Cell-mediated Delayed-type Hypersensitivity Reaction Research Articles

Neutrophil Infiltration in Allergic Contact Dermatitis to Nickel.

Allergic contact dermatitis (ACD) is traditionally recognized as a T-cell-mediated delayed-type hypersensitivity reaction. However, many patients with ACD have been reported to experience rapid-onset ACD reactions within hours of re-exposure on skin areas previously exposed to the contact allergen. In this study, three nickel-allergic patients were patch tested for nickel twice at the same skin site over 21 days. The results demonstrated that neutrophils are rapidly recruited to the skin sites previously exposed to nickel, leading to the rapid onset of ACD. Considering that many patients with ACD are frequently re-exposed to contact allergens on the same skin areas in their daily lives, we propose that mechanisms involved in neutrophil recruitment could be potential targets for future ACD treatment.

Regulation of the immune response to contact sensitizers by Nrf2.

The skin is frequently exposed to chemical stress by organic chemicals or metal ions that can directly or indirectly challenge its immune components and may lead to T-cell-mediated delayed-type hypersensitivity reactions. The disruption of the skin's homeostasis by exposure to contact sensitizers (CSs) can trigger an inflammatory immune response that results in eczema and allergic contact dermatitis. The recognition of these chemicals depends on the expression of pattern recognition receptors on sentinel skin cells, mainly the innate resident immune cells orchestrating the skin's immune response and involving both oxidative and inflammatory pathways. The main driver of these both pathways is the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress, activated in various innate immune cells of the skin, including keratinocytes and epidermal Langerhans cells in the epidermis and dermal dendritic cells in the dermis. Nrf2 also shows a strong protective capacity by downregulating inflammatory pathways. In this review, the important role of Nrf2 in the regulation of the immune response to CSs will be discussed and highlighted.

Early Failure of Metal-on-Metal Artificial Disc Prostheses Associated with Lymphocytic Reaction

Report of four collected cases. The purpose of this report is to describe the presentation, diagnostic workup, treatment, and pathologic findings in four cases of lymphocytic reaction in patients receiving a metal-on-metal total disc replacement (TDR). Metal-on-metal designs in hip arthroplasty have gained popularity because of decreased volumetric wear rates and theoretically increased implant longevity. Systemic metal ions produced have not been associated with adverse clinical sequelae, although there have been reports of local soft-tissue reactions leading to early prosthetic failure. Histologic evaluation in these cases suggested a cell-mediated delayed-type hypersensitivity reaction. Metal-on-metal bearings have also emerged in lumbar and cervical TDR. This report is on four patients, from three centers, who underwent TDR, using a metal-on-metal implant, and later presented with symptoms that were determined to be due to lymphocytic reaction. Details of their symptoms, diagnostic work-up, treatment, and outcomes were compiled. All four patients initially had a good surgical outcome, followed by the onset and worsening of axial pain, and/or radicular symptoms months later. All patients had imaging findings of a mass lesion with neurologic impingement. All three of the lumbar patients underwent a decompressive posterior procedure before the eventual device removal and fusion. Intraoperatively, in all the lumbar cases, a thick, yellowish, avascular soft-tissue mass was found to be responsible for an epidural-mass effect on the thecal sac. In the cervical case, there was a gray-tinged soft-tissue response around the implant, suggestive of metallosis. Independent laboratory analysis confirmed a lymphocytic reaction to the implant. Three of the patients had a good outcome after the explant and revision surgery. The remaining patient continued to have residual symptoms related to the neural compression caused by the mass. In this group of patients from three centers, a metal-on-metal TDR resulted in a lymphocytic reaction causing subsequent failure of the surgery. This phenomenon has previously been recognized with metal bearings in hip arthroplasty. Surgeons using metal-on-metal TDRs should be aware of this possible occurrence.

