fibrin and Dermatitis--Contact

Topics: Adult; Animals; Cattle; Dermatitis, Contact; Dyspnea; Female; Fibrin; Humans; Tooth Extraction; Urticaria

When elicited in the skin of mice, either IgE-dependent immediate hypersensitivity reactions or T cell-dependent contact sensitivity (CS) reactions result in local extravasation of [125I]fibrinogen and deposition of [125I]fibrin. However, these two types of reaction differ in kinetics and in requirement for IgE, mast cells, or T cells. In the present study, we investigated the kinetics and magnitude of [125I]fibrin deposition in combined IgE-dependent and CS reactions elicited simultaneously at the same site and compared the results with those obtained when the two reactions were elicited at separate sites. We found that [125I]fibrin deposition in pure IgE-dependent reactions was greater at 2 or 6 h after challenge than at 24 h, but that significant fibrin deposition persisted at those sites 24 h after challenge. In CS reactions, [125I]fibrin deposition was detected as early as 2 h after challenge, indicating that fibrin deposition accompanies the "early component" of CS detected by Van Loveren et al. with the use of measurements of tissue swelling. But much more [125I]fibrin deposition was present in CS reactions at 24 h than at 2 or 6 h after Ag challenge. When IgE-dependent and CS reactions were elicited at the same site, [125I]fibrin deposition at early intervals (2 to 6 h) after challenge was increased three- to 25-fold compared with that seen in isolated CS reactions, but at 24 h the results in the combined reactions were virtually identical to those in CS responses. Studies in genetically mast cell-deficient and congenic normal mice indicated that mast cells were required for expression of the IgE-dependent augmentation of [125I]fibrin deposition observed at early intervals in combined IgE-dependent and CS reactions, but not for the [125I]fibrin deposition associated with "pure" CS reactions. These findings indicate that the net effect of IgE-dependent mast cell activation on CS responses is to increase the fibrin deposition associated with these responses, but this effect is appreciated only at early intervals after elicitation of the reaction.

Topics: Animals; Dermatitis, Contact; Female; Fibrin; Immunoglobulin E; Iodine Radioisotopes; Mast Cells; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Skin; T-Lymphocytes

Topics: Dermatitis, Contact; Diagnosis, Differential; Fibrin; Fluoroimmunoassay; Humans; Irritants

The role of mast cells in the elicitation of contact sensitivity (CS) responses was evaluated by transferring different aliquots of the same preparations of immune lymph node cells (I-LNC) into naive, genetically mast cell-deficient (WBB6F1-W/Wv or WCB6F1-S1/S1d) mice and the corresponding congenic normal (+/+) mice. We found that the 24-hr CS responses elicited in the recipient mast cell-deficient mice were statistically indistinguishable from those in the congenic +/+ mice according to four different criteria: micrometer measurements of ear swelling, ratios of the weight or [125I]iododeoxyuridine-labeled leukocyte infiltration-associated cpm in challenged and contralateral control ears, and amount of 125I-fibrin deposition. We also transferred I-LNC into WBB6F1-W/Wv mice which, 5 months earlier, had undergone local repair of their mast cell deficiency by the intradermal injection (into the left ear only) of growth factor-dependent cultured mast cells derived from congenic +/+ mice. When 24-hr CS responses were elicited in both ears of these mice, the reactions in the mast cell-reconstituted left ears were similar to those in the mast cell-deficient right ears. We also found that treatment of antigen-specific cloned T cells with reserpine in vitro markedly impaired their ability to transfer reactivity for CS, providing further evidence that reserpine can interfere with the expression of T-cell-mediated responses through effects independent of its action on mast cells.

Topics: Animals; Dermatitis, Contact; Ear; Fibrin; Hypersensitivity, Delayed; Immunity, Cellular; Immunization, Passive; Mast Cells; Mice; Mice, Inbred Strains; Reserpine; T-Lymphocytes

