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Rakočević S, Mališ V, Kozić L, Dubovina A, Drakul M, Bokonjić D, Čolić M, Mihajlović D. Dapsone Alters Phenotypical and Functional Properties of Human Neutrophils In Vitro. Molecules 2024; 30:113. [PMID: 39795170 PMCID: PMC11722540 DOI: 10.3390/molecules30010113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 01/13/2025] Open
Abstract
Dapsone is a sulfone used in treating inflammatory skin conditions. Despite its widespread dermatological use, the pharmacological actions of dapsone remain poorly understood. Here, we examined how different aspects of neutrophil functions are affected by dapsone. Peripheral blood neutrophils from healthy donors were stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), or calcium ionophore (CaI) or primed with cytokines prior to stimulation, in the presence of different concentrations of dapsone (from 10 to 50 µg/mL), followed by analyses of their survival, phenotype, and functional properties. We found that dapsone at the concentration of 50 μg/mL induced a significant neutrophil apoptotic rate during 6 h and 18 h, while other concentrations were well tolerated compared to control non-treated cells. However, dapsone significantly decreased the induced oxidative burst of neutrophils at all non-cytotoxic concentrations. Additionally, dapsone showed a dose-dependent suppression of NETosis in activated neutrophils. The production of IL-8 by dapsone-treated neutrophils was decreased under both stimulated (fMLP) and primed (TNF-α/fMLP) conditions. Moreover, dapsone inhibited the expression of CD11b/CD18, CD66, and CD89 and reversed or significantly mitigated the downregulation of CD16, CD32, CD181, CD88, and CD62L on neutrophils after priming and fMLP stimulation. In conclusion, our results indicate the complexity of dapsone actions on neutrophil functions, extending previous knowledge on the suppression of oxidative burst and IL-8 production upon neutrophils' activation. Suppressed NETosis and modulation of marker expression associated with different neutrophil functions under inflammatory conditions are new findings, not recognized previously.
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Affiliation(s)
- Sara Rakočević
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Vanja Mališ
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Ljiljana Kozić
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Anđela Dubovina
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Marija Drakul
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Dejan Bokonjić
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
| | - Miodrag Čolić
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
- Serbian Academy of Sciences and Arts, Kneza Mihajla 35, 11000 Belgrade, Serbia
| | - Dušan Mihajlović
- Faculty of Medicine Foča, University of East Sarajevo, Studentska 5, 73 300 Foča, Bosnia and Herzegovina; (S.R.); (V.M.); (L.K.); (A.D.); (M.D.); (D.B.); (M.Č.)
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Crnotravska 17, 11040 Belgrade, Serbia
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Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res 2013; 306:103-24. [PMID: 24310318 PMCID: PMC3927068 DOI: 10.1007/s00403-013-1409-7] [Citation(s) in RCA: 215] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 07/30/2013] [Accepted: 08/19/2013] [Indexed: 12/21/2022]
Abstract
Dapsone (4,4′-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. In 1937 against the background of sulfonamide era the microbial activity of dapsone has been discovered. Shortly thereafter, the use of dapsone to treat non-pathogen-caused diseases revealed alternate antiinflammatory mechanisms that initially were elucidated by inflammatory animal models. Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs. The latter capabilities primarily were used in treating chronic inflammatory disorders. Dapsone has been investigated predominantly by in vitro methods aiming to get more insights into the effect of dapsone to inflammatory effector cells, cytokines, and/or mediators, such as cellular toxic oxygen metabolism, myoloperoxidase-/halogenid system, adhesion molecules, chemotaxis, membrane-associated phospholipids, prostaglandins, leukotrienes, interleukin-8, tumor necrosis factor α, lymphocyte functions, and tumor growth. Moreover, attention has been paid to mechanisms by which dapsone mediates effects in more complex settings like impact of lifespan, stroke, glioblastoma, or as anticonvulsive agent. Additionally, there are some dermatological investigations in human being using dapsone and its metabolites (e.g., leukotriene B4-induced chemotaxis, ultraviolet-induced erythema). It could be established that dapsone metabolites by their own have anti-inflammatory properties. Pharmacology and mechanisms of action are determining factors for clinical use of dapsone chiefly in neutrophilic and/or eosinophilic dermatoses and in chronic disorders outside the field of dermatology. The steroid-sparing effect of dapsone is useful for numerous clinical entities. Future avenues of investigations will provide more information on this fascinating and essential agent.
