Aetiology and Pathogenesis of Hidradenitis Suppurativa

K. Wolk; O. Join-Lambert; R. Sabat


The British Journal of Dermatology. 2020;183(6):999-1010. 

In This Article

Pathogenetic Processes

HS disease starts around the hair follicle.[59] The first histologically detectable events include infundibular acanthosis, hyperkeratosis and perifollicular immune cell infiltration (Figure 3).[56,57,60,61] Whether the immune cell infiltration or the infundibular alteration is the primary event that induces the other one has not been finally determined. Specific predisposing factors (Figure 1) directly induce immune cell infiltration (obesity), while others provoke infundibular acanthosis (nicotine).

Figure 3.

Pathogenetic events in hidradenitis suppurativa (HS). Disease-predisposing factors (Figure 1) induce perifollicular immune activation as well as occlusion, sebum stasis, and dilatation of the hair follicle unit. This leads to growth of bacteria within the occluded hair follicles and release of damage-associated molecules, which stimulate local immune cells, especially macrophages, to produce inflammatory cytokines like tumour necrosis factor (TNF)-α and interleukin (IL)-1β. Via their epithelium-activating and chemokine-inducing properties, these cytokines provoke the infiltration of various immune cell populations. These include neutrophilic granulocytes, monocytes (which in the skin can differentiate into macrophages or dendritic cells), B/plasma cells, and different functional subgroups of effector/memory T cells (which had been generated in the skin-area-associated draining lymph nodes). While T helper (Th)1 cells and Th17 cells and their main mediators interferon (IFN)-γ (Th1), IL-17A/F and IL-26 (Th17) become abundant in HS skin, Th22 cells and IL-22 are not. Due to the limited upregulation of IL-22, epidermal production of antimicrobial proteins [including β-defensins (BDs) and S100A7] is too low to confine cutaneous bacterial growth. Neutrophilic granulocytes, whose infiltration is supported by chemokines (e.g. CXCL1, 2 and 8, which are highly produced by dermal fibroblasts), leukotriene B4 (LTB4), the complement component C5a and lipocalin (LCN)2, are important phagocytes and producers of proinflammatory cytokines. These cells also form neutrophil extracellular traps (NETs), which can inhibit bacterial growth but also favour autoimmune features. Infiltrated B/plasma cells produce antibodies and may contribute to the activation of the complement system. Secreted proteolytic enzymes may further increase the fragility of the basement membrane surrounding the hair follicle unit. The amount of bacteria within HS skin lesions increases, with progressively reduced frequency of prototypical skin commensals and high enrichment of strictly anaerobic Gram-negative species. Bacterial growth further boosts inflammation. The inflammatory process and hair follicle fragility lead to rupture of the hair follicle unit with release of its immune-stimulatory content into the surrounding tissue. Continuous inflammation with pus formation, epithelialization within the disintegrated tissue, and abundance of extracellular matrix-degrading enzymes (matrix metalloproteinases, MMPs) finally lead to the formation of pus-draining epithelialized tunnels and destruction of skin architecture. Self-amplifying inflammatory pathways that involve many further cytokines (e.g. IL-17C, IL-19, IL-36 and LCN2) and persistent anaerobic bacteria support the chronification and recurrent nature of lesions. DC, dendritic cell; Fb, fibroblast; Gr, neutrophilic granulocyte; Mo, monocyte. [Colour figure can be viewed at]

The infundibular alterations lead to follicular occlusion and consequent stasis with dilatation of the hair follicle (Figure 3).[1] This may lead to multiplication of anaerobic bacteria within the occluded hair follicles, as suggested by 16S rRNA gene amplicon sequencing.[62] Bacterial components and DAMPs released from damaged follicular cells may further stimulate inflammatory responses in local cells, especially macrophages. The PRRs activated by these stimuli include Toll-like receptor 2 and the inflammasome component NLRP3, both of which are upregulated in HS skin[63–65] and mediate the release of cytokines such as IL-1β and tumour necrosis factor (TNF)-α. These pleiotropic mediators have two major functions that support immune cell infiltration into the tissue: the activation of endothelia and the induction of chemokine production by local tissue cells (Figure 3). The influx of neutrophilic granulocytes might be further promoted by leukotriene B4, a lipid mediator that is produced by macrophages via hyperactivation of the 5-lipoxygenase pathway in HS.[66]

Individual proinflammatory cytokines are strong inducers of extracellular matrix-degrading enzymes, the matrix metalloproteinases (MMPs).[64] At this stage, these enzymes may be involved in the thinning of the basement membrane surrounding the hair follicle unit, as detected in perilesional HS skin. This thinning may increase the fragility of the inflamed and dilated hair follicle.[67] In γ-S-associated familial HS, the potential decrease of notch-mediated support of the hair follicle epithelium could also reduce the stability of the hair follicle unit. The consequence of these processes probably favours the rupture of the hair follicle (Figure 3). Hair follicle stem cells in HS lesions show an increased proliferation rate. This is associated with elevated numbers of micronuclei and presence of cytoplasmic single-stranded DNA in proliferating cells.[68] Activating PRRs, cytoplasmic DNA might also strengthen local inflammation.

