell functions.

IL-13 Induces Airways Hyperreactivity Independently of the IL-4Rα Chain in the Allergic Lung1

It is shown that T cell-derived IL-13 plays a key role in regulating AHR, mucus hypersecretion, eotaxin production, and eosinophilia in the allergic lung and is critically linked to downstream effector pathways regulated by eotAXin and STAT6.

Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis.

The genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while Hla-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma.

Enhanced expression of B7.2 (CD86) in patients with atopic dermatitis: a potential role in the modulation of IgE synthesis.

The predominant expression of B7.2 in AD, but not psoriasis, is demonstrated, and a novel role for this molecule in IgE synthesis is demonstrated.

Role of NK1.1+ T Cells in a TH2 Response and in Immunoglobulin E Production

CD1-specific splenic CD4+NK1.1+ T cells, a numerically minor population, produced IL-4 promptly on in vivo stimulation and was essential for the induction ofIL-4-producing cells and for switching to immunoglobulin E, an IL- 4-dependent event, in response to injection of antibodies to immunglobulin D.