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Affiliation(s)
- Gottfried Wozel
- Study Centre for Clinical Trials, Dermatology, Gesellschaft für Wissens- und Technologietransfer der Technischen Universität Dresden mbH, Blasewitzer Str. 43, 01307 Dresden, Germany
| | - Christian Blasum
- Private Practice of Dermatology, Marktplatz 25, 73728 Esslingen, Germany
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Cardones ARG, Hall RP. Pathophysiology of Dermatitis Herpetiformis: A Model for Cutaneous Manifestations of Gastrointestinal Inflammation. Immunol Allergy Clin North Am 2012; 32:263-74, vi. [DOI: 10.1016/j.iac.2012.04.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Cardones ARG, Hall RP. Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation. Dermatol Clin 2011; 29:469-77, x. [PMID: 21605814 DOI: 10.1016/j.det.2011.03.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.
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Abstract
The major treatment strategies for DH are gluten restriction or medical treatment with sulfones. Control of the cutaneous manifestations, but not the gastrointestinal changes, is rapid with dapsone. In addition to control of the cutaneous signs and symptoms of DH, dietary gluten restriction also induces improvement of gastrointestinal morphology and is possibly protective against the development of lymphoma.
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Abenavoli L, Proietti I, Leggio L, Ferrulli A, Vonghia L, Capizzi R, Rotoli M, Amerio PL, Gasbarrini G, Addolorato G. Cutaneous manifestations in celiac disease. World J Gastroenterol 2006; 12:843-52. [PMID: 16521210 PMCID: PMC4066147 DOI: 10.3748/wjg.v12.i6.843] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is an autoimmune gluten-dependent enteropathy characterized by atrophy of intestinal villi that improves after gluten-free diet (GFD). CD is often associated with extra-intestinal manifestations; among them, several skin diseases are described in CD patients. The present review reports all CD-associated skin manifestations described in the literature and tries to analyze the possible mechanisms involved in this association. The opportunity to evaluate the possible presence of CD in patients affected by skin disorders is discussed.
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Affiliation(s)
- L Abenavoli
- Institute of Internal Medicine, Catholic University, L.go Gemelli 8, 00168 Rome, Italy
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Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Clin Microbiol Rev 2000. [PMID: 11023961 DOI: 10.1128/cmr.13.4.615-650.2000] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Professional phagocytes (polymorphonuclear neutrophils and monocytes/macrophages) are a main component of the immune system. These cells are involved in both host defenses and various pathological settings characterized by excessive inflammation. Accordingly, they are key targets for immunomodulatory drugs, among which antibacterial agents are promising candidates. The basic and historical concepts of immunomodulation will first be briefly reviewed. Phagocyte complexity will then be unravelled (at least in terms of what we know about the origin, subsets, ambivalent roles, functional capacities, and transductional pathways of this cell and how to explore them). The core subject of this review will be the many possible interactions between antibacterial agents and phagocytes, classified according to demonstrated or potential clinical relevance (e.g., neutropenia, intracellular accumulation, and modulation of bacterial virulence). A detailed review of direct in vitro effects will be provided for the various antibacterial drug families, followed by a discussion of the clinical relevance of these effects in two particular settings: immune deficiency and inflammatory diseases. The prophylactic and therapeutic use of immunomodulatory antibiotics will be considered before conclusions are drawn about the emerging (optimistic) vision of future therapeutic prospects to deal with largely unknown new diseases and new pathogens by using new agents, new techniques, and a better understanding of the phagocyte in particular and the immune system in general.
