ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the clinical syndrome COVID-19 is associated with an exaggerated immune response and monocyte infiltrates in the lungs and other peripheral tissues. It is now increasingly recognised that chronic morbidity persists in some patients. We recently demonstrated profound alterations of monocytes in hospitalised COVID-19 patients. It is currently unclear whether these abnormalities resolve or progress following patient discharge. We show here that blood monocytes in convalescent patients at their 12 week follow up, have a greater propensity to produce pro-inflammatory cytokines TNF and IL-6, which was consistently higher in patients with resolution of lung injury as indicated by a normal chest X-ray and no shortness of breath (a key symptom of lung injury). Furthermore, monocytes from convalescent patients also displayed enhanced levels of molecules involved in leucocyte migration, including chemokine receptor CXCR6, adhesion molecule CD31/PECAM and integrins VLA-4 and LFA-1. Expression of migration molecules on monocytes was also consistently higher in convalescent patients with a normal chest X-ray. These data suggest persistent changes in innate immune function following recovery from COVID-19 and indicate that immune modulating therapies targeting monocytes and leucocyte migration may be useful in recovering COVID-19 patients with persistent symptoms.
ABSTRACT
Wealth of structural data on theurapeutic targets in complex with monoclonal antibodies (mAbs) and advances in molecular modeling algorithms present exciting opportunities in the field of novel biologic design. Interleukin 23 (IL23), a well-known drug target for autoimmune diseases, in complex with mAb 7G10 offers prospect to design potent lead antibodies by traversing the complete epitope-paratope interface. Herein, key interactions aiding antibody-based neutralization in IL23-7G10 complex are resolute through PyMOL, LigPlot+, Antibody i-Patch, DiscoTope and FoldX. Six amino acids Ser31, Val33, Asn55, Lys59 in heavy chain and His34, Ser93 in light chain are subjected to in silico mutagenesis with residues Met, Trp, Ile, Leu and Arg. A set of 431 mutant macromolecules are outlined. Binding affinities of these molecules with IL23 are estimated through protein-protein docking by employing ZDOCK, ClusPro and RosettaDock. Subsequently, the macromolecules revealed comparable result with 7G10 are cross validated through binding free-energy calculations by applying Molecular Mechanics/Poisson Boltzman Surface Area method in CHARMM. Thirty nine designed theoretical antibodies showed improved outcome in all evaluations; from these, top 10 molecules showed at least nine unit better binding affinity compared to the known mAb. These molecules have the potential to act as lead antibodies. Subsequent molecular dynamics simulations too favored prospective of best ranked molecule to have therapeutic implications in autoimmune and inflammatory diseases. Abbreviations: IL23: interleukin 23; IL17: interleukin17; Ab: antibody; Ag: antigen; mAbs: monoclonal antibodies; STAT3: signal transducer and activator of transcription 3; STAT4: signal transducer and activator of transcription 4; PDB: protein databank; MM/PBSA: molecular mechanics Poisson-Boltzmann surface area; Ag-Ab: antigen- antibody complex; SPC/E: extended simple point charge; SD: steepest descents; PME: particle mesh ewald; dG: binding free energies; Fv: variable fragment.
Subject(s)
Antibodies, Monoclonal/immunology , Autoimmune Diseases/immunology , Inflammation/immunology , Interleukin-23/chemistry , Antibodies, Monoclonal/chemistry , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Binding Sites, Antibody , Computational Biology , Epitopes/chemistry , Epitopes/immunology , Humans , Hydrogen Bonding , Inflammation/drug therapy , Inflammation/genetics , Interleukin-23/immunology , Molecular Dynamics Simulation , STAT3 Transcription Factor/chemistry , STAT3 Transcription Factor/immunology , STAT4 Transcription Factor/chemistry , STAT4 Transcription Factor/immunologyABSTRACT
Ossifying fibromas are benign fibro-osseous tumors of mesenchymal origin. Although ossifying fibromas have principally been found in the jaw, they have also been reported in the frontal, ethmoid, sphenoid, and temporal bones, as well as the orbit and anterior cranial fossa. Ossifying fibromas affecting the jaw exhibit variable behaviors ranging from slow growth to occasionally aggressive local destruction. In the present article, we discuss a differential diagnosis considered for maxillary swellings and report a rare case of ossifying fibroma occurring in the maxilla.
Subject(s)
Bone Neoplasms , Cranial Fossa, Anterior , Diagnosis, Differential , Fibroma, Ossifying , Jaw , Maxilla , Orbit , Temporal BoneABSTRACT
Adenoid cystic carcinoma is a rare epithelial tumour, and comprises about 1% of all malignant tumours of the oral and maxillofacial region. It is a malignant tumour which may develop in the trachea, bronchus, lungs or mammary glands, in addition to the head and neck region. Occurrences in the head and neck are mostly detected in the major salivary gland, oral cavity, pharynx and paranasal sinus where it presents as a slow growing firm nodular swelling. The aim of the article is to highlight the unique presentation of adenoid cystic carcinoma as a solitary ulcer on the floor of the mouth.
