Thomas S. McCormick

IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T Cells

T memory/effector cells (Tmem/eff) isolated from psoriatic patients are chronically activated and poorly suppressed by regulatory T cells (Treg). The proinflammatory cytokine IL-6, which signals through Stat3, allows escape of Tmem/eff cells from Treg-mediated suppression in a murine system. We show here that IL-6 protein is markedly elevated and most highly expressed by CD31+ endothelial cells and CD11c+ dermal dendritic cells (DCs) in lesional psoriatic skin. We hypothesized that exposure to high IL-6 in lesional tissue may lead to the dampened Treg function observed in psoriasis patients. Indeed, we found that IL-6, but not other Stat3-activating cytokines, was necessary and sufficient to reverse human T cell suppression by Treg in an in vitro model using activated DCs as a source of IL-6. IL-6Rα and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6Rα expression on Treg exceeded that of effector T cells, and both populations phosphorylated Stat3 in response to IL-6. Phosphorylation of Stat3 in T cells contributes to Th17 differentiation and we identify cells within lesional tissue that coexpress CD3, IL-17, and IL-6, indicating that Th17 cells are present in vivo within the psoriatic Tmem/eff population and contribute to IL-6-mediated resistance to Treg suppression. Taken together, T lymphocytes trafficking into lesional psoriatic skin encounter high IL-6 from endothelial cells, DCs, and Th17 cells, enabling cutaneous T cell escape from Treg suppression and Th17 participation in inflammation. Targeting IL-6 signaling pathways in psoriasis may rebalance Treg/T effector activity and ameliorate disease.

Regulatory T Cells in Psoriasis

Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be central in the pathogenesis. Recently, a T cell subset population was identified, whose role is to suppress inflammatory responses triggered by T effector cells. T cells in this new population are referred to as T regulatory cells. We studied their number and activity in psoriatic lesions and found that they are both numerically and functionally deficient in their ability to suppress the abnormally persistent psoriatic immune response. This deficiency may shed more light on the complex pathophysiology of psoriasis.

Isotype determination of anti-Trypanosoma cruzi antibody in murine Chagas' disease.

Isotypic analysis of anti-parasite humoral responses of C57B1/6 and C3H (He) mice surviving acute Trypanosoma cruzi infection showed that both mouse strains demonstrate IgG1, IgG2a, IgG2b, and IgM enzyme-linked immunosorbent assay titers from days 21 to 300 of infection. Using the western blot technique to determine the antigen specificity of the isotypic responses, 100-day infected C3H mice showed strong IgG1, IgG2a, and IgG2b responses to many antigens, whereas C57B1/6 mice showed weak responses to fewer antigens. Isotype western blots showed that reactivity to the T. cruzi antigen of 75-77 kDa is present in the humoral response of day 21-infected mice that will survive and missing in those that will not survive. In general, surviving immunized C3H mice respond with IgG1, IgG2a, and IgG2b reactions to the 75-77-kDa and other antigens, whereas resistant B6 mice concentrate their anti-T. cruzi response in the IgG2b isotype to the 75-77-kDa antigen. Perhaps induction of ineffective antibody responses to nonprotective antigens is beneficial to the parasite and detrimental to the host.

Single administration of lesion-limited high-dose (TURBO) ultraviolet B using the excimer laser: clinical clearing in association with apoptosis of epidermal and dermal T cell subsets in psoriasis

Development of effective therapy for psoriasis is confounded by numerous factors contributing to disease pathogenesis, including pathogenic immunocytes which appear to drive epidermal keratinocyte hyperproliferation. Our objective was to study clinical and biomarker effects of a single dose of TURBO laser UVB (308 nm) applied directly to psoriatic plaques.

Infection Characteristics of an Ecuadorian Trypanosoma cruzi Strain with Reduced Virulence

A human isolate of Trypanosoma cruzi obtained from Guayaquil, Ecuador (Guayas strain) was examined for its infectivity of the resistant C57Bl/6 (B6) and the susceptible C3H (He) mouse strains and compared to infection with the known virulent Brazil strain. C3H mice were capable of surviving acute Guayas infection, whereas the Brazil infection was fatal for this mouse strain. Both C3H and B6 mice showed a greatly reduced (over 10-fold) parasitemia during Guayas infection compared to Brazil infection. Histologic examination of heart tissue from Guayas-infected B6 and C3H mice indicates little inflammation, unlike what is typically seen in B6 mice chronically infected with the Brazil strain. There appears to be no remarkable difference in the anti-parasite antibody responses (as measured by ELISA and western blot) in mice infected 100 days with Guayas or Brazil parasites. Western blot analysis of the anti-heart response indicates no response during Guayas infection to a 43-kDa heart tissue glycoprotein that is a target of antibodies from B6 mice infected with Brazil strain. The Guayas strain, therefore, provides an infection that generates a low parasitemia and strong anti-parasite responses in the absence of specific anti-heart autoimmunity and obvious myocarditis. In vitro infection characteristics of these 2 parasite strains were studied in cultures of macrophages, myocytes, and fibroblasts by microscopic examination of stained slide cultures. In both short-term (24 hr) and long-term (15 day) experiments, Brazil strain infection was shown to have a greater infection rate with a higher number of parasites per cell than Guayas infection for all host cell types.(ABSTRACT TRUNCATED AT 250 WORDS)

