Pathogen and autoantigen homologous regions within the cystic fibrosis transmembrane conductance regulator (CFTR) protein suggest an autoimmune treatable component of cystic fibrosis

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel provides the glutathione and hypochlorous acid necessary for bactericidal/viricidal actions. CFTR mutations block these effects, diminishing pathogen defence and allowing extracellular pathogen accumulation, where antibody encounter is likely. KEGG pathway analysis of the CFTR interactome shows that CFTR is involved in pathogen entry pathways and immune defence as well as in pathways relevant to comorbid conditions (diabetes, cardiomyopathies and sexual organ development). Pseudomonas aeruginosa and Staphylococcus aureus infections decrease the lifespan of cystic fibrosis patients and Stenotrophomonas maltophilia colonization is increased. Autoantibodies, targeting myeloperoxidase, the bactericidal/permeability-increasing protein and calgranulin may further compromise pathogen defence. Short consensus sequences, within immunogenic extracellular regions of the CFTR protein, are homologous to proteins expressed by P. aeruginosa, S. aureus and S. maltophilia, and to several autoantigens, with a universal overlap between autoantigen/pathogen/CFTR consensi. Antibodies to pathogens are thus likely responsible for the creation of these autoantibodies, which, with pathogen antibodies, may target the CFTR protein acting as antagonists, further compromising its function. This creates a feedforward cycle, diminishing the function of the CFTR protein and increasing the probability of pathogen accumulation and antibody production at every turn. Interruption of this cycle by antibody adsorption or immunosuppressant therapy may be beneficial in cystic fibrosis.

Antisera preparation and epitope mapping of a recombinant protein comprising three peptide fragments of the cystic fibrosis transmembrane conductance regulator

“…For instance, 29 RQRLEL 34 is present in P. aeruginosa and S. maltophilia [12]; 104 RIIASY 109 and 111 PDN 113 partially overlap with proteins in S. maltophilia, P. aeruginosa, S. aureus, and the autoantigens proteinase 3 and myeloperoxidase; and 1447 VKLF 1450 overlaps completely with S. maltophilia and partially with P. aeruginosa and S. aureus proteins as well as the autoantigen bactericidal/permeabili ty-increasing protein. However, the predicted B cell epitopes 104 RIIASY 109 and 111 PDN 113 were not in complete agreement with previously reported immunogenicity indices, while the predicted B cell epitopes 29 RQRLEL 34 and 1447 VKLF 1450 also showed discrepancy with predicted indices [12]. These findings may be explained by subtle differences between recombinant and native proteins.…”

“…This combined with our experimental evidence that CFTR B cell epitopes react with antiserum against the CFTR protein suggests that protein functions may be impaired by antibodies to pathogens and by the generation of autoantigens when epitopes share sequence similarity with bacteria or autoantigens [12]. Moreover, short consensus sequences of the CFTR protein are homologous to proteins expressed by Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Staphylococcus aureus as well as to several autoantigens.…”

“…Infection by bacteria or viruses with sequence homology to CFTR may elicit the mass production of antibodies that affect CFTR function by binding to immunogenic regions of the protein in different cells [12]. For example, human sperm CFTR plays an important role in fertilization capacity and quality [35,36].…”

“…For instance, short CFTR consensus sequences that are homologous to proteins expressed by bacteria or viruses can induce autoimmunity via molecular mimicry [12]. Accordingly, epitope mapping of CFTR is important for understanding autoimmune and immune responses [13], gaining insight into mechanisms of therapeutic antibodies [14,15], and securing and protecting intellectual property [16].…”

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation

“…20,21 The presence of autoimmunity and autoantibodies in CF with as-yetunknown cross-reactivities and pro-inflammatory immune responses in the presence of recipient HLA polymorphisms (HLA-DR4 and HLA-DR7) and persistent infections after transplant due to colonization may also contribute. 22 It has also been demonstrated that T-lymphocytes in CF patients exhibit a pattern of cytokine production different from that of normal T-lymphocytes, and this could be the direct influence of the CFTR gene on normal T-lymphocyte expression. 23,24 The median time to DSAs detection was 557 days after transplant and all were de novo.…”