Cutaneous Delayed-type Hypersensitivity Research Articles

Individual and sociodemographic factors associated with polysensitization at a New York City hospital

Allergic contact dermatitis (ACD) is a cutaneous delayed-type hypersensitivity response with a global prevalence estimated at over 20%.1 The gold standard for diagnosis is patch testing, in which allergens are applied to a patient's skin to elicit cutaneous responses in sensitized individuals. Many patients undergoing patch testing test positive for 3 or more unrelated allergens, termed polysensitization.2 A recent North American Contact Dermatitis Group study found that 32.1% of patients tested were positive to at least three allergens, but reported rates vary.3

Acute and chronic inflammation alter immunometabolism in a cutaneous delayed-type hypersensitivity reaction (DTHR) mouse model

T-cell-driven immune responses are responsible for several autoimmune disorders, such as psoriasis vulgaris and rheumatoid arthritis. Identification of metabolic signatures in inflamed tissues is needed to facilitate novel and individualised therapeutic developments. Here we show the temporal metabolic dynamics of T-cell-driven inflammation characterised by nuclear magnetic resonance spectroscopy-based metabolomics, histopathology and immunohistochemistry in acute and chronic cutaneous delayed-type hypersensitivity reaction (DTHR). During acute DTHR, an increase in glutathione and glutathione disulfide is consistent with the ear swelling response and degree of neutrophilic infiltration, while taurine and ascorbate dominate the chronic phase, suggesting a switch in redox metabolism. Lowered amino acids, an increase in cell membrane repair-related metabolites and infiltration of T cells and macrophages further characterise chronic DTHR. Acute and chronic cutaneous DTHR can be distinguished by characteristic metabolic patterns associated with individual inflammatory pathways providing knowledge that will aid target discovery of specialised therapeutics.

The abstracts published here were accepted as online posters. 35180 “Could I be allergic to my new hidradenitis suppurativa Medication?” Characterization of a cutaneous delayed-type drug hypersensitivity reaction to secukinumab

Patient history and physical: A 32-year-old Asian-American female presented with widespread, pruritic, red papules involving the ears, trunk, and extremities for approximately 6 weeks’ duration. The lesions first developed several days after her second secukinumab injection, which was originally initiated for recalcitrant stage III hidradenitis suppurativa. Physical examination revealed numerous erythematous, scaly papules on the bilateral ears, upper chest, inframammary folds, bilateral upper extremities, and abdomen (including umbilicus).

Easy approach to detect cell immunity to COVID vaccines in common variable immunodeficiency patients.

Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function. Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test. Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR. The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID. There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations. Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning.

Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions

Rationale: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production.Methods: TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91phox-/-), myeloperoxidase-deficient (MPO-/-), and inducible nitric oxide synthase-deficient (iNOS-/-) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production in vivo by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive ex vivo analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences.Results: The in vivo L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91phox-/- mice, up to 90 % decreased ROS/RNS production in the ears of MPO-/- mice and unaffected ROS/RNS production in the ears of iNOS-/- mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our in vivo L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91phox-/- mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91phox-/- mice with chronic DTHR, while the inflamed ears of MPO-/- mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91phox-/- mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR.Conclusions: MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.

Orally Administered Exosomes Suppress Mouse Delayed-Type Hypersensitivity by Delivering miRNA-150 to Antigen-Primed Macrophage APC Targeted by Exosome-Surface Anti-Peptide Antibody Light Chains.

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies are aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes similarly induced CD3+CD8+ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced an exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration.

Nickel Allergic Contact Dermatitis: Identification, Treatment, and Prevention.