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Labro MT. Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Clin Microbiol Rev 2000; 13:615-50. [PMID: 11023961 PMCID: PMC88953 DOI: 10.1128/cmr.13.4.615] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Professional phagocytes (polymorphonuclear neutrophils and monocytes/macrophages) are a main component of the immune system. These cells are involved in both host defenses and various pathological settings characterized by excessive inflammation. Accordingly, they are key targets for immunomodulatory drugs, among which antibacterial agents are promising candidates. The basic and historical concepts of immunomodulation will first be briefly reviewed. Phagocyte complexity will then be unravelled (at least in terms of what we know about the origin, subsets, ambivalent roles, functional capacities, and transductional pathways of this cell and how to explore them). The core subject of this review will be the many possible interactions between antibacterial agents and phagocytes, classified according to demonstrated or potential clinical relevance (e.g., neutropenia, intracellular accumulation, and modulation of bacterial virulence). A detailed review of direct in vitro effects will be provided for the various antibacterial drug families, followed by a discussion of the clinical relevance of these effects in two particular settings: immune deficiency and inflammatory diseases. The prophylactic and therapeutic use of immunomodulatory antibiotics will be considered before conclusions are drawn about the emerging (optimistic) vision of future therapeutic prospects to deal with largely unknown new diseases and new pathogens by using new agents, new techniques, and a better understanding of the phagocyte in particular and the immune system in general.
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Affiliation(s)
- M T Labro
- INSERM U 479, Faculté Xavier Bichat, 75018 Paris, France.
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Abstract
Dapsone, a synthetic sulfone with chemical similarities to sulfapyridine, has been used for a number of years to treat leprosy and dermatitis herpetiformis. Recently, a number of prospective, randomized, double-blind trials have shown their success in the management of rheumatoid arthritis, with dapsone being superior to placebo and comparable to chloroquine and hydroxychloroquine. Its mode of anti-inflammatory actions in rheumatoid arthritis is not clearly understood, but modulation of neutrophil activity or inhibition of neutrophil inflammatory product formation or release appear to play a role. The major limiting side effect is hemolytic anemia, which may be mitigated through careful patient selection, conservative drug dosing, close monitoring, and possibly, concurrent administration of antioxidants or cytochrome P450 inhibitors. Methemoglobinemia is another common finding among patients receiving dapsone therapy, but rarely does it result in prominent symptoms other than transient pallor. Less common adverse events to dapsone include the idiosyncratic reactions of leukopenia and agranulocytosis, cutaneous eruptions, peripheral neuropathy, psychosis, toxic hepatitis, cholestatic jaundice, nephrotic syndrome, renal papillary necrosis, severe hypoalbuminemia without proteinuria, an infectious mononucleosis-like syndrome, and minor neurological and gastrointestinal complaints. In this report, two patients with advanced rheumatoid arthritis, who were safely and effectively treated with dapsone after failure with other second-line agents, are described and the literature is reviewed. We suggest that dapsone is an effective second-line agent in the treatment of rheumatoid arthritis.
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Affiliation(s)
- D J Chang
- Division of Rheumatology and Connective Tissue Research, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School 08903-0019, USA
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Thuong-Nguyen V, Kadunce DP, Hendrix JD, Gammon WR, Zone JJ. Inhibition of neutrophil adherence to antibody by dapsone: a possible therapeutic mechanism of dapsone in the treatment of IgA dermatoses. J Invest Dermatol 1993; 100:349-55. [PMID: 8454897 DOI: 10.1111/1523-1747.ep12471811] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Dapsone is frequently effective in cutaneous diseases characterized by antibody deposition and accumulation of neutrophils. We hypothesized that this mechanism of action of dapsone may involve the inhibition of neutrophil adherence to antibody. The neutrophil adherence assay, which measures the binding of neutrophils to basement membrane zone-bound antibody on skin sections, was used to evaluate the effect of dapsone on neutrophil adherence to immunoglobulin A and immunoglobulin G. We evaluated the effect of dapsone on adherence of normal neutrophils to immunoglobulin A and immunoglobulin G from sera of linear immunoglobulin A bullous dermatosis and bullous pemphigoid patients, respectively. Linear immunoglobulin A bullous dermatosis or bullous pemphigoid antibody were bound to the basement membrane zone of normal skin sections as a substrate for the neutrophil adherence assay. Dapsone was added directly to the neutrophils or to the antibody source in concentrations of 0-50 micrograms/ml (pharmacologic range). Addition of dapsone to neutrophils produced an incremental inhibition of neutrophil adherence up to 75% at 50 micrograms/ml. Dapsone produced similar inhibition when added directly to the antibody itself, despite washing prior to usage in the neutrophil-adherence assay. Control specimens including irrelevant fractions of patient sera failed to demonstrate binding. Serum from a patient on dapsone therapy also showed inhibition of neutrophil adherence compared to the same patient on no therapy. We conclude that dapsone inhibits the adherence of neutrophils to basement membrane zone antibody in a dose-dependent manner. This may be related to an effect directly on antibody. This inhibition may contribute to the clinical efficacy of dapsone in antibody-mediated diseases.
