Skin diseases, immune-mediated

The development of nevirapine-induced disease is clearly immune-mediated as upon re-challenge with nevirapine the rash developed faster in previously exposed and fully recuperated rats. In addition, memory for skin reactions in response to nevirapine were transferable by splenocytes from treated to naive animals [15]. In summary, nevirapine-induced skin reactions in rat are immune-mediated and dependent on genetic background, including gender. 

Figure 16.7. Microscopic appearance of necrosis. (A) Coagulative necrosis in a virally infected avian liver. Hepatocytes in the lower half of the photo are in various stages of necrosis, with small, pyknotic or fragmented nuclei and increased cytoplasmic eosinophilia. (B) Necrotic cells in immune-mediated skin disease, canine. The central cell has a pyknotic nucleus and intensely eosinophilic cytoplasm, while the cells at lower left and upper left are injured and swollen. The smaller cells are neutrophils. See color insert.

Cervical lymphadenopathy, fever, and a maculopapular skin rash developed in a 17-year-old boy after he had taken carbamazepine for 3 weeks (up to 600 mg/day) (66). Lymph node biopsies showed features typical of Kikuchi disease, a rare and self-limited immune-mediated lymphadenopathy that affects mostly the cervical region. The condition cleared rapidly after withdrawal. 

Drugs are common causes of vasculitis, often occurring in the skin, but other organ involvement can occur. The pathogenesis of inflammation of small and medium-sized blood vessel walls caused by drugs is poorly understood. Even drugs used to treat inflammatory and immune-mediated disease, such as NSAIDs, sulfasalazine, and etanercept, can cause vasculitis. 

It is notable that cadmium as well as mercury and gold can initiate or aggravate autoimmune manifestations in normal or autoimmune-prone animals, respectively. It would seem likely that these heavy metals have the same effects on humans, presumably by a similar mechanism. Autoimmune manifestations induced by heavy metals include lupus-type nephritis, autoimmune haemolytic anaemia, and skin diseases, such as pemphigus and scleroderma-like lesion. Some manifestations of immune-mediated nephritis and elevation of circulating autoantibodies have been noted in case-studies of persons exposed to gold and cadmium as well as mercury (Ohsawa, 1993 Bigazzi, 1994, 1999). 

Recently, nevirapine has been found to cause skin rash in 100% of high-exposed (150mg/kg by oral gavage) female BN rats (Shenton et al., 2003). Female Sprague-Dawley rats were less sensitive (21% of rats showed a rash), and male BN, Sprague-Dawley rats, and female Lewis rats were resistant. Nevirapine-induced disease was shown to be immune-mediated because upon rechallenge with nevirapine, the rash developed faster in previously exposed rats, and because skin reactions were transferable by splenocytes from nevirapine-treated to naive animals (Shenton et al., 2003). 

In aggregate, these results provide new insights into the novel mechanisms of action of topical tacrolimus treatment. This would suggest that topically applied tacrolimus represents a significant advance in the treatment of atopic dermatitis and potentially other immune-mediated diseases of the skin [91]. We now review the available clinical data to confirm this postulate. 

The unique ability of tacrolimus to be effective when used topically has ushered in a new era in the treatment of immune-mediated skin diseases. As experience is gained both with longer term use of this agent in atopic dermatitis as well as in treating other dermatologic conditions, the macrolides, especially tacrolimus, will no doubt become a major therapeutic class for this important and common group of conditions. 

Papulosquamous Diseases. The group of disorders known as papulosquamous diseases are characterized by scaly papules and plaques. Psoriasis, an immune-mediated skin and joint inflammatory disease, develops when inflammation primes basal stem kerati-nocytes to proliferate excessively. Initial red, scaling papules coalesce to form round-oval plaques. The scales are adherent, silvery white, and show bleeding points when removed (Auspitz sign). Inflammatory arthritis is present in some patients. 

Immunologic Skin testing of 26 patients clinically diagnosed with immediate (type I) hypersensitivity to infliximab found seven positives (30%) and six of these had infliximab-reactive serum IgE antibo es. One skin test-positive patient had no detectable IgE antibodies to the mAb [155 ]. After multiple infusions with infliximab, a 61-year-old woman with Crohn s disease experienced an acute anaphylactic reaction immediately after the start of an infusion. Although anti-infliximab IgE antibodies were not detected, the concentration of anti-infliximab IgG was high and this remained the case 1 year after the mAb was discontinued. Substitution of adalimumab for infliximab 1 week after the anaphylactic reaction was tolerated until the 12th day when the patient displayed a delayed, type IV hypersensitivity reaction mediated by IgG antibodies specific for adalimumab [ISb ]. In addition to types I and IV hypersensitivities to infliximab, other immune-mediated reactions representing the other hypersensitivity states also occur to infliximab. This is illustrated by a recent report of a case of a 27-year-old woman of infliximab-induced systemic lupus erythematosus [157 ], an autoimmune connective tissue disease which is both a type II and a type III hypersensitivity response. 

Aside from their utility for the treatment of multiple skin manifestations, psoralens and UVA radiation could be used as a therapeutic alternative for several immune-mediated disorders as Crohn s disease and ulcerative colitis. Both are chronic inflammatory diseases of the gastrointestinal tract and are collectively known as inflammatory bowel disease. This disorder is produced by a dysfunction of the immtme system that leads to the accumulation of abtmdant lymphocytes and monocytes in the mucosa of the bowel, together with the secretion of cytokines and proinflammatory mediators. There are several genetic, environmental, and physiological factors that contribute to the pathogenesis of inflammatory bowel disease [151]. 

Psoriasis is a T-lymphocyte-mediated inflammatory disease that results from a complex interplay between multiple genetic factors and environmental influences. Genetic predisposition coupled with some precipitating factor triggers an abnormal immune response, resulting in the initial psoriatic skin lesions. Keratinocyte proliferation is central to the clinical presentation of psoriasis. 

Fig. 4. Regulation by chemokines of recruited DC-mediated immune responses, (a) The effect of CCL21 on mDC migration in liver disease model, (b) The effect of CXCL9 on pDC migration in skin infection model.

The newer derivatives seem less likely to cause hypersensitivity reactions, perhaps because the protein adducts generated are shorter lived. All four types of hypersensitivity reaction have been observed with penicillin. Thus, high doses may cause hemolytic anemia and immune complex disease and cell-mediated immunity may give rise to skin rashes and eruptions, and the most common reactions are urticaria, skin eruptions, and arthralgia. Antipenicillin IgE antibodies have been detected consistently with an anaphylactic reaction. The anaphylactic reactions (type 1 see above), which occur in 0.004% to 0.015% of patients, may be life threatening. 

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it increases the magnitude of delayed hypersensitivity or T cell-mediated immunity in humans. In immunodeficiency associated with Hodgkin s disease, levamisole has been noted to increase the number of T cells in vitro and to enhance skin test reactivity. Levamisole has also been widely tested in rheumatoid arthritis and found to have some efficacy. However, it has induced severe agranulocytosis (mainly in HLA-B27-positive patients), which required discontinuation of its use. The drug may also potentiate the action of fluorouracil (5-FU) in adjuvant therapy of colorectal cancer, and this combination has been approved for clinical use in the treatment of Dukes class C colorectal cancer after surgery. Its use in these cases reduces recurrences, and the mechanism... 

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