Mast Cells Regulate the Magnitude and the Cytokine Microenvironment of the Contact Hypersensitivity Response

The role that mast cells play during contact hypersensitivity (CS) response is unclear because some studies have shown that mast cell-deficient mice have relatively intact CS responses whereas others have shown opposing results. Mast cells secrete a wide range of immunomodulatory mediators and can potentially influence the type of immune response generated in the skin during CS. Therefore, we examined the type of microenvironment generated during CS in both W/Wv mast cell-deficient and wild-type mice in response to different immunizing doses of hapten (oxazolone). The CS response elicited after low-dose oxazolone was significantly diminished in W/Wv mice compared with wild-type mice. Unexpectedly, the CS response elicited in W/Wv mice immunized with high-dose oxazolone was more severe compared with wild-type mice. In addition, after immunization with high-dose oxazolone, the granulocyte infiltrate in W/Wv mice was increased by twofold compared with wild-type mice. A shift in the cytokine milieu toward the expression of type-1 cytokines as well as a significant increase in the local adhesion of neutrophils and CD4 T cells in the microvasculature of the skin was observed after hapten challenge in W/Wv mice immunized with high-dose oxazolone compared with wild-type mice. These results suggest that mast cells can act as regulators and inducers of the inflammatory response depending on immunizing stimulus strength.

OSTEOLYSIS IN PATIENTS WITH A METAL‐ON‐METAL HIP ARTHROPLASTY

Despite design and manufacturing improvements in contemporary metal-on-metal hip replacements, the problem of wear particles persists. The local and systemic biological consequences of this ionic debris have been the subject of much investigation and it has become clear that cell-mediated delayed-type hypersensitivity reactions are a discrete mode of osteolysis in susceptible patients. We have carried out a consecutive series of 125 primary hip replacements using the Metasul (Zimmer, Warsaw, IN, USA) bearing couple. The radiographs, periprosthetic tissue and retrieved implants of patients undergoing revision for osteolysis were analysed. Three patients underwent revision procedures during a follow-up period of 3-9 years. Histological analysis showed a perivascular lymphocytic infiltrate of the pseudocapsule. Infection was excluded in each patient, there was no implant loosening and no evidence of impingement between trunion and acetabular component. We report a prevalence of 2.6% of patients displaying femoral osteolysis associated with characteristic clinical and histological findings.

Control of Pseudomonas aeruginosa Skin Infections in Mice Is Mast Cell-Dependent

Mast cells (MCs) have recently been shown to be essential for the elicitation of efficient immune responses in murine sepsis. To explore whether MCs also contribute to the control of bacterial skin infections, we studied skin lesions induced by Pseudomonas aeruginosa (PA) in genetically MC-deficient Kit(W)/Kit(W-v) mice, normal Kit(+/+) mice, and MC-reconstituted Kit(W)/Kit(W-v) mice. PA injections resulted in strikingly (>2-fold) larger skin lesions in Kit(W)/Kit(W-v) mice than in Kit(+/+) mice, which exhibited pronounced MC degranulation at infection sites. In addition, neutrophil recruitment following PA injections and bacterial clearance from sites of infection was significantly impaired in Kit(W)/Kit(W-v) mice compared with Kit(+/+) mice. Notably, the adoptive transfer of MCs to the skin of Kit(W)/Kit(W-v) mice before PA infection resulted in normal neutrophil accumulation as well as skin lesions comparable with those in Kit(+/+) mice in both bacterial burden and size. These findings demonstrate for the first time that activated MCs are crucial for the induction of protective innate immune responses to bacterial skin infections.

Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis

Uric acid, the naturally occurring degradation product of purine metabolism, is a danger signal, driving maturation of dendritic cells. It is well known that uric acid crystals display potent proinflammatory properties--the cause of gout--whereas the biological properties of soluble uric acid are less well documented. We have demonstrated previously that nucleic acids of endogenous and exogenous origin display proinflammatory properties. The aim of the present study was to assess the impact of soluble uric acid on in vivo inflammatory responses. Mice were administered with uric acid suspension in saline or saline alone prior to induction of neutrophil-mediated inflammation, delayed-type hypersensitivity, histamin-induced edema (measure of vasodilation capacity), as well as double-stranded (ds)RNA-triggered arthritis. Frequency and severity of arthritis were decreased significantly in mice exposed to dsRNA and simultaneously treated with uric acid as compared with saline-treated controls. Also, granulocyte-mediated inflammatory response and vasodilation capacity were reduced significantly in mice treated with uric acid as compared with their control group. The data suggest that down-regulation of inflammation was mediated by skewing the inflammatory response from the peripheral sites to the peritoneal cavity and down-regulating vasodilatatory capacity and thereby affecting leukocyte migration. In contrast, the T cell-mediated delayed-type hypersensitivity reaction was not affected significantly in mice exposed to uric acid. These findings demonstrate that uric acid displays a potent, distant anti-inflammatory effect in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult.

