Gene Array Profiling and Immunomodulation Studies Define a Cell-Mediated Immune Response Underlying the Pathogenesis of Alopecia Areata in a Mouse Model and Humans

Abstract

Alopecia areata is a suspected autoimmune hair loss disease. In a rodent model, alopecia areata can be induced in normal haired C3H/HeJ mice by transfer of skin grafts from mice with spontaneous alopecia areata. At weeks 2, 4, 6, and 10 after surgery, grafted mice were euthanized, skin collected and processed for histology, and RNA extracted. Age-matched sham-grafted mice, and mice with and without spontaneous alopecia areata, were similarly processed. For comparison, skin biopsies from alopecia areata and androgenetic alopecia affected humans were also collected. Skin mRNA processed to cDNA was analyzed using Affymetrix mouse 11K and human 6800 gene chip(R) array technology. Microarray results indicated 42 known genes upregulated or downregulated during onset of mouse alopecia areata consistent with an inflammatory cell-mediated disease pathogenesis involving antigen presentation, costimulation, and a T helper 1 lymphocyte response. In contrast, 114 genes, many regulating immunoglobulin response, were altered late in disease development. In alopecia areata affected humans, 95 genes were significantly modulated. As confirmation of microarray analysis results, lymph node and spleen cells from alopecia areata affected mice injected into normal haired littermates transferred the alopecia areata phenotype. Alopecia areata onset could be inhibited in skin-grafted mice by modulation with B7.1- and B7.2-specific monoclonal antibodies. In addition, depletion of CD4+ CD8+ expressing cells in chronic alopecia areata affected mice using monoclonal antibodies permitted hair regrowth. The results consistently demonstrated the importance of an immune cell-mediated disease mechanism in alopecia areata pathogenesis and suggested targeting antigen-presenting cells and reactive lymphocytes may be effective in alopecia areata treatment.

Peripheral blood gene expression in alopecia areata reveals molecular pathways distinguishing heritability, disease and severity

“…Comparison of differential gene expression in AA blood vs that in skin reveals a set of shared genes and pathways A total of 35 dysregulated genes in the AA blood 'disease' signature correspond to those genes found to be dysregulated in AA lesional skin in our own studies 28 and in others 29 ( Table 3). Several of these overlapping genes are involved in T-cell immunity, cell adhesion/leukocyte migration, stress response and protein metabolism and modification.…”

“…24 Microarray studies on organ-specific autoimmune diseases have advanced our understanding of autoimmune disease pathogenesis, and revealed targets for clinical biomarkers, prognostic factors and subtype distinction for individualized therapy. [25][26][27] Our recent microarray analysis in AA patient skin samples, 28 along with a previous microarray study in murine and human AA skin, 29 help to substantiate AA as a Th1-cell-mediated autoimmune disorder with a late secondary humoral response. No study, however, has previously used gene microarray technology as a large-scale screening tool to investigate gene regulatory alterations in the peripheral blood of AA patients.…”

Lymphocytes, neuropeptides, and genes involved in alopecia areata

“…Microarray analysis of mRNA transcription in involved versus uninvolved skin has been performed both from human scalp biopsies and C3H/HeJ mice (84). Involved skin of mice demonstrates increased mRNA for a multitude of immune-associated genes including those encoding MHC molecules, adhesion molecules, complement components, immunoglobulin genes, antigen processing proteins, and lymphocyte markers (e.g., CD3).…”

La Alopecia Areata

“…En modelos animales (34) si se eliminan de forma selectiva CD4+ y CD8+ con inyecciones de anticuerpos monoclonales, hay recrecimiento del pelo y cuando estas células se reemplazan se desarrolla de nuevo el fenotipo de AA. Si separamos CD4+ y CD8+ y los trasferimos no inducen caída de pelo, pero si se trasfieren combinados sí la producen (35,36).…”