The first description of lupus erythematosus, made by Cazenave in 1851, arose from a case presentation of a patient who had skin lesions which resembled discoid lupus.¹ This initial discovery spurred on further investigation into the disease, and it was found that the presence of discoid lupus affected multiple organs.²  This instance exemplifies the importance of skin disease in lupus, as it could often be the key finding that unveils the correct diagnosis.

Dr. James N. Gilliam classified cutaneous lupus erythematosus (CLE) into three forms: acute (ACLE), sub-acute (SCLE) and chronic (CCLE).³ The acute form, which is always associated with systemic lupus erythematosus (SLE), is characterized by the transient malar rash and erythema in photosensitive areas. SCLE can present as polycyclic erythematous plaques with peripheral scaling or psoriasiform papules and plaques in photosensitive areas. CCLE contains various subtypes, with discoid lupus erythematosus (DLE) as the most common subtype. DLE lesions begin as erythematous macules and papules with follicular plugging that evolve into atrophic dyspigmented scarring patches and plaques. The factors that dictate the subtype of cutaneous lupus in an individual remain unknown.

The multiple manifestations of CLE provide an indication of the complex etiology of this disease. It has a multi-factorial pathogenesis that includes genetic, environmental, and immunological causes. Although each factor alone is not sufficient for disease induction, the interplay between these three factors is essential to the formation of CLE. The genetic makeup distinguishes individuals who are more susceptible to this disease. Environmental factors such as ultraviolet light (UV) and viruses can initiate a cascade of events that leads to a heightened immune system activity that involves autoantibody formation.

Genetics

Genetics can predispose individuals towards developing CLE by highlighting genes that drive one's immune response toward hyperactivity or losing the ability to distinguish from self and non-self. Numerous genes linked to CLE have been found within the major histocompatibility complex (MHC), which encodes proteins such as human leukocyte antigen (HLA), complement components, and tumor necrosis factor (TNF) -α and -β. Specifically, patients with various HLA subtypes have been associated with different types of CLE, which suggests that abnormal antigen presentation could lead to a dysregulated immune system in CLE. Furthermore, SCLE has been linked to several HLA subtypes, such as HLA-B8, especially those with polycyclic plaques,⁴ -A1 and -DRw3.⁵ Moreover, both class I and II HLA alleles have been associated with DLE, such as HLA-DQA1,⁶ -Cw7, -DR2 and -DR3.⁷ Genetic deficiencies in complement components have also contributed to the formation of CLE. Racila et al. reported a single nucleotide polymorphism in the C1QA gene in SCLE patients, which correlated with decreased levels of serum C1q, and which binds to apoptotic keratinocytes and aids in their clearance.⁸  Furthermore, C1q,⁹ C2¹⁰ and C5 deficiencies¹¹ have been reported in patients with DLE. Finally, the frequency of the genetic polymorphism in the TNF-α promoter -308A, which increases TNF-α production,¹² was determined to be augmented in SCLE patients and responsive to ultraviolet B (UVB) light.¹³

Environment

Whereas genetics might set up the foundation for a hyperactive immune system, the formation of CLE depends on environmental factors, such as UV light and viruses. Inflammatory responses can be activated by UV light by prompting keratinocyte release of the primary cytokines, IL-1α¹⁴ and TNF-α,¹⁵ which enhance the presence of adhesion molecules on dermal venules¹⁶, cytokine¹⁷ and chemokine production.¹⁸ Keratinocyte apoptosis can also be induced by UV light. When cultured keratinocytes irradiated with UVB underwent apoptosis, nuclear antigens such as Ro/SSA were transported to the cellular surface and formed apoptotic blebs, which resulted in their exposure to the immune system.¹⁹ Human keratinocytes from SLE and SCLE patients who were irradiated with UVB showed heightened antibody binding to nuclear antigens, which led to increased antibody-mediated cytotoxicity.²⁰ These in vitro findings have been confirmed by the amplified presence of apoptotic keratinocytes in CLE skin by immunohistochemistry.²¹ Viruses might also instigate formation of CLE lesions by inducing keratinocyte apoptosis.²² Molecular mimicry, in which foreign antigens such as viruses cross-react with lupus autoantigens, and epitope spreading, in which the immune response against an epitope of a specific antigen extends to other epitopes on the same antigen or similarly structured antigens, can be responsible for this phenomenon. Specifically, animals immunized with the Epstein-Barr virus antigen-1 developed anti-Ro antibodies.²³

Autoantibodies

As mentioned earlier, autoantibodies, which appear downstream in the events initiated by environmental influences, recognize nuclear antigens on the surface of apoptotic keratinocytes and induce antibody-mediated cytotoxicity and complement activation. Anti-Ro antibodies, which have been linked to SCLE patients,⁴ have demonstrated this pathogenic potential. Keratinocytes cultured from SCLE patients demonstrated increased cytotoxicity when exposed to sera containing anti-Ro antibodies compared with anti-ssDNA sera and normal human sera.²⁰ Bennion and colleagues noted that the principal subclass of anti-Ro antibodies in SCLE skin was IgG1, which is capable of activating the complement pathway.²⁴ Anti-La antibodies are often concomitantly present with anti-Ro antibodies, which is probably due to intermolecular epitope spreading and which has been observed in mice immunized with Ro and La.²⁵ However, although autoantibodies have been involved in renal damage in lupus nephritis through the formation of immune complexes bound to the glomerular basement membrane,²⁶  the ability of autoantibodies to induce skin damage has yet to be explained .

In Conclusion

The evolution of CLE depends on several steps, which include having a genetic makeup that renders individuals susceptible to CLE by having hyperactive immune systems, being exposed to environmental triggers including sunlight and viruses, and by igniting a dysregulated chain of events that enhance the presence and activity of autoantibodies through epitope spreading and molecular mimicry. The importance of this multi-step model is reflected in the treatment regimens, such as sun-protective measures and immunomodulatory therapies, because they target the latter two steps to inhibit disease progression. The reversal of genetic abnormalities that predispose individuals to CLE through gene therapy could be even more beneficial because it would inhibit the cascade of events early on. In fact, genetically engineered anti-cytokine inhibitors²⁷ and anti-inflammatory cytokines such as TGF-β²⁸ have been explored as treatments for SLE in murine models and could have therapeutic value in SLE and CLE patients. The exciting potential of these therapies and other investigational drugs might revolutionize future treatment in CLE.

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