Russell P. Hall

Characterization of a rare IL-10–competent B-cell subset in humans that parallels mouse regulatory B10 cells

Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10-competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10-competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24(hi)CD27(+) B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10-dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.

Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus

Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

Defective Fc-Receptor Functions Associated with the HLA-B8/DRw3 Haplotype: Studies in Patients with Dermatitis Herpetiformis and Normal Subjects

Dermatitis herpetiformis is associated with the HLA-B8/DRw3 haplotype in over 90 per cent of patients, and various percentages have been reported to have circulating immune complexes. Since removal of immune complexes from the circulation is thought to depend on the Fc-receptor function of tissue macrophages, we studied this function by measuring the clearance of IgG-sensitized autologous erythrocytes in 16 patients with dermatitis herpetiformis, in normal controls with the HLA-B8/DRw3 haplotype, and in randomly selected controls. All patients were HLA-B8 positive, and all of 12 patients tested were HLA-DRw3 positive. Erythrocyte clearance was reduced in eight of the 16 patients, but did not correlate with immune-complex levels. Four of eight controls with HLA-B8/DRw3 also had delayed Fc-receptor-mediated clearance as compared with normal controls. In addition, both patients and HLA-B8/DRw3-positive controls had decreased percentages and total numbers of T cells bearing Fc receptors for IgG. These findings indicate a functional Fc-receptor defect associated with the HLA-B8/DRw3 antigens.

Bullous eruption of systemic lupus erythematosus. Dramatic response to dapsone therapy.

Four patients with systemic lupus erythematosus developed a nonpruritic vesiculobullous eruption that was unresponsive to high-dose systemic corticosteroid therapy. In three patients the eruption was not associated with a flare of systemic disease. Biopsy results showed neutrophilic microabscesses at the dermal papillary tips and perivascular lymphohistiocytic infiltrates. Direct immunofluorescence of normal appearing skin not exposed to the sun was positive in all four patients. Due to the unresponsiveness to corticosteroid therapy and the striking histologic resemblance to dermatitis herpetiformis, each of the patients was treated with dapsone. Within 24 hours each patient had prompt cessation of the appearance of new lesions. Improvement of the eruption did not correlate with improvement of the systemic manifestations of their lupus erythematosus. The rapid response to dapsone therapy suggests that dapsone is useful in treating bullous lesions of systemic lupus erythematosus.

Epidermal keratinocytes express the adhesion molecule intercellular adhesion molecule-1 in inflammatory dermatoses

Using indirect immunofluorescence assays on frozen tissue sections of skin from healthy subjects and subjects with inflammatory skin diseases, we found that intercellular adhesion molecule-1 (ICAM-1) was expressed in a cell surface pattern on epidermal keratinocytes at the site of lymphoid infiltration in cutaneous dermatoses. ICAM-1 was not expressed on epidermal keratinocytes in noninflamed skin. Its expression was not related solely to epidermal hyperproliferation, as hyperproliferative, tape-stripped epidermis did not express ICAM-1. We have reported previously that ICAM-1 expression on epidermal keratinocytes was upregulated by treatment with interferon gamma and that activated T lymphocytes bound to cultured epidermal keratinocytes in vitro by lymphocyte function associated-1 (LFA-1) molecules on T cells and ICAM-1 on epidermal keratinocytes. Taken together, these data suggest that upregulation of expression of ICAM-1 is an important feature of cutaneous inflammation.

Dermatitis Herpetiformis: The Skin and the Gut

Dermatitis herpetiformis is an intensely itchy, chronic, papulovesicular eruption that is usually symmetrically distributed on extensor surfaces. Histologically, it is characterized by dermal papillary collections of neutrophils and subepidermal vesicle formation. The skin has IgA deposits in areas corresponding to the earliest histopathologic change; that is, at the epidermal-dermal junction. Most patients have an associated asymptomatic gluten-sensitive enteropathy that mimics ordinary gluten-sensitive enteropathy (celiac disease) both morphologically and in its response to gluten protein. There is a marked increase in the prevalence of the major histocompatibility antigens, HLA-B8 and HLA-Dw3, and in certain B cell antigens in these patients. Although the sulfones or sulfapyridine have been the mainstay of treatment, it is now clear that the skin disease responds to strict adherence to a gluten-free diet. These findings are reviewed and from them are drawn certain conclusions as to possible pathophysiologic mechanisms involved in dermatitis herpetiformis.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation

BACKGROUND Skin cancer and photoaging changes result from ultraviolet (UV)-induced oxidative stress. Topical antioxidants may protect skin from these effects. OBJECTIVE We sought to determine whether a stable topical formulation of 15% L-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid (CEFer) could protect human skin in vivo from substantial amounts of solar-simulated UV radiation. METHODS CEFer and its vehicle were applied to separate patches of normal-appearing human skin for 4 days. Each patch was irradiated with solar-simulated UV, 2 to 10 minimal erythema doses, at 2-minimal erythema dose intervals. One day later, skin was evaluated for erythema and sunburn cells, and immunohistochemically for thymine dimers and p53. UV-induced cytokine formation, including interleukin (IL)-1alpha, IL-6, IL-8, and IL-10, and tumor necrosis factor-alpha, were evaluated by real-time polymerase chain reaction. RESULTS CEFer provided significant and meaningful photoprotection for skin by all methods of evaluation. LIMITATIONS The number of patients evaluated was relatively small. CONCLUSION CEFer provided substantial UV photoprotection for skin. It is particularly effective for reducing thymine dimer mutations known to be associated with skin cancer. Its mechanism of action is different from sunscreens and would be expected to supplement the sun protection provided by sunscreens.

Reliability and Convergent Validity of Two Outcome Instruments for Pemphigus

A major obstacle in performing multicenter controlled trials for pemphigus is the lack of a validated disease activity scoring system. Here, we assess the reliability and convergent validity of the PDAI (pemphigus disease area index). A group of 10 dermatologists scored 15 patients with pemphigus to estimate the inter- and intra-rater reliability of the PDAI and the recently described ABSIS (autoimmune bullous skin disorder intensity score) instrument. To assess convergent validity, these tools were also correlated with the Physicians Global Assessment (PGA). Reliability studies demonstrated an intra-class correlation coefficient (ICC) for inter-rater reliability of 0.76 (95% confirdence interval (CI)=0.61-0.91) for the PDAI and 0.77 (0.63-0.91) for the ABSIS. The tools differed most in reliability of assessing skin activity, with an ICC of 0.39 (0.17-0.60) for the ABSIS and 0.86 (0.76-0.95) for the PDAI. Intra-rater test-retest reliability demonstrated an ICC of 0.98 (0.96-1.0) for the PDAI and 0.80 (0.65-0.96) for the ABSIS. The PDAI also correlated more closely with the PGA. We conclude that the PDAI is more reproducible and correlates better with physician impression of extent. Subset analysis suggests that for this population of mild-to-moderate disease activity, the PDAI captures more variability in cutaneous disease than the ABSIS.

IgA-containing circulating immune complexes in patients with IgA nephropathy

The role of circulating immune complexes in the pathogenesis of IgA nephropathy (Bergers disease) is controversial. Previous studies have shown that a minority of these patients have immune complexes, but the methods used have been able to detect only IgG- or IgM-containing circulating immune complexes. Using a sensitive specific Raji cell radioimmunoassay for IgA-containing circulating immune complexes, we have examined serum specimens from 12 patients with IgA nephropathy for the presence of IgA-containing circulating immune complexes. In addition, the Raji cell IgG assay and the 125I-C1q binding assay were used for the detection of IgG- or IgM-containing circulating immune complexes. Purified monoclonal antibodies against human IgA1 and IgA2 were used to determine the subclass of IgA present in renal biopsy specimens from five of these patients. Six of 12 (50 percent) patients had IgA-containing circulating immune complexes, whereas only two of 12 (17 percent) had positive results in the Raji IgG assay and one of 12 (8 percent) in the 125I-C1q binding assay. There was no correlation between serum IgA, C3 C4, or factor B levels and the presence or level of IgA-containing circulating immune complexes. None of the three patients with renal failure had circulating immune complexes of any type. Of the seven patents with disease duration of two years or less, five (71 percent) had IgA-containing circulating immune complexes and three (43 percent) had IgG- or IgM-containing complexes. In all five renal biopsy specimens examined for IgA subclass, diffuse heavy, mesangial deposits of IgA1 were seen, whereas IgA2 staining was absent or present in only trace amounts. These findings suggest that IgA1 is the predominant antibody in renal biopsy specimens from patients with IgA nephropathy. The finding of IgA-containing circulating immune complexes in these patients--and their more frequent occurrence in patients with early stages of the disease--suggests that IgA-containing circulating immune complexes may play a role in the pathogenesis of IgA nephropathy.