We investigated the clotting associated with delayed hypersensitivity (DH) responses in the mouse by sensitizing the animals to the contactant oxazolone (Ox), and then administering 125I-guinea pig fibrinogen i.v. 10 to 30 min before antigen challenge 5 days later. Early (4 to 8 hr) contact sensitivity (CS) responses in immunized mice were barely detectable by three conventional measures of CS, but the total 125I-cpm in ears challenged with hapten was 3.6 to 4.5 X that in control ears challenged with vehicle alone; moreover, the amount of urea-insoluble cpm (cross-linked 125I-fibrin-associated cpm) in the reactions to Ox was 6.5-fold to 8.2-fold that present in the control reactions. In 24 hr reactions that were near peak intensity by measurements of ear swelling, ear weight ratios, and ratios of 125I-5-iodo-2-deoxyuridine-labeled leukocyte infiltration, the cpm in antigen-challenged ears exceeded that in control ears by 13-fold to 53-fold. In addition, antigen-challenged ears contained 27 to 300 X the urea-insoluble cpm present in control ears. 125I-Fibrin deposition was not a specific characteristic of CS reactions, because a small amount of urea-insoluble reactivity was also detected in some reactions to Ox in native mice. Nevertheless, the assay was exquisitely sensitive and readily detected quantitative differences between the immunologically specific and nonspecific reactions at very early intervals after challenge or with suboptimal doses of antigen. Furthermore, it was more sensitive than conventional tests of CS in detecting the reactions elicited in mice that had been passively sensitized to Ox by adoptive transfer of immune lymph node cells. Finally, we showed that the assay gave similar results when we tested CS reactions elicited in mast cell deficient WBB6F1-W/Wv and littermate normal (+/+) mice, demonstrating yet another similarity in the phenotype of DH reactions elicited in the presence or absence of mast cells.

Topics: Animals; Blood Coagulation; Dermatitis, Contact; Female; Fibrin; Fibrinogen; Hypersensitivity, Delayed; Immunization, Passive; Mast Cells; Mice; Oxazolone; T-Lymphocytes

The studies reviewed here emphasize both the complexity and the heterogeneity of cell-mediated immunity. In addition to the round cell infiltrate of the classic descriptions, cell-mediated immunity includes reactions that feature many types of inflammatory cells, that exert profound effects on the blood microvasculature, and that initiate extravascular clotting and, possibly, angiogenesis. The common denominator of all of these reactions is a subset or subsets of sensitized T lymphocytes that, on exposure to specific antigen, recruit and collaborate in other ways with one or more populations of circulating bone marrow-derived cells. Although the reactions generally resemble chronic inflammation by virtue of the lymphocytes and monocytes present, cell-mediated immunity may also take the guise of acute or subacute inflammation when neutrophils or eosinophils predominate and an entirely different morphologic pattern when basophils predominate, as in CBH. Tissue mast cells undergo changes (activation, proliferation) that are generally observed at later stages of delayed hypersensitivity, but no convincing evidence has been presented that these cells play an essential role in the elicitation of cell-mediated immunity. The concept that an essential prerequisite for the elicitation of delayed hypersensitivity is the mast cell-dependent generation of microvascular gaps, favoring inflammatory cell diapedesis, is clearly incorrect. First, lymphocytes fail to traverse certain of the vessels that exhibit such gaps (i.e., those of the SCV) in delayed hypersensitivity reactions in humans. Second, there is no diminution in the cellular infiltration associated with cell-mediated immunity reactions in mast cell-deficient mice. Cell-mediated immunity does not consist of an inflammatory cell infiltrate alone. The local microvasculature is rendered hyperpermeable to varying extents, with resulting extravasation of plasma proteins, including fibrinogen. The majority of extravasated fibrinogen is clotted to cross-linked fibrin, presumably as the result of the actions of procoagulants associated with fixed connective tissue cells and perhaps also because of the activity of infiltrating cells, such as monocytes/macrophages. Clotted fibrin forms a water-trapping gel, which accounts for the induration seen in many delayed hypersensitivity reactions. The microvasculature may also be affected in other ways. Endothelial cells may undergo hypertrophy and cell division or, alternativel

Topics: Animals; Basophils; Blood Proteins; Blood Vessels; Capillaries; Capillary Permeability; Dermatitis, Contact; Endothelium; Fibrin; Guinea Pigs; Humans; Hypersensitivity, Delayed; Hypertrophy; Immunity, Cellular; Mice; Vasodilation

Guinea pigs primed for cutaneous basophil hypersensitivity (CBH) with several soluble proteins or with sheep erythrocytes developed a systemic, delayed-onset, maculopapular rash when challenged parenterally with specific antigen. The rash was most readily induced 5 to 7 days after immunization, at a time when local CBH skin test reactivity was also optimal. Miscroscopically, the rash resembled local CBH skin test reactions, being comprised of a papillary dermal infiltrate of basophils and lymphocytes and a striking dilatation and compaction of superficial venules. In addition to the systemic rash, animals expressing systemic CBH (SCBH) exhibited a striking eosinophilia at 24 hr which gave way to basophilia at 48 hr. Focal collections of eosinophils, and of smaller numbers of basophils, were found in the lungs and spleen; both eosinophils and basophils infiltrated the medulla of the thymus. Thus, basophil-rich infiltrations are favored in the skin even after systemic challenge with antigen and occur only to a much smaller extent in other organs where eosinophils may predominate. These differences in the response of various organs to challenge with parenteral antigen suggest that as yet unidentified local factors play a determinative role in regulating the inflammatory response. The pathogenesis of SCBH is not yet established, but it shares many of the properties of local CBH: histology, carrier specificity, development early after sensitization in the absence of detectable antibodies. Passive transfer has not been accomplished with serum alone but has been achieved irregularly with cells plus serum. SCBH may serve as a useful model for several disease states in man characterized by a systemic rash and eosinophilia, including certain types of drug reaction.

