Abnormalities Of Cell-mediated Immunity Research Articles

Exploration of potential immune mechanisms in cervical dystonia

BackgroundAlthough there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. ObjectiveThe goal was to explore the potential role of multiple different immunological mechanisms in CD. MethodsFirst, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. ResultsScreens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. ConclusionsAltogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Disseminated Strongyloides stercoralis Infection Associated with Endogenous Hypercortisolism - A Case Report.

Patients with Strongyloides stercoralis infections are usually asymptomatic but massive hyperinfection may occur in patients with diseases associated with abnormal cell-mediated immunity or receiving immunosuppressive therapy.The authors present the clinical case of a 49-year-old man with a history of diarrhoea and cramping abdominal pain, generalized oedema, petechial rash, melanoderma, cough and dyspnoea. He presented hypokalaemia and arterial hypertension and was admitted with the diagnostic hypothesis of Cushing’s syndrome or adrenocorticotropic hormone ectopic production. The patient developed respiratory failure associated with bilateral lung opacities and was admitted to the Intensive Care Unit. The abdominal computed tomography scan revealed liver and duodenal masses. The duodenal biopsy showed the presence of Strongyloides stercoralis and the liver biopsy showed the presence of small cell neuroendocrine carcinoma. The patient died 50 days after hospital admission. The high level of endogenous cortisol observed in this patient may have facilitated the progression to severe fatal infection.LEARNING POINTSStrongyloides stercoralis hyperinfection and disseminated disease can present as a multiorgan infection in immunocompromised patients with an appropriate clinical and epidemiological context.Strongyloides stercoralis hyperinfection and disseminated disease can present with no eosinophilia and negative parasitological stool tests in more than 70% of cases.

Social geography of Rhinoscleroma and qualitatively and quantitatively abnormal cell-mediated immunity

Rhinoscleroma is a progressive chronic granulomatous disease of the upper respiratory tract that may extend to the tracheobronchial tract. It is common belief that the pathology is determined by Klebsiella Rhinoscleromatis. In the authors' opinion, the infection with Klebsiella Rhinoscleromatis may not represent the only etiopathogenic factor of the disease.Rhinoscleroma is reported in many countries, but has a peculiar social and geographic distribution, in that it assumes an endemic character only in some regions of the Middle East, West Russia, North Africa, Indonesia, Central and South America. In Europe, most of the cases are reported in Poland, Hungary and Romania. In Italy, Rhinoscleroma is almost exclusively located in the southern and island regions. Rhinoscleroma is predominantly reported in rural areas, in the presence of poor socio-economic conditions, which according to many authors would be a co-factor triggering the disease.In this article, the authors review some inconsistencies in etiology, histology and epidemiology of Rhinoscleroma. Based on the overall picture, they propose that intrinsic factors, possibly of genetic origin, may give rise to the disease, and suggest possible lines of research to distinguish between extrinsic and intrinsic factors as determinants for Rhinoscleroma.

Association of insulin-like growth factor-1 receptor polymorphism and insulin-like growth factor-1 plasma level with chronic immune thrombocytopenia in Chinese population

