Richard S. Kalish

Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice.

Alopecia areata is a tissue-restricted autoimmune disease of the hair follicle, which results in hair loss and baldness. It is often psychologically devastating. The role of T lymphocytes in this disorder was investigated with cell transfer experiments. Scalp explants from patients were transplanted to severe combined immunodeficiency (SCID) mice and injected with autologous T lymphocytes isolated from involved scalp. T lymphocytes which had been cultured with hair follicle homogenate along with antigen-presenting cells were capable of inducing the changes of alopecia areata, including hair loss and perifollicular infiltrates of T cells, along with HLA-DR and ICAM-1 expression of the follicular epithelium. Similar changes were not noted in grafts injected with scalp-derived T cells that had not been cultured with follicular homogenate. These data indicate that alopecia areata is mediated by T cells which recognize a follicular autoantigen.

Lymphocytes, neuropeptides, and genes involved in alopecia areata

Many lessons in autoimmunity - particularly relating to the role of immune privilege and the interplay between genetics and neuroimmunology - can be learned from the study of alopecia areata, the most common cause of inflammation-induced hair loss. Alopecia areata is now understood to represent an organ-restricted, T cell-mediated autoimmune disease of hair follicles. Disease induction is associated with collapse of hair follicle immune privilege in both humans and in animal models. Here, the role of HLA associations, other immunogenetic factors, and neuroendocrine parameters in alopecia areata pathogenesis are reviewed. This instructive and clinically significant model disease deserves more widespread interest in the immunology community.

Molecular mechanisms of CD8+ T cell–mediated delayed hypersensitivity: Implications for allergies, asthma, and autoimmunity

Delayed-type hypersensitivity (DTH) is defined as the recruitment of T cells into tissues to be activated by antigen-presenting cells to produce cytokines that mediate local inflammation. CD8+ T cells are now known to mediate DTH responses in allergic contact dermatitis, drug eruptions, asthma, and autoimmune diseases. This inflammatory effector capability of CD8+ cytotoxic T cells was previously poorly recognized, but there is now considerable evidence that these diseases may be mediated by CD8+ DTH. The difference between CD8+ T cells and CD4+ T cells mediating DTH relates to the molecular mechanisms by which antigens are processed and presented to the T cells. Antigens external to the cell are phagocytosed and processed for presentation on MHC class II molecules (eg, HLA-DR) to CD4+ T cells. In contrast, internal cytoplasmic antigens are processed by the endogenous pathway for presentation on MHC class I molecules (eg, HLA-A, -B, and -C) to CD8+ T cells. External allergens can also enter the endogenous pathway to be presented to CD8+ T cells. These include many contact sensitizers, chemical and protein respiratory allergens, viral antigens, metabolic products of drugs, and autoantigens. The resulting CD8+ T-cell response explains the role of CD8+ T-cell DTH mechanisms in allergic contact dermatitis, asthma, drug eruptions, and autoimmune diseases.

Suicide by mass murder: Masculinity, aggrieved entitlement, and rampage school shootings

Abstract School shootings have become more common in the United States in recent years. Yet, as media portrayals of these ‘rampages’ shock the public, the characterisation of this violence obscures an important point: many of these crimes culminate in suicide, and they are almost universally committed by males. We examine three recent American cases, which involve suicide, to elucidate how the culture of hegemonic masculinity in the US creates a sense of aggrieved entitlement conducive to violence. This sense of entitlement simultaneously frames suicide as an appropriate, instrumental behaviour for these males to underscore their violent enactment of masculinity.

Alopecia Areata: Autoreactive T Cells Are Variably Enriched in Scalp Lesions Relative to Peripheral Blood

BACKGROUND AND DESIGN Alopecia areata is a condition characterized by hair loss in association with perifollicular infiltration of T cells and antigen-presenting cells. Autoreactive T cells are postulated to amplify this abnormality by interacting with DR+ follicular epithelium. These cells may recognize either autologous major histocompatibility complex class II antigen or an autoantigen restricted by major histocompatibility complex class II. Limiting dilution analysis was used to determine the frequency of autoreactive lymphocytes in scalp biopsy specimens and peripheral blood from seven adult patients with alopecia areata. Autoreactive T cells are defined for this study as those that proliferate in response to autologous irradiated peripheral blood mononuclear cells. RESULTS Autoreactive lymphocytes were enriched in scalp biopsy specimens relative to peripheral blood in five of seven patients. This enrichment was statistically significant in four of five patients. Five autoreactive T-cell clones derived from lesional scalp were characterized. Four of these clones were CD3+CD4+CD8- and one clone was CD3+CD4-CD8+. CONCLUSIONS Enrichment of autoreactive cells in lesions of alopecia areata supports a role for these cells in the pathogenesis of this condition. Enrichment of autoreactive lymphocytes is also found in allergic contact dermatitis. Thus, these autoreactive lymphocytes may have a general role in inflammation.

