急性犬瘟热感染组织脏器的研究

临床中犬瘟热多分为急性和亚急性,3月龄犬多发本病,急性病例和亚急性病例的临床症状和病毒复制的脏器与慢性病例有很大区别。临床上急性病例的病变主要集中在肺脏和淋巴组织,组织病理学可观察到淋巴结炎和多核巨细胞性肺炎。根据免疫组织化学染色结果发现,在犬瘟热急性病例的淋巴结皮质中犬瘟热抗原呈强阳性,且密度很高。而病犬虽然表现出严重的肺炎症状,但在犬的肺脏中犬瘟热病毒抗原阳性反应弱,仅在支气管上皮和少量的巨噬细胞胞浆中观察到。犬瘟热病毒首先在犬的淋巴组织中进行复制、增殖,破坏被膜下淋巴窦和淋巴小节中的T淋巴细胞和B淋巴细胞,影响淋巴组织输出到外周血液循环中的淋巴细胞数量。本研究结果表明,犬瘟热虽然临床上以肺脏病变最严重,但在急性和亚急性病例,犬瘟热病毒主要在淋巴组织的T淋巴细胞、B淋巴细胞和巨噬细胞中增殖,故应以淋巴组织作为犬瘟热病毒的主要分离脏器。     

兔圆小囊及肠道组织中抗菌肽的免疫组织化学和免疫电镜细胞化学定位

采用免疫组织化学和免疫电镜细胞化学技术观察了兔圆小囊及其他肠道组织中产抗菌肽细胞的分布定位。免疫组织化学观察发现,产抗菌肽细胞在兔圆小囊的黏膜上皮、圆顶上皮以及淋巴组织的滤泡生发中心、圆顶区和帽区均有分布;在兔感染多杀性巴氏杆菌后,圆小囊及其他肠道组织中的抗菌肽免疫组织化学阳性细胞数量明显增多,阳性反应增强。免疫电镜细胞化学观察结果显示,除肠道黏膜上皮细胞、异嗜性白细胞、巨噬细胞中存在抗菌肽免疫组织化学阳性反应信号外,在淋巴细胞内也发现阳性反应信号,尤其是在圆小囊淋巴组织中的DNES细胞内发现抗菌肽免疫组织化学阳性反应信号。表明圆小囊的DNES细胞和淋巴细胞均可产生抗菌肽。     

动物免疫功能药剂的发展与应用

动物机体的免疫系统包括参与免疫反应的各种免疫细胞、组织与器官，包括巨噬细胞、淋巴细胞、浆细胞以及胸腺和淋巴组织（淋巴结、脾、扁桃体）。在执行免疫过程中，巨噬细胞分化为B细胞、T细胞和浆细胞。在抗原的刺激下，B细胞和T细胞分别增殖、分化为浆细胞和致敏小淋巴细胞；而后由将浆细胞合成多种免疫球蛋白IgG、IgM、IgA、IgD、IgE等抗体，并与抗原发生反应，产生体液免疫；由致敏小淋巴细胞与抗原发生反应，产生细胞免疫。此外，淋巴细胞、巨噬细胞还可产生干扰素、白细胞介素、巨噬细胞因子等参与免疫功能的调节。颗粒白细胞…     

B细胞亚群与牛白血病发生的关系

对8头流行性白血病病牛,用8种单克隆杭体（McAb）,经过免疫组织化学ABC法和免疫荧光流式细胞检测法,观察了其免疫病理组织变化和外周血及肿瘤组织的B细胞亚群变化。结果7例病牛的BoCD5、BoCD11b和sIgM为阳性反应,表明肿瘤细胞来源于B1a细胞;1例病牛的BoCD11b和sIgM呈阳性反应,而BoCD5则呈阴性反应,说明该肿瘤细胞来源于B1b细胞。另外,在免疫组织化学染色肿瘤组织切片上在浸润的淋巴细胞中不仅见有较多的CD3和CD5阳性细胞,而且也见有较多的CD3和CD5阳性肿瘤细胞。表明流行性牛白血病的肿瘤细胞主要来源于Bla细胞,其他类型的淋巴细胞也有可能突变为白血病的肿瘤细胞。     