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated low platelet count and suppression of megakaryocyte development. Abnormalities of cell-mediated immunity have drawn more and more attention in the pathologic process of ITP. Insulin-like growth factor-1(IGF-1) plays an important role in the regulation of immune response and inflammation, which takes place in innate and acquired immunity. A series of studies had demonstrated IGF-1/IGF-1R pathway was involved in several autoimmune disorders. Thus, we speculated that the IGF-1R rs2229765 polymorphism might be associated with genetic susceptibility to ITP in a Chinese Han population. We compared distributions of rs2229765 polymorphism in 197 patients with chronic ITP and 262 normal controls by polymerase chain reaction and direct sequencing. We also investigated IGF-1 plasma level in normal controls and ITP patients associated with gender, age, genotype, and severity by enzyme-linked immunosorbent assay (ELISA). Both A allele and AA genotype distributions revealed statistical difference in male between childhood ITP and gender-matched controls (p<0.05). However, neither the allele nor genotype frequencies reached significant differences among patients with chronic ITP patients, adult ITP group, female in childhood ITP group and normal controls (p>0.05). The IGF-1 plasma level in ITP patients was significantly decreased compared with the controls (p<0.05). In addition, we observed that the IGF-1 concentration of severe group was evidently lower than non-severe group (p<0.05). However, when ITP patients were respectively stratified by gender, age, and genotype, no significant differences were observed. These results suggest IGF-1R rs2229765 polymorphism may have no relationship with chronic ITP in a Chinese population, but it confirmed at least that IGF-1R rs2229765 polymorphism can be used as an independent predictor for the male in childhood ITP. Abnormal IGF-1 plasma level has contributed to the pathogenesis of chronic ITP patients. IGF-1 plasma level may be used to access the severity of disease, but it has no relationship with IGF-1R rs2229765 polymorphism. These results suggest IGF-1R rs2229765 polymorphism may have no relationship with chronic ITP in a Chinese population, but it confirmed at least that IGF-1R rs2229765 polymorphism can be used as an independent predictor for the male in childhood ITP. Abnormal IGF-1 plasma level has contributed to the pathogenesis of chronic ITP patients. IGF-1 plasma level may be used to access the severity of disease, but it has no relationship with IGF-1R rs2229765 polymorphism.

Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease with significant morbidity and mortality and no effective, targeted therapies. It is most often observed in association with abnormalities of cell-mediated immunity, in particular human immunodeficiency virus (HIV) infection, but also occurs in association with lymphoproliferative diseases, certain immunosuppressive and immunomodulatory regimens, and other conditions. The etiologic agent of PML is a small, ubiquitous polyomavirus, the JC virus (JCV, also known as JCPyV), for which at least 50% of the adult general population is seropositive. PML results when JCV replicates within cerebral oligodendrocytes and astrocytes, leading to oligodendrocyte death and demyelination. Unfortunately, no treatments have been convincingly demonstrated to be effective, though some have been employed in desperation; treatment otherwise includes attempts to restore any immune system defect, such as the withdrawal of the causative agent if possible, and general supportive care.

Immune Thrombocytopenia: Pathophysiologic and Clinical Update

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both reduced platelet survival and suppression of megakaryocyte and platelet development. It can either be primary or secondary to other autoimmune disorders, infections, vaccines, lymphoproliferative disorders, and drugs. Antibodies reacting against platelet glycoproteins are typical of ITP; these antibodies can mediate destruction of platelets by the monocyte-macrophage system as well as suppress megakaryocyte proliferation and maturation. Abnormalities of cell-mediated immunity are known to contribute to the pathologic process. Like many other autoimmune diseases, ITP has a T helper cell type 1 bias and a reduced activity of T-regulatory cells. Cytotoxic T cells may directly lyse platelets and possibly suppress megakaryopoiesis. Recent studies suggest that mesenchymal stem cells are dysfunctional in ITP and may contribute to an aberrant amplification of the autoimmune response. Significant advances in the treatment of chronic ITP have been witnessed in the past decade, first with the introduction of rituximab and more recently with the thrombopoietin-receptor agonists. While splenectomy is still considered the gold standard in this setting, effective medical therapy is now available for patients in whom surgery is not an option.

Listeria monocytogenes meningitis in a young woman with systemic lupus erythematosus

Listeria meningitis, a rare but life-threatening infection in patients with systemic lupus erythematosus, often represents a diagnostic and therapeutic challenge because of its rarity and non-representative manifestations. L. monocytogenes is an intracellular pathogen capable of spreading directly from cell to cell without exposure to the extracellular humoral immune system. With the evolving trend of intense immunosuppressive therapy, patients with SLE usually have abnormal cell-mediated immunity and are susceptible to L. monocytogenes infections. The gastrointestinal tract is usually the portal of entry, and a transient gastroenteritis may precede the full-blown meningitides. Ampicillin and penicillin G are the drugs of choice. For patients who are allergic to penicillin, trimethoprim-sulfamethoxazole is an eligible alternative. Delay in diagnosis and inappropriate antibiotics are detrimental to the outcome. Herein, we report a young woman with systemic lupus erythematosus who developed listeria meningitis. Clinicians are advised to be aware of the clinical presentations of this disease.