The release of the content of ruptured hair follicles (including bacteria, DAMPs, keratin fibres and sebum components) into the surrounding tissue massively boosts inflammation. Inflammation eventually leads to clinically visible dermal nodules and abscesses. The formation of pus-draining epithelialized sinus tracts and fistulas may be supported by the continued formation of pus, known to occur in the massive presence of neutrophilic granulocytes and bacteria, the seeding of follicular stem cells into the disintegrated tissue,[67] the abundance of MMPs,[64] and the loosening of cell–cell adhesive junctions in the epidermis[69] (Figure 3). Chronification of inflammation leads to destruction of skin architecture, recurring development of abscesses, wounding, and subsequent fibrotic scarring.[1] Macrophage-dependent chronic WNT activity may play a role in fibrotic scarring.[70] HS lesions and adjacent areas also contain areas of interfollicular inflammation with acanthosis, as known from psoriatic skin.[56–58,71]

Established HS lesions contain massive immune cell infiltrates. Apart from neutrophilic granulocytes, macrophages and dendritic cells are the most abundant cells. Furthermore, T cells, mast cells, natural killer cells and B/plasma cells are found.[57,65,71,72] Neutrophilic granulocytes are important phagocytes of bacteria and producers of proinflammatory cytokines, and they have the ability to release antimicrobial and cytotoxic molecules by degranulation. Furthermore, these cells form neutrophil extracellular traps (NETs), which have been detected in HS lesions.[73] These web-like structures are composed of a scaffold of decondensed chromatin loaded with cytosolic and granule proteins.[74] In HS, lesional NET formation has been suggested to be linked to the presence of autoantibodies.[73]

Surprisingly, the extent of T-cell infiltration in HS lesions is comparable with that found in psoriasis,[21] a well characterized T-cell-mediated chronic inflammatory skin condition.[75] T cells, after being primed in the regional lymph nodes, circulate through blood and lymph nodes (central memory T cells) or exert their effector functions in the tissue (effector T cells, effector/memory T cells).[75] B/plasma cells may be part of lymphoid structures formed in chronically inflamed peripheral tissues.[76] B cells serve as antigen-presenting cells and as producers of antibodies and anti-inflammatory and proinflammatory cytokines. Apart from antigen neutralization, antibodies may contribute to the complement activation seen in HS.[52]

In the course of HS pathogenesis, bacteria become abundantly present within HS skin lesions, with their composition further changing compared with the microbiome of unaffected intertriginous skin (Figure 2). Staphylococcus lugdunensis, an opportunistic pathogenic coagulase-negative Staphylococcus species, was detected in 25% of nodules as the sole or predominant pathogen, but not in chronic suppurative lesions.[77] Interestingly, Staphylococcus aureus, a well-known cause of folliculitis, furuncles and acute skin abscesses, is not associated with HS.[43,77] Chronic lesions show clearly reduced abundance of prototypical skin commensals and high enrichment of strictly anaerobic Gram-negative bacteria such as Prevotella and Porphyromonas ssp., along with Streptococcus anginosus and Actinomyces spp., which often cause opportunistic infections (Figure 2).[43,78] Furthermore, Fusobacterium nucleatum, a Gram-negative anaerobic rod with invasive properties, is associated with the most severe form of HS.[43,77,79]

Together, HS lesions show abundance of opportunistic pathogens but not highly pathogenic bacteria and commensals. Accordingly, optimized antibiotic treatment demonstrated therapeutic efficacy especially in patients with HS with mild disease, but required much longer treatment times than in classical soft tissue and skin infections.[80–82] Bacterial colonization appears important due to immunostimulatory effects unrelated to a proper infection.[83] Some studies showed increased biofilm formation, especially within inflamed hair follicles and tunnels.[84] The epidermal antimicrobial defence mechanisms in HS lesions appear too weak to counteract local bacterial growth effectively (see below).