鸡脾脏中B淋巴细胞的发育及其定位分布

应用IgM、IgG和IgA单克隆抗体的免疫组织化学方法,研究IgM+、IgG+和IgA+B淋巴细胞在鸡脾脏中的出现、迁移、数量变化规律等一系列的发育过程以及组织定位分布特点。结果显示,IgM+和IgA+细胞在胚胎15日龄时开始出现,IgG+细胞在胚胎18日龄时出现,21日龄雏鸡脾脏的红髓和生发中心中出现以IgG型为主的浆细胞。各日龄IgM+、IgG+和IgA+细胞主要分布在脾脏的特征性组织结构—椭球周围淋巴鞘和生发中心中,这些结构也随着B淋巴细胞的增多而不断发育成熟。B淋巴细胞的数量随着日龄增长持续增加,直至21日龄时趋于稳定,各日龄B淋巴细胞数量始终以IgG+细胞最多,IgM+细胞次之,IgA+细胞最少。结果表明,鸡出壳初期,脾脏的体液免疫功能逐渐增强,并在21日龄时达到成熟水平。     

全身型及神经型犬瘟热的发病机理和免疫病理特性

犬瘟热是由麻疹病毒引起的犬易感的一种全球性传染性疾病,与麻疹和牛瘟病毒关系密切。该病毒的自然宿主主要是食肉动物。犬瘟热病毒（CDV）是有囊膜的负链RNA病毒,可以感染不同类型的细胞,包括上皮细胞、骨髓细胞、神经内分泌细胞和各种器官与组织中的造血干细胞。感染犬瘟热病毒的犬出现特征性的系统型和/或神经型的临床表现,病毒持续存在于特定的器官,包括中枢神经系统（CNS）和淋巴组织。主要临床表现包括：呼吸道和胃肠道症状、免疫抑制和脱髓鞘脑膜脑炎。免疫功能受损与淋巴器官耗竭有关,包括一种与败血症相关的淋巴细胞的减少,尤其是早期感染阶段淋巴组织细胞凋亡引起的CD4^＋T细胞的减少。病毒在外周血中被清除后,尽管淋巴器官种群恢复,但可能由于抗原递呈减少及淋巴细胞成熟过程的改变导致持续的免疫抑制。早期阶段的脱髓鞘脑膜脑炎是直接由病毒介导的病变及CD8^＋细胞毒性T细胞渗透所形成的后遗症,伴随相关前炎症细胞因子（如IL-6、IL-8、TNF-α、IL-12）的上调和免疫调节细胞因子（如IL-10和TGF-β）的缺乏。慢性阶段髓磷脂的减少是由CD4^＋介导的迟发型超敏反应和细胞毒性CD8^＋T细胞引起的。另外,在更进一步的病变中,干扰素-γ和IL-1可能上调。此外,基质金属蛋白酶及其抑制剂平衡的改变,似乎在脱髓鞘脑膜脑炎的发生过程中发挥关键作用。总之,脱髓鞘脑膜脑炎代表了由最初的直接病毒介导的过程和免疫介导的蚀斑进展组成的双相疾病过程。免疫抑制是由于感染早期病毒介导的淋巴细胞裂解,以及一些还不清楚的影响抗原递呈和淋巴细胞成熟的机制所造成的。     

鸡食管扁桃体的组织学和免疫组织化学研究

本研究通过组织学和免疫组织化学方法,观察鸡新型肠相关性淋巴组织-食管扁桃体的组织结构特征。并研究其中T淋巴细胞及其亚群和抗体生成细胞的定位分布。研究发现,食管扁桃体的粘膜形成数目和结构与食管一致的皱襞,粘膜固有层中分布大量的淋巴组织,并存在于前胃腺;在隐窝固有层中,抗体生成细胞以IgM^＋和IgA^＋细胞为主,并主要分布在生发中心中,而CD3^＋、CD4^＋和CD8^＋T淋巴细胞也有大量分布,主要存在于生发中心周围的滤泡间区域;在皱襞固有层中,各种淋巴细胞都分布在上皮下固有层中,数量明显少于隐窝固有层中的相应阳性细胞,抗体生成细胞以IgA^＋细胞为主,T淋巴细胞则以CD3和CD4为主。研究表明：食管扁桃体位置特殊,将接触到大量的外界未消化抗原,并且它具有参与粘膜免疫的组织基础和细胞基础,此研究结果对食物过敏、免疫耐受和肠道感染的研究具有重要意义。     