Nickel is a ubiquitous metal added to jewelry and metallic substances for its hardening properties and because it is inexpensive. Estimates suggest that at least 1.1 million children in the United States are sensitized to nickel. Nickel allergic contact dermatitis (Ni-ACD) is the most common cutaneous delayed-type hypersensitivity reaction worldwide. The incidence among children tested has almost quadrupled over the past 3 decades. The associated morbidities include itch, discomfort, school absence, and reduced quality of life. In adulthood, individuals with Ni-ACD may have severe disabling hand eczema. The increasing rate of Ni-ACD in children has been postulated to result from early and frequent exposure to metals with high amounts of nickel release (eg, as occurs with ear piercing or with products used daily in childhood such as toys, belt buckles, and electronics).To reduce exposure to metal sources with high nickel release by prolonged and direct contact with human skin, Denmark and the European Union legislated a directive several decades ago with the goal of reducing high nickel release and the incidence of Ni-ACD. Since then, there has been a global reduction in incidence of Ni-ACD in population-based studies of adults and studies of children and young adults being tested for allergic contact dermatitis. These data point to nickel exposure as a trigger for elicitation of Ni-ACD and, further, provide evidence that legislation can have a favorable effect on the economic and medical health of a population.This policy statement reviews the epidemiology, history, and appearances of Ni-ACD. Examples of sources of high nickel release are discussed to highlight how difficult it is to avoid this metal in modern daily lives. Treatments are outlined, and avoidance strategies are presented. Long-term epidemiological interventions are addressed. Advocacy for smarter nickel use is reviewed. The American Academy of Pediatrics supports US legislation that advances safety standards (as modeled by the European Union) that protect children from early and prolonged skin exposure to high-nickel-releasing items. Our final aim for this article is to aid the pediatric community in developing nickel-avoidance strategies on both individual and global levels.

Cocamidopropyl betaine is commonly found in hypoallergenic personal care products for children

To the Editor: Atopic dermatitis (AD), found in approximately 15% of pediatric patients in the United States, is an inflammatory skin condition associated with poor skin barrier function, resulting in significantly higher rates of cutaneous delayed-type hypersensitivity and allergic contact dermatitis (ACD) compared with populations without AD,1 particularly to weaker allergens.2

The Allergic Bone Marrow? The Immuno-Capacity of the Human Bone Marrow in Context of Metal-Associated Hypersensitivity Reactions.

Arthroplasty ranks among the greatest achievements of surgical medicine, with total hip replacement termed “the operation of the century.” Despite its wide success, arthroplasty bears risks, such as local reactions to implant derived wear and corrosion products. Prevalence of allergies across Western society increases and along the number of reported hypersensitivity reactions to orthopedic implant materials. In this context the main focus is on delayed hypersensitivity (DTH). This mechanism is mainly attributed to T cells and an overreaction of the adaptive immune system. Arthroplasty implant materials are in direct contact with bone marrow (BM), which is discussed as a secondary lymphoid organ. However, the mechanisms of sensitization toward implant wear remain elusive. Nickel and cobalt ions can form haptens with native peptides to activate immune cell receptors and are therefore common T helper allergens in cutaneous DTH. The rising prevalence of metal-related allergy in the general population and evidence for the immune-modulating function of BM allow for the assumption hypersensitivity reactions could occur in peri-implant BM. There is evidence that pro-inflammatory factors released during DTH reactions enhance osteoclast activity and inhibit osteoblast function, an imbalance characteristic for osteolysis. Even though some mechanisms are understood, hypersensitivity has remained a diagnosis of exclusion. This review aims to summarize current views on the pathomechanism of DTH in arthroplasty with emphasis on BM and discusses recent advances and future directions for basic research and clinical diagnostics.

