Involvement of ILC1-like innate lymphocytes in human autoimmunity, lessons from alopecia areata.

Here, we have explored the involvement of innate lymphoid cells-type 1 (ILC1) in the pathogenesis of alopecia areata (AA), because we found them to be significantly increased around lesional and non-lesional HFs of AA patients. To further explore these unexpected findings, we first co-cultured autologous circulating ILC1-like cells (ILC1lc) with healthy, but stressed, organ-cultured human scalp hair follicles (HFs). ILClc induced all hallmarks of AA ex vivo: they significantly promoted premature, apoptosis-driven HF regression (catagen), HF cytotoxicity/dystrophy, and most important for AA pathogenesis, the collapse of the HFs physiological immune privilege. NKG2D-blocking or IFNγ-neutralizing antibodies antagonized this. In vivo, intradermal injection of autologous activated, NKG2D+/IFNγ-secreting ILC1lc into healthy human scalp skin xenotransplanted onto SCID/beige mice sufficed to rapidly induce characteristic AA lesions. This provides the first evidence that ILC1lc, which are positive for the ILC1 phenotype and negative for the classical NK markers, suffice to induce AA in previously healthy human HFs ex vivo and in vivo, and further questions the conventional wisdom that AA is always an autoantigen-dependent, CD8 +T cell-driven autoimmune disease.

Is pyoderma gangrenosum associated with solid malignancies? Insights from a population-based cohort study.

BACKGROUND: The question of whether solid malignancies (SMs) are associated with pyoderma gangrenosum (PG) remains to be conclusively answered. OBJECTIVE: To evaluate the risk of SM among patients with PG and the odds of PG after a diagnosis of SM. METHODS: A population-based retrospective cohort study was conducted to study the risk for SM in patients with PG (n = 302) as compared with age-, sex- and ethnicity-matched control subjects (n = 1799). A case-control design was used to estimate the odds of PG in those with a preexisting history of SM. RESULTS: The prevalence of a preexisting SM was comparable in patients with PG and controls (7.5% vs. 8.8%, respectively; P = 0.490). The odds of having PG following a diagnosis of a SM was not statistically increased (OR, 0.85; 95% CI, 0.53-1.36). The incidence of SM was 6.8 (95% CI, 3.5-12.2) and 7.9 (95% CI, 6.1-10.1) per 1000 person-years among patients with PG and controls, respectively. Patients with PG were not more likely to develop SM as compared to controls (HR, 0.86; 95% CI, 0.44-1.69). Patients with a dual diagnosis of PG and SM were older and had more frequent comorbid conditions and increased mortality. CONCLUSIONS: SM is not associated with provoking PG, and patients with PG are not at an increased risk of developing SM. A thorough routine screening for SM in patients with new-onset PG is an unnecessary approach based on the study findings.

Mouse Models of Alopecia Areata: C3H/HeJ Mice Versus the Humanized AA Mouse Model.

The C3H/HeJ model has long dominated basic alopecia areata (AA) in vivo research and has been used as proof-of-principle that Jak inhibitors are suitable agents for AA management in vivo. However, its histologic features are not typical of human AA, and it is questionable whether it is sufficiently clinically predictive for evaluating the therapeutic effects of candidate AA agents. Instead, the humanized mouse model of AA has been used to functionally demonstrate the role of key immune cells in AA pathogenesis and to discover human-specific pharmacologic targets in AA management. Therefore, we advocate the use of both models in future preclinical AA research.

Red Blood Cell Distribution Width Is Increased in Patients with Pemphigus: A Case-Control Study.

BACKGROUND: Red blood cell distribution width (RDW) has recently emerged as an inflammatory marker in several inflammatory diseases but has not been investigated in patients with pemphigus. OBJECTIVE: We aimed to examine RDW percentage in patients with pemphigus relative to control subjects and to assess the association between this biomarker and the morphological characteristics of the disease. METHODS: This case-control study included 183 pemphigus patients and 915 age- and sex-matched control subjects. RDW, hemoglobin, and mean corpuscular volume (MCV) were measured for all study participants. RESULTS: The RDW was significantly higher in patients with pemphigus than in controls (13.7±1.3 vs. 13.4±1.1%, respectively; P=0.001). A significant association between RDW and pemphigus was demonstrated in multivariate analysis (odds ratio, 1.22; 95% confidence interval, 1.01-1.46; P=0.036). The RDW was higher in patients with pemphigus vulgaris (PV) than in pemphigus foliaceus (PF; P=0.043), and in those with mucocutaneous PV relative to those with mucosal only and cutaneous only PV. The RDW increased significantly following treatment (P<0.001). CONCLUSION: Pemphigus patients demonstrated elevated RDW as compared with healthy controls. RDW may be a feasible biomarker in patients with pemphigus. Although it clearly does not replace any of the accepted diagnostic immunopathological criteria, increased RDW may be more suggestive of PV than PF, and of mucocutaneous rather than cutaneous PV. The remarkable increase following treatment may be ascribed to the corticosteroid-induced erythropoiesis.

Frontiers in alopecia areata pathobiology research.

This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential "new" players in AA pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8+ T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called "unconventional" T cells (invariant NK T cells, γδ T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-γ, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8+ T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, γδ regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.

The relationship between pemphigus and systemic lupus erythematosus: a cross-sectional study, systematic review, and meta-analysis.

The coexistence of pemphigus and systemic lupus erythematosus (SLE) had been reported anecdotally. Anti-desmoglein (Dsg)1 and anti-Dsg3 antibodies were detected concomitantly with antinuclear autoantibodies among blood donors. The aim of the current study was to study the association between pemphigus and SLE in Israeli patients and to synthesize existing data on this association in the current literature. The current study included two sections. Initially, a cross-sectional study was performed to compare pemphigus patients with age-, sex-, and ethnicity-matched control subjects regarding the prevalence of SLE using a real-life large-scale computerized database. Next, a systematic review and meta-analysis of similar observational studies in Medline, Embase, and Web of Science (1823-2017) was conducted. As for the cross-sectional study, a total of 1985 patients with pemphigus and 9874 controls were included in the study. The prevalence of SLE was slightly higher among patients with pemphigus as compared to controls (OR, 1.85; 95% CI, 0.89-3.82). In a sensitivity analysis that included patients who received pemphigus-related treatments, the association between pemphigus and SLE had been substantiated and was statistically significant (OR, 2.10; 95% CI, 1.00-4.48). In the meta-analysis section, three eligible studies, comprising 10,389 pemphigus patients met the eligibility criteria. The overall pooled multivariate OR was 2.50 (95% CI 1.54-4.07, I2 = 44.19%, P = 0.167) across all studies. In conclusion, the meta-analysis provides epidemiologic evidence that these B cell-driven diseases are significantly associated. Further research is required to elucidate the molecular mechanism underlying this association.