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Affiliation(s)
- V Thuong-Nguyen
- Dermatology Section, Veterans Affair Medical Center, Salt Lake City, Utah
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Affiliation(s)
- R P Hall
- Department of Medicine, Duke University Medical Center, Durham, NC 27710
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Kadunce DP, McMurry MP, Avots-Avotins A, Chandler JP, Meyer LJ, Zone JJ. The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis. J Invest Dermatol 1991; 97:175-82. [PMID: 2071933 DOI: 10.1111/1523-1747.ep12479517] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Elemental diets are reported to decrease activity of patients with dermatitis herpetiformis. We tested the hypothesis that gluten, given in addition to an elemental diet, is responsible for the intestinal abnormalities, cutaneous immunoreactant deposition, and skin disease activity in dermatitis herpetiformis. At entry eight patients with dermatitis herpetiformis, who were consuming unrestricted diets, were stabilized on their suppressive medications at dosage levels that allowed individual lesions to erupt. Six patients were then given an elemental diet plus 30 of gluten for 2 weeks, followed by the elemental diet alone for 2 weeks. Conversely, two patients received an elemental diet alone for 2 weeks followed by an elemental diet plus gluten during the final 2 weeks. Small bowel biopsies, skin biopsies, and clinical assessments were done at 0, 2, and 4 weeks. Suppressive medication dose requirement decreased over the 4 weeks by a mean of 66%. Six of eight subjects significantly improved clinically during the gluten-challenge phase of the elemental diet and all were improved at the end of the study. The amount of IgA in perilesional skin did not change significantly, but the amount of C3 increased in five of seven evaluable subjects after gluten challenge. Circulating anti-gluten and anti-endomysial antibodies were not significantly affected by the diets. All subjects completing evaluable small bowel biopsies (seven of seven) demonstrated worsening of their villus architecture (by scanning electron microscopy and intraepithelial lymphocyte counts) during gluten challenge and improvement (six of six subjects) after 2 weeks of elemental dietary intake. We conclude that 1) there is a significant improvement in clinical disease activity on an elemental diet, independent of gluten administration, 2) small bowel morphology improves rapidly on an elemental diet, and 3) complement deposition but neither IgA deposition nor circulating antibody levels correlate with gluten intake. It seems likely that dietary factors other than gluten are important in the pathogenesis of the skin lesions in dermatitis herpetiformis.