Topics: Animals; Antigens; Basophils; Dermatitis, Contact; Eosinophilia; Epitopes; Erythrocytes; Female; Fibrin; Fibrinogen; Guinea Pigs; Hypersensitivity, Delayed; Immunity, Cellular; Immunization, Passive; Lymphokines; Male; Mitogens; Skin; Time Factors

Topics: Adolescent; Adult; Allergens; Antigens, Bacterial; Basophils; Biopsy; Capillary Permeability; Chlorobenzenes; Dermatitis, Contact; Edema; Endothelium; Erythrocytes; Female; Fibrin; Fluorescent Antibody Technique; Humans; Hypersensitivity, Delayed; Male; Mast Cells; Microscopy, Electron; Middle Aged; Skin; Skin Tests

The expression of delayed-type hypersensitivity in animals has been inhibited by a variety of anticoagulants, but direct evidence for activation of clotting in the evolution of these reactions has been lacking. Using the fluorescent antibody technique we here demonstrate that fibrin deposition is a prominent and consistent feature of both allergic contact dermatitis and classic delayed hypersensitivity skin reactions in man. Fib was detected in 55 of 58 delayed reactions studied at the peak of their intensity. The characteristic distribution of Fib-principally in the intervascular portions of the reticular dermis with sparing of vessels and their associated cuffs of mononuclear cells-is unusual and quite different from that described in antibody-mediated lesions in animals or man. Fib was found in vessel walls in only 2 of 94 biopsies studied. With a single exception, deposition of immunoglobulins and complement was not observed. The pathogensis and significance of Fib deposition in these reactions are not yet clear. Fib is ultimately derived from circulating fibrinogen, and its accumulation provides additional evidence for locally increased vascular permeability in delayed hypersensitivity. Polymerization of extravascular fibrinogen could be triggered nonspecifically by dermal elements (e.g., collagen) or by a product of sensitized lymphocytes. The appearance of Fib early in the development of these reactions (4-8 h after epicutaneous test with DNCB) and inhibition studies with anticoagulants together suggest that clotting may have a role in their pathogenesis, possibly by the release of bioactive peptides from fibrinogen/fibrin or by contributing to the induration characteristic of delayed hypersensitivity.

Topics: Adolescent; Adult; Biopsy; Blood Coagulation; Dermatitis, Contact; Female; Fibrin; Fluorescent Antibody Technique; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Male; Middle Aged; Skin; Skin Tests

A variety of cell-mediated hypersensitivity reactions in experimental animals include a prominent infiltrate of basophilic leukocytes. This form of reactivity has been designated cutaneous basophil hypersensitivity and is favored when sensitization to several types of antigen is accomplished without the use of complete Freund's adjuvant. A similar type of hypersensitivity response was sought in man using morphologic techniques which permit identification of basophilic leukocytes. Eight individuals with allergic contact dermatitis to a variety of allergens were studied and six of these developed typical contact reactions with erythema, edema, and epidermal vesicles. The microscopic findings in 3-day biopsies from these individuals differed significantly from classic descriptions of tuberculin hypersensitivity and showed, in addition to mononuclear cells and the characteristic epidermal changes, a substantial infiltrate of basophilic leukocytes and evidence of altered vascular permeability with vascular compaction, dermal edema, and fibrin deposition. Serial biopsies from one individual permitted analysis of the microscopic pathology as it unfolded at successive intervals after patch test. The initial lesion consisted of perivascular accumulations of lymphocytes; this was followed by an influx of basophils and, subsequently, of eosinophils. These findings associate contact allergy in man with the parallel reactions of cutaneous basophil hypersensitivity in animals and provide further evidence for the heterogeneity of the cellular immune response. The data are consistent with the hypothesis that interaction between sensitized lymphocytes and antigen, at a local test site, is responsible for the attraction of basophils. They also directly implicate the clotting system in delayed-type reactions and suggest the possibility of a synergistic relationship between cellular immunity and reactions mediated by basophil-bound, homocytotrophic antibody.

Topics: Adult; Alkenes; Basophils; Biopsy; Catechols; Dermatitis, Contact; Edema; Eosinophils; Fibrin; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Lymphocytes; Male; Skin; Skin Tests