不同日龄鸡喉黏膜淋巴组织中的T和B淋巴细胞分布检测

为了解鸡喉黏膜不同时期的免疫状态,采集不同日龄海兰白鸡的喉组织,利用免疫组织化学方法研究CD3+ T淋巴细胞和Bu-1+ B淋巴细胞的出现、定位分布及数量变化过程。结果显示：4日龄时,CD3+ T淋巴细胞和Bu-1+ B淋巴细胞都首次出现在喉黏膜中,而且都主要分布在喉腔底壁的正中黏膜嵴中;7日龄时喉黏膜中CD3+ T淋巴细胞和Bu-1+ B淋巴细胞急剧增多,并形成淋巴聚集物,CD3+细胞占据淋巴聚集物的中下部区域,而Bu-1+细胞主要位于淋巴聚集物外周;14日龄时Bu-1+细胞虽仍主要分布于CD3+细胞的外周,但分界不如7日龄时明显,有部分Bu-1+细胞穿插分布于CD3+细胞之间;21日龄和35日龄时,喉黏膜固有层中淋巴细胞更为集中;56日龄时,黏膜固有层底端出现主要由Bu-1+ B淋巴细胞构成的生发中心,而CD3+ T淋巴细胞则分布在生发中心周围的滤泡间区域。在数量变化上,随着日龄增长,CD3+ T淋巴细胞和Bu-1+ B淋巴细胞数量均逐渐增加,且14日龄之前CD3+细胞数量多于Bu-1+细胞,而此后各日龄Bu-1+细胞的数量均显著多于CD3+细胞（P＜0.05）。结果表明,鸡喉黏膜中T、B淋巴细胞的分布和数量均呈现日龄相关性变化,并且其变化可以反映出14日龄之前喉黏膜以细胞免疫为主,而之后则倾向于体液免疫。本试验为进一步研究家禽喉黏膜的免疫机制奠定了基础。     

健康中国恒河猴各淋巴组织中T淋巴细胞表型及分布

试验旨在明确T淋巴细胞在中国恒河猴各组织中的表型与分布,为疾病模型研究提供基础数据。取外周血、腹股沟淋巴结、肠系膜淋巴结及肠道组织,从中分离出淋巴细胞。使用流式细胞术检测分析各种表型的淋巴细胞在组织间的分布。结果表明,淋巴结中CD4⁺ /CD8⁺ T细胞比值高于外周血,肠道固有层中最低,三者差异显著。记忆性T细胞在外周血和肠道固有层T细胞中比重较大,而淋巴结中主要为幼稚T细胞。CD4⁺ T细胞中中心记忆T细胞Tcm为主要亚群,而CD8⁺ T细胞主要为效应记忆细胞Tem。外周血与肠道固有层中增殖T细胞比例相当,而淋巴结中T细胞增殖水平相对较低。各组织中CXCR4受体表达量普遍高于CCR5受体,其中肠道固有层CCR5受体表达水平最高。值得注意的是,有一小群表型CD3⁺ CD4⁺ CD8low的细胞仅在肠道固有层中存在,经分析其功能活性应高于肠道CD4单阳性T细胞。因此,测定了健康中国恒河猴各表型T淋巴细胞在多种淋巴组织中的基础数值,为相关模型研究奠定基础。     

犬瘟热病毒特异性T淋巴细胞过继免疫输入治疗犬瘟热试验

为了探讨犬瘟热病毒(CDV)特异性T淋巴细胞免疫输入疗法的抗病毒效果,试验采用体外增殖培养的特异性T淋巴细胞进行过继免疫输入疗法治疗犬瘟热30例,作为诊疗组;同时设未采用过继免疫输入疗法和干扰素、抗病毒药物等治疗的病犬20例,采用常规治疗及支持疗法,作为对照组。观察治疗后第2,4周免疫细胞机能、CDV-RNA阴转率等的变化,并追踪回访3周。结果表明:经该疗法治疗后病犬的临床症状明显改善,治疗组病犬T、B淋巴细胞的增殖均显著高于对照组(P0.05);治疗4周后CDV-RNA阴转率达60%,且进一步研究发现治疗前病犬体内CDV-RNA的含量≤1×10~5copies/mL时病毒阴转率显著高于CDV-RNA的含量为1×10~5copies/mL时的病毒阴转率。说明CDV特异性T淋巴细胞免疫输注治疗犬瘟热是安全有效的。     

