Analysis of possible structures of inducible skin‐associated lymphoid tissue in lupus erythematosus profundus

Abstract

Lupus erythematosus profundus (LEP) is a variant of lupus erythematosus, involving the deep dermis and subcutaneous fat. LEP is characterized by the presence of lymphoid follicles (LF) and germinal centers (GC). However, it remains unknown whether these lymphoid structures correspond to the lymphoid tissues such as cutaneous tertiary lymphoid organs (TLO). Previously, we identified dynamically orchestrated cellular elements in murine contact dermatitis that resembled lymphoid structures, which we termed inducible skin-associated lymphoid tissues (iSALT). We subsequently reported structures analogous to iSALT in human secondary syphilis, suggesting that iSALT can also exist in humans. Here, we studied ectopic lymphoid tissues in the lesions of LEP by immunohistochemistry and compared their characteristics with those of TLO. We demonstrated that LF of LEP were composed of B-cell follicles intermingled with CXCL13-expressing cells, distinct aggregations of T cells, and some blood vessels expressing peripheral node addressin. These findings indicate that LF of LEP can be considered as a type of iSALT.

Skin-Associated B Cells in Health and Inflammation

“…Skin-associated B cells and Ig-secreting cells are also conserved in the skin of lower vertebrates, such as teleost fish (16). In mammalian skin, B cells localize to the dermis where they are sparsely scattered as individual cells during homeostasis and often as cell clusters or more-organized lymphoid structures during inflammation (14,(17)(18)(19)(20) Skin-associated B cells are a heterogenous population with both conventional (B-2) and innate-like (B-1-like) B cells (8,14). Relative to their blood-borne counterparts, IgG + skin-infiltrating human B-2 B cells have a lower representation of the IgG1 subclass and show a preferred usage of certain Vh genes, suggesting the existence of skin-specific B cell subsets (15).…”

“…Recently, B cells are increasingly recognized as an important part of the infiltrating immune compartment in autoimmune and inflammatory skin diseases. B cell numbers are elevated in lesional skin relative to control skin specimens in a number of inflammatory diseases, including, but not limited to, psoriasis (47), pemphigus (18), lupus profundus (19,20), systemic sclerosis (scleroderma) (48), discoid lupus erythematosus (49,50), Sjögren's syndrome (51), IgG4related skin diseases (33,34), atopic dermatitis (52), and allergic contact dermatitis (53). Although an increase in skininfiltrating B cells already suggested a role for B cells in cutaneous inflammation, the therapeutic success of systemic B cell depletion with rituximab confirmed a pathogenic role for B cells in a number of these diseases (54)(55)(56).…”

“…Even though TLO-like structures that support interactions between skin B and T cells exist in certain inflammatory skin diseases, little is known about the role of TLOs in the pathogenesis of cutaneous pathologies. In lupus erythematosus panniculitis (lupus profundus; a form of cutaneous lupus that is typified by inflammation of the s.c. adipose tissue), aggregates of B cells and plasma cells or lymphoid follicles containing distinct GCs are found in the majority of cutaneous lesions (19,20). Kogame et al (20) showed that additional components of a TLO are present in these lupus profundus lesions, including CXCL13 + cells, peripheral node addressin + (PNAd + ) high endothelial venules, and podoplanin + lymphatic vessels.…”

B Cell Responses in the Development of Mammalian Meat Allergy

“…There is limited knowledge of the role for skin-associated B cells in this process, where they may perpetuate local inflammation by enhancing cutaneous allergen-specific IgE titers. In many chronic inflammatory human diseases that have been presumed to be driven by T cells, such as atopic dermatitis ( 172 ), psoriasis ( 173 ), pemphigus ( 174 ), cutaneous lupus ( 175 – 177 ), allergic contact dermatitis ( 178 ), and scleroderma ( 179 ), B cells accumulate in inflamed skin. Many roles for B cells have been postulated in these diseases beyond their contributions to pathogenic antibody production, including their ability to present antigen and secrete pro-inflammatory cytokines, like IL-6, GM-CSF, IFN-γ, all of which promote local inflammation ( 180 ).…”

Is Local Production of Autoantibodies in Skin Lesions Relevant in Pemphigus?

“…Although little is known about the functions of TLSs in skin, several features are coming to light through studies of dermatological diseases. For example, aggregates of B cells and plasma cells or lymphoid follicles containing GCs have recently been identified in lesions of lupus profundus (Kogame et al, 2018). Assemblages of B cells and T cells have also been detected in skin manifestations of Sjö gren syndrome (Roguedas et al, 2010).…”