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Affiliation(s)
- D P Kadunce
- Department of Medicine (Dermatology), University of Utah School of Medicine, Salt Lake City
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Affiliation(s)
- C C Otley
- Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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Affiliation(s)
- R P Hall
- Department of Medicine, Duke University Medical Center, Durham, NC
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Affiliation(s)
- J B van der Meer
- Department of Dermatology, Medical Center Leeuwarden, The Netherlands
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Roberts DE, Curd JG. Sulfonamides as antiinflammatory agents in the treatment of Wegener's granulomatosis. ARTHRITIS AND RHEUMATISM 1990; 33:1590-3. [PMID: 2222542 DOI: 10.1002/art.1780331020] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Affiliation(s)
- J Uetrecht
- Faculty of Pharmacy, University of Toronto, School of Medicine, Ontario, Canada
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Affiliation(s)
- G G Krueger
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City
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Affiliation(s)
- G Wozel
- Department of Dermatology, Medical Academy Carl Gustav Carus, Dresden, German Democratic Republic
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Moss C, Hamilton PJ. Thrombocytopenia in systemic lupus erythematosus responsive to dapsone. BMJ (CLINICAL RESEARCH ED.) 1988; 297:266. [PMID: 3416146 PMCID: PMC1833929 DOI: 10.1136/bmj.297.6643.266] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- C Moss
- Royal Victoria Infirmary, Newcastle upon Tyne
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Akahoshi Y, Kanda G, Anan S, Yoshida H. Dermo-epidermal blister formation by linear IgA dermatosis sera in normal human skin in organ culture. J Dermatol 1987; 14:352-8. [PMID: 3320129 DOI: 10.1111/j.1346-8138.1987.tb03592.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Abstract
Over the last two decades a rapid expansion of our knowledge regarding dermatitis herpetiformis has occurred, including the discovery of IgA in the skin, the discovery of an associated gluten-sensitive enteropathy, the noting of an increased prevalence of the human lymphocyte antigens (HLA)-B8 and -DRw3, and the documentation that the skin disease of many dermatitis herpetiformis patients can be controlled by a gluten-free diet. It has also been noted that two distinct forms of dermatitis herpetiformis occur, those with granular deposits of IgA at the dermoepidermal junction (85%-95% of dermatitis herpetiformis patients) and those with linear IgA deposits (10%-15% of dermatitis herpetiformis patients). These findings are reviewed with particular emphasis on the form of dermatitis herpetiformis associated with granular IgA deposits. The current findings regarding the nature and origin of the cutaneous IgA deposits, the role of the gluten-sensitive enteropathy, and the spectrum of both the immunologic and the nonimmunologic abnormalities associated with dermatitis herpetiformis are presented, and from these data pathophysiologic mechanisms are proposed that may be involved in dermatitis herpetiformis.
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Wilson BD, Beutner EH, Kumar V, Chorzelski TP, Jablonska S. Linear IgA bullous dermatosis. An immunologically defined disease. Int J Dermatol 1985; 24:569-74. [PMID: 3905638 DOI: 10.1111/j.1365-4362.1985.tb05853.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Linear IgA bullous dermatosis (LABD) can mimic bullous pemphigoid (BP) and/or dermatitis herpetiformis (DH) both clinically and histologically. LABD, however, can be distinguished from BP and DH by direct immunofluorescent (IF) demonstration of linear IgA deposits along the basement membrane zone. A retrospective study of 234 cases of BP, 27 cases of LABD, 60 cases of DH, and 20 cases of cicatricial pemphigoid (CP) revealed that BP patients are significantly older than LABD or DH patients and LABD patients are significantly older than DH patients. BP and CP occur more frequently in women (65-70%) than LABD or DH (44-48%). The frequencies of C3 deposits in the basement membrane zone (BMZ) are significantly higher in BP (85%) compared with LABD (18.5%) and DH (28.3%). LABD patients varied in their response to various therapeutic agents. Some responded to corticosteroids and some to sulfones alone, whereas others required a combination of corticosteroids and sulfones.
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Webster GF, Alexander JC, McArthur WP, Leyden JJ. Inhibition of chemiluminescence in human neutrophils by dapsone. Br J Dermatol 1984; 110:657-63. [PMID: 6733037 DOI: 10.1111/j.1365-2133.1984.tb04701.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Dapsone at doses of 0.5 to 5.0 micrograms/ml was found to produce a dose-dependent inhibition of opsonized zymosan-induced human polymorphonuclear leukocyte (PMN) chemiluminescence (CL) in vitro. Simultaneous exposure of PMN to dapsone and zymosan was as effective in reducing CL as preincubation of PMN with dapsone. Preincubation of PMN with dapsone followed by washing, resulted in the loss of dapsone-mediated CL inhibition, indicating that dapsone did not permanently alter the CL-generating mechanism and that the drug had to be present to inhibit CL. Dapsone did not absorb light at the wavelength of CL and was not toxic to PMN at concentrations tested. Sodium azide, an inhibitor of myeloperoxidase-mediated CL inhibited PMN CL to the same degree as dapsone. When incubated together with PMN, dapsone and azide did not produce an additive inhibition of CL. These data suggest that inhibition of myeloperoxidase may be the mechanism by which dapsone inhibits PMN CL.