Fixed Drug Eruption to Biologics and Role of Lesional Patch Testing

A 40-year-old cashier with ankylosing spondylitis (AS) on anti–TNF-α therapy presented to the Immunology Clinic with an intermittent rash over her shin. She had been on regular subcutaneous adalimumab (AbbVie, North Chicago, IL) for the past 5 years and her AS was in remission. For the past 3 months, there was consistent recurrence of a solitary rash over her left anterior shin around 4 hours after every dose of adalimumab. Adalimumab was administered every 2 weeks to alternating thighs without history of local injection-site reactions. The lesions were well demarcated, beginning with an intense itch and burning sensation followed by a fixed erythematous oval plaque about 10 cm in diameter. The lesion would last for days with residual hyperpigmentation (Figure 1, A) and recurred after each dose. There was no interruption of her injections and no recent change in the “citrate-free” autoinjector formulation (confirmed with supplier). There were no new medications and she had no history of dermatological conditions. There was no history of trauma. The lesions got progressively worse with subsequent injections, and there was a localized vesicular eruption on her most recent episode (Figure 1, B). She declined a skin biopsy. Adalimumab was stopped and there was no recurrence of the rash. A fixed drug eruption (FDE) was suspected and drug patch testing was performed 2 months later after complete healing of the rash. Patch testing was performed using IQ Ultra chambers and adalimumab (directly extracted from the autoinjector and diluted 1:10 aqueous) with both control (uninvolved upper back skin) and lesional (residual pigmented lesion) patch test application. The patch tests were read on day 2 (D2) and day 4 (D4), in accordance with International Contact Dermatitis Research Group criteria. Patch testing result was negative at the control site at D2 and D4. Patch testing result was negative at the lesional site at D2 (Figure 2, A), but strongly positive (++) at D4 (Figure 2, B) with reactivation of the residual FDE lesion with a crescendo effect. Given the positive lesional patch test result and the suggestive clinical features, she was diagnosed with an FDE due to adalimumab. In view of her favorable response to TNF-α blockade, she consented to provocation testing with subcutaneous golimumab (another anti–TNF-α antagonist), which was well tolerated. Her AS continues to be in remission with golimumab. We previously reported on immediate-type hypersensitivity to adalimumab, and hypersensitivity reactions to biologics have been increasingly identified.1Li P.H. Watts T.J. Lui M.S. Lau C.S. Chung H.Y. Recall urticaria in adalimumab hypersensitivity.J Allergy Clin Immunol Pract. 2018; 6: 1032-1033Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 2Corominas M. Gastaminza G. Lobera T. Hypersensitivity reactions to biological drugs.J Investig Allergol Clin Immunol. 2014; 24: 212-225PubMed Google Scholar In this case, we report the first case of biologics-related FDE. An FDE is a delayed-type cutaneous hypersensitivity reaction to medication that recurs at the same site on further exposure and cross-reactivity is uncertain. In this case, tolerance to golimumab was demonstrated, suggesting a lack of cross-reactivity with an alternative anti–TNF-α antagonist. Adalimumab and golimumab are humanized IgG1 anti–TNF-α antibodies but likely structurally dissimilar, because both are complex macromolecules derived from different biological cell lines. We highlight the utility of lesional patch testing in biologics-related FDE and suggest that tolerance to other anti–TNF-α antagonists is possible, but more studies are required to determine the true rate of cross-reactivity.

Imaging fibrosis in inflammatory diseases: targeting the exposed extracellular matrix.

