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Nikhil Yawalkar

Publications and source records attributed to Nikhil Yawalkar.

16 recordsLinked to original sources
PubMed2007

Hypersensitivity reaction against patent blue during sentinel lymph node removal in three melanoma patients.

BACKGROUND: In order to identify the sentinel lymph node (SLN) in melanoma patients intradermal injection of a radiocolloid tracer and a blue dye are commonly used. Life-threatening side effects such as allergic reactions to the injected dye have been described. We report 3 cases with systemic allergic reactions. METHODS: Three patients suffering from systemic reactions such as hypotension and rash during SLN biopsy were tested for sensitisation against patent blue and methylene blue with skin prick, scratch, and intradermal test. RESULTS: All 3 patients showed positive skin tests to patent blue confirming allergic reaction to the injected dye. In addition, all patients showed positive skin tests with methylene blue indicating immunologic cross-reactivity between patent blue and methylene blue. CONCLUSIONS: Although allergic reactions to blue dye during SLN biopsy are rare, they may be life threatening. It is important that the attending anesthetist is aware of this.

Adult↗
PubMed2006

Involvement of drug-specific T cells in acute drug-induced interstitial nephritis.

Drug-induced interstitial nephritis can be caused by a plethora of drugs and is characterized by a sudden impairment of renal function, mild proteinuria, and sterile pyuria. For investigation of the possible pathomechanism of this disease, drug-specific T cells were analyzed, their function was characterized, and these in vitro findings were correlated to histopathologic changes that were observed in kidney biopsy specimens. Peripheral blood mononuclear cells from three patients showed a proliferative response to only one of the administered drugs, namely flucloxacillin, penicillin G, and disulfiram, respectively. The in vitro analysis of the flucloxacillin-reactive cells showed an oligoclonal immune response with an outgrowth of T cells bearing the T cell receptor Vbeta9 and Vbeta21.3. Moreover, flucloxacillin-specific T cell clones could be generated from peripheral blood, they expressed CD4 and the alphabeta-T cell receptor, and showed a heterogeneous cytokine secretion pattern with no clear commitment to either a Th1- or Th2-type response. The immunohistochemistry of kidney biopsies of these patients revealed cell infiltrations that consisted mostly of T cells (CD4+ and/or CD8+). An augmented presence of IL-5, eosinophils, neutrophils, CD68+ cells, and IL-12 was observed. In agreement with negative cytotoxicity assays, no cytotoxicity-related molecules such as Fas and perforin were detected by immunohistochemistry. The data indicate that drug-specific T cells are activated locally and orchestrate a local inflammation via secretion of various cytokines, the type of which depends on the cytokine pattern secreted and which probably is responsible for the renal damage.

Aged↗
PubMed2005

T cell-regulated neutrophilic inflammation in autoinflammatory diseases.

Previous studies of acute generalized exanthematous pustulosis, a peculiar drug hypersensitivity reaction, suggested that CXCL8-producing T cells regulate sterile, polymorphonuclear neutrophil-rich skin inflammations. In this study, we test the hypothesis of whether CXCL8-producing T cells are present in autoinflammatory diseases like pustular psoriasis and Behçet's disease. Immunohistochemistry of normal skin revealed few CD4+ and CD8+ T cells, few CXCL8+ cells, and no neutrophilic infiltration, whereas in acute exacerbations of atopic dermatitis, numerous CD4+ T cells but few CD8+ T cells, neutrophils, or CXCL8+ cells were detected. In contrast, a pronounced infiltration of neutrophils and of predominantly CD4+ T cells was observed in skin biopsies from pustular psoriasis, Behçet's disease, and acute generalized exanthematous pustulosis, with infiltrating T cells strongly positive for CXCL8 and the chemokine receptor CCR6. Skin-derived T cell clones from pustular skin reactions were positive for CCR6 but negative for CCR8 and secreted high amounts of CXCL8 and GM-CSF, often together with IFN-gamma and TNF-alpha after in vitro stimulation. Moreover, some skin-derived T cell clones from Behçet's disease and from pustular psoriasis predominantly produced CXCL8 and GM-CSF, but failed to secrete IL-5 and IFN-gamma. These cells might represent a particular subset as they differ from both Th1 as well as Th2 T cells and are associated with a unique, neutrophil-rich sterile inflammation. Our findings suggest that CXCL8/GM-CSF-producing T cells may orchestrate neutrophil-rich pathologies of chronic autoinflammatory diseases like pustular psoriasis and Behçet's disease.

Adult↗
PubMed2005

Decreased T-cell receptor excision circles in cutaneous T-cell lymphoma.