Cryptococcosis in systemic lupus erythematosus: a series of six cases

The aims of this study were to describe the clinical features of patients with systemic lupus erythematosus (SLE) who developed cryptococcal infection and ascertain their outcomes when treated with glucocorticoids and immunosuppressive agents in conjunction with long-term maintenance antifungal therapy. Six cases of cryptococcal infection in SLE were reviewed retrospectively. The mean age at the time of infection was 26.3 (11.7) years. Three patients had active SLE and all were receiving glucocorticoids [median prednisone dose of 40 (21.2-60.0) mg/day] at the time of infection diagnosis. Concomitant cytotoxic agents were used in five patients. Meningitis was the most common clinical manifestation (n = 5) and cryptococcemia was found in three cases. The patient, who developed pulmonary cryptococcosis, died from respiratory distress syndrome. All patients received induction anti-fungal therapy with amphotericin B and the five surviving patients switched to oral fluconazole indefinitely as maintenance therapy and none of them has had relapses of cryptococcal infection to last medical evaluation. As SLE patients have intrinsic abnormalities of cell-mediated immunity and receive immunosuppressive therapy, indefinite maintenance therapy with fluconazole is recommended in SLE patients with cryptococcosis.

Autoimmune Mechanisms Underlying Dilated Cardiomyopathy

Autoimmune abnormalities, as well as viral infection and genetic abnormalities, appear to be major predisposing factors for dilated cardiomyopathy (DCM). Abnormalities of cell-mediated immunity are mainly involved in the onset of cardiomyopathy secondary to myocarditis. However, various antimyocardial antibodies are detected in the serum of patients with DCM. The appearance of these antibodies was considered to be an epiphenomenon associated with myocyte injury resulting from myocarditis, but recent findings have suggested that at least some of them are directly related to the pathophysiology of DCM. In particular, an autoantibody targeting the beta1-adrenergic receptor that exhibits an agonist-like effect is related to the persistent myocardial damage resulting in DCM and provides substrates for fatal ventricular arrhythmias. In addition, an antibody for the muscarinic M2 receptor is related to atrial fibrillation, an antibody targeting Na-K-ATPase is closely related to sudden cardiac death as a result of fatal ventricular arrhythmias, and an autoantibody for troponin I increases the L-type calcium current and is related to the myocardial damage. Based on these findings, immunoadsorption therapy was developed to remove such autoantibodies in patients with refractory heart failure as a result of DCM.

Premature senescence of T lymphocytes from patients with β-thalassemia major

Several researches have demonstrated a suppressed cell mediated immunity in patients with β-thalassemia major. To know whether the premature aging of T cells is involved in abnormalities of cell mediated immunity, the biomarkers of immunosenescence including telomerase activity, apoptosis, and the expression of CD28 and CD95 were evaluated in T lymphocytes from β-thalassemia major patients. The ex vivo spontaneous apoptosis in CD4 + or CD8 + T cells from patients and healthy subjects was assessed by an in situ TdT mediated dUTP-biotin nick end labelling (TUNEL) assay after 24 h incubation in medium. Flow cytometric data revealed that lymphocytes from β-thalassemia patients were resistant to spontaneous apoptosis compared to the normal lymphocytes. Moreover, the percentages of TUNEL +CD4 + or TUNEL +CD8 + T cells from patients were significantly lower than those control cells. Quantitative determination of telomerase activity in resting and activated T cells was performed using the Telomeric Repeat Amplification Protocol (TRAP). The results showed a decreased telomerase activity of activated T cells in patients with thalassemia major compared to that in healthy controls. However, the percentages of CD8 +CD28 − and CD3 +CD95 + T lymphocytes were significantly higher in thalassemia patients, indicating the phenotypes associated with senescent T lymphocytes. These data provide evidences for the occurrence of accelerated aging of T cells in β-thalassemia major; possibly result in abnormal T cell function leading to suppressed cell mediated immunity.

