T细胞免疫在带状疱疹发病及治疗中的作用

带状疱疹是一种由潜伏在脊髓后根神经节或脑神经的感觉神经节中的水痘-带状疱疹病毒再激活而导致的皮肤病,其发生与水痘-带状疱疹病毒特异性的细胞免疫功能下降有关.为高危人群接种水痘-带状疱疹病毒特异性细胞免疫的带状疱疹疫苗,可以有效的降低带状疱疹的发病率和疾病的严重程度.带状疱疹发生后,应及早应用抗病毒药物及合适的止痛治疗来缓解患者的临床症状,并预防后遗神经痛的发生.通过对带状疱疹患者T细胞免疫机制的深入研究,为免疫治疗提供理论依据.

Abstract：

Herpes zoster is a skin disease caused by the reactivation of latent varicella zoster virus (VZV)in the posterior root ganglia of spinal nerves or sensory ganglia of cranial nerves.It is associated with a decline in VZV-specific cell-mediated immunity.To boost VZV-specific cell-mediated immunity via immunizing with VZV-targeted vaccines may reduce the incidence and severity of herpes zoster in high-risk populations.Once herpes zoster develops, antivirals and appropriate analgesics should be administrated as early as possible to relieve symptoms and prevent the development of post-herpetic neuralgia.Further research into the mechanisms of T lymphocyte-mediated immunity in herpes zoster may provide a solid theoretical basis for the immunotherapy of herpes zoster.     

Risk of Herpes Zoster and Family History: A Meta-analysis of Case-control Studies

Background:Herpes zoster (HZ) results from the reactivation of latent varicella zoster virus (VZV) residing in dorsal root and cranial nerve ganglia. Advanced age and dysfunctional cell-mediated immune responses are well-established risk factors for VZV reactivation. There have been recent interests in whether there is an increased risk of the disease associated with a positive family history.Results:Five studies, yielding a total of 4169 subjects, were identified for meta-analysis. Cases with HZ were 3.03 (95% confidence interval [CI]: 1.86–4.94, P < 0.001) and 3.27 (95% CI: 1.75–6.10, P < 0.001) times more likely to report the first-degree relatives and total relatives with a history of HZ, respectively. A significant positive dose-response relationship between the risk of HZ infection and the number of relatives with a history of HZ was also demonstrated (P < 0.001).Conclusions:This meta-analysis demonstrated that family history is a significant risk factor for HZ infection. This risk has a dose-response relationship with the number of relatives with a history of HZ.     

Varicella-zoster virus antigen expression of eccrine gland and duct epithelium in herpes zoster lesions

Background It is well known that varicella‐zoster virus (VZV) exhibits tropism for the epidermis and follicular epithelium, while little attention has been paid to eccrine gland and duct involvement by VZV. The presence of herpetic syringitis in immunocompromised hosts suggested the possibility of eccrine gland and duct involvement by VZV. Objectives To determine whether VZV antigens could be detected in eccrine gland or duct epithelium of herpes zoster (HZ) lesions obtained at various intervals after the onset of a rash, and whether this expression could also be detected in eccrine units from other inflammatory disease lesions suggestive of VZV infection. Methods We investigated immunohistochemically in vivo localization of VZV glycoprotein E (gE) antigen in HZ lesions and control inflammatory disease lesions, using the murine monoclonal antibody directed against the VZV gE. Results VZV gE was differentially detected in the epidermis, follicular and eccrine epithelium, and dermal infiltrating cells in HZ lesions obtained at various intervals after onset. The VZV gE was most persistently detected in eccrine units, regardless of the age of individual HZ lesions, compared with keratinocytes and follicular epithelium. The gE expression was also observed in other inflammatory disease lesions suggestive of VZV infection. Conclusions Immunohistochemical detection of VZV gE in eccrine epithelium can be a subtle clue to the diagnosis of HZ which displays most unusual manifestations, and VZV‐related disorders.     

水痘-带状疱疹病毒抗体与带状疱疹患者疼痛的关系

用酶标SPA法对68例带状疱疹(HZ)和带状疱疹后遗神经痛(PHN)及HZ半年后无PHN的患者的血清中抗水痘-带状疱疹病毒(VZV)抗体进行了检测,并与35例正常人和非HZ患者血清对照.结果显示HZ在发病一周内其抗VZV抗体大都处于低水平,抗体滴度与年龄无关,仅与疼痛程度有关.HZ在发病一周后其抗体滴度明显升高,该滴度与患者年龄、疼痛程度均呈正相关,即年龄越大,抗VZV抗体滴度越高,疼痛程度也越剧烈.无PHN者在发病半年后其抗VZV抗体均降至正常水平,而有PHN的HZ在一年后抗体仍呈高滴度,显示PHN的发生与抗VZV抗体有密切关系.而对照组抗VZV抗体呈阴性或低滴度阳性.     