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Kazmierowski JA, Ross JE, Peizner DS, Wuepper KD. Dermatitis herpetiformis: effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity. J Clin Immunol 1984; 4:55-64. [PMID: 6321539 DOI: 10.1007/bf00915288] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity were studied using in vitro assays to measure these parameters. Leukocyte iodination was documented using a quantitative assay to measure the iodination of protein by human neutrophils undergoing phagocytosis. Cytotoxicity for the tumor cell line LSTRA by human neutrophils activated by exposure to phorbol myristate acetate was measured by a 51Cr release assay. Dapsone, diasone, and sulfapyridine, at concentrations comparable to serum levels obtained by therapeutic doses of drug, effectively inhibited iodination and cytotoxicity mediated by human neutrophils. Other sulfonamides showed little inhibition of either iodination or cytotoxicity. The amount of inhibition was comparable to that seen with the inhibitors azide or cyanide and occurred in a dose dependent manner with all three drugs. A cell-free cytotoxic system using myeloperoxidase, iodide, a H2O2 generating system, and target cells also showed inhibition by dapsone, diasone and sulfapyridine in a similar fashion. The active drugs inhibited both the intra- and the extracellular myeloperoxidase-H2O2-halide cytotoxic systems. Serial iodination studies of four dermatitis herpetiformis patients, evaluated while taking dapsone or sulfapyridine, showed inhibition of iodination by either drug. Levels of IgA immune complexes, as measured by the Raji cell radioimmune assay adapted for IgA, did not change when medication was withheld. These studies demonstrate that dapsone, diasone, and sulfapyridine inhibit both neutrophil iodination and cytotoxicity for tumor cells, while other sulfonamides have no effect. This confirms previous studies showing inhibition by myeloperoxidase mediated iodination by dapsone. Furthermore, the effect on neutrophils is quickly reversible; in vivo administered drug has no effect on in vitro function. The active drugs inhibit both intra- and extracellular cytotoxic systems. This may represent an important mechanism by which these drugs produce their therapeutic effects when used to treat inflammatory skin diseases.
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Lawley TJ, Yancey KB. Dermatitis Herpetiformis. Dermatol Clin 1983. [DOI: 10.1016/s0733-8635(18)31036-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Reitamo S, Reunala T, Konttinen YT, Saksela O, Salo OP. Inflammatory cells, IgA, C3, fibrin and fibronectin in skin lesions in dermatitis herpetiformis. Br J Dermatol 1981; 105:167-77. [PMID: 7025880 DOI: 10.1111/j.1365-2133.1981.tb01202.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Skin lesions were produced by application of 50% potassium iodide to twelve patients with dermatitis herpetiformis (DH). Perivascular cellular infiltrates were found to be characteristic of developing lesions. The cells were mainly round cells; alpha-naphthyl acetate esterase staining revealed that in 24-h lesions the mean percentage of T-lymphocytes was 43%, that of mononuclear phagocytes 6% and that of non-T/non-M cells (mainly B-lymphocytes) 44%. The percentage of the latter was highest (mean 81%) in 6-h specimens, suggesting that these cells are participating in the early stages of lesion formation. The infiltrating cells in dermal papillae and within subepidermal vesicles were predominantly polymorphonuclear leukocytes (mean 86%) with some mononuclear phagocytes and non-T/non-M cells. Immunofluorescence examination confirmed that fibrin deposition is characteristic of the initial lesions of DH and showed that the same is true of fibronectin. Seven out of eight patients had fibronectin deposits in dermal papillae. IgA was found in all and C3 in most of the specimens and, with the exception of papillary vesicles and blister cavities, the intensity of IgA and C3 fluorescence showed no marked alterations during the development of lesions.