Phenotypical characterization of T and B cell areas in lymphoid tissues of dogs with spontaneous distemper

CD3, CD4, CD5, and CD8 antigen expression of T cells and IgG expression of B cells and canine distemper virus (CDV) antigen distribution were immunohistochemically examined in lymphoid tissues (lymph node, spleen, thymus, and tonsil) of control dogs and animals with spontaneous canine distemper. In addition, CNS tissue of all animals was studied for neuropathological changes and CDV antigen distribution. Based on the degree of depletion distemper dogs were classified into two groups. Group I represented animals with moderate to marked lymphoid depletion, while group II dogs displayed mild or no depletion. CDV antigen was mainly found in lymphocytes and macrophages of group I dogs, whereas CDV expression was most prominent in dendritic cells of group II animals. In group I dogs, a marked loss of CD3, CD4, CD5, CD8, and IgG expression was noticed, hereby loss of CD4+ cells was more prominent than depletion of CD8+ cells. In the lymphoid tissues of group II animals, a significant increase in the number of T and B cells was observed compared to group I dogs. The number of CD3+, CD4+, and CD8+ cells in group II dogs was similar to the findings in controls, however, CD5 and IgG expression was mildly reduced in T and B cell areas, respectively. Additionally, in groups I and II dogs, CD3+ and CD5- T cells were detected in T cell areas. Whether this cell population represents a cell type with autoimmune reactive potential remains to be determined. Surprisingly in group II animals, viral antigen was found predominantly in dendritic cells indicating a change in the cell tropism of CDV during chronic infection and a possible mechanism of viral persistence. The two patterns of lymphoid depletions correlated to two different types of canine distemper encephalitis (CDE). Group I dogs displayed acute non-inflammatory CDE, whereas group II dogs suffered from chronic inflammatory demyelinating CDE, indicating a pathogenic relationship between lymphocytic depletion and inflammatory brain lesions in distemper.     

Lymphoid apoptosis in acute canine distemper

The relationship between the canine distemper virus (CDV) infection and apoptosis in the canine lymphoid tissues was investigated using immunostaining for single stranded DNA (ssDNA), TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method, and electron microscopy. Twenty-six lymphoid tissues from 8 spontaneously CDV-infected dogs and 1 non-infected dog were used, and lesions were classified into 4 groups according to frequency of the CDV-antigen. Histologically, the degree of lymphoid depletion tended to depend on amount of CDV antigen. The numbers of ssDNA- and TUNEL-labeling cells were significantly high in the lymphoid tissues with abundant viral antigen. However, ssDNA- and TUNEL-positive lymphocytes were also frequently found even in the lymphoid tissues where there was only a small amount of CDV-antigen in sinus histiocytes. The incidence and distribution of apoptotic cells in the CDV-antigens-negative lymphoid tissues from infected dogs were equal to those from a non-infected dog. Double labeling immunostaining using a ssDNA and a CDV nucleocapsid protein (CDV-NP) antibody revealed that there were ssDNA positive but CDV-NP negative cells besides those stained doubly positive. Ultrastructurally, lymphocytes in the CDV-infected lymphoid tissues frequently had characteristic morphological features of apoptosis such as apoptotic bodies. All these results suggest that CDV leads to lymphocytic apoptosis directly or indirectly, resulting in severe lymphoid depletion and immunosuppression in acute or subacute phase of CDV infection.     

Canine distemper virus-induced depletion of uninfected lymphocytes is associated with apoptosis

Canine distemper virus (CDV), a negative stranded RNA morbillivirus, causes a multisystemic disease in dogs, which is associated with a severe immune suppression. The aim of the study was to examine the influence of early CDV infection on leukocyte depletion, lymphopenia and virus-induced cell death in dogs infected with a virulent CDV strain. From 10 infected dogs, peripheral blood leukocytes were harvested periodically, phenotyped and analyzed for CDV antigen content and apoptosis using Annexin V-FITC and propidium iodide labeling. CDV infection induced a severe CD3+ T cell and CD21+ B cell depletion in all animals at 3 days post-infection (d.p.i.). For dogs with severe distemper, developing virus persistence in the lymphoid tissue and central nervous system, this lymphopenia lasted until the end of the experiment. Increased levels of lymphocyte apoptosis were found at 3 d.p.i., and monocyte apoptosis at 6 d.p.i. This was more prominent in the group of animals with severe distemper. At 3 d.p.i. no leukocyte infection was detectable indicating that the early lymphocyte depletion and apoptosis was not a direct consequence of virus infection. Taken together, our results demonstrate that CDV-induced lymphopenia is an early event and that the degree of lymphocyte depletion correlates with the severity of disease and virus persistence in the lymphoid tissue and central nervous system.     