A specific thrombin inhibitor, argatroban, alleviates herpes zoster-associated pain.

We report the result of a randomized, controlled, open trial of anti-thrombin therapy for herpes zoster-associated pain. Fifty-five herpes zoster patients within 8 days after the onset of skin lesion were enrolled in the trial. Patients were treated with an optimal dose of oral acyclovir (4000 mg/day for 7 days) with or without intravenous administration of a specific anti-thrombin agent, argatroban (10 mg/day, three times a week). Administration of argatroban reduced pain intensity at the 4th through 21st day after the initiation of treatment as determined by visual analogue scale (Mann-Whitney U test, p < 0.05). It also shortened the median time to cessation of analgesic use (14 days vs. 24 days, p = 0.02, logrank test), although it did not significantly reduce the median time to cessation of pain (21 days vs. 43 days, p = 0.07, logrank test). None of the enrolled patients showed evidence of adverse effects including hemorrhagic diathesis. The results suggested that relatively low doses of argatroban are effective in reducing herpes zoster-associated pain. Up-regulation of prothrombin expression by the vascular endothelial and sweat gland epithelial cells in the active skin lesion and transient elevation of plasma thrombin-antithrombin III complex levels in a proportion of patients suggest a lesional generation of thrombin in herpes zoster. This may be relevant to the beneficial effects of the anti-thrombin treatment on the resolution of herpes zoster-associated pain.     

Close correlation of herpes zoster‐induced voiding dysfunction with severity of zoster‐related pain: A single faculty retrospective study

Herpes zoster (HZ), a common vesiculo‐erythematous skin disease associated with reactivation of varicella zoster virus in the cranial nerve, dorsal root, and autonomic ganglia, is accompanied by several related symptoms represented by postherpetic neuralgia. Among them, involvement of vesicorectal dysfunction is relatively rare. The vesicorectal symptom can usually be recovered in transient course, but is quite important in terms of impaired quality of life. Male individuals affected with HZ and skin lesions on sacral dermatome have been reported as independent risk factors of zoster‐related voiding dysfunction. In this study, urinary symptoms were focused upon and six patients with zoster‐related voiding dysfunction at a single faculty of dermatology in Japan from 2009 to 2014 were retrospectively analyzed. All patients showed HZ lesions on the sacral area and the urinary symptom recovered in approximately 2 months (14 days to 7 months). The term of treatment for zoster‐associated urinary dysfunction was positively correlated with that for zoster‐related pain without significance (r = 0.661, P = 0.153). Average treatment term for pain relief of sacral HZ accompanied by voiding dysfunction (91.3 ± 76.44 days) was significantly longer than that of sacral HZ without urinary symptom (18.9 ± 20.42 days) (P = 0.032). These results suggested that zoster‐related voiding dysfunction would mainly be involved in sacral HZ and closely associated with severity of zoster‐related pain. Dermatologists should be aware that severe zoster‐related pain accompanied by sacral HZ, which is related to prolonged treatment of pain relief, can be a predictive factor of voiding dysfunction.     

Infektionen mit dem Varizella-zoster-Virus

Lernziel Kenntnis der: Biologie des Varizella-zoster-Virus, klinischen Manifestationen von Prim?rinfektion (Varizellen) und Reaktivierung (Herpes zoster), Komplikationen des Herpes zoster, insbesondere der postherpetischen Neuralgie, Therapie und Prophylaxe von Infektionen mit dem Varizella-zoster-Virus. Infektionen mit dem Varizella-zoster-Virus (VZV) sind h?ufige Erkrankungen. Die Prim?rinfektion mit dem VZV erfolgt dabei in der Regel in früher Kindheit unter dem Bild der Varizellen. Nach Jahren oder Jahrzehnten der Latenz kann es zur Reaktivierung des zuvor akquirierten Virus und damit zum Herpes zoster (HZ) kommen. Pro Jahr sind ungef?hr 1.000 F?lle von HZ pro 1 Mio. Einwohner zu verzeichnen. In der Gruppe der 85-J?hrigen hat bereits jeder Zweite einen HZ erlitten. Da der HZ v. a. bei ?lteren und immunkompromittierten Menschen vorkommt, wird angesichts der demographischen Entwicklung eine steigende Zahl von Erkrankten zu erwarten sein. Insbesondere die Komplikationen wie die postherpetische Neuralgie k?nnen bei den Erkrankten und ihren Umgebungspersonen zu einer erheblichen Einschr?nkung der Lebensqualit?t führen.     