Cell-mediated immunity in patients with chronic fatigue syndrome, healthy control subjects and patients with major depression

The chronic fatigue syndrome (CFS) is characterized by severe persistent fatigue and neuropsychiatric symptoms. It has been proposed that the abnormalities in cell-mediated immunity which have been documented in patients with CFS may be attributable to a clinical depression, prevalent in patients with this disorder. Cell-mediated immune status was evaluated in patients with carefully defined CFS and compared with that of matched subjects with major depression (non-melancholic, non-psychotic) as well as healthy control subjects. Patients with CFS demonstrated impaired lymphocyte responses to phytohaemagglutinin (PHA) stimulation, and reduced or absent delayed-type hypersensitivity (DTH) skin responses when compared either with subjects with major depression or with healthy control subjects (P less than 0.05 for each analysis). Although depression is common in patients with CFS, the disturbances of cell-mediated immunity in this disorder differ in prevalence and magnitude from those associated with major depression. These observations strengthen the likelihood of a direct relationship between abnormal cell-mediated immunity and the etiology of CFS.

Aberrancies in Antigen-presenting Cells and T Cells in Autoimmune Thyroid Disease. A Role in Faulty Tolerance Induction

Various thyrocyte, monocyte, macrophage, DC and T cell abnormalities exist in the animal models of spontaneously developing autoimmune thyroiditis and in patients with autoimmune thyroid disease. An aberrant interaction between such abnormal thyrocytes, abnormal professional antigen-presenting cells (APC) and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. In the atypical interaction more than one gene and various environmental factors are involved. The genetic and environmental factors must act together to induce full-blown disease. Although there is a general blueprint for the development of destructive autoimmune thyroiditis, thyrocyte and immune cell abnormalities differ between the various animal models and the various forms of autoimmune thyroid disease (either associated with type 1 diabetes, associated with bipolar disorder or not associated). This tells us that there are different etio-pathogenic forms of destructive autoimmune thyroiditis. Whether such heterogeneity is also the case for the etio-pathogenesis of Graves' disease remains unknown. Animal models of spontaneously developing Graves' disease would be helpful in unraveling this question. If indeed there are various etio-pathogenic routes in different patients that lead to destructive autoimmune thyroiditis, then tailor-made therapeutic approaches need to be carried out in attempts to correct the underlying immune abnormalities in individual patients or to prevent the development of destructive autoimmune thyroiditis in individuals at risk. While in some forms of destructive autoimmune thyroiditis (f.i. those associated with bipolar disorder) immune suppression should be the first choice of intervention, other forms (f.i. those associated with type 1 diabetes) may benefit from immune stimulation in certain pre-stages of the disease (to restore f.i. the faulty APC function characteristic of this condition). Obviously a more precise determination of the spectrum of cell-mediated immune abnormalities is required in individual cases of destructive autoimmune thyroiditis, before therapies that aim at correcting the immune abnormalities can be tested successfully.

Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity

Therapeutic use of type I IFN (IFN-α/β) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4+ T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-γ production from T and NK cells. The ability of IFN-α/β to suppress IL-12 production while up-regulating IFN-γ production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.

Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity.

Therapeutic use of type I IFN (IFN-alpha/beta) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4(+) T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-gamma production from T and NK cells. The ability of IFN-alpha/beta to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.

Cell-Mediated Immunity and Postpartum Thyroid Dysfunction: A Possibility for the Prediction of Disease?1

