Krueger Gr

Complement C2 Receptor Inhibitor Trispanning: A Novel Human Complement Inhibitory Receptor

The complement system presents a powerful defense against infection and is tightly regulated to prevent damage to self by functionally equivalent soluble and membrane regulators. We describe complement C2 receptor inhibitor trispanning (CRIT), a novel human complement regulatory receptor, expressed on hemopoietic cells and a wide range of tissues throughout the body. CRIT is present in human parasites through horizontal transmission. Serum complement component C2 binds to the N-terminal extracellular domain 1 of CRIT, which, in peptide form, blocks C3 convertase formation and complement-mediated inflammation. Unlike C1 inhibitor, which inhibits the cleavage of C4 and C2, CRIT only blocks C2 cleavage but, in so doing, shares with C1 inhibitor the same functional effect, of preventing classical pathway C3 convertase formation. Ab blockage of cellular CRIT reduces inhibition of cytolysis, indicating that CRIT is a novel complement regulator protecting autologous cells.

Human Herpesvirus-6: A Short Review of Its Biological Behavior

HHV-6 shows a widespread distribution with life-long persistence. The virus is frequently reactivated, yet remains clinically inapparent unless the patient is immunodeficient in some way. Even then, HHV-6 reactivation may simply enhance the pathogenicity of other viruses or existing autoimmune disorders rather than becoming a pathogen itself. Future clinical studies need to focus on such indirect viral influences mediated through molecular mimicry and interference with cell receptor expression, and cytokine and chemokine network regulation. Nevertheless, such disturbances may afford therapeutic intervention to disrupt herpesvirus interference and improve certain disease processes. There are only a few diseases for which an immediate causal relationship to HHV-6 infection has been suggested.

Immunologic Aspects of Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the immune system. A symposium was organized in October 2001 to explore the possibility of an association between immune dysfunction and CFS, with special emphasis on the interactions between immune dysfunction and other abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting. Data suggest that persons with CFS manifest changes in immune responses that fall outside normative ranges, but current research does not provide definitive evidence on whether these immune abnormalities are a cause or result of the illness. It has become clear that CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular, or autonomic nervous system dysfunction. This panel encourages a new emphasis on multidisciplinary research into CFS.

Chromosomally integrated human herpesvirus 6 in heart failure: prevalence and treatment

Human herpesvirus 6 (HHV‐6) A and B are two betaherpesviruses that are associated with many conditions including roseola, drug‐induced hypersensitivity syndrome, limbic encephalitis, and myocarditis. HHV‐6 is integrated in the germline [chromosomically integrated HHV‐6 (ciHHV‐6)] in ∼0.8% of the human population. To date, the prevalence, species distribution, and treatment responses of ciHHV‐6 are unknown for cardiac patients.

Pathologic Features of HHV-6A, HHV-6B, and HHV-7 Infection (Light and Electron Microscopy)

Acute infection with HHV-6 and HHV-7 and its reactivation may cause various diseases that deserve medical attention. Pathologic changes show features of a viral infection without specific cytopathic effects for HHV-6A, HHV-6B, and HHV-7. Intranuclear inclusions (preferentially Cowdry type B) and giant cells are seen rarely in tissues, and in all such cases coincident viral infections must be excluded. Dual infections have been reported for HHV-6, HHV-7, EBV, CMV, HSV-2, HIV, parvovirus (heart), and measles (lung), and suggestively for other viruses such as papillomavirus, coxsackievirus (heart), and JC virus (brain). Most patients were immunodeficient (transplant or AIDS patients, tumor carriers, children with immune deficiency syndromes) or suffered from autoimmune disorders (collagen vascular diseases, drug- associated hypersensitivity syndromes). To unequivocally relate pathologic lesions to a given virus infection, meticulous microscopic, immunohistologic, and molecular diagnostics should be combined with serology and viral culture. Identification of HHV-6 or HHV-7 as the specific pathogen in a given case is usually tentative, but effective treatment offers improvement and recovery.

Active HHV-6 infection of cerebellar Purkinje cells in mood disorders

Early-life infections and associated neuroinflammation is incriminated in the pathogenesis of various mood disorders. Infection with human roseoloviruses, HHV-6A and HHV-6B, allows viral latency in the central nervous system and other tissues, which can later be activated causing cognitive and behavioral disturbances. Hence, this study was designed to evaluate possible association of HHV-6A and HHV-6B activation with three different groups of psychiatric patients. DNA qPCR, immunofluorescence and FISH studies were carried out in post-mortem posterior cerebellum from 50 cases each of bipolar disorder (BPD), schizophrenia, 15 major depressive disorder (MDD) and 50 appropriate control samples obtained from two well-known brain collections (Stanley Medical Research Institute). HHV-6A and HHV-6B late proteins (indicating active infection) and viral DNA were detected more frequently (p < 0.001 for each virus) in human cerebellum in MDD and BPD relative to controls. These roseolovirus proteins and DNA were found less frequently in schizophrenia cases. Active HHV-6A and HHV-6B infection in cerebellar Purkinje cells were detected frequently in BPD and MDD cases. Furthermore, we found a significant association of HHV-6A infection with reduced Purkinje cell size, suggesting virus-mediated abnormal Purkinje cell function in these disorders. Finally, gene expression analysis of cerebellar tissue revealed changes in pathways reflecting an inflammatory response possibly to HHV-6A infection. Our results provide molecular evidence to support a role for active HHV-6A and HHV-6B infection in BPD and MDD.

Human herpesvirus 6-induced inflammatory cardiomyopathy in immunocompetent children

Over the last decade, human herpesvirus 6 (HHV-6) has been implicated in the etiology of pediatric myocarditis and subsequent dilated cardiomyopathy (DCM). This review provides an overview of recent literature investigating the pathophysiological relevance of HHV-6 in inflammatory cardiomyopathy. We examined 11 cases of previously published pediatric myocarditis and/or DCM associated with HHV-6 and also our experience of detection of virus particles in vascular endothelium of HHV-6 positive endomyocardial biopsy tissue by electron microscopy. The exact role of the presence of HHV-6 and its load remains controversial as the virus is also found in the heart of healthy controls. Therefore, the question remains open whether and how cardiac HHV-6 may be of pathogenetic importance. Quantitative polymerase chain reaction or mRNA testing allows differentiation between low-level latent virus found in asymptomatic myocardium and active HHV-6 infection. Although only a small number of pediatric cases have been reported in literature, HHV-6 should be considered as a causative agent of inflammatory cardiomyopathy, especially in children under three who might be experiencing a primary infection. Future studies are needed to establish a threshold for determining active infection in biopsy samples and the role of coinfections other cardiotropic viruses.

Pathology of the Gastrointestinal Tract

This chapter presents representative photographs of common diseases in the esophagus, stomach, small and large intestines, appendix, and rectum. Most of the diseases discussed here are infectious or neoplastic; a few others appear that students should be able to identify. A few microscopic photographs are added to support the understanding of gross lesions.

Pathology of Bones and Soft Tissues

This chapter focuses primarily on diseases that are seen in a classic department of orthopedics. It does not include acute traumatic diseases (e.g., fractures) more common in a trauma center.

Pathology of the Respiratory Tract

This chapter discusses six common entities of respiratory disease: obstructive and restrictive disorders of gas exchange, infectious and inflammatory diseases, immunologic disorders, vascular diseases of the lung, tumors of the lung and pleura, and miscellaneous other diseases of the respiratory tract.