PURPOSE: The T cell repertoire in patients with advanced cutaneous T cell lymphoma (CTCL) is significantly contracted despite the presence of relatively normal absolute numbers of T cells. We propose that many normal T cells were being lost in patients with CTCL, with the remaining normal T cells expanding clonally to fill the T cell compartment. T-cell receptor excision circles (TREC) form as a result of the initial gene rearrangement in naïve T cells. Although they are stable, they do not replicate and are subsequently diluted with the expansion of a population of T cells. Their concentration is therefore a measure of unexpanded naïve T cells relative to T cells that have undergone expansion. EXPERIMENTAL DESIGN: We analyzed TRECs from unfractionated peripheral blood T cells from 108 CTCL patients by quantitative PCR. In patients with obvious peripheral blood involvement, we also analyzed TRECs from clonal and nonclonal T cells. RESULTS: We found a decrease in the number of TRECs in peripheral blood of patients with CTCL at all stages of disease, and this decrease was proportional to the loss of complexity of the T cell repertoire as measured by complementarity-determining region 3 spectratyping. In patients with leukemic CTCL and a numerically expanded clone, we also found a significantly lower-than-expected number of TRECs in the nonclonal normal T cells. CONCLUSIONS: We hypothesize that the nonmalignant T cells have proliferated to fill the empty T cell repertoire space left by the loss of other T cells, leading to diminished TRECs and loss of T-cell receptor diversity.

Adult↗
PubMed2005

Drug-induced exanthems.

Cutaneous adverse reactions to drugs can comprise a broad spectrum of clinical and histopathological features. Recent evidence from immunohistological and functional studies of drug-reactive T cells suggest that distinct T-cell functions may be responsible for this broad spectrum of different clinical reactions. Maculopapular exanthems represent the most commonly encountered cutaneous drug eruption. Previous studies on maculopapular exanthems indicate that drug-specific CD4+ T cells expressing cytotoxic granule proteins such as perforin and granzyme B are critically involved in killing activated keratinocytes. These cells are particularly found at the dermo-epidermal junction and may contribute to the generation of vacuolar alteration and destruction of basal keratinocytes, which are typical found in drug-induced maculopapular exanthems. In contrast to maculopapular exanthems, the preferential activation of drug-specific cytotoxic CD8+ T cells may lead to more severe reactions like bullous drug eruptions. Furthermore, activation of drug-specific T with distinct cytokine and chemokines profiles may also explain the different clinical features of drug-induced exanthems. IL-5 and eotaxin are upregulated in maculopapular exanthems and explain the eosinophilia often found in these reactions.

Animals↗
PubMed2005

Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis.

Mast cell chymase is a chymotrypsin-like serine proteinase primarily stored in secretory mast cell granules. Mast cell chymase has various effects on angiotensin, metalloproteases, lipoproteins, procollagen, neuropeptides and cytokines. Recent studies have demonstrated that chymase inhibitors inhibit skin inflammation. In this study we sought to determine the role of mast cell chymase in atopic dermatitis (AD) in comparison with its role in psoriasis and normal skin. Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD and psoriasis and from normal skin of non-atopic and non-psoriatic controls. The number of mast cells containing chymase was determined by immunohistochemistry using a chymase-specific monoclonal antibody. A significantly (P < 0.05) enhanced number of chymase-positive cells was found in lesional AD skin as compared to normal skin as well as to lesional and non-lesional skin of patients with psoriasis. A significant (P < 0.05) increase in the number of chymase-positive cells was also found in non-lesional AD skin in comparison to psoriasis. An enhanced, albeit not statistically significant difference was noted in non-lesional AD skin as compared to normal skin. In conclusion, these results suggest that mast cell chymase may play an integral part in eliciting and maintaining cutaneous inflammation in AD but not in psoriasis. The increased proteinase activity of mast cell chymase may also be involved in promoting a skin barrier defect in AD, which subsequently enhances the skin's permeability to allergens and microbes and thereby aggravates the eczema.

Adult↗
PubMed2005

Histopathology of drug-induced exanthems: is there a role in diagnosis of drug allergy?

PURPOSE OF REVIEW: Cutaneous eruptions are among the most common adverse drug reactions and may often represent a challenging diagnostic problem. This review focuses on histopathological and immunohistochemical findings of drug-induced maculo-papular exanthems and discusses the value of skin biopsies and consequent histopathological examination in the diagnosis of these reactions. RECENT FINDINGS: Data from immunohistological studies indicate that CD4+ T cells expressing cytotoxic granule proteins such as perforin and granzyme B are critically involved in the pathogenesis and contribute to the generation of typical histopathological features of drug-induced maculo-papular exanthems, i.e. an interface dermatitis with vacuolar alteration and some apoptotic basal keratinocytes. In addition, an upregulation of both type 1 (i.e. IFN-gamma, TNF-alpha) and type 2 (i.e. IL-5) cytokines has been reported. IL-5 together with other chemokines (i.e. eotaxin/CCL-11) provides an explanation for tissue eosinophilia, which may be suggestive of a drug eruption if present. SUMMARY: There are no absolute histological or immunohistological criteria for the diagnosis of drug-induced maculo-papular exanthems and even if the observed histological changes are compatible with a drug-induced eruption, biopsy may not definitely exclude alternative causes since there is considerable overlap with features seen in other entities. In mild cases with no severe signs or symptoms and a clear temporal relationship, clinical information and the morphologic pattern of skin lesions are often sufficient for diagnosis. However, in complex and severe cases or when the precise morphology is unclear, histopathological findings may provide some clues and assist in reaching a correct diagnosis.