Postpartum (pp) thyroid dysfunction (PPTD) is thought to be caused by an autoimmune (AI) destruction of thyroid follicles during the pp period. The chronic thyroid AI process [already present in pregnancy, as shown by the positivity for thyroid peroxidase antibodies (TPO-Ab)] becomes overt disease in the pp period, and one assumes that this exacerbation represents a rebound phenomenon after a general immunosuppression during pregnancy. The presence of TPO-Ab in pregnancy has been suggested as a predictor for later PPTD development. Apart from B cells, e.g. production of autoantibodies, various functions of the cell-mediated immune (CMI) system, including those of peripheral T cells, monocytes, and dendritic cells (DC), are also disturbed in AI states. The objectives of the present study were: determining alterations in various CMI parameters in pregnancies followed by PPTD vs. those not followed by PPTD; and determining the usefulness of these parameters in the prediction of PPTD. In a prospective study (region: Kempenland, southeast Netherlands), a random sample of 291 women were tested at 12 and 32 weeks gestation and 4 weeks pp for TPO-Ab. Women were followed until 9 months pp, for developing PPTD. PPTD was defined as both: an abnormal TSH, and fT4 pp women developing PPTD and/or being positive for TPO-Ab (n = 26); and thyroidological uneventful control women of the same cohort, matched for age and parity (n = 21), were tested for thyroid-stimulating antibodies, percentages of peripheral blood lymphocyte subsets using fluorescence-activated cell sorter analysis (CD3, CD4, CD8, CD16, CD56, major histocompatibility complex-class II), for monocyte polarization, and for cluster capability of monocyte-derived DC. Results were: 1) 31 women (10.7%) were positive for TPO-Ab (TPO-Ab+) in gestation (12 and/or 32 weeks); 2) 15 women (5.2%) developed PPTD, of whom 10 were TPO-Ab+ in gestation; 3) pregnancy-related CMI alterations consisted of low percentages of CD16+CD56+ natural killer (NK), cells and a low DC cluster capability at 12 weeks gestation (these functions were normalized at 32 weeks gestation); 4) the TPO-Ab+ PPTD+ women (4 hyper, 5 hypo, and 1 hyper/hypo) were characterized by a persistently low percentage of NK cells, a lowered monocyte polarization, and a raised percentage of major histocompatibility complex-class II+CD3+ T cells; 5) the TPO-Ab- PPTD+ women (all 5 hyper) had neither thyroid-stimulating antibodies nor CMI alterations, apart from those normally seen in pregnancy; 6) 21 women were positive for TPO-Ab in pregnancy but did not develop PPTD (they had the same lowered NK cell percentages and monocyte polarization as the TPO-Ab+ PPTD+ cases, but they had normal percentages of activated peripheral T cells and a lower titer of TPO-Ab); 7) determination of the number of NK cells and monocyte polarization hardly contributed to the prediction of PPTD (as compared with TPO-Ab status), because of strong interindividual variation and close association with the presence of TPO-Ab; and 8) combining TPO-Ab assays with testing for activated T cells was the most optimal parameter for the prediction of TPO-Ab+ cases of PPTD in our small test set. We conclude that TPO-Ab+ pregnant women who develop PPTD show several CMI abnormalities other than those seen in normal pregnant women, such as persistently lower percentage of NK cells, a lowered monocyte polarization, and a raised percentage of activated T cells. The latter seems rather specific for the actual PPTD development and is not found in TPO-Ab+ (but PPTD) uncomplicated pregnancies. TPO-Ab- (but PPTD+) women had no signs of CMI abnormalities (apart from those specific for the pregnancy state). Although studied cases are low in number, our data are suggestive for the existence of two forms of PPTD: a TPO-Ab+ (AI) form (two-thirds of patients, classical PPTD pattern); and a TPO-Ab- (non-AI) form (one-third of patients, only hyper). Such assumption implies that, at best, two

Unique presentation of Crohn's disease during treatment of Hodgkin's disease

Although Hodgkin's disease and Crohn's disease are associated with abnormalities in cell-mediated immunity, their co-existence in an individual patient is uncommon. To our knowledge, this is the first report of the clinical presentation of Crohn's disease during treatment for Hodgkin's disease. The basic immunologic mechanisms underlying these two pathologic states as well as chemotherapy-related effects are postulated as potential etiologic mechanisms for the codevelopment of these diseases. A brief review of the literature and basic immunologic defects associated with Crohn's disease and Hodgkin's disease are presented.

Iron requirements of human lymphocytes: relative contributions of intra- and extra-cellular iron.

A supply of iron is of vital importance if lymphocyte proliferation is to proceed successfully and two major sources of iron are available, intracellular stores and serum transferrin. We have investigated the relative importance to the human T lymphocyte of these two sources of iron by depleting them of intracellular iron with the chelator desferrioxamine and by culturing them in medium completely depleted of transferrin iron. The chelator decreased mitogen-stimulated proliferation of human peripheral blood T cells, in a dose-dependent manner, in the absence of extracellular transferrin-iron. By culturing the cells in iron-depleted medium, we found that normal lymphocytes proliferated, to a degree, in the absence of extracellular transferrin-iron. We also observed that transferrin receptor mRNA expression was sustained in mitogen-stimulated, iron-deprived lymphocytes, compared with untreated cells suggesting that up-regulation of transferrin receptor may occur in these cells through stabilization of the mRNA. We propose that intra- and extra-cellular iron may contribute to early and late activation processes and that a low level of intracellular iron in lymphocytes, chronically activated in the iron-deficient environment associated with chronic inflammatory diseases such as rheumatoid arthritis, may be a factor in the abnormal cell-mediated immunity associated with such diseases.