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Hall RP, Lawley TJ, Katz SI. Dermatitis herpetiformis. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 1981; 4:33-43. [PMID: 7022720 DOI: 10.1007/bf01891883] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Ruzicka T, Bauer A, Glück S, Born M. Effects of dapsone on passive Arthus reaction and chemotaxis and phagocytosis of polymorphonuclear leukocytes. Arch Dermatol Res 1981; 270:347-51. [PMID: 6455972 DOI: 10.1007/bf00403939] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The effects of dapsone (diaminodiphenyl sulfone) on the polymorphonuclear leukocyte (PMNL) function and on the elicitation of the passive Arthus reaction were investigated in rabbits and guinea-pigs. NBT-reduction was markedly enhanced in PMNL of animal receiving 5 mg dapsone/kg for 3 days, whereas chemotaxis and phagocytosis were not influenced. Passive Arthus reaction was clearly suppressed by the same treatment regimen. 2 mg/kg of the drug had no effect on the parameters examined.
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Lawley TJ, Strober W, Yaoita H, Katz SI. Small intestinal biopsies and HLA types in dermatitis herpetiformis patients with granular and linear IgA skin deposits. J Invest Dermatol 1980; 74:9-12. [PMID: 7351496 DOI: 10.1111/1523-1747.ep12514565] [Citation(s) in RCA: 133] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
In this study we determined whether dermatitis herpetiformis patients whose skin contained linear IgA deposits differ from those whose skin contained granular IgA deposits with regard to the presence of gluten-sensitive enteropathy and with regard to the prevalence of certain histocompatibility antigens. We performed multiple Rubin tube intestinal biopsies on 11 patients, 6 with linear and 5 with granular IgA deposits. The gut biopsies were evaluated histopathologically in a blinded fashion. We found that none of the patients with linear deposits (5 with lamina lucida and 1 with sub-basal lamina deposits) h-d detectable jejunal abnormalities whereas all of those with granular deposits had jejunal abnormalitites (villous atrophy and increased numbers of intraepithelial lymphocytes). In parallel studies HLA typing was performed in 10 patients with linear IgA deposits and in 49 patients with granular deposits. Only 30% of those with linear deposits had HLA-B8, a prevalence not significantly different from that of the normal population (24%); in contrast, 88% of those with granular deposits had HLA-B8, a prevalence significantly greater than in the normal population ( less than 0.001). We therefore conclude that patients with linear IgA deposits have a disease which is pathophysiologically different from those with granular IgA deposits.
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Abstract
Although dapsone and sulfapyridine have been used for years in dermatology, there has not always been a clear understanding of how these agents work. Recent investigation, however, has shed new light on thes agents which now allows a more rational approach to their use. This review is an attempt to familiarize the clinician with how these agents work, in what disease states they are effective, how to administer them, what adverse effects may occur, and how to monitor the patient to detect these adverse effects.
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Gemmell DK, Cottney J, Lewis AJ. Comparative effects of drugs on four paw oedema models in the rat. AGENTS AND ACTIONS 1979; 9:107-16. [PMID: 157060 DOI: 10.1007/bf02024141] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The development of novel anti-inflammatory drugs (AID) has been claimed to be dependent on the discovery of models of inflammation that differ from those currently used for drug screening, e.g. carrageenen paw oedema and u.v. erythema. We have thus evaluated the effect of a variety of drugs in a number of novel models of inflammation in the rat produced in the hind paw. We have utilized kaolin, zymosan, anti-rat IgG (anti-IgG) and the Reversed Passive Arthus (RPA) reaction to produce these oedema models. We found that the non-steroidal AID's, e.g. aspirin, flufenamic acid, indomethacin, naproxen, and phenylbutazone, were active in all four tests. Of the nine novel AID examined, levamisole and tetramisole demonstrated considerable activity in all four tests and dapsone was especially active in the anti-IgG and RPA tests. In contrast, the anti-rheumatic d-penicillamine was inactive in all four models. Each of the ten compounds tested which has been claimed to influence complement function, was active in the RPA but not in the kaolin model. These results are discussed in the context of the aetiology of each oedema and the suspected mode of action of the various drugs.