Comparative immunological and histopathological study in fifty cases of mucosal/nonmucosal lichen planus

Lichen planus is a common disorder and 40-50% of LP patients also reveal mucosal lesions. It is well known that mucosal LP lesions take very long to heal in comparison to cutaneous lesions. Rarely erosive mucosal LP can turn malignant. Both CMI and humoral immunity may play role in aetiopathogenesis of LP. Present study was conducted to study and compare CMI, Humoral Immunity, histopathology in mucosal and nonmucosal LP.     

Thermography as a predictor of postherpetic neuralgia in acute herpes zoster patients: a preliminary study

Background/purpose: Infrared thermal images in patients suffering from herpes zoster (HZ) may exhibit thermal asymmetry due to the unilateral distribution of HZ lesions. This study examined the usefulness of infrared thermography in acute HZ as a predictor for the development of postherpetic neuralgia (PHN). Methods: The authors collected demographic and clinical data including age, sex, onset of skin lesion, pain intensity by a visual analogue scale (VAS) and the development of PHN from a total of 55 patients diagnosed with HZ. We evaluated the body surface thermographic parameters between the lesion and contralateral normal skin: maximal difference in the temperature (ΔT) and the size of the body surface area (BSA) showing thermal asymmetry. Results: Temperatures of the lesions were found to be warmer than the control side in most patients with acute HZ. We compared the patient group who developed PHN with those who did not. In univariate analysis, patients with PHN were older (P=0.004), had a higher VAS score for pain (P<0.001), higher ΔT (P<0.001) and larger BSA (P=0.001). In logistic regression analysis to identify independent risk factors of PHN, older age (>60 years old) and ΔT more than 0.5 °C were found to be statistically significant.     

Possible enhancement of BP180 autoantibody production by herpes zoster

Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies against type XVII collagen/BP180 (BP180). Although the mechanisms of autoantibody production remain to be elucidated, herpes virus infections have been identified as a possible triggering factor for pemphigus. We report a case of herpes zoster (HZ) having anti‐BP180 serum antibodies. The patient developed sudden‐onset, tense blisters and edematous erythema on the right anterior chest, shoulder and upper back. Histopathology showed remarkable degeneration of keratinocytes, acantholysis and blister formation with ballooning cells, indicating herpes virus infection. A polymerase chain reaction analysis of varicella zoster virus (VZV) was positive in crusts and effusions from the skin lesions, confirming the definitive diagnosis of HZ. Notably, we found that the patient had anti‐BP180 serum antibodies in association with the occurrence of HZ. After successful treatment with valacyclovir hydrochloride for 7 days, the serum levels of anti‐BP180 antibodies decreased in accordance with the improvement of skin lesions. These findings suggest that the production of anti‐BP180 antibodies could be triggered by the reactivation of VZV.     

Varicella zoster virus as a possible trigger for the development of pityriasis lichenoides et varioliformis acuta: retrospective analysis of our institutional cases

Although numerous infective agents, including varicella zoster virus (VZV), have been described in association with pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC), none has been identified consistently in these lesions. We sought to immunohistochemically identify VZV glycoprotein (g)E antigens in the vascular endothelium in PLEVA and PLC lesions, based on our previous observation that gE was detected in the vascular endothelium and eccrine unit up until 2 months and 2.5, respectively, years after herpes zoster (HZ) infection. In five of the six cases of PLEVA, VZV gE was identified in the endothelial cells and eccrine epithelium, as observed in HZ lesions, whereas VZV gE was detected in only one of seven patients with PLC. None of the patients with PLEVA who had VZV gE‐positive vascular endothelial cells had experienced previous episodes of HZ. VZV may be one of the aetiological agents for PLEVA while other aetiological factors could exist in PLC.     

Immunohistochemical Study of Cellular Events in Lesional Skin during Common Virus Infections

Determination was made of epidermal Langerhans cell (LC) distribution and infiltrating cellular events in lesional skin during varicella zoster virus (VZV) infection, and the results were compared with those for herpes simplex (HS), measles, and rubella by immunohistochemical staining with cell surface markers. CD1 a positive epidermal LCs increased in number, particularly in measles and rubella. The number of LCs was within the normal range or slightly increased in the epidermis of VZV infection. In herpes zoster (HZ) and varicella, HLA-DR positive epidermal cells were present in the basal part of the epidermis. In measles, HLA-DR positive cells aggregated in papular lesions. In measles and rubella, the number of HLA-DQ positive epidermal cells appeared to increase. In HS cases, CD11b (OKM1) positivity of the upper epidermal keratinocytes was quite pronounced, but not in the basal layer. CD8 positive suppressor/cytotoxic cells extensively infiltrated the dermis of HZ and varicella. Dermal infiltrates were identified as CD8 positive cell dominant in measles, HZ, and varicella. These results provide a partial explanation as to why cellular events in skin lesions act immunosuppressively.     

