The current study provides evidence that oral fluids reflect systemic changes that accompany NS; and highlights the potential use of saliva as a bio-fluid for systemic monitoring. Furthermore, the results show a unique inflammatory pattern in children with NS, characterized by low salivary IL-8. However, this pattern does not clearly differentiate between remission and relapse states.
While the main characteristic of NS is significant proteinuria and a general decrease in circulating plasma proteins, its impact on capillary permeability in various organs, such as the salivary gland, is unknown. In the current cohort of children with NS, saliva showed a similar pattern to serum, with lower protein levels, especially in the relapse state. Therefore, despite the increased permeability of the glomerular filter in NS, capillary permeability of the salivary gland appears to be unaffected. Decreased serum protein levels correlate with changes in saliva composition that are evident in other diseases [10, 11], and corroborate the intimate relation between serum and saliva characteristics. Furthermore, similar correlations have been shown between saliva and systemic markers for various conditions such as diabetes [8] and autoimmune disorders [9] in adults. In children, changes in salivary markers have also been shown for various conditions, such as autistic spectrum disorder [12], Down Syndrome [13], pertussis [14], pneumonia [15] and asthma [16].
Children with NS are prone to infections due to a loss in immune system factors such as immunoglobulins in the urine [17]. Furthermore, the steroidal treatment that is administered as an immune suppressive may impair general and oral health. The current study supports these premises, and showed reduced inflammatory markers (IL-6 and IL-8) in children with NS versus healthy children. Similarly, in their cohort of children with NS, Guimarães et al. found low levels of systemic inflammatory markers including circulating B lymphocytes, NK and NKT cells [18].
A possible etiology of NS is abnormalities in the immune system, either in the humoral or cellular arms [19]. This is based on a number of observations. One is the sensitivity of most forms of primary NS to inhibitors of T lymphocyte: mycophenolate mofetil, corticosteroids, calcineurin inhibitors and alkylating agents. Second is the frequent occurrence of measles and malaria, following remission of NS, both of which are diseases that impair cell-mediated immunity. Third is the detection of MCNS as a paraneoplastic manifestation of lymphoreticular malignancies and other Hodgkin’s disease. Furthermore, depressed cell-mediated immunity has been observed during relapses of MCNS. This has been shown in conjunction with alterations in T cell subsets and increased cell surface expression of IL-2 receptors on T cells, reflective of T cell activation [20, 21]. In a transcriptome analysis of SRNS vs. SSNS, Gyung Kang et al. recently showed a significant difference in the IL-4 pathways of mononuclear cells [22]. However, the current study did not find a difference in salivary IL-4 between the two groups. This discrepancy may be explained by the participation of immune cells other than mononuclear cells, in saliva cytokine secretion. Furthermore, Gyung Kang et al. found that the differences in these pathways are associated with IL-4 receptors, and not with the cytokine itself.