ADAM17 deficiency D82.-

In the 1990s, it was recognized that some membrane proteins such as TNFalpha, 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 known as 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 dermatological 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.

An LOF mutation in ADAM17 was detected in 2 adolescent siblings (sister and brother) with autosomal recessive neonatal inflammatory skin and intestinal lesions. Clinically, neonatal pustular psoriasis was diagnosed. Later, bloody diarrhea and cardiomyopathy were added. The girl died suddenly at the age of 12 from parvovirus B19-associated myocarditis. Peripheral blood mononuclear cells (PBMCs) taken from the brother at the age of 17 years showed high levels of lipopolysaccharide-induced production of interleukin-1beta and interleukin-6, but decreased release of TNF-alpha. Despite repeated skin infections, the brother led a normal life (Blaydon DC et al. 2011).

1. de Jesus AA et al. (2015) Molecular mechanisms in genetically defined autoinflammatory diseases: disordersof amplified danger signaling. Annu Rev Immunol 33:823-874
2. Blaydon DC et al. (2011) Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 365:1502-1508.
3. Schumacher N et al. (2022) ADAM17 orchestrates Interleukin-6, TNFα and EGF-R signaling in inflammation and cancer. Biochim Biophys Acta Mol Cell Res 1869(1):119141.
4. Zunke F et al. (2017) The shedding protease ADAM17: Physiology and pathophysiology. Biochim Biophys Acta Mol Cell Res 1864:2059-2070.