Seroepidemiologic Survey of Varicella-Zoster Virus in Korean Adults Using Glycoprotein Enzyme Immuno Assay and Fluorescent Antibody to Membrane Antigen Test

Background

Herpes zoster (HZ) occurs mainly in the elderly and Korea is rapidly becoming an aging society. Therefore, it is important to know the immune status against varicella-zoster virus (VZV) in Korean adults to prevent the disease.

Objective

The aim of this study was to survey the immune status of Korean adults over 40 years of age against VZV.

Methods

Antibody titer was measured using a VaccZyme™ VZV glycoprotein enzyme immunoassay (gpEIA) (Binding Site, UK). Fluorescent antibody to membrane antigen (FAMA) test was performed to measure the seropositive rate.

Results

HZ incidence in the 214 adults enrolled in this study was 10.3%. The gpEIA geometric mean titer (GMT) was 490 mIU/ml and 90.2% of the subjects had a protective level of gpEIA antibody titer against varicella. The average gpEIA GMT of adults who previously had HZ was 1,122 mIU/ml, which was higher than the average gpEIA GMT of 457 mIU/ml in adults who had not had HZ. The FAMA positive rate was 98.6%.

Conclusion

Most (90.2%) Korean adults ≥40-years-of-age have a protective level of gpEIA antibody against varicella and 98.6% were FAMA seropositive. The GMT of gpEIA antibody was significantly increased with age, and was higher in adults with a history of HZ.     

Serotonin Expression in Lichen Planus Lesions and Its Relationship with Depression/Anxiety

BackgroundPsychological factors such as stress, depression, and anxiety have been documented to contribute to the development of lesions in lichen planus (LP).ObjectiveTo evaluate the relationship between serotonin expression in LP lesions and depression/anxiety.MethodsForty patients (22 females, 18 males) with LP and 20 healthy control subjects were included in this study. The severity of LP was assessed with the palmar method (using the measurement of affected body surface area [BSA]). The depression and anxiety scores were measured with Beck''s depression inventory (BDI) and Beck''s anxiety inventory (BAI). The expression of serotonin was determined via immunohistochemistry in LP lesions and in the control group skin using a monoclonal antibody to serotonin.ResultsThe skin biopsies of the LP patients had significantly higher levels of serotonin than those of the control subjects (p<0.001). In the LP patients, and there was a positive correlation between serotonin expression and LP severity (p=0.022). Based on the results from the BDI and BAI, there was a significant relationship between the severity of depression/anxiety and intensity of serotonin expression (p<0.001).ConclusionData from this study suggest that serotonin may have a possible role in the pathogenesis of LP. Further, the relationship between serotonin expression in acute cutaneous lesions and the depression/anxiety scores indicates that serotonin may be a mediator for the association of LP and depression/anxiety simultaneously. There is a need for more specific studies showing the expression of serotonin in the lichen planus to demonstrate the cause or effect.     

Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare disease that usually begins in childhood and is characterized by a generalized infection by human papilloma virus (HPV), frequent associations with cutaneous carcinomas, and abnormalities of cell-mediated immunity (CMI). We studied nonspecific CMI in 13 patients with EV by bacterial skin tests, allergic reactions to dinitrochlorobenzene (DNCB), measurement of responses to phytohemagglutinin (PHA), and quantification of T lymphocytes and T lymphocytes subsets in peripheral blood. Impairment of CMI was manifested by the cutaneous anergy to a variety of common skin antigens and, by the reduction of the lymphocyte transformation to PHA. There were no correlation between the severity of cases and abnormalities of CMI in our patients, however; the impairment of CMI was lower in cases of short duration, suggesting that the impairment of CMI in EV might reflect a long period of disease.     

