Cytotoxic granules in distinct subsets of cutaneous lupus erythematosus

Abstract

In cutaneous lupus erythematosus (CLE), the pathogenetic role of cytotoxic granules has been demonstrated in the subacute and discoid subtypes, which show interface dermatitis, but little is known about tumid (T)CLE, which does not show this interface dermatitis, and evolves with minimal epidermal changes. We studied cytotoxic T lymphocytes and cytotoxic granules in discoid (n = 21), subacute (n = 17), and tumid (n = 21) CLE samples. Skin sections were immunohistochemically stained for CD8, CD56, perforin, granzyme A, granzyme B, and granulysin. Inflammatory cells containing the four subtypes of cytotoxic granules were found in all the three CLE forms; however, only the TCLE group showed a positive correlation between the density of CD8+ cells and each subtype of cytotoxic granule-positive cells. In addition, only the TCLE group showed synergy between the densities of cells containing cytotoxic granule subtypes. Cytotoxic granules are important in the pathomechanism of TCLE. They may perform functions other than apoptosis, including maintenance of inflammation and dermal mucinous deposits in TCLE.

In silico Analyses of Skin and Peripheral Blood Transcriptional Data in Cutaneous Lupus Reveals CCR2-A Novel Potential Therapeutic Target

“…In addition to UV induction of apoptosis, cellular cytotoxic mechanisms involving CTLs, and natural killer (NK) cells have also been implicated in CLE (4, 104–107). Our analysis finds several more NK cell associated genes (65 DEGs, mostly UP) in the CCLE lesional skin than in the blood profile (14 DEGs, mostly UP), with 7 DEGs shared between the two environments.…”

Clinical perspectives and murine models of lichenoid tissue reaction/interface dermatitis

“…Granulysin may be a diagnostic marker of SJS/TEN, because the serum levels of granulysin were elevated in patients with SJS/TEN but not in patients with drug-induced maculopapular exanthema [31]. Similarly to aGVHD and SJS/TEN, granulysin + cell densities are increased in CLE lesions [32]. These clinical studies found that granulysin is an important cytotoxic molecule produced by CTLs in LTR/IFD reactions in addition to perforin/granzyme B.…”

Granzyme B Induces IRF-3 Phosphorylation through a Perforin-Independent Proteolysis-Dependent Signaling Cascade without Inducing Cell Death

“…Regardless, after entering cells, GrB-mediated apoptotic death is induced by group II caspase activation and cleavage of a diverse array of intracellular substrates, either by activated caspases or directly by GrB [the GrB degradome (24)]. It is noteworthy that activated CTL infiltrates expressing perforin and GrB are present in affected tissues in a variety of disease states, including atherosclerosis, solid transplant rejection, and a wide spectrum of autoimmune rheumatic diseases, including scleroderma skin and lung disease, Sjogren syndrome sialadenitis, rheumatoid arthritis synovium, diseased muscle in inflammatory myositis, lupus skin and kidney, and the arterial walls in giant cell arteritis (5,(25)(26)(27)(28)(29)(30)(31)(32). The extent, however, to which lymphocyte cytotoxicity mediated by perforin-GrB cooperativity contributes to overall tissue dysfunction in such diseases remains unresolved.…”