The role of Malassezia in atopic dermatitis affecting the head and neck of adults.

Atopic dermatitis is a common chronic skin condition. A subset of patients with head and neck dermatitis may have a reaction to Malassezia flora fueling their disease. Although there are no documented differences in Malassezia species colonization, patients with head and neck atopic dermatitis are more likely to have positive skin prick test results and Malassezia-specific IgE compared with healthy control subjects and patients with atopy without head and neck dermatitis. There is no clear relationship with atopy patch testing. The reaction to Malassezia is likely related to both humoral- and cell-mediated immunity. Clinically, Malassezia allergy may be suspected in patients with atopic dermatitis and: (1) head and neck lesions; (2) exacerbations during adolescence or young adulthood; (3) severe lesions recalcitrant to conventional therapy; and (4) other atopic diseases. There is literature to suggest that these patients will benefit from a 1- to 2-month course of daily itraconazole or ketoconazole followed by long-term weekly treatment.

Infectious complications in patients with psoriasis and rheumatoid arthritis treated with antitumor necrosis factor agents and methotrexate.

Treatment of patients with moderate-severe psoriasis and/or psoriatic arthritis includes systemic biologic, antimetabolite, and immunosuppressive therapy. However, adverse events such as serious infectious complications must be considered before starting therapy and throughout treatment. The authors describe the case of a male on combination etanercept and methotrexate for psoriasis and psoriatic arthritis for years who developed a spontaneous epidural abscess with resulting quadriplegia. In addition, a review of the literature was performed looking at the risk of serious infectious complications with antitumor necrosis factor (anti-TNF) monotherapy or combination therapy with methotrexate fro the treatment of psoriasis and rheumatoid arthritis. Serious infectious risk does not appear to be increased with etanercept or other anti-TNF agents either alone or in combination with methotrexate. Nevertheless, clinicians are cautioned to carefully weigh the risks and benefits of treating with anti-TNF agents in patients who are prone to infection.

Generalized eruptive histiocytomas and rosai-dorfman disease presenting concurrently in a patient with myelodysplastic syndrome.

Non-Langerhans cell histiocytoses were originally described as individual diagnoses. However, evidence has been mounting that these entities are manifestations on a spectrum of the same disease. The authors present a patient who initially presented with lymphadenopathy, pancytopenia, splenomegaly, and high-grade fevers. A bone marrow biopsy was performed and she was diagnosed with myelodysplastic syndrome with trisomy 8. Several months later, her persistent pulmonary lymphadenopathy was biopsied revealing Rosai-Dorfman disease. Two years after her initial hospitalization, the patient presented with lesions consistent with generalized eruptive histiocytomas. This case highlights the difficulty that clinicians encounter when trying to separate generalized eruptive histiocytomas, Rosai-Dorfman disease, and the other non-Langerhans cell histiocytoses. While further research needs to be performed in the field of histiocytoses, this case provides clinical support that these diseases are closely linked.

Wells syndrome (eosinophilic cellulitis): a clinical imitator of bacterial cellulitis.

OBJECTIVE: To report a case of Wells syndrome (eosinophilic cellulitis) in a patient who was previously hospitalized twice and received several antibiotic treatments. SETTING: Inpatient hospital consultation. PARTICIPANT: One patient diagnosed with Wells Syndrome based on supporting clinical history, histopathological examination, and other laboratory data. MEASUREMENT: Change in signs and symptoms over time. RESULTS: Improvement of skin lesions after administration of corticosteroids. CONCLUSION: Wells syndrome is a clinical condition that mimics bacterial cellulitis. It is characterized as an erythematous, edematous tender plaque with predilection for the lower extremity. The authors report this case to warn clinicians about other primary dermatological disorders that resemble infectious cellulitis in order to avoid misdiagnoses and delayed treatment.

Cutaneous rosai-dorfman disease persisting after surgical excision: report of a case treated with acitretin.

OBJECTIVE: Cutaneous Rosai-Dorfman disease is rare, and there is a lack of literature on clinical evidence for treatment options. The objective of this report is to illustrate that acitretin may be effective in treating cutaneous Rosai-Dorfman disease. DESIGN: A patient with cutaneous Rosai-Dorfman disease refractory to antibiotics, steroids, and surgical excision was treated with acitretin for a period of four months and was closely monitored for improvement in the lesion. SETTING: This was a patient in the authors' medical dermatology clinic. PARTICIPANTS: A single patient was involved. RESULTS: The patient had continuous improvement in her cutaneous Rosai-Dorfman disease throughout a four-month treatment course with softening of the plaque and decreased erythema. She chose to discontinue treatment after four months due to hair loss with acitretin. CONCLUSION: Cutaneous Rosai-Dorfman disease is a rare, benign, generally self-limited, lymphoproliferative disease of unknown etiology. It typically occurs as histiocyte-rich inflammatory infiltrates, manifesting as red papules and plaques in older women, without predilection for site. Treatment is usually unnecessary, unless the lesions persist and are bothersome to the patient or cause functional deficits. Treatments are based on case reports and include surgery, radiation, and medical options. Our experience with a patient with a case of cutaneous Rosai-Dorfman disease persisting after surgical excision demonstrates that acitretin may be an effective therapeutic option for cutaneous Rosai-Dorfman disease.

New targets of therapy in T-cell lymphomas.

T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T-cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line.

A New Kid on the Block: IL-10+ Regulatory B Cells and a Possible Role In Psoriasis.