Afferent and Efferent Phases of Allergic Contact Dermatitis (ACD) Can Be Induced After a Single Skin Contact with Haptens: Evidence Using a Mouse Model of Primary ACD

Allergic contact dermatitis is a T cell-mediated delayed type hypersensitivity reaction that occurs upon hapten challenge in sensitized individuals. The inflammatory response in classical allergic contact dermatitis requires both a sensitization phase and an elicitation phase responsible for the recruitment and activation of specific T cells at the site of hapten skin challenge. Conversely, previously unsensitized patients may develop a "primary allergic contact dermatitis" after the first skin contact with potent contact sensitizers leading to a skin inflammation with all the features of classical allergic contact dermatitis. In this study we used an experimental murine model, referred to as contact hypersensitivity, to study the pathophysiology of primary allergic contact dermatitis and its relationship to classical allergic contact dermatitis. We show that one epicutaneous application of a nonirritant dose of hapten (2,4-dini-trofluorobenzene, fluorescein isothiocyanate) was sufficient to induce an optimal allergic contact dermatitis reaction at the site of primary contact with the hapten without subsequent challenge. As in classical allergic contact dermatitis, the skin inflammation in primary allergic contact dermatitis was mediated by interferon-gamma producing, CD8+ effector T cells that were induced in the draining lymph nodes at day 5 postsensitization and downregulated by CD4+ T cells. Reverse transcription-polymerase chain reaction analysis revealed that the primary allergic contact dermatitis reaction was mediated by a recruitment of CD8+ T cells at the sensitization skin site at day 6 postsensitization. Analysis of the fate of the hapten fluorescein isothiocyanate applied once on the skin revealed its persistence in the epidermis for up to 14 d after skin painting. These results suggest that the development of primary allergic contact dermatitis (i.e., without secondary challenge) is associated with persistence of the hapten in the skin, which allows the recruitment and activation of CD8+ T cells at the site of the single hapten application.

Fucosyltransferase VII-deficient mice with defective E-, P-, and L-selectin ligands show impaired CD4+ and CD8+ T cell migration into the skin, but normal extravasation into visceral organs.

The first step of leukocyte extravasation, leukocyte rolling, is mediated by E-, P-, and L-selectins. Mice deficient for alpha-1,3-fucosyltransferase VII (FucTVII)(-/-) are characterized by deficiency of E-, P-, and L-selectin ligand activity. This model system was used to evaluate the role of the interactions of selectins with their ligands in T and B cell responses. In the present study, FucTVII(-/-) mice showed reduced CD4+ T cell-mediated contact hypersensitivity reactions of the ears to FITC as well as reduced CD8+ T cell-mediated delayed-type hypersensitivity reactions of the footpads against lymphocytic choriomeningitis virus infection. As Langerhans cell migration to local lymph nodes as well as CD4+ and CD8+ T cell induction were found to be normal, the afferent arm of these reactions was not impaired. The reduced inflammatory reactions of the skin were due to inefficient lymphocyte extravasation into the skin. In contrast, extravasation of CD4+ and CD8+ T cells into visceral organs, such as the ovaries or the brain, was not impaired in FucTVII(-/-) mice. Elimination of vaccinia virus and of lymphocytic choriomeningitis virus from ovaries and brain, as well as elimination of tumor cells from several visceral organs was normal. Thus, interactions of selectins with their ligands are important for lymphocyte homing into the skin, but not for lymphocyte extravasation into visceral organs.

Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2.

Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell-mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell-mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon gamma-producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell-dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-)(v) (Kit(W)/Kit(W)(-v)) mice. T cell-dependent PMN recruitment was reduced >60% by anti-MIP-2 antibodies and >80% in mast cell-deficient Kit(W)/Kit(W)(-v) mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2-dependent PMN recruitment in Kit(W)/Kit(W)-(v) mice, whereas mast cells from TNF(-/)- mice did not. Thus, mast cell-derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell-mediated DTHRs.

Antigen-presenting cells in nasal allergy.

Antigen-presenting cells in nasal allergy.

The Fate of T Cells in the Brain: Veni, Vidi, Vici and Veni, Mori

Since the dawn of modern immunology, immune responses within the central nervous system (CNS) have puzzled immunologists. On one hand, the immune-privileged status of the CNS has been known for a long time; along with the eye, the gonads, and the placenta, the CNS is among the few organs that accept grafted foreign cells more readily than the rest of the body. 1 On the other hand, the CNS has been known to be particularly susceptible to autoimmune disease. The first and best characterized autoimmune model, experimental allergic encephalomyelitis (EAE), which resembles multiple sclerosis (MS), is the result of an autoimmune attack by T lymphocytes on the CNS. 2 A report on EAE in this issue 3 by Bauer et al provides data of exceptional clarity that should help in understanding this apparent contradiction. Neuroantigen-specific T cells, which can mount an autoimmune attack against the CNS, are detectable in healthy individuals. This is particularly well established for T cells that are specific for myelin basic protein (MBP), the best-characterized target antigen in the CNS. Studies using MBP-specific T cell receptor-transgenic mice suggested that these T cells normally ignore the autoantigen. 4-6 Like lymphocytes that have not encountered their antigen before, they retain a naive/resting phenotype. Such T cells dramatically change their behavior as soon as they become activated in the course of an immune response; they start to infiltrate the CNS and cause inflammatory damage there. In experimental models EAE is initiated either by immunization with a CNS antigen (for active EAE) or by in vitro injection of activated CNS antigen-specific T cells (for passive EAE, the model used by Bauer et al). In MS, infections with crossreactive microorganisms are thought to initiate the autoimmune attack. It remains unclear why activated myelin-reactive T cells “see” and attack the autoantigen that resting T cells with the same specificity had ignored. The information needed to promote resolution of this question pertains to the rules that govern the entry of lymphocytes into CNS tissue. This issue was addressed by Bauer et al. They injected into rats congenic T cells specific for either various CNS “self” antigens (Bauer et al, Table 1) or for the irrelevant “foreign” antigen ovalbumin (OVA). To distinguish clearly between injected T cells with a defined specificity and activation state and recruited host-derived T cells of unknown specificity and activation state, the authors took advantage of a TK-tsa-transgenic model. The detection of the TK-tsA transgene by in situ hybridization facilitated reliable discrimination of the injected T cells from those of the host.

Protein S is inducible by interleukin 4 in T cells and inhibits lymphoid cell procoagulant activity.

Extravascular procoagulant activity often accompanies cell-mediated immune responses and systemic administration of pharmacologic anticoagulants prevents cell-mediated delayed-type hypersensitivity reactions. These observations suggest a direct association between coagulation and cell-mediated immunity. The cytokine interleukin (IL)-4 potently suppresses cell-mediated immune responses, but its mechanism of action remains to be determined. Herein we demonstrate that the physiologic anticoagulant protein S is IL-4-inducible in primary T cells. Although protein S was known to inhibit the classic factor Va-dependent prothrombinase assembled by endothelial cells and platelets, we found that protein S also inhibits the factor Va-independent prothrombinase assembled by lymphoid cells. Thus, protein S-mediated down-regulation of lymphoid cell procoagulant activity may be one mechanism by which IL-4 antagonizes cell-mediated immunity.