Identification of CD4+ and CD8+ T cell subsets and B cells in the brain of dogs with spontaneous acute, subacute-, and chronic-demyelinating distemper encephalitis

CD4 and CD8 antigen expression of T cells as well as B cell and canine distemper virus (CDV) antigen distribution were immunohistologically examined in the cerebellum of dogs with spontaneous distemper encephalitis. Cellular and viral antigen expression were evaluated at intralesional and extralesional sites and in the perivascular space. Histologically, acute and subacute non-inflammatory encephalitis and subacute inflammatory and chronic plaques were distinguished. Demyelination was a feature of all subacute and chronic lesions, although the majority of plaques exhibited no or only a low level of active demyelination as demonstrated by single macrophages with luxol fast blue positive material in their cytoplasm. CDV antigen expression, observed in all distemper brains, was reduced in chronic plaques. CD4+, CD8+, and B cells were absent in controls and in some brains with acute encephalitis. A mild infiltration of CD8+ cells was noticed in the neuropil of the remaining brains with acute and all brains with subacute non-inflammatory encephalitis. Single CD4+ cells were found in two brains with acute and in all brains with subacute non-inflammatory encephalitis. Numerous CD8+ and CD4+ cells and few B cells, with a preponderance of CD8+ cells, were detected in subacute inflammatory and chronic lesions. In contrast, in perivascular infiltrates (PVI) of subacute and chronic lesions a dominance of CD4+ cells was detected. The dominating CD8+ cells in acute and subacute non-inflammatory encephalitis might be involved in viral clearance or contribute as antibody-independent cytotoxic T cells to early lesion development. In subacute inflammatory and chronic lesions CD8+ cells may function as cytotoxic effector cells and CD4+ cells by initiating a delayed-type hypersensitivity reaction. The simultaneous occurrence of perivascular B and CD4+ cells indicated that an antibody-mediated cytotoxicity could synergistically enhance demyelination. Summarized, temporal and spatial distribution of CD4+, CD8+ and B cells and virus antigen in early and late lesions support the hypothesis of a heterogeneous in part immune-mediated plaque pathogenesis in distemper demyelination.     

犬实验感染CDV的病理学研究

对实验感染犬瘟热病毒的病犬进行了系统的病理学观察，并用酶标ＳＰＡ法对病犬脏器组织中ＣＤＶ抗原进行了定位检查。结果表明，淋巴系统各器官组织是ＣＤＶ急性感染早期首先侵犯的靶器官。脏器组织的病理改变与ＣＤＶ抗原检出呈正相关。脏器组织中包涵体的检出与形态结构具有一定的特征性和示病意义，但采用免疫组化方法检查ＣＤＶ抗原，更具优越性。作者认为，ＣＤＶ９３０３９株和ＣＤＶ９３０４１株是致病力很强的泛嗜性ＣＤＶ。     

Immunohistochemical demonstration of the putative canine distemper virus receptor CD150 in dogs with and without distemper

Signaling lymphocyte activation molecule (SLAM) or CD150 can function as a receptor for the canine distemper virus (CDV) in vitro. The expression of SLAM was studied using immunohistochemistry in order to evaluate the presence and distribution of the receptor in dogs in vivo. Additionally, receptor expression was assessed after experimental infection of dogs with CDV. In 7 control dogs without distemper virus, the receptor was found in various tissues, mostly on cells morphologically identified as lymphocytes and macrophages. In 7 dogs with early distemper lesions characterized by presence of the virus, higher numbers of SLAM-expressing cells were found in multiple tissues recognized as targets of CDV compared with those in control dogs. These findings suggest that SLAM, a putative distemper receptor, is expressed in dogs in vivo. Additionally, virus infection is associated with up-regulation of SLAM, potentially causing an amplification of virus in the host.     