Parasite antigen-induced IFNγ and IL-4 production by cells from pathopermissive and pathoresistant strains of mice infected with Trypanosoma cruzi

The cardiac pathology associated with infection by Trypanosoma cruzi in mice has been suggested to be partially dependent upon cytokine responses. The pathoresistant B10.D2 mice, which display little infection-induced myocarditis, and the pathopermissive DBA/2 mice, which show significant cardiac damage, were compared for their in vitro interferon (IFN)-gamma and interleukin (IL)-4 production. Concanavalin A-stimulated spleen cells from infected B10.D2 mice produce a greater amount of IFN-gamma than DBA/2 mice, whereas the IL-4 production is only slightly greater in the B10.D2 mice than the DBA/2 mice. Parasite antigen stimulation of spleen cells from these mice results in a clearly greater IFN gamma production by the B10.D2 and a higher IL-4 level for the DBA/2 mice. The data presented suggest a relationship between an enhanced TH1-type response and decreased chronic cardiac pathogenesis, whereas a lower level of TH1 activity may play a role in cardiac involvement.

Current knowledge on psoriasis and autoimmune diseases

Psoriasis is a prevalent, chronic inflammatory disease of the skin, mediated by crosstalk between epidermal keratinocytes, dermal vascular cells, and immunocytes such as antigen presenting cells (APCs) and T cells. Exclusive cellular “responsibility” for the induction and maintenance of psoriatic plaques has not been clearly defined. Increased proliferation of keratinocytes and endothelial cells in conjunction with APC/T cell/monocyte/macrophage inflammation leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Despite the identification of numerous susceptibility loci, no single genetic determinant has been identified as responsible for the induction of psoriasis. Thus, numerous other triggers of disease, such as environmental, microbial and complex cellular interactions must also be considered as participants in the development of this multifactorial disease. Recent advances in therapeutics, especially systemic so-called “biologics” have provided new hope for identifying the critical cellular targets that drive psoriasis pathogenesis. Recent recognition of the numerous co-morbidities and other autoimmune disorders associated with psoriasis, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus suggest common signaling elements and cellular mediators may direct disease pathogenesis. In this review, we discuss common cellular pathways and participants that mediate psoriasis and other autoimmune disorders that share these cellular signaling pathways.

Case report of individual with cutaneous immunodeficiency and novel 1p36 duplication

Introduction Crusted or Norwegian scabies is an infectious skin dermatopathology usually associated with an underlying immunodeficiency condition. It is caused when the mite Sarcoptes scabiei infects the skin, and the immune system is unable to control its spread, leading to a massive hyperinfestation with a simultaneous inflammatory and hyperkeratotic reaction. This is the first report of a novel 1p36 duplication associated with a recurrent infection of crusted scabies. Case report We describe a 34-year-old patient with a cutaneous immunodeficiency characterized by recurrent crusted scabies infestation, diffuse tinea, and recurrent staphylococcal cellulitis, who we suspected had an undiagnosed syndrome. The patient also suffered from mental retardation, renal failure, and premature senescence. A cytogenetic fluorescence in situ hybridization analysis revealed a 9.34 Mb duplication within the short (p) arm of chromosome 1, precisely from 1p36.11 to 1p36.21, with an adjacent 193 kb copy gain entirely within 1p36.11. In addition, chromosome 4 had a 906 kb gain in 4p16.1 and chromosome 9 had a 81 kb copy gain in 9p24.3. Over 100 genes localized within these duplicated regions. Gene expression array revealed 82 genes whose expression changed >1.5-fold compared to a healthy age-matched skin control, but among them only the lipolytic enzyme arylacetamide deacetylase-like 3 was found within the duplicated 1p36 region of chromosome 1. Discussion Although genetic duplications in the 1p36 region have been previously described, our report describes a novel duplicative variant within the 1p36 region. The patient did not have a past history of immunosuppression but was afflicted by a recurrent case of crusted scabies, raising the possibility that the recurrent infection was associated with the 1p36 genetic duplication. Conclusion To our knowledge, the specific duplicated sequence between 1p36.11 and p36.21 found in our patient has never been previously reported. We reviewed and compared the clinical, genotyping, and gene microarray results of our patient in order to characterize this novel 1p36 duplication syndrome, which might have contributed to the recurrent scabies infection in this patient.

Integrin Expression and Macrophage Resistance to Apoptosis in Atherosclerosis

Development and progression of atherosclerosis is a complex pathologic event involving cells from both the arterial vessel wall and the immune system, including monocyte-derived macrophages. Monocytes are recruited to the atherosclerotic lesion via an elaborate process involving adhesion to and migration through the endothelial cell layer and into the arterial wall. Adhesion and migration of monocytes is accompanied by activation/differentiation to tissue macrophages. Once inside the atheroma, macrophages are exposed to many factors which further stimulate the cells. Cytokines, low density lipoproteins, and low oxygen levels (hypoxia; a product of tissue thickening in the absence of neovascularization [1]) are all factors which have profound effects on the state of differentiation, function, and survival of macrophages within the atheroma.