The pivotal role of T cells in the etiology of psoriasis has been elucidated; however, the mechanisms that regulate these T cells are unclear. Recently, it has been shown that an IL-10 producing B cell population may downregulate T cell function and it has been hypothesized that depletion of this B cell population may lead to exacerbation of T-cell mediated autoimmune disease. We present the case of an adolescent male with autoimmune lymphoproliferative syndrome (ALPS) being treated with the anti-CD20 chimeric monoclonal antibody rituximab in addition to intravenous immune globulin (IVIG) for immune thrombocytopenia (ITP) who developed a psoriasiform rash on his hands following mechanical trauma with concomitant severely decreased B cell count. We propose that depletion of the patient's B cells due to rituximab treatment may have led to abrogation of IL-10+ B-cell regulation of T cells. The development of a psoriasiform rash in this predisposed individual may have been triggered by mechanical trauma to his hands (koebnerization). In addition, we believe the patient's rash may have been tempered by concomitant treatment with IVIG, which has been used as treatment in cases of psoriasis. We discuss the immunologic mechanism of psoriasis and the role that a recently described IL-10+ B cell may play in preventing the pathologic process. Further studies are needed to more clearly elucidate this process.

Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients.

Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2(+) cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only approximately 50% of patients treated for 12 wk. We studied the immunologic effects of alefacept in a group of psoriasis patients during treatment. We found that T cells, especially CD8(+) T cells, were rapidly decreased in the peripheral circulation. Decreases in circulating T cells were not associated with induced apoptosis. Unexpectedly, in addition to suppression of inflammatory genes, we found a marked induction of mRNAs for STAT1, IL-8, and monokine induced by IFN-gamma during the first day of treatment in PBMC. We confirmed the agonistic effects of alefacept in PBMC in vitro, which were similar to CD3/CD28 ligation on T cells. These data establish that alefacept activates gene expression programs in leukocytes and suggest that its therapeutic action may be as a mixed agonist/antagonist. Furthermore, responding patients to alefacept treatment show unique patterns of gene modulation. Whereas alefacept down-regulated TCRs CD3D and CD2 in responders, nonresponders reveal a higher expression of T cell activation genes such as CD69 in pretreatment PBMC. These finding suggest a potential basis for categorizing responders vs nonresponders at an early time point in treatment or before treatment of a broad range of proinflammatory diseases. This study 1) establishes alefacept as a novel CD2 agonist molecule for induction of leukocyte activation genes (prior work proposed its mechanism as a CD2 antagonist) and 2) that differential activation of genes may categorize clinical responders to this agent, critical for cost-effective use of this drug.

Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment.

Basal cell carcinoma (BCC), the most common human cancer, undergoes spontaneous regression in certain circumstances, which is potentially immune-mediated. To understand the immune response surrounding BCCs, we characterized the genomic, protein, and cellular microenvironment associated with BCC in comparison to normal skin. Our results demonstrated the following: (1) CD4+ CD25+ Foxp3+ surround epithelial tumor aggregates; (2) Immature dendritic cells (DCs) were abundant in the tumor microenvironment; (3) BCC showed increased expression of IL-4, IL-10, and CCL22 and increased expression of interferon-associated genes (IFI27, IRF1, IRF7, and G1P2) and IL-12/23, gene indicating a Th2 dominant microenvironment. Our findings suggest a dynamic state within the immune microenvironment associated with BCC. The finding of phenotypic T regs, in conjunction with immature DCs and Th2 cytokines, suggests an attenuated state of immunity to human BCC. In contrast, abundant CD8+ T cells, an interferon signal, and IL-12/23 suggest partial host antitumor response. A better understanding of these opposing forces within the immune microenvironment may facilitate development of more potent immune-based treatment for BCC and other human carcinomas.

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine.

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cytotoxic T lymphocyte-associated protein 4 (CTLA4+)-, Forkhead box P3 (FOXP3+)-, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+)-, CD62L+-, transforming growth factor beta1 (TGF-beta1+)-, interleukin 10 (IL-10+)-Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended disease. Most surprisingly, in the majority of patients with CLL treated with fludarabine-containing therapy regimens the inhibitory function of Treg cells was decreased or even abrogated. In addition, frequencies of Treg cells were significantly decreased after therapy with fludarabine. In light of similar findings for cyclophosphamide the combination of fludarabine and cyclophosphamide might be further exploited in strategies reducing immunosuppression prior to cancer immunotherapy.

The third signal in T cell-mediated autoimmune disease?

The initial event in the pathogenesis of autoimmune disease is thought to be the priming of naive autoreactive T cells by an infection with a cross-reactive microorganism. Although such cross-reactive priming should be a common event, autoimmune disease does not frequently develop. This situation is reflected after the immunization of C57BL/6 mice with the neuroantigen myelin oligodendrocyte glycoprotein (MOG) with CFA, which primes a type 1 T cell response but does not lead to clinical or histological manifestation of experimental allergic encephalomyelitis unless pertussis toxin is injected in addition. We show in this study that, in MOG:CFA-primed mice, the autoimmune CNS pathology develops after intracerebral deposition of TLR9-activating CpG oligonucleotides, but not following non-CpG oligonucleotide injection or after aseptic cryoinjury of the brain. Thus, access of primed MOG-specific Th1 cells to the uninflamed CNS or to CNS undergoing sterile inflammation did not suffice to elicit autoimmune pathology; only if the APC in the target organ were activated in addition by the TLR9-stimulating microbial product did they exert local effector functions. The data suggest that such licensing of APC in the target organ by microbial stimuli represents a checkpoint for functional self-tolerance. Therefore, microorganisms unrelated to the cross-reactive agent that primes the autoreactive T cells could dictate the onset and exacerbation of autoimmune diseases.