Multiple sclerosis: multiple etiologies, multiple genes?

Multiple sclerosis is a chronic inflammatory disease characterized by multifocal damage of the central nervous system myelin. Both humoral and cell-mediated immune abnormalities have been observed in patients with multiple sclerosis, but their relation to the demyelination process is not understood. The etiology of the disease is still unknown; however, evidence exists for an interplay between environmental and genetic factors. Several genes are involved in determining the disease susceptibility, at least one of them encoded within human leukocyte antigen gene complex. Other genomic regions coding for components of the immune system or myelin have also been suggested. Clinical, immunological and genetic data suggest that multiple sclerosis may turn out to be a heterogeneous disease. Therefore, molecular genetic dissection of this complex disease should provide important clues to its pathogenesis as well as unravel metabolic pathways for potential therapeutic or preventive strategies. This review will give an overview of recent progress and future challenges in identifying susceptibility genes for multiple sclerosis.

Immune Dysregulation in Atopic Eczema

In this review, present knowledge of atopic eczema immunopathogenesis is summarized, emphasizing recent new findings. Systemic abnormalities in cell-mediated immunity have not been demonstrated firmly in patients with atopic eczema. Within the skin itself, there is evidence for decreased cell-mediated immunity, which is partially correlated with the severity of skin disease. Atopic eczema, however, cannot be regarded as a direct result of decreased cutaneous cell-mediated immunity, since immunophenotyping studies have revealed activated T cells as well as dendritic cells within involved skin. In addition, disease marker studies in peripheral blood indicate vigorous T-cell activation in atopic dermatitis. The original observation of IgE molecules on the membranes of Langerhans cells may indicate trapping of IgE allergen complexes, their processing, and subsequent presentation to allergen-specific T cells within involved skin. Recent findings as to the abnormal regulation of IgE synthesis in atopy point to a preferential expansion of interleukin 4 and interleukin 5 producing allergen-specific T cells, leading to increased production of interleukin 4 and thus increased levels of allergen-specific IgE. We have prepared atopic skin as well as peripheral blood-derived T-cell clones and determined their specificity and cytokine production profile. Results indicate in situ production of interleukin 4 and interleukin 5 within involved skin in response to environmental antigens. These new findings as to the basis of IgE dysregulation in atopy, as well as to the identification of an abnormal cytokine secretion pattern by T cells presumed to be central in immunopathogenesis of atopy-related disorders, suggest a distorted and cytokine-mediated self-perpetuating response of the skin immune system to environmental allergen(s) in the pathogenesis of skin disease in atopy. These observations may have important implications for the development of new therapies for atopic eczema.

Influence of Human Immunodeficiency Virus Infection on Cell-Mediated Immunity in Chronic D Hepatitis

To determine whether the abnormalities of cell-mediated immunity described in chronic D hepatitis are associated with hepatitis D virus (HDV) infection or concomitant human immunodeficiency virus (HIV) infection, serologic and tissue hepatitis B virus (HBV) and HDV markers and T lymphocyte subsets were studied in serum samples from 38 patients with chronic D hepatitis, 26 of whom had HIV infection. Patients with chronic D hepatitis and HIV infection had significantly lower peripheral blood T4:T8 ratios resulting from a significant increase in T8+ (suppressor/cytotoxic) cells, while numbers of T lymphocyte subsets were normal in cases with chronic D hepatitis only. HIV+ patients showed an increase in HBV replication (identified by hepatitis B core antigen in liver and hepatitis B e antigen and HBV DNA in serum) and in HDV replication (tissue D antigen and HDV RNA) without evidence of more active liver disease. Probably the immunologic disturbances detected in chronic D hepatitis are secondary to HIV infection, do not contribute to the pathogenesis of liver injury, and are associated with increased viral B and D replication.