Immune response against HtrA proteases in children with cutaneous mastocytosis

Abstract

Mast cells play an important role in both, the innate and adaptive immunity, however, clonal proliferation of abnormal mast cells in various organs leads to mastocytosis. A skin variant of the disease, cutaneous mastocytosis (CM) is the most frequent form of mastocytosis in children. HtrA proteases are modulators of important cellular processes, including cell signaling and apoptosis, and are related to development of several pathologies. The above and the observation that mast cells constitutively release the HtrA1 protein, prompted us to investigate a possible involvement of the HtrA proteins in pediatric CM. Levels of the serum autoantibodies (IgG) against the recombinant HtrA proteins (HtrA1-4) in children with CM (n=36) and in healthy controls (n=62) were assayed. Anti-HtrA IgGs were detected using enzyme linked immunosorbent assay (ELISA) and Western-blotting. In the CM sera, levels of the anti-HtrA1 and anti-HtrA3 autoantibodies were significantly increased when compared to the control group, while the HtrA protein levels were comparable. No significant differences in the anti-HtrA2 IgG level were found; for the anti-HtrA4 IgGs lower levels in CM group were revealed. In healthy children, the IgG levels against the HtrA1, -3 and -4 increased significantly with the age of children; no significant changes were observed for the anti-HtrA2 IgG. Our results suggest involvement of the HtrA1 and HtrA3 proteins in pediatric CM; involvement of the HtrA4 protein is possible but needs to be investigated further. In healthy children, the autoantibody levels against HtrA1, -3 and -4, but not against HtrA2, increase with age.

Tumor Suppressors—HTRA Proteases and Interleukin-12—in Pediatric Asthma and Allergic Rhinitis Patients

“…Nevertheless, while in CM as in a lymphoproliferative disorder, the release of HTRA2 from abnormal MCs into extracellular space (ECS) might be expected; the reason why HTRA2 is assessed in serum in higher amounts than in controls in allergy remains unclear. Moreover, in a previous study we have found that anti-HTRA1, 3 and 4 antibody levels were importantly higher in CM group than in controls in accordance with its recently proved presence in ECS [ 19 , 30 ]. Anti-HTRA2 levels were at the same range as in controls [ 27 ].…”

“…It correlates with the general clinical observation that atopic patients are less prone to develop certain types of neoplasms [ 4 ]. These results were found interesting since the HTRA protein levels and anti-HTRA antibodies in mast cell–related disorders were analyzed in our earlier study concerning pediatric patients with cutaneous mastocytosis (CM), a disease due to abnormal accumulation of MCs [ 30 ]. This lymphoproliferative mast cell disorder in adulthood is always linked with augmented risk of hematologic malignancies [ 31 ].…”

“…MCs support tumor invasiveness by releasing a broad range of matrix metalloproteinases (MMPs) [ 13 ]. Our data concerning the serum level of HTRA family apoptosis regulators in pediatric CM, among them HTRA1 constitutively released from MCs, has shown similar levels of HTRA1, 3 and 4 proteins as in healthy, pediatric group [ 30 ]. Unexpectedly, it was only HTRA2 serum level that was higher in CM than in controls.…”

Cellular Functions of High-Temperature Requirement Factor A4 in Placenta

“…Several studies have demonstrated that HtrA4 is highly expressed in the sera of patients with preeclampsia, and can affect the invasion and migration of trophoblasts, leading to this condition [6,9,13]. In addition, HtrA4 has been upregulated in breast carcinoma [14], while it is downregulated in glioblastoma [15], pancreatic cancer [16], and pediatric disease compared to normal samples [17]. Moreover, Varambally et al reported that the expression of HtrA4 is lower in hormone-refractory metastatic prostate cancer than in primary prostate carcinoma [18].…”