Study on the T-helper cell 1/2 cytokine profile in blister fluid of patients with herpes zoster and its clinical significance

Herpes zoster (HZ) is a Varicella zoster virus infection disease. Previous studies have presumed the connection between development of HZ and involvement of cellular immunity in peripheral blood. However, whether cellular immunity plays a role in the local skin lesion has not been addressed. To explore the levels of T-helper cell (Th)1/Th2 type cytokine profiles in the blister fluid of the skin lesions from the patients with HZ and its role in pathogenesis, we used the cytometric bead array kit to compare the levels of cytokines (interleukin [IL]-2, tumor necrosis factor [TNF]-α, IL-10 and IL-4) in blister fluid from 46 patients with those from the suction blister fluids from 20 volunteers without any infectious disease (the control group). The results indicated that the levels of Th1 cytokines, IL-2 and TNF-α in the blister fluid from the patients' skin lesions were significantly lower than those from the control group, whereas the levels of Th2 cytokines IL-10 and IL-4 were significantly higher than those in the control group. Moreover, significant variation of the levels of Th1/Th2 cytokines (IL-2, TNF-α, IL-10 and IL-4) in the blister fluid from the HZ patients' lesions was also observed among different stages of the disease. It is concluded that a cytokine imbalance was present in the local lesions of patients with HZ during disease development. Our data suggested that the Th immunity was associated with disease activity, which may play an important role in the pathogenesis of HZ.     

SUPPRESSED CELL-MEDIATED IMMUNITY IN TWO ADULTS WITH ATOPIC DERMATITIS

Summary.— Tests of immune function over a 12-month period in a young woman and a young man with life-long atopic dermatitis showed depressed cell-mediated immunity (CMI) (delayed-type skin test unresponsiveness, inability to be sensitized to DNCB, diminished responsiveness of cultured lymphocytes to phytohaemagglutinin, enlarged subcutaneous lymph nodes without any cell-mediated immunopathology, but with the structure of a node involved in humoral antibody production). Direct immunofluorescence localized IgE in the germinal centres of these subcutaneous lymph nodes. No anti-immunoglobulin or anti-C₃ complement fluorescent conjugates were localized in their involved or uninvolved skin. Cells corresponding to small-and medium-sized lymphocytes in concentrated peripheral leucocyte smears stained with FITC antiserum to human IgE. The woman's lymphocyte transformation suppression improved during a remission and relapsed during an exacerbation of the dermatitis.     

水痘-带状疱疹病毒的免疫逃逸机制

水痘-带状疱疹病毒初次感染人体后,易引起水痘,感染控制后,病毒潜伏在感觉神经节内,当机体免疫力降低时,病毒被再次激活,在神经元内大量复制并经神经元突起传播至皮肤后引起带状疱疹.机体拥有强大的免疫监视系统,能及时清除突变或病毒感染的细胞.水痘-带状疱疹病毒要成功地在体内复制、扩散和引起皮损,或者长期潜伏于神经节,必需具备能够编码逃避免疫防御的功能.对水痘-带状疱疹病毒限制机体免疫识别,影响相关免疫分子表达下调,干扰抗原提呈等多种机制进行概述.     

Incidence of and Risk Factors for Cutaneous Scarring after Herpes Zoster

Background

About 20% of children have cutaneous scars following chickenpox. In contrast, skin scars are not often reported after herpes zoster (HZ). Risk factors for post-HZ scarring remain undetermined.

Objective

Our objective was to prospectively study the incidence of and risk factors for post-HZ scarring.

Methods

This was a 3-year prospective study of patients with HZ attending a tertiary university hospital. Baseline data, including age, sex, immunosuppression, prior history of scarring, severity and extension of HZ, afflicted HZ dermatome, and antiviral treatment received, were recorded. At 1 month after the HZ skin lesions had healed, patients were screened for skin scars at the prior HZ site. These patients were followed every 2 months for 6 months.

Results

At 6 months, 11 (9.7%) of 113 HZ patients still had post-HZ scarring (fair-skinned patients: hypopigmented [n?=?3], hyperpigmented [n?=?2], atrophic cicatricial [n?=?3], and hypertrophic cicatricial [n?=?1]; dark-skinned patients: severe hyperpigmented hypertrophic scarring [n?=?2]). HZ was extensive and severe in all cases. Nine of the 11 patients were immunocompromised. Three cases had a history of hypertrophic/keloid scarring but no post-varicella scars. The most frequent location was the trunk (n?=?5), followed by the cervical region (n?=?3) and the face (n?=?3). Given the study setting, it is possible that immunocompromized patients with severe HZ were overrepresented in this study.

Conclusions

Scarring after HZ is probably overlooked. The principal risk factors seem to be severe HZ and immunosuppression. Hence, prompt instigation of antiviral treatment for HZ and HZ vaccination could help reduce the incidence of post-HZ scarring.