Human Cutaneous Mast Cells: Current Concepts

Skin mast cells play an important role in cutaneous inflammation, especially immunoglobulin-E (IgE)-mediated early type, complement-mediated, and T cell-mediated delayed type hypersensitivity reactions. They can synthesize and release various preformed and newly formed mediators that are important in the pathobiology of certain diseases such as urticaria, mastocytosis, atopic dermatitis, contact dermatitis, bullous pemphigoid, scleroderma, psoriasis, and parasitic skin infections. They also have important functions in parasite infestations, angiogenesis, and tissue remodeling besides allergy and inflammation. Their origin, morphology, distribution, heterogeneity, function, activation, and mediators are included in the subject. Interactions of mast cells with their microenvironment and the other cells, and their role in some pathobiological situations are briefly outlined. This article will reinforce the reader's knowledge of the recent concepts on human cutaneous mast cells.

Mechanisms of dichotomous action of IL-2-Pseudomonas exotoxin 40 (IL-2-PE40) on cell-mediated and humoral immune response.

IL-2-PE40 is a chimeric protein composed of human IL-2 genetically fused to the amino terminus of a modified form of Pseudomonas exotoxin lacking its cell recognition domain. The immunosuppressive efficacy of IL-2-PE40 was demonstrated in several experimental murine transplant and autoimmune models. However, some observations suggested that IL-2-PE40 could not inhibit the humoral response. In this report, we describe the dichotomous effects of IL-2-PE40 on humoral and cell-mediated immune response in a simple, well characterized in vivo model. Although IL-2-PE40 inhibited the cell-mediated delayed type hypersensitivity reaction to SRBC, it increased the humoral immune response to the same Ag. To understand the mechanism of dichotomous action of IL-2-PE40 on the immune response, IL-2R-bearing T cells were treated with IL-2-PE40 in vitro and the cytokine expression was studied at mRNA and protein level. Similar to IL-2, IL-2-PE40 promoted the expression of T helper 1-like (IFN-gamma) as well as T helper 2-like (IL-4, IL-10) cytokines. These in vitro studies show that IL-2-PE40 can induce signal transduction in activated T cells through the IL-2R before exerting its cytotoxic effect. In contrast to DTH reaction, humoral immune response requires T cell help only for a limited period. Therefore, the short-term stimulation of T helper cells by IL-2-PE40 may be sufficient in vivo to mediate a B cell response in the local environment, whereas the DTH reaction and other cell-mediated immune responses are inhibited by the toxin moiety of the chimeric protein.

Enhancement of histamine-induced vascular leakage by pertussis toxin in SJL/J mice but not BALB/c mice

Pertussis toxin (PTX) from Bordetella pertussis is known to enhance inflammatory responses which involve histamine and serotonin, including cell-mediated delayed-type hypersensitivity reactions. In this study we examined the effects of PTX on histamine-modulated microvascular responses. The actions of histamine on arteriole diameter and post-capillary leaky site formation in the cremaster muscle were measured intra-vitally in two inbred strains of mice (viz. BALB/c and SLJ). In SJL mice the rate and extent of histamine-induced leaky site formation were greatly enhanced (from 8.3 to 21.0 leaky sites per 0.1 cm 2) by pre-exposure to PTX. In sharp contrast, PTX did not alter histamine-induced leaky site formation in BALB/c mice. Histamine-mediated dilation in arterioles in both strains of mice were not enhanced by PTX. PTX may enhance the development of inflammatory responses by enhancing histamine-induced leaky site formation of the microvasculature.

Production of Macrophage Inhibitory Factor by Patients With Leprosy

Patients with lepromatous (low resistance) leprosy exhibit depressed cell-mediated immunologic reactivity. This is reflected by anergic responses to intradermal injection of various antigens, including lepromin, by relative inability to become sensitive to haptenes (dinitrochlorobenzene), and by poor blastogenic response of lymphocytes to various mitogens in cell culture. Patients with tuberculoid (high resistance) leprosy usually respond normally to these stimuli. Ability of lymphocytes to produce macrophage migration inhibition factor (MIF) has been shown to correlate with patient's ability to exhibit cell-mediated delayed-type hypersensitivity reactions. Lymphocytes of patients with lepromatous leprosy who are anergic fail to produce or produce only small amounts of MIF in response to lepromin in vitro, but lymphocytes of patients with tuberculoid leprosy who exhibit normal cell-mediated reactions respond to lepromin in vitro by production of greater amounts of MIF.