ADAM17 deficiency

In the 1990s, it was recognized that some membrane proteins such as TNF-alpha, both TNF receptors, ligands of EGF-R and the interleukin-6 receptor are proteolytically cleaved and excreted from the cell membrane as soluble proteins. The main protease responsible is a metalloprotease that has been designated ADAM17.

ADAM17 deficiency is considered a very rare systemic autoinflammatory disease (de Jesus AA et al. 2015) characterized by autosomal recessive mutations in the ADAM17 gene, which encodes the TNF-α converting enzyme (TACE), a metalloprotease. To date, almost 100 substrates, including cytokines, cytokine receptors, chemokines and adhesion molecules of ADAM17 are known. Therefore, ADAM17 regulates many different signaling pathways and is a central hub in inflammation and carcinogenesis (Blaydon DC et al. 2011). ADAM17 plays an important role in the biology of interleukin-6 , as the formation of the soluble interleukin-6 receptor (sIL-6R) is required for trans-signaling, which has been identified as the pro-inflammatory activity of this cytokine. Due to its broad substrate spectrum, ADAM17 is essential for life. Thus, most human individuals with (the rare) ADAM17 gene defects die at a young age. Although the potential of ADAM17 as a therapeutic target has been recognized, specific blockade of ADAM17 is not trivial because the metalloprotease domain of ADAM17 has high structural homology with other proteases, especially matrix metalloproteases (Schumacher N et al. 2022). ADAM178 has been shown to play a crucial role in the regulation of the immune system and in cancer development (Schumacher N et al. 2022; Zunke F et al. 2017). ADAM17 is expressed in human dopaminergic neurons

Cutaneous: Infections are frequently observed. Other dermatologic manifestations include hair abnormalities (short or brittle hair and wiry eyelashes and eyebrows) and thickened nails with frequent episodes of paronychia.

T cell infiltrates in the epidermis. CD3+ T cells are found around the skin follicles and in the epithelium, CD4+ T cells in the perifollicular region, CD8+ T cells in the epithelium and perifollicular. Furthermore, the infiltrate is composed of B cells (CD20+), natural killer cells (CD56+) and neutrophil granulocytes (Blaydon DC et al. 2011).

Treatment with acitretin, ciclosporin, methotrexate and adalimumab has not proven effective in patients with ADAM17 deficiency. Therapies with anti-IL1/anti-IL6 antibodies are conceivable.