title: Monocyte activation is a feature of common variable immunodeficiency irrespective of plasma lipopolysaccharide levels.
abstract: Common variable immunodeficiency disorders (CVID), the most frequent cause of symptomatic primary immunodeficiency, are defined by impaired antibody production. Notwithstanding, T cell activation and granulomatous manifestations represent the main causes of CVID morbidity even in patients receiving immunoglobulin (Ig) G replacement therapy. Additionally, gut pathology is a frequent feature of CVID. In this study, we investigated monocyte imbalances and their possible relationship with increased microbial translocation in CVID patients. Monocyte subsets were defined according to CD14 and CD16 expression levels and evaluated in terms of human leucocyte antigen D-related (HLA-DR), CD86 and programmed death-1 molecule ligand 1 (PD-L1) expression by flow cytometry, in parallel with the quantification of plasma lipopolysaccharide (LPS) and serum levels of soluble CD14 (sCD14), LPS-binding protein (LBP) and anti-LPS antibodies. CVID patients (n=31) featured significantly increased levels of serum sCD14 and an expansion of CD14(bright) CD16(+) monocytes in direct correlation with T cell and B cell activation, the latter illustrated by the frequency of the CD21(low) CD38(low) subset. Such alterations were not observed in patients lacking B cells due to congenital agammaglobulinaemia (n=4). Moreover, we found no significant increase in circulating LPS or LBP levels in CVID patients, together with a relative preservation of serum anti-LPS antibodies, in agreement with their presence in commercial IgG preparations. In conclusion, CVID was associated with monocyte imbalances that correlated directly with T cell activation markers and with B cell imbalances, without an association with plasma LPS levels. The heightened monocyte activated state observed in CVID may represent an important target for complementary therapeutic strategies.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa Serviço de Imunoalergologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.
authors.forename: R R
authors.initials: RR
authors.lastname: Barbosa
authors.forename: S P
authors.initials: SP
authors.lastname: Silva
authors.forename: S L
authors.initials: SL
authors.lastname: Silva
authors.forename: R
authors.initials: R
authors.lastname: Tendeiro
authors.forename: A C
authors.initials: AC
authors.lastname: Melo
authors.forename: E
authors.initials: E
authors.lastname: Pedro
authors.forename: M P
authors.initials: MP
authors.lastname: Barbosa
authors.forename: M C P
authors.initials: MC
authors.lastname: Santos
authors.forename: R M M
authors.initials: RM
authors.lastname: Victorino
authors.forename: A E
authors.initials: AE
authors.lastname: Sousa
mesh_terms: D000209:Acute-Phase Proteins; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000097:blood / Q000276:immunology; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D002352:Carrier Proteins / Q000097:blood; D017074:Common Variable Immunodeficiency / Q000097:blood / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008070:Lipopolysaccharides / Q000097:blood*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency; D017452:Receptors, IgG / Q000097:blood; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000907:Antibodies, Bacterial; D002352:Carrier Proteins; D016207:Cytokines; D004731:Endotoxins; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D017452:Receptors, IgG; D000099231:Lipopolysaccharide-Binding Protein; C428200:FCGR3B protein, human; C042058:core endotoxin