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Lewis AJ, Gemmell DK, Stimson WH. The anti-inflammatory profile of dapsone in animal models of inflammation. AGENTS AND ACTIONS 1978; 8:578-86. [PMID: 311146 DOI: 10.1007/bf01998887] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dapsone has been shown to possess anti-inflammatory activity in a variety of animal models. It possesses oral anti-oedema activity especially pronounced in novel models of acute inflammation, viz. anti-IgG and reversed passive Arthus oedemas. However, it is not very active in the guinea pig u.v. erythema model. It is effective in chronic models such as adjuvant arthritis and the cotton pellet granuloma although multiple administration may also produce cyanosis. Antipyretic and analgesic effects for dapsone have been demonstrated and are similar to those produced by phenylbutazone. It inhibits zymosan-induced beta-glucuronidase release from cultured macrophages and also the activity of this enzyme. Dapsone does not appear to be ulcerogenic in the rat.
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Matthews CN, Saihan EM, Warin RP. Urticaria-like lesions associated with systemic lupus erythematosus: response to dapsone. Br J Dermatol 1978; 99:455-7. [PMID: 708619 DOI: 10.1111/j.1365-2133.1978.tb06188.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A cases of systemic lupus erythematosus is reported, presenting with urticaria-like lesions and complement deficiencies, which was completely controlled by dapsone.
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Abstract
The effects of several chemotherapeutic agents on the chemotaxis of human leukocytes were studied in an in vitro system using a Sykes-Moore chamber and a double-filter technique. Chemotactic factor was generated by the interaction of normal human serum and zymosan. At concentrations comparable to and below therapeutic blood levels, tetracycline HCl, erythromycin base and clindamycin HCl were all inhibitory, causing marked suppression of leukocyte chemotaxis and slight reduction of random migration. Penicillin G-Na, dapsone, and sulfapyridine did not alter white cell motility at the concentrations of drug tested. It is postulated that the capacity of some of these agents to inhibit leukocyte chemotaxis may account, in part, for their efficacy in inflammatory skin diseases such as acne vulgaris.
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Reunala T. Gluten-free diet in dermatitis herpetiformis. II. Morphological and immunological findings in the skin and small intestine of 12 patients and matched controls. Br J Dermatol 1978; 98:69-78. [PMID: 626715 DOI: 10.1111/j.1365-2133.1978.tb07335.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Twelve patients with dermatitis herpetiformis whose skin condition responded to a gluten-free diet (GFD) were re-examined after diet treatment. The findings were compared with those in matched patients on a normal diet. Jejunal histology revealed morphological improvement in every patient on a GFD whereas all patients on a normal diet continued to have villous atrophy. Intra-epithelial lymphocyte counts were normal in 8 patients on a GFD in contrast to one on a normal diet. Immunofluorescence examination of the jejunal mucosa revealed that the numbers of cells containing IgA and IgM were increased significantly in the normal diet group. The figures were lower in the GFD group but these also exceeded the values in the controls. IgA deposits were found in the uninvolved skin of every patient irrespective of the diet treatment, but the fluorescence seemed to be less intense in patients on a GFD. A clear difference was found in the occurrence of C3 deposits in the uninvolved skin. Three patients on a GFD had C3 deposits; two of these did not follow a strict diet. However C3 was found in 8 patients on a normal diet. Circulating dietary and auto-antibodies were found in two patients on a GFD and in 9 on a normal diet. Serum immunoglobulin (IgG, IgA, IgM) and complement (C3, C4) levels were within normal limits in both patient groups.
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McDougall AC. Onchocerciasis and streptocerciasis in patients with leprosy. Trans R Soc Trop Med Hyg 1977; 71:360-1. [PMID: 563635 DOI: 10.1016/0035-9203(77)90125-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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