Biopsy, Needle↗
PubMed2004

Identification of autoantigens in psoriatic plaques using expression cloning.

To search for autoantigens in psoriatic plaques, we screened cDNA libraries of plaque epidermis with psoriatic serum samples. This approach has been highly successful in identifying tumor antigens, but has not been widely applied to autoimmune disease. We identified 11 autoantigens including three with prominent reactivity and plausible disease relevance. These are keratin 13 (K13), heterogeneous nuclear ribonucleoprotein-A1 (hnRNP-A1), and a previously uncharacterized protein, FLJ00294. Serum antibody screening for these demonstrated reactivity in 40%, 38%, and 27% of psoriasis patients, respectively. Most positive samples reacted with all three, and we found that this was due to cross-reactivity among them. Enzyme-linked immunospot assay (ELISPOT) analysis of psoriatic peripheral blood T cells confirmed that these autoantigens are also recognized by T cells. This demonstrates that this is a feasible method to identify autoantigens in an autoimmune target tissue, and suggests that these antigens warrant further study in psoriasis. Furthermore, but peripheral blood of normal controls reacted to these autoantigens with essentially the same frequencies as patients, suggesting that psoriatics may have not only an immune system which is capable of reacting to certain autoantigens, but also to a skin immunoregulatory alteration which allows this normal reactivity to develop into abnormal inflammation.

Autoantigens↗
PubMed2003

Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease.

Adult↗
PubMed2003

Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy.

BACKGROUND: The prognosis of patients with stage IV cutaneous T-cell lymphoma (CTCL) is grim and therapeutic options are limited. Treatment of advanced-stage CTCL is aimed at suppressing the dominant T-cell clone, which is typically present in the skin, peripheral blood, and lymph nodes. OBSERVATIONS: We detected the expansion of 1 T-cell clone expressing the T-cell receptor V beta 14 in the peripheral blood of a patient with stage IVA CTCL. Before initiation of combination therapy with photopheresis and low-dose interferon alpha, the dominant T-cell clone represented 84% of the total T-cell population. After successful therapy, this clone showed a dramatic decrease to 6% of the T-cell population after 6 months of treatment. This reduction in the percentage of the malignant T-cell population in response to therapy was paralleled by clinical skin improvement from initial generalized erythroderma to undetectable skin disease. CONCLUSIONS: This case demonstrates that response to combination treatment with photopheresis and low-dose interferon alpha in patients with advanced CTCL may be accurately and quantitatively followed up by monitoring the percentage of the malignant T-cell clone (when identifiable) within the total circulating T-cell population by flow cytometry.

Antineoplastic Agents↗
PubMed2002

Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation.

Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4(+) as well as CD8(+) T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.

Animals↗
PubMed2002

Cytotoxic HIV-1 p55gag-specific CD4+ T cells produce HIV-inhibitory cytokines and chemokines.

CD4+ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4+ T cell help. In order to investigate the function of HIV-specific CD4+ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4+ TCC produced substantial amounts of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4+ T cells suggest that they may exert direct antiviral activity.

Anti-HIV Agents↗
PubMed2002

Cellular and molecular pathophysiology of cutaneous drug reactions.

Hypersensitivity reactions to drugs can cause a variety of skin diseases like maculopapular, bullous and pustular eruptions. In recent years increasing evidence indicates the important role of T cells in these drug-induced skin diseases. Analysis of such drug-specific T cell clones has revealed that drugs can be recognized by alpha beta-T cell receptors, not only if bound covalently to peptides, but also if the drug binds in a rather labile way to the presenting major histocompatibility complex (MHC)-peptide. This presentation is sufficient to stimulate T cells. In maculopapular exanthema (MPE), histopathological analysis typically shows a dominant T cell infiltration together with a vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and to a lesser degree of CD8+ T cells, which contain perforin and granzyme B. They are close to keratinocytes that show signs of cell destruction. Expression of Fas ligand is barely detectable, suggesting that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. While in MPE, the killing of cells seems to be predominantly mediated by CD4+ T cells, patients with bullous skin disease show a strong CD8+ T cell migration to the epidermis. This is probably due to a preferential presentation of the drug by MHC class I molecules, and a more extensive killing of cells that present drugs on MHC class I molecules. This might lead to bullous skin diseases. In addition to the presence of cytotoxic T cells, drug-specific T cells also orchestrate the inflammatory skin reaction through the release and induction of various cytokines [i.e. interleukin (IL)-5, IL-6, tumor necrosis factor-alpha and interferon-gamma] and chemokines (RANTES, eotaxin or IL-8). The increased expression of these mediators seems to contribute to the generation of tissue and blood eosinophilia, a hallmark of many drug-induced allergic reactions. However, in acute generalized exanthematous pustulosis (a peculiar form of drug allergy), neutrophils represent the predominant cell type within pustules, probably due to their recruitment by IL-8 secreting drug specific T cells and keratinocytes.

Drug Eruptions↗