Autoantibody prevalence in children with liver disease due to chronic hepatitis C virus (HCV) infection

HCV infection and interferon-alpha (IFN-α) therapy have been associated with autoimmunity. To assess whether chronic liver disease (CLD) due to HCV infection or its treatment with IFN-α cause autoimmune manifestations, the prevalence of tissue autoantibodies in 51 children with chronic HCV infection and 84 with other CLD was analysed by standard techniques. Sixty-five percent of patients with chronic HCV infection, 66% with chronic hepatitis B infection and 60% with Wilson's disease were positive for at least one autoantibody. In the 51 subjects with chronic HCV infection (29 treated with IFN-α, 22 untreated), tested on 165 occasions over a median of 9 months (range 5–42 months), autoantibodies to nuclei (ANA), smooth muscle (SMA), gastric parietal cell (GPC) and/or liver kidney microsomal type 1 (LKM-1) were similarly prevalent in treated and untreated patients (90% versus 68%, P = 0.12). Positivity for SMA was present in 67%, GPC in 32%, ANA in 10%, LKM-1 in 8% of cases. Treatment with IFN-α had to be suspended due to transaminase elevation in one SMA-positive, one ANA-positive but in three of four LKM-1-positive patients. Our results show that: (i) autoantibodies are common in viral-induced hepatitis and Wilson's disease; (ii) positivity for SMA, GPC, ANA is part of the natural course of chronic HCV infection, their prevalence being unaffected by IFN-α; and (iii) IFN-α should be used cautiously in the treatment of LKM-1/HCV-positive patients

Argininosuccinate lyase: a new autoantigen in liver disease

Anti-liver cytosol 1 autoantibody (LC1) characterizes a severe form of autoimmune hepatitis (AIH), staining the cytoplasm of periportal hepatocytes and targeting an unidentified 60-kD liver cytosolic antigen. To identify its target, we used high-titre anti-LCI+ sera from two patients with AIH to screen 18 cytoplasm enzymes with periportal location by double immunodiffusion (DDI). Both sera gave a broad precipitin line against human liver cytosol, suggesting that they may recognize two distinct antigens, a possibility confirmed by the appearance of two precipitin lines when DDI conditions were optimized (0.8% agarose and 3% polyethylene glycol (PEG)). Experiments by DDI and Western blot (WB) identified a liver cytosolic autoantigen of 50 kD, different from LC1, giving a line of identity with argininosuccinate lyase (ASL). Reactivity to ASL was then investigated by DDI and WB in 57 patients with AIH, 17 with primary biliary cirrhosis (PBC), 15 with chronic hepatitis B virus (HBV) infection, 13 with αl-antitrypsin deficiency, 17 with Wilson's disease, 18 with extrahepatic autoimmune disorders, and in 48 healthy controls. Anti-ASL was found in 16% of AIH and 23% of PBC patients by DDI and in 14% of AIH, 23% of PBC and 20% of HBV patients by WB. No argininosuccinate was present in the urine of four anti-ASL+ patients tested, excluding an inhibition of enzymatic activity by anti-ASL. The addition of anti-ASL+ serum to human fibroblast cultures induced a significant increase in ASL activity. ASL is a new autoantigen in liver disease and its clinical relevance warrants further investigation

Expression of macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response

The in vivo response of the immune system after HIV infection in regard to cytokine production and C-C chemokine synthesis is not well known. Here we have analysed cytokine and chemokine mRNA production in lymph nodes with follicular hyperplasia (FHLN) of HIV-infected patients by in situ hybridization using anti-sense mRNA probes. The synthesis of mRNAs for interferon-gamma (IFN-γ), IL-12p35, IL-12p40, IL-4, and for the C-C chemokines RANTES, MIP-1α, and MIP-1β was compared with that of lymph nodes from non-infected individuals to define HIV-specific events. Only few cells expressing IFN-γ, RANTES, MIP-1α, and MIP-1β mRNAs were detectable in the T-dependent area of lymph nodes