In a variety of diseases, from benign to life-threatening ones, inflammation plays a major role. Monitoring the intensity and extent of a multifaceted inflammatory process has become a cornerstone in diagnostics and therapy monitoring. However, the current tools lack the ability to provide insight into one of its most crucial aspects, namely, the alteration of the extracellular matrix (ECM). Using a radiolabeled platelet glycoprotein VI-based ECM-targeting fusion protein (GPVI-Fc), we investigated how binding of GPVI-Fc on fibrous tissue could uncover the progression of several inflammatory disease models at different stages (rheumatoid arthritis, cutaneous delayed-type hypersensitivity, lung inflammation and experimental autoimmune encephalomyelitis).Methods: The fusion protein GPVI-Fc was covalently linked to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and subsequently labeled with 64Cu. We analyzed noninvasively in vivo 64Cu-GPVI-Fc accumulation in murine cutaneous delayed-type hypersensitivity, anti-glucose-6-phosphate isomerase serum-induced rheumatoid arthritis, lipopolysaccharide-induced lung inflammation and an experimental autoimmune encephalomyelitis model. Static and dynamic Positron Emission Tomography (PET) of the radiotracer distribution was performed in vivo, with ex vivo autoradiography confirmation, yielding quantitative accumulation and a distribution map of 64Cu-GPVI-Fc. Ex vivo tissue histological staining was performed on harvested samples to highlight the fusion protein binding to collagen I, II and III, fibronectin and fibrinogen as well as the morphology of excised tissue.Results: 64Cu-GPVI-Fc showed a several-fold increased uptake in inflamed tissue compared to control tissue, particularly in the RA model, with a peak 24 h after radiotracer injection of up to half the injected dose. Blocking and isotype control experiments indicated a target-driven accumulation of the radiotracer in the case of chronic inflammation. Histological analysis confirmed a prolonged accumulation at the inflammation site, with a pronounced colocalization with the different components of the ECM (collagen III and fibronectin notably). Binding of the fusion protein appeared to be specific to the ECM but unspecific to particular components.Conclusion: Imaging of 64Cu-GPVI-Fc accumulation in the ECM matrix appears to be a promising candidate for monitoring chronic inflammation. By binding to exposed fibrous tissue (collagen, fibronectin, etc.) after extravasation, a new insight is provided into the fibrotic events resulting from a prolonged inflammatory state.

Cysteine-type cathepsins promote the effector phase of acute cutaneous delayed-type hypersensitivity reactions.

Cysteine-type cathepsins such as cathepsin B are involved in various steps of inflammatory processes such as antigen processing and angiogenesis. Here, we uncovered the role of cysteine-type cathepsins in the effector phase of T cell-driven cutaneous delayed-type hypersensitivity reactions (DTHR) and the implication of this role on therapeutic cathepsin B-specific inhibition.Methods: Wild-type, cathepsin B-deficient (Ctsb-/-) and cathepsin Z-deficient (Ctsz-/-) mice were sensitized with 2,4,6-trinitrochlorobenzene (TNCB) on the abdomen and challenged with TNCB on the right ear to induce acute and chronic cutaneous DTHR. The severity of cutaneous DTHR was assessed by evaluating ear swelling responses and histopathology. We performed fluorescence microscopy on tissue from inflamed ears and lymph nodes of wild-type mice, as well as on biopsies from psoriasis patients, focusing on cathepsin B expression by T cells, B cells, macrophages, dendritic cells and NK cells. Cathepsin activity was determined noninvasively by optical imaging employing protease-activated substrate-like probes. Cathepsin expression and activity were validated ex vivo by covalent active site labeling of proteases and Western blotting.Results: Noninvasive in vivo optical imaging revealed strong cysteine-type cathepsin activity in inflamed ears and draining lymph nodes in acute and chronic cutaneous DTHR. In inflamed ears and draining lymph nodes, cathepsin B was expressed by neutrophils, dendritic cells, macrophages, B, T and natural killer (NK) cells. Similar expression patterns were found in psoriatic plaques of patients. The biochemical methods confirmed active cathepsin B in tissues of mice with cutaneous DTHR. Topically applied cathepsin B inhibitors significantly reduced ear swelling in acute but not chronic DTHR. Compared with wild-type mice, Ctsb-/- mice exhibited an enhanced ear swelling response during acute DTHR despite a lack of cathepsin B expression. Cathepsin Z, a protease closely related to cathepsin B, revealed compensatory expression in inflamed ears of Ctsb-/- mice, while cathepsin B expression was reciprocally elevated in Ctsz-/- mice.Conclusion: Cathepsin B is actively involved in the effector phase of acute cutaneous DTHR. Thus, topically applied cathepsin B inhibitors might effectively limit DTHR such as contact dermatitis or psoriasis. However, the cathepsin B and Z knockout mouse experiments suggested a complementary role for these two cysteine-type proteases.

Goblet cell loss abrogates ocular surface immune tolerance.

