We discuss here the mechanism by which dendritic cells mistake human or self-DNA for pathogenic DNA. When self-DNA fragments form aggregates with LL37, it results in psoriasis.
We have learned that the skin is resident to T cells and dendritic cells. These cells conduct surveillance for detecting and dealing with bacteria and viruses. At the same time, they are tolerant to signals that arise from self or the person. In Part I and Part II of this blog series, we have been alluding to the disease state that could arise if there was a breakdown in communication in the skin.
It is a normal physiological event for human cells in the body to die and turnover. There are enzymes outside cells (extracellular nucleases) that rapidly degrade self-DNA released by dying cells. Receptors for bacterial and viral DNA (toll like receptor 9) (TLR9) are strategically located inside live cells along pathways to pick up signals from these pathogens. In psoriasis, the barriers that keep self-DNA and pathogen signals separated get mixed.
Scientists have deduced the mechanism which leads dendritic cells to mistake human or self-DNA for pathogenic DNA. There is confusion because self-DNA fragments form aggregates with LL37. LL37 is anti-bacterial protein made by keratinocytes (skin cells) in response to skin damage by infection or injury. The LL37-bound self-DNA structures resist degradation and they trigger dendritic cells to signal an invasion. T cells respond and the end result is a reaction by local keratinocytes that undergo abnormal cell differentiation. What we then see are lesional psoriasis skin, with thickened epidermis and redness due to inflammation.
Psoriasis is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Today, we have specific antagonists or drugs that block specific signaling pathways. These pharmaceuticals in combination with accessibility to diseased tissue have permitted the dissection of pathogenic pathways – a feat not possible in less accessible diseased tissues such as rheumatoid arthritis and Crohn’s disease. Several single genetic mutations have also been identified that contribute to disease risk. In particular, two gene mutations (IL36RN and CARD14), can cause psoriasis as well as effect the immune system.
Acquiring psoriasis can lead to the development of other immune related diseases. There is continuous progress in research and development towards better understanding of the disease and development of drugs. Last month, for example, the FDA approved Otezla for psoriatic arthritis. We at HemaCare provide disease-state cells including myeloid cells, dendritic cells, and T cells from psoriasis donors to enable researchers in their work for management of this debilitating disease.
1. Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014 Mar 21;32:227-55. PMID: 24655295.