Brent Kelly

Type I IFN Receptor Regulates Neutrophil Functions and Innate Immunity to Leishmania Parasites

Type I IFNs exert diverse effector and regulatory functions in host immunity to viral and nonviral infections; however, the role of endogenous type I IFNs in leishmaniasis is unclear. We found that type I IFNR-deficient (IFNAR−/−) mice developed attenuated lesions and reduced Ag-specific immune responses following infection with Leishmania amazonensis parasites. The marked reduction in tissue parasites, even at 3 d in IFNAR−/− mice, seemed to be indicative of an enhanced innate immunity. Further mechanistic analyses indicated distinct roles for neutrophils in parasite clearance; IFNAR−/− mice displayed a rapid and sustained infiltration of neutrophils, but a limited recruitment of CD11b+Ly-6C+ inflammatory monocytes, into inflamed tissues; interactions between IFNAR−/−, but not wild-type (WT) or STAT1−/−, neutrophils and macrophages greatly enhanced parasite killing in vitro; and infected IFNAR−/− neutrophils efficiently released granular enzymes and had elevated rates of cell apoptosis. Furthermore, although coinjection of parasites with WT neutrophils or adoptive transfer of WT neutrophils into IFNAR−/− recipients significantly enhanced infection, the coinjection of parasites with IFNAR−/− neutrophils greatly reduced parasite survival in WT recipients. Our findings reveal an important role for type I IFNs in regulating neutrophil/monocyte recruitment, neutrophil turnover, and Leishmania infection and provide new insight into innate immunity to protozoan parasites.

Urticaria : a review.

Urticaria is often classified as acute, chronic, or physical based on duration of symptoms and the presence or absence of inducing stimuli. Urticarial vasculitis, contact urticaria, and special syndromes are also included under the broad heading of urticaria. Recent advances in our understanding of the pathogenesis of chronic urticaria include the finding of autoantibodies to mast cell receptors in nearly half of patients with chronic idiopathic urticaria. These patients may have more severe disease and require more aggressive therapies. Extensive laboratory evaluation for patients with chronic urticaria is typically unrevealing and there are no compelling data that associate urticaria with chronic infections or malignancy. Pharmacologic therapy consists primarily of the appropriate use of first- and second-generation histamine H(1) receptor antihistamines. Additional therapy may include leukotriene receptor antagonists, corticosteroids, and immunomodulatory agents for severe, unremitting disease. Despite our greater understanding of the pathogenesis of urticaria, the condition remains a frustrating entity for many patients, particularly those with chronic urticaria.

Lymphatic invasion detected by D2-40/S-100 dual immunohistochemistry does not predict sentinel lymph node status in melanoma

BACKGROUND Sentinel lymph node biopsy provides important prognostic information with controversial therapeutic advantages. D2-40 is a novel immunohistochemical stain specific for lymphatic endothelium often utilized to study tumor lymphangiogenesis and lymphatic invasion. OBJECTIVE To increase the detection of lymphatic invasion in primary cutaneous melanomas with D2-40/S-100 dual immunohistochemistry, and then apply the technique to melanomas with known sentinel lymph node status. The primary aim was to assess whether the presence or absence of lymphatic invasion could predict sentinel lymph node status. The secondary aims were to assess whether lymphatic invasion and/or sentinel lymph node involvement were associated with clinicopathologic parameters commonly studied in melanomas. METHODS Twenty-seven biopsy specimens of primary cutaneous melanoma from 27 patients with known sentinel lymph node status were retrospectively reviewed and labeled with D2-40/S-100 dual immunohistochemistry. The following clinicopathologic variables were evaluated: age, gender, histologic type, Breslow thickness, Clark level, ulceration, mitoses, lymphovascular invasion by routine staining and D2-40/S-100 dual immunohistochemistry, and overall survival. Statistical analyses were performed to assess for associations. RESULTS D2-40/S-100 dual immunohistochemistry showed unequivocal lymphatic invasion in 10 of 27 melanomas compared with 1 of 27 with routine histology. Eight of 10 melanomas with lymphatic invasion were sentinel lymph node negative. There was no statistical association between the presence or absence of lymphatic invasion and sentinel lymph node status. LIMITATIONS The major limitation was the small sample size. CONCLUSION D2-40/S-100 dual immunohistochemistry increases the sensitivity of detection of lymphatic invasion in melanoma but does not predict sentinel lymph node involvement.

Nephrogenic systemic fibrosis is associated with transforming growth factor β and Smad without evidence of renin-angiotensin system involvement

BACKGROUND The mechanisms of fibrosis associated with nephrogenic systemic fibrosis (NSF) are largely unknown. Transforming growth factor beta (TGF-beta), a known profibrotic cytokine, is theorized to play a central role. The renin-angiotensin system has been linked with both TGF-beta expression and fibrosis in other organ systems. OBJECTIVE We sought to investigate whether these mechanisms were involved with NSF. METHOD Eleven biopsy specimens from 8 patients with NSF were evaluated by immunohistochemistry for the expression of TGF-beta, Smad 2/3, angiotensin-converting enzyme (ACE), and angiotensin II receptor 1 (AT1). RESULTS TGF-beta was detected in 8 of 11 samples of NSF. Smad 2/3 nuclear staining was seen in 8 of 11 samples. Conversely, only faint staining for ACE was seen in 2 of the 11 specimens. No AT1 staining was seen. LIMITATIONS We did not perform our studies on a cohort of comparable patients with renal dysfunction without NSF. Our technique may not have been sufficiently sensitive to detect renin-angiotensin system involvement. CONCLUSIONS TGF-beta, as well as its second messengers, Smad 2/3, appears to be associated with the fibrosis seen in NSF. No definitive evidence of renin-angiotensin system involvement could be determined.