Ageing of human epidermis: the role of apoptosis, Fas and telomerase

Background  Aged human epidermis is characterized by morphological changes including flattening of the dermal–epidermal junction and a decrease in thickness.

Unilateral linear lichenoid eruption after bone marrow transplantation: An unmasking of tolerance to an abnormal keratinocyte clone?

Chronic cutaneous graft-versus-host disease may appear clinically as a lichenoid eruption. We describe a 26-year-old man who developed a unilateral linear lichenoid eruption 7 months after allogeneic bone marrow transplantation. We believe this represents an unusual form of localized, chronic graft-versus-host disease. The possible relationship to viral infection or cellular mosaicism and the clinical, histologic, and immunologic similarities to idiopathic lichen planus are discussed.

Sulfonamide-reactive lymphocytes detected at very low frequency in the peripheral blood of patients with drug-induced eruptions.

BACKGROUND The role of T lymphocytes in mediating drug eruptions is uncertain. METHODS Twenty-four patients with eruptions induced by sulfonamide-related drugs were studied to detect lymphocyte reactivity to drugs. Both the lymphocyte transformation test and limiting dilution analysis were used as assays for drug-reactive lymphocytes. Peripheral blood lymphocytes were expanded in interleukin-2 and tested for reactivity to sulfamethoxazole and furosemide. RESULTS The lymphocyte transformation test results to sulfamethoxazole, sulfisoxazole, and furosemide were found to be generally unreliable with a high rate of false-negative and false-positive results. However, as determined by limiting dilution analysis, sulfamethoxazole-reactive lymphocytes were detected in the peripheral blood of one patient at a frequency of 1/172,000. This is within the lower range of frequencies of urushiol-reactive T cells in the peripheral blood of patients with allergic contact dermatitis to urushiol (poison ivy). Two sulfonamide-reactive lymphocyte lines were cultured from two patients. Both lines proliferated in response to sulfamethoxazole but not in response to furosemide, suggesting that furosemide does not cross-react with the sulfonamides. CONCLUSIONS Lymphocytes reactive to sulfamethoxazole were detected at low frequencies in the peripheral blood of three patients with drug eruptions secondary to administration of sulfamethoxazole.

Transfer of alopecia areata in the human scalp graft/Prkdcscid (SCID) mouse system is characterized by a TH1 response

Alopecia areata is an autoimmune condition directed at hair follicles, which results in loss of hair. We have previously demonstrated that it is possible to transfer hair loss, along with the immunohistologic findings of alopecia areata, to human scalp grafts on Prkdc(scid) (SCID) mice by injection of autologous activated lesional T-cells. This study examines the cytokine profile of T-cells and follicular epithelium following transfer of hair loss. Two consistent findings significantly (P < 0.01) associated with hair loss were production of interferon-gamma-inducible protein-10 kDa (IP-10) by follicular epithelium (13/13), and production of INF-gamma by infiltrating T-cells (10/12). Noninjected control grafts regrew hair, and were generally negative for IP-10 (positive 2/9), and INF-gamma (positive 2/9), but expressed of IL-10 on the follicular epithelium (7/9). These data support an INF-gamma TH1 pathogenesis for hair loss in alopecia areata.

Antigen processing: The gateway to the immune response

The T-lymphocyte response to an antigen is governed by the source of that antigen and the way in which it is processed. Before recognition by T lymphocytes, proteins must be degraded to peptides by antigen-presenting cells. The peptides are then presented on major histocompatibility complex (MHC) molecules for recognition by the T cells. Antigens arising outside the cell (e.g., bacteria) are phagocytosed and processed by the exogenous pathway for presentation on MHC class II molecules (e.g., DR) to CD4+ cells. Antigens derived from the cytoplasm (e.g., viral proteins) are processed by the endogenous pathway for presentation by MHC class I molecules (e.g., HLA-A, -B, -C) to CD8+ cells. The response to a hapten or drug is a function of the antigen processing pathway and is determined by its chemical properties. Antigen processing also governs the T-cell response to pathogens, vaccines, and autoimmune conditions.