Intestinal epithelial cells condition tolerogenic properties in DCs. Aqueous-deficient dry eye is associated with goblet cell (GC) loss and increased IFN-γ expression in the conjunctiva. We hypothesized that loss of GCs reduces tolerance-inducing properties of antigen presenting cells (APCs) in the conjunctiva and draining nodes. Mice lacking the SAM pointed domain containing ETS transcription factor (Spdef) that is required for GC differentiation had an increased frequency of macrophages in the conjunctiva and CD11b+CD11c+ DCs in the conjunctiva and draining nodes, and these cells had greater IL-12 expression than WT mice. Conditioned media from cultured WT conjunctival GCs suppressed LPS-induced IL-12 production by conjunctival APCs. OVA antigen-specific OTII CD4+ T cells primed by Spdef-KO draining lymph node APCs showed greater proliferation, lower frequency of Foxp3+, increased frequency of IFN-γ+ and IL-17+ cells, and greater IFN-γ production than those primed by WT APCs. The immune tolerance to OVA antigen topically applied to the conjunctiva measured by cutaneous delayed type hypersensitivity (DTH) reaction, OVA-specific T cell proliferation, Foxp3 induction, and IFN-γ production observed in WT mice was lost in the Spdef-KO mice. We concluded that conjunctival GCs condition tolerogenic properties in APCs that suppress IL-12 production and Th1 polarization.

Goblet Cells Contribute to Ocular Surface Immune Tolerance-Implications for Dry Eye Disease.

Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef−/−) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not Spdef−/−. OTII CD4+ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of Spdef−/− had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye.

A noninvasive cutaneous delayed type hypersensitivity test is effective for evaluating the effects of handling on immunological stress levels in rats

Abstract Rats are a common model for human physiology and psychology, yet routine handling associated with animal maintenance and treatment administration has been shown to impact behavioral and physiological measures in rats, which raises concerns about their use as a model. Adolescent and adult female rats (Sprague-Dawley, n=6 per group) were subjected to handling treatments (restraint, tickling, or playful handling) to evaluate the potential to minimize the physiological impacts of handling stress. Treatments were administered every other day for 21 days, and body weights, blood smears, and ultrasonic vocalizations were collected throughout this time and for 14 subsequent days without handling treatments. A noninvasive delayed type hypersensitivity test was performed by sensitizing rats to 2,4-Dinitrochlorobenzene on abdominal skin and later assessing the response to ear lobe exposure by measuring ear thickness. The greatest increase in lobe thickness was consistently observed at 48 hours post exposure, with few animals showing inflammation that persisted more than 72 hours. Assessments in the middle of the handling period (day 10) and at the end of the handling period (day 21) showed significantly less swelling for adolescent rats receiving the restraint treatment as compared to rats in the tickling or playful handling groups. This effect was observed in both adolescent and adult rats, however the adolescent rats showed more significant changes in circulating blood cell populations and body weight than did adults. No differences were detected outside of the handling treatment period. These results further establish that routine handling can impact immunological measures in rats and demonstrate efficacy of this noninvasive assay.

Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.

Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required.

Anomalies in the dominant sarcoidosis paradigm justify its displacement

The prevailing paradigm defines sarcoidosis as a disease of unknown etiology characterized by a systemic noncaseating epithelioid granulomatous response (SGR). This formulation fails to account for the elusiveness of the etiological agent, the nature of the Kveim response, the paradox of cutaneous delayed type hypersensitivity anergy in a setting of intense immune response and the appearance of SGR, indistinguishable from sarcoidosis, in persons with lymphohematogenous and solid neoplasms and a variety of cellular immune deficiencies. Displacing this formulation with an evidence-based alternative in which the SGR is viewed as an etiologically diverse, primitive immunological fallback due to inefficient cellular immune processing eliminates these shortcomings, providing a unifying accounting for the puzzles and violations of expectations associated with the prevailing paradigm. Its clinical import resides in the reported annual three-percent increase in sarcoidosis mortality in the past two decades (Swigris et al., 2011), which may be attributable, in part, to unneeded suppressive treatment.

A subset of AID-dependent B-1a cells initiates hypersensitivity and pneumococcal pneumonia resistance.

We propose that there is a special B-1a B cell subset ("sB-1a" cells) that mediates linked processes very early after immunization to initiate cutaneous contact sensitivity (CS), delayed-type hypersensitivity (DTH), and immune resistance to pneumococcal pneumonia. Our published data indicate that in CS and DTH, these initiating processes are required for elicitation of the delayed onset and late-occurring classical T cell-mediated responses. sB-1a cells resemble memory B2 cells, as they are stimulated within 1 h of immunization and depend on T helper cytokines-uniquely IL-4 from hepatic iNKT cells--for activation and rapid migration from the peritoneal cavity to the spleen to secrete IgM antibody (Ab) and Ab-derived free light chains (FLCs) by only 1 day after immunization. Unlike conventional B-1a (cB-1a) cell-produced IgM natural Ab, IgM Ab produced by sB-1a cells has high Ag affinity owing to immunoglobulin V-region mutations induced by activation-induced cytidine deaminase (AID). The dominant cB-1a cells are increased in immunized AID-deficient mice but do not mediate initiation, CS, or pneumonia resistance because natural Ab has relatively low Ag affinity because of unmutated germ-line V regions. In CS and DTH, sB-1a IgM Ag affinity is sufficiently high to mediate complement activation for generation of C5a that, together with vasoactive mediators such as TNF-α released by FLC-sensitized mast cells, activate local endothelium for extravascular recruitment of effector T cells. We conclude by discussing the possibility of functional sB-1 cells in humans.

Cutaneous Delayed-Type Hypersensitivity to Surfactants

Repeated and prolonged use of surfactants can cause irritant as well as allergic contact dermatitis. This study reports the frequency of positive patch test results to surfactants tested on the North American Contact Dermatitis Group screening series including cocamidopropyl betaine (CAPB), amidoamine (AA), dimethylaminopropylamine (DMAPA), oleamidopropyl dimethylamine (OPD), and cocamide diethanolamide (CDEA), and correlations of positive reactions between CAPB and the other surfactants. This was a retrospective analysis of 10 877 patients patch tested between 2009 and 2014 to the surfactants CAPB, AA, DMAPA, OPD, and CDEA. Frequencies of positive reactions to these surfactants were calculated, and trends of reactivity between the surfactants analyzed. The OPD had the highest rate of positive patch reactions (2.3%) followed by DMAPA (1.7%), and CAPB (1.4%). The AA and CDEA had the lowest rate of positive reactions (0.8%). There was a high degree of overlap in positive patch tests between the surfactants. The CDEA was the least likely to coreact with another surfactant.

Histopathological Characterization of Cutaneous Delayed-type Hypersensitivity and Correlations with Intestinal Pathology and Systemic Immune Responses in Sheep with Paratuberculosis

Cell-mediated immunity has been exploited historically in the diagnosis of mycobacterial diseases through elicitation of a delayed-type hypersensitivity (DTH) reaction following intradermal injection of an antigen. Here we describe the histopathological features of the cutaneous DTH reaction and its association with intestinal pathology and systemic immune responses in sheep with Mycobacterium avium subspecies paratuberculosis (MAP) infection. A mixed mononuclear cellular infiltrate dominated the DTH reaction and was present in perivascular and periadnexal patterns. Multiple multinucleate giant cells were present in the cellular infiltrate in one sheep while plasma cells were an obvious feature in six others. Sheep with paucibacillary intestinal lesions had the greatest degrees of cutaneous induration, more severe cellular infiltration in DTH lesions and high systemic interferon (IFN)-γ production. In contrast, sheep with multibacillary intestinal lesions, and particularly those with dissemination of MAP to extra-intestinal tissues, had minimal cutaneous induration, nil to mild cellular infiltration in DTH lesions and high serum anti-MAP antibody levels. Systemic IFN-γ production generally was augmented following skin sensitization. In general, the gross and histopathological features of the cutaneous DTH response matched the stage of paratuberculosis reflected by intestinal pathology and systemic measures of humoral and cellular immunity.