Comparison of B-cell anomalies in the peripheral blood from human pulmonary arterial hypertension (PAH) patients and the lungs from animal pulmonary hypertension (PH) models
| Human diseases (peripheral blood) | References | Experimental diseases (lungs) | References | |
| B-cell homeostasis | ↓ Total B-cells ↑ Naïve B-cells ↑ Plasmablasts and plasma cells ↓ Memory B-cells ↑ Activated B-cells | [10] | ↑ Total B-cells (MCT, Su/Hx) ↑ Memory B-cells (Hx) ↑ Expression of B-cell activation genes (MCT) | [22, 30, 119] |
| BCR signalling | ↑ Expression of BCR signalling genes ↑ Expression of BTK gene in total B-cells, naïve B-cells, memory B-cells ↑ BTK activity in total B-cells, correlated with ANA positivity | [8, 21] | ↑ Expression of BCR signalling genes, correlated with disease severity (MCT) ↑ BTK staining, mostly colocalised with macrophages (MCT) B-cell-specific overexpression of BTK induces PH and generates anti-endothelial cell Abs in mice exposed to intratracheal BLM | [5, 22, 23] |
| Th2 cells, IL-4, IL-6 and IL-13 | ↑ IgE levels and IgE+ B-cells | [26] | ↑ IgE+ B-cells (Hx/OVA, MCT) ↑ Expression of CD86, CD40 and GLε by B-cells, suggesting B-cell/T-cell interaction and IgE production (MCT) Th2 inhibition and IL-4/13 neutralisation decrease IgE+ B-cell infiltration and attenuate PH (Hx/OVA) | [25, 26] |
| Tfh cells and IL-21 | ↑ cTfh cells (especially cTfh17 subset), correlated with BTK levels in B-cells cTfh cells induce preferential plasmablast differentiation and IgG/IgM production, an effect that is neutralised by IL-21 antagonist (SSc) | [5, 34] | ↑ Tfh cells (Hx) ↑ Expression of IL-21 gene (MCT) | [22, 119] |
| BAFF system | Correlation of BAFF levels with PH markers (SSc-PAH) | [45] | ↑ Expression of BAFF and BAFF-R genes, correlated with disease severity (MCT) | [22] |
| Anti-endothelial cell Abs | Frequent occurrence of anti-endothelial cell Abs Induction of pro-inflammatory and pro-adhesive properties in endothelial cells | [74, 80] | ICs decorate lumen-obliterating endothelial cells (Su/OVA) Serum IgA stains PA intima (PH model induced by cDC-specific A20 deficiency) | [103, 115] |
| Anti-fibroblast Abs | Frequent occurrence of anti-fibroblast Abs Anti-fibroblasts target vimentin, calumenin, PI3K, tropomyosin 1, HSP27, HSP70 Induction of pro-inflammatory, pro-adhesive and pro-fibrotic properties in fibroblasts | [84, 85] | Serum IgG stains PA adventitia (MCT) Anti-fibroblast Abs target vimentin, PI3K and HSP27 in lung fibroblasts (MCT) | [60] |
| Anti-AT1R/ETAR Abs | Frequent occurrence of AT1R/ETAR Abs Agonistic properties in endothelial cells and SMCs | [62, 86] | Passive transfer of human anti-AT1R Abs induces pulmonary vasculopathy in healthy mice Passive transfer of human anti-ETAR worsens PH in MCT rats | [86, 110] |
| Bregs | ↓ CD24hi CD27+ Bregs (SSc-PAH) | [14] | ↓ Expression of blimp1 (Breg transcription factor) Adoptive transfer of Bregs improves PH in Hx mice Bregs co-cultured with PA-SMCs inhibit their hypoxia-induced proliferation | [119] |
Human data usually refer to idiopathic (i)PAH and connective tissue disease (CTD)-PAH patients, except when otherwise stated. Animal data are gathered from several animal models, mostly monocrotaline (MCT) rats and variations of hypoxia (Hx) and Sugen (Su) mice (sometimes with additional exposure to ovalbumin (OVA)). BCR: B-cell receptor; Th: T-helper cell; IL: interleukin; Tfh: T follicular helper cell; BAFF: B-cell activating factor; Ab: antibody; AT1R: angiotensin receptor 1; ETAR: endothelin receptor A; Breg: regulatory B-cell; BTK: Bruton tyrosine kinase; ANA: antinuclear antibody; BLM: bleomycin; Ig: immunoglobulin; CD: cluster of differentiation; GL: germline; cTfh: circulating Tfh; SSc: systemic sclerosis; BAFF-R: BAFF receptor; IC: immune complex; PA: pulmonary artery; cDC: conventional dendritic cell; PI3K: phosphoinositide 3-kinase; HSP: heat-shock protein; SMC: smooth muscle cell; blimp1: B-lymphocyte-induced maturation protein 1.