Detection of intracellular canine distemper virus antigen in mink inoculated with an attenuated or a virulent strain of canine distemper virus

Using an indirect immunofluorescence technique, the distribution of viral antigen in various tissues and blood mononuclear leukocytes was studied in wild mink, either vaccinated with an attenuated vaccine strain of canine distemper virus (CDV) or experimentally inoculated with the virulent Snyder-Hill strain of CDV. Viral antigen was detected in cells of the lymphoid system 6 to 12 days after vaccination. From 2 to 3 days after inoculation with the virulent strain, CDV antigen was demonstrated in cells of the lymphoid system and, during the incubation period, the antigen had spread to the epithelia and brain at days 6 and 12, respectively. In clinical cases of acute fatal canine distemper, the viral antigen was detected in a wide variety of tissues, including the cells of the lymphoid system, epithelial cells of skin, mucous membranes, lung, kidney, and cells of the CNS. The diagnostic importance of CDV antigen detection is discussed on the basis of these findings.     

Canine distemper virus infection of canine footpad epidermis

Infection of the footpad epidermis can occur in natural canine distemper virus (CDV) infection of dogs. Footpads from 19 dogs experimentally inoculated with virulent distemper strain A75/17 and from two nonexposed dogs were examined histopathologically and assessed for the presence of viral antigen and nucleoprotein mRNA, as well as number of inflammatory and apoptotic cells. Dogs were divided into four groups based on inoculation status and postmortem examination: inoculated dogs with severe distemper (group 1, n = 7); inoculated dogs with mild distemper (group 2, n = 4); inoculated dogs without distemper (group 3, n = 8); and noninoculated dogs (group 4, n = 2). Footpads from dogs of all groups had a comparably thick epidermis. Eosinophilic viral inclusions and syncytial cells were present in footpad epidermis of one dog of group 1. Footpads of group 1 dogs contained viral antigen and mRNA in the epidermis with strongest staining in a subcorneal location. Additionally, in these dogs footpad dermal structures including eccrine glands and vascular walls were positive for virus particles. No CDV antigen or mRNA was present in the footpad epidermis and dermis of any other dog. Group 1 dogs had more CD3-positive cells and apoptotic cells within the basal layer of the epidermis when compared to the other groups. These findings demonstrate that in experimental infection CDV antigen and mRNA were colocalized in all layers of the infected canine footpad epidermis. The scarcity of overt pathological reactions with absence of keratinocyte degeneration indicates a noncytocidal persisting infection of footpad keratinocytes by CDV.     

Pathogenesis and immunopathology of systemic and nervous canine distemper

Canine distemper is a worldwide occurring infectious disease of dogs, caused by a morbillivirus, closely related to measles and rinderpest virus. The natural host range comprises predominantly carnivores. Canine distemper virus (CDV), an enveloped, negative-sense RNA virus, infects different cell types, including epithelial, mesenchymal, neuroendocrine and hematopoietic cells of various organs and tissues. CDV infection of dogs is characterized by a systemic and/or nervous clinical course and viral persistence in selected organs including the central nervous system (CNS) and lymphoid tissue. Main manifestations include respiratory and gastrointestinal signs, immunosuppression and demyelinating leukoencephalomyelitis (DL). Impaired immune function, associated with depletion of lymphoid organs, consists of a viremia-associated loss of lymphocytes, especially of CD4+ T cells, due to lymphoid cell apoptosis in the early phase. After clearance of the virus from the peripheral blood an assumed diminished antigen presentation and altered lymphocyte maturation cause an ongoing immunosuppression despite repopulation of lymphoid organs. The early phase of DL is a sequel of a direct virus-mediated damage and infiltrating CD8+ cytotoxic T cells associated with an up-regulation of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-12 and a lacking response of immunomodulatory cytokines such as IL-10 and transforming growth factor (TGF)-β. A CD4+-mediated delayed type hypersensitivity and cytotoxic CD8+ T cells contribute to myelin loss in the chronic phase. Additionally, up-regulation of interferon-γ and IL-1 may occur in advanced lesions. Moreover, an altered balance between matrix metalloproteinases and their inhibitors seems to play a pivotal role for the pathogenesis of DL. Summarized, DL represents a biphasic disease process consisting of an initial direct virus-mediated process and immune-mediated plaque progression. Immunosuppression is due to early virus-mediated lymphocytolysis followed by still poorly understood mechanisms affecting antigen presentation and lymphocyte maturation.