Recurrent pericarditis: Autoimmune or autoinflammatory?

Idiopathic recurrent acute pericarditis (IRAP) represents the most troublesome complication of acute pericarditis and occurs in up to 20–50% of patients. It is generally idiopathic or postcardiac injury. IRAP is a disease of suspected immune-mediated pathogenesis. On the other hand, it has been suggested that some of these patients might have an atypical or subclinical form of an autoinflammatory disease, e.g. genetic disorders characterized by primary dysfunction of the innate immune system and caused by mutations of genes involved in the inflammatory response.We found that IRAP patients were negative for mutations associated with familial Mediterranean fever, but 6% (8/131 patients) carry a mutation in the TNFRSF1A gene, encoding the receptor for tumor necrosis factor-alfa.C-reactive protein (CRP) may be useful to follow the disease activity and guide the appropriate length of therapy, with continuation of the attack doses of the drugs until CRP normalization, at which time tapering may be considered.IRAP often needs a multidrug therapy: NSAIDs or aspirin at high dosages every 6–8 h, corticosteroids only rarely, at low dosages and with a very gradual tapering (months) and colchicine at low dosages if tolerated. Anakinra could be a solution for patients who do not tolerate other therapies.     

Prion: toxic or infectious agent?

Prions are proteins that cause a number of invariably fatal neuro-degenerative diseases, which can be classified into two groups: genetic or sporadic diseases (GSD) and transmissible spongiform encephalopathies (TSE). Both types of disease require the development of both normal prion (PrP) and abnormal prion (PrP(sc)) which differs from PrP in having a tertiary structure rich in beta-sheets. In fact, PrP(sc) is a totally dehydrated protein with an anhydrous environment, probably a thin carbon dioxide gas gap, that is why it appears highly resistant to proteases, to chemical disinfectants in water phase except in certain conditions to sodium hydroxide and sodium hypochlorite, to heat and to radiation. GSD and TSE diseases differ in incubation time, primary symptoms, and nature of CNS lesions. This paper argues that diseases of the GSD type as inherited or hereditary metabolic disorders and diseases of the TSE type could be regarded as chemical poisonings. TSE is caused by a deficiency in the chemo-defense system (CDS), which is unable to destroy or eliminate PrP(sc). As a result, the immune defense system (IDS) accommodates PrP(sc) as an inert particle if not a virus lure and routes it through to the nervous central system and the brain via the body's lymphoreticular system. In TSE PrP(sc) acts inside the cells as a toxic disruptor of post-translational phase of PrP biosynthesis. Unfortunately, CDS and IDS appear unable to neutralize PrP(sc).     

Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis?

The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA) are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.     

Recurrent cholangitis in the tropics: worm or cast?

The development of biliary casts is very rare, especially in non-liver transplant patients. The etiology of these casts is uncertain but several factors have been proposed which lead to bile stasis and/or gallbladder hypo-contractility and promote cast formation. Here, we report a 54-year-old male, with diabetes and ischemic heart disease, who presented with recurrent attacks of cholangitis. Magnetic resonance cholangiopancreatography revealed linear T1 hyperintense and T2 hypointense filling defects in the right and left hepatic ducts extending into the common hepatic duct, and a calculus in the lower common bile duct, raising a suspicion of worm in the biliary tree. In view of failed attempts at extraction on endoscopy, patient underwent surgery. At exploration, biliary casts and stones were extracted from the proximal and the second order bile ducts, with the help of intraoperative choledochoscopy and a bilio-enteric anastomosis was accomplished. Although endoscopic retrieval of the biliary cast can be employed as first-line management, surgery should be considered in case it fails.     

Retroviruses in autoimmune liver disease: genetic or environmental agents?

Retroviruses have been implicated in the pathogenesis of several human autoimmune conditions including Sj?gren's syndrome, primary biliary cirrhosis, immune mediated diabetes, and multiple sclerosis. The human intracisternal A type particle derived from Sj?gren's syndrome patients' salivary glands was the first retrovirus to be isolated from a human autoimmune disorder but the agent has yet to be cloned. In primary biliary cirrhosis patients, virus like particles have been observed by electron microscopy in biliary epithelium, endogenous retroviral sequences have been cloned from liver samples, and antibody reactivity to the human intracisternal A type particle has been observed in the majority of patients tested. However, there is no evidence to link the endogenous retroviral sequences in primary biliary cirrhosis patients to the retroviral antibody reactivity or virus like particles. In other patients with liver disease, reactivity to the human intracisternal A type particle was observed in a small but significant proportion of patients with hepatitis C virus infection. If the intracisternal A type particle is an endogenous retrovirus, it is interesting to speculate that hepatitis C virus infection may modulate the endogenous retroviral expression, as chronic hepatitis C has been linked with the development of Sj?gren's syndrome. Furthermore, many patients with chronic hepatitis C virus infection have reactivity to an autoantigen of unknown significance known as GOR that has protein sequence homology with both hepatitis C virus nucleocapsid protein as well as HTLV-1 gag. This may be an another example of an endogenous retroviral protein acting as an autoantigen in liver disease patients. At this time, there is little evidence to suggest that endogenous retroviruses are infectious agents that cause autoimmune disease but they may be implicated as either genetic elements or antigens. Further studies will be required to characterize the role that both exogenous and endogenous retroviruses play in the pathogenesis of autoimmune liver diseases.     

Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?

Nitric oxide (NO) is released locally during inflammatory autoimmune diseases and is believed to contribute to tissue destruction. However, recent studies are not fully consistent with such a simple role for NO. Here, Hubert Kolb and Victoria Kolb-Bachofen discuss data that suggest a role for NO in autoimmune diseases as an important regulator of the T helper 1 (Th1)/Th2 balance.     

Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: targeting the infectious trigger, the autoimmune response, or both?

Mixed cryoglobulinemia syndrome (MCsn) is a systemic vasculitis prevalently mediated by immune complexes, i.e., mixed cryoglobulins, and characterized by non-neoplastic B-cell lymphoproliferation favouring the progression into frank B-cell non-Hodgkin lymphoma (NHL) in 5-10% of patients. The hepatitis C virus (HCV) infection is the etiologic agent in the large majority of MCsn cases and chronic antigenic stimulation by HCV is considered a key mechanism sustaining the proliferation of the RF-secreting B-cell clones. Besides chronic antigenic stimulation, cytokines and growth factors may also play a key role in sustaining B-cell overactivation. B-lymphocyte stimulator (BlyS) was recently described as a critical survival factor for B cells, promoting their activation and maturation. Abnormal production of BLyS alters immune tolerance by allowing the survival of autoreactive B cells, thus triggering autoimmune disorders. BLyS inhibits B-cell apoptosis, and B-cell apoptosis is implicated in the pathogenesis of MCsn, as well as of other autoimmune diseases. Both antiviral therapy and B- cell depletive therapy in MCsn may influence BlyS expression. Antiviral therapy, monotherapy against biologic targets downstream viral infection, or the combination of the two, should be optimized in the single patient and stage of the disease, based on disease pathobiology, efficacy and safety issues.     

Psychosis: an autoimmune disease?

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B‐cell markers CD19 and CD20 achieve genome‐wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19⁺ and reduced CD3⁺ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post‐mortem studies have found CD3⁺ and CD20⁺ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody‐mediated (NSAb) central nervous system disease provides an antigen‐specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo‐controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.     

HCV infection and pericarditis: an extrahepatic manifestation?

The authors describe a clinical case in which they found the unusual combination of acute hepatitis caused by HCV and pericarditis in a young person, resulting in complete recovery from the pericarditis but in a deterioration of the chronic HCV. A close examination of the literature on this subject revealed that, although no similar case was recorded, an aetiological relationship between the hepatitis C virus and pericarditis cannot be excluded since an HCV infection often gives rise to extra-hepatic cardiac problems.     

Gene expression profiling in autoimmune diseases: chronic inflammation or disease specific patterns?

A central issue in autoimmune disease is whether the underlying inflammation is a repeated stereotypical process or whether disease specific gene expression is involved. To shed light on this, we analysed whether genes previously found to be differentially regulated in rheumatoid arthritis (RA) patients and healthy individuals were specific for the arthritic process or likewise altered in other chronic inflammatory diseases such as chronic autoimmune thyroiditis (Hashimoto's thyroiditis, HT) and inflammatory bowel disease (IBD). Using qPCR for 18 RA-discriminative genes, there were no significant differences in peripheral blood mononuclear cell (MNC) gene expression patterns between 15 newly diagnosed HT patients and 15 matched healthy controls. However, the MNC expression levels of five genes were significantly upregulated in 25 IBD patients, compared to 18 matched healthy controls (CD14, FACL2, FCN1, RNASE2, VNN2). There was concordance in the directional change for all genes between IBD and RA patients, i.e. increased expression compared to controls. These data show that one third of the genes significantly upregulated in MNC from RA patients were upregulated in patients with other chronic immunoinflammatory diseases, but only if accompanied by pronounced systemic manifestations. This suggests that at least some of the genes activated in RA are predominantly or solely related to general and disease-nonspecific autoimmune processes.