Autoinflammatory keratinization disease:

A review of the clinical, histological, and molecular evidence

 

Link to full research: https://www.jaadinternational.org/article/S2666-3287(20)30022-5/fulltext

 

RESEARCH SUMMARY

 

Who? 

 

A literature review conducted by the Laboratory of Investigative Dermatology from Rockefeller University in New York. 

Aim? 

Re-evaluate and integrate current clinical, histological, and molecular data into a model explaining the causes of HS disease with the hope to advance novel therapeutic targets and disease management.

How was it done? 

Scholarly review of existing clinical, histological and molecular data that supports the autoinflammatory model of HS pathogenesis 

What did they find out? 

  • Both patient data and experimental lab data show that follicular occlusion is the product of inflammation rather than a cause. Clinical data observations from acne prone skin have shown that inflammation and inflammatory processes are present first before the onset of a comedogenesis. Looking at the same concept in experimental studies, researchers were able to elicit comedo formation by adding pro-inflammatory molecules, such as IL-1α, to the follicular infundibulum (the upper half of the hair follicle). In the same experiments comedo formation was halted when adding molecules that would inhibit IL-1α. In addition, knowledge from other inflammatory diseases, suggest that subclinical inflammatory state of HS skin is a primer for comedo formation, which can explain why we see comedones formed around hair follicles and distant sites.  

  • Skin fold occlusion is associated with microbiome alterations and subsequent proinflammatory keratinocyte responses. The common areas often associated with HS clinically such as the armpit, inguinal folds, and underneath the breasts are favorable anatomical sites for follicular occlusion because they can easily experience environmental changes. These changes can be in the form of moisture levels, acidity or pH, and microorganism that inhabit the area.  For example, an increase in moisture in these areas 🡪 decreases pH = more acidic environment 🡪 better environment for colonization of bacteria, proteins, and the release of inflammatory molecules 🡪 leading to follicular occlusion.

  • Inflammation in HS: Evidence from existing studies. Multiple tissue and molecular studies have established the autoinflammatory signature of HS. However, these studies have also focused on tissue collection from individuals with long standing severe disease, resulting in a lack of knowledge about the initiating disease events and early and mild HS. The diversity in the morphology of HS skin sites also makes it challenging to make general assumption about all tissue sites. Therefore, when reading studies about HS it is important to consider carefully how severity, lesions types biopsied, and treatments are defined. The mechanism of lesion development in HS is still unclear and the molecular similarities between inflammation before and after lesion formation make it even more challenging for researchers to figure out what is going on. 

  • Disease initiation is associated with systemic subclinical inflammation and dysregulated infundibular keratinocytes. Clinical and epidemiological studies overall illustrate a number of systemic disorders, such as obesity and insulin resistance, to be associated with HS and contribute to the inflammatory state of the condition. While still a topic of discussion in the research community, clinical evidence has suggested that that weight loss, smoking cessation, and dietary counseling can play a substantial role in HS management. For example, studies have shown that the polycyclic aromatic hydrocarbons found in cigarettes can change the differentiation of follicular keratinocytes (epidermal cells that make up the upper layer of the skin) which can result in more comedogenesis. It is perhaps the combination of systemic disease inflammation and inflammation from dysregulated infundibular hair follicle pathways that leads to HS.

  • T-helper Cell 17 feed-forward inflammation is prominent in established disease. T-helper 17 cells are a unique type of white blood cells that are essential in the immune system and are broadly expressed in epithelial tissue. Building on the strong body of psoriasis literature, researchers believe that a Th-17amplification pathways plays a role in the tunneling and inflammation seen in HS. 

  • The role of B Cells, despite their dominance, remains unclear. Histological studies have identified higher levels of B-cells and plasma cells in long standing and severe HS. The presence of high B cell and plasma cell numbers in skin and blood of HS patients draws similarities to the immunological profile of other autoinflammatory diseases (i.e. psoriasis, atopic dermatitis). The exact role of B cells in HS is unclear in both severe and mild cases of HS.

  • Genetic Variants in HS may act via EGFR-associated pathways linking follicles, T-helper Cell-17 mediated inflammation, and drug-induced disease. A minority of patients with familial and spontaneous HS have been identified to have GSC mutations. GSC stands for Gamma Secretase Complex and is a big protein that is made of four subunits. This protein helps split up over 70 substrates such as EGFR and Notch. Notch is the name of a complex signaling pathway that is proposed to be the underlying feature in HS pathogenesis. Dysregulation in Notch signaling pathway is also witnessed in smoking and keratinocyte proliferation which further strengthens a possible role in HS development. EGFR stands for Epidermal growth factor receptor and is a member of large class of proteins called tyrosine kinase. This pathway is involved in many cellular activities revolving around cell proliferation, growth and survival. Components of the EGFR pathway that are involved with the follicular infundibulum and IL-17A production have been identified with HS disease.

  • The evidence and proposed mechanism for follicular rupture. This study reports that follicular rupture 🡪 follicular occlusion 🡪 leads to dermal inflammation in HS.  The exact molecular mechanisms of this proposed model have not been figured out. However, when observing clinical studies researchers have pointed to the existence of inflammation around and within the hair follicle in combination with disassembly of the skin growth and healing pathways. The well documented persistent inflammation characterized in HS is hypothesized to contribute to a breakdown of skin membrane components. This weakening of the skin matrix combined with the follicular inflammation perhaps can lead to follicular rupture and eventually occlusion. These collective findings may shed more understanding on what see in long standing HS disease with tunneling, poor wound healing, and absence of follicular and adnexal structures. 

  • Dermal tunnels are active inflammatory structures and their development is orchestrated by dermal inflammation. The mechanism leading to tunneling in HS is unclear, however, evidence is strong that it is an inflammation driven process. This study suggests that the process starts with inflammation near the outer root sheath of hair follicles leading to additional inflammatory cell recruitment. Ultimately a positive inflammation feedback loop is established, generating keratinocyte amplification. The over production of these keratinocytes is believed to be part of the tunneling.  Once tunnels are established more inflammatory cells are attracted to the site, such as neutrophils. Specifically, neutrophils are able to form extracellular traps (NETS) that are able to trap and bind pathogens as part of their role in the immune system. The gelatinous mass and biofilms seen in the tunneling areas of HS skin is a result of this cyclic inflammation and NET formation by neutrophils.  

 

What does it all mean?

Inflammation! Inflammation! Inflammation! The central component of HS is inflammation and it is the primary driver of the disease.

 

References: 

Frew, J. W. (2020). Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence. JAAD International, 1(1), 62-72. doi:10.1016/j.jdin.2020.05.005

Disclaimer 

Summary written by Ghazal Ghafari and reviewed with Denise Panter-Fixsen.  This research summary is meant for educational and informational purposes only. Neither this summary nor any information contained within it are a substitute for professional care by a doctor or other qualified medical professional. This research summary does not constitute medical or other professional advice or services. If you have a medical concern, please consult with your physician.

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