Omalizumab as a Desensitizing Agent and Treatment in Mastocytosis: A Review of the Literature and Case Report

Patients with all forms of mastocytosis can experience urticaria, abdominal cramps, nausea, diarrhea, or hypotension due to release of mediators by mast cells. Patients with mastocytosis and Hymenoptera venom allergy can develop severe adverse reactions to Hymenoptera stings. In addition, patients with mastocytosis and on venom immunotherapy are at high risk for incomplete protection and fatal reactions. Recent literature has reported the use of omalizumab as an adjunctive treatment in patients with mastocytosis, used for both symptom improvement and to dampen adverse effects caused by venom immunotherapy. This article reviews the literature regarding omalizumab use in the treatment of mastocytosis and for protection against the adverse effects during venom immunotherapy. In addition, we report the case of a patient at high risk and with cutaneous mastocytosis, whose symptoms improved with concomitant administration of omalizumab and venom immunotherapy.

The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis.

BACKGROUND Nephrogenic systemic fibrosis (NSF) occurs in patients with renal dysfunction and gadolinium exposure. Although little is known about the pathogenesis of this disease, increased expression of transforming growth factor-beta has been recently demonstrated. Other fibrosing conditions have been shown to express an imbalance in matrix metalloproteinase (MMP) expression and their corresponding inhibitors. Myofibroblast differentiation, in which cells often express alpha-smooth muscle actin and achieve the ability to contract, is also a hallmark of fibrosis. OBJECTIVE We theorized that NSF may overexpress tissue inhibitor of metalloproteinase-1 (TIMP-1), while simultaneously showing decreased expression of MMP-1. As a secondary aim, we sought to evaluate the presence of smooth muscle actin in our samples. METHODS We applied immunohistochemistry to 16 skin biopsies from 10 patients with NSF using antibodies to TIMP-1, MMP-1, MMP-2, MMP-9, and alpha-smooth muscle actin. Samples from normal skin, scar, keloid and scleroderma were stained for comparison. RESULTS TIMP-1 was strongly expressed in all NSF specimens compared to normal skin. MMP-1 expression was nearly absent in all tested samples. In all 16 NSF cases, the dermal spindle cells did not stain for alpha-smooth muscle actin. MMP-2 and MMP-9 expression was variable but was increased compared to normal skin. LIMITATIONS The expression is semiquantitative and based on immunohistochemistry and unconfirmed by other techniques. CONCLUSIONS In NSF, TIMP-1 is strongly expressed and MMP-1 is nearly absent, characteristic of the MMP imbalances seen in other fibrosing processes. Using smooth muscle actin immunohistochemistry, there was no evidence of myofibroblast differentiation.

Connexin 26 mutation in keratitis–ichthyosis–deafness (KID) syndrome in mother and daughter with combined conductive and sensorineural hearing loss

Background  Keratitis–ichthyosis–deafness (KID) syndrome most commonly results from a mutation in the gap‐junctional protein connexin 26 (Cx26) gene, GJB2. Most cases are sporadic and are associated with sensorineural hearing loss.

Ulcerative sarcoidosis in the legs with granulomatous vasculitis

We present a case of a patient with pulmonary sarcoidosis who developed ulcerative sarcoidosis with granulomatous vasculitis on the lower legs. Ulceration is a rare presentation for sarcoidosis and this case gives further evidence that an underlying vasculitis may be an aetiological factor. Granulomatous vasculitis, classically associated with Wegener’s granulomatosis, lymphomatoid granulomatosis, or Churg–Strauss syndrome, is also commonly described in pulmonary sarcoidosis. It has, however, only rarely been described in cutaneous sarcoidosis. Our patient’s leg ulcers have responded well to immunosuppressive therapy with tapered corticosteroid and low‐dose azathioprine.

Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis

Background  Primary cutaneous nodular amyloidosis (PCNA) is thought to be a plasma cell dyscrasia. The amyloid deposits are found in the dermis and subcutis, and they contain clonal immunoglobulin light chains, produced by a local proliferation of plasma cells. New insights into amyloid diseases have revealed that the pathology is due more to the presence of small, misfolded protein species termed oligomers than to the deposition of fibrillar material.

Pancreatic Panniculitis Associated with Allograft Pancreatitis and Rejection in a Simultaneous Pancreas–Kidney Transplant Recipient

Pancreatic panniculitis is an uncommon condition that can occur in association with pancreatic disease. We present a case of pancreatic panniculitis in a female pancreas–kidney transplant recipient 5 months post‐transplant. The patient was on standard immunosuppressive medications and had acute rejection of her renal allograft. The diagnosis of allograft pancreatitis and rejection presenting with pancreatic panniculitis was supported clinically, histopathologically and by laboratory and imaging data. This is the fourth case of pancreatic panniculitis occurring in a transplant recipient and the first in a simultaneous pancreas–kidney transplant recipient. It is also the first case associated with allograft rejection. Clinicians should be aware that pancreatic panniculitis may be a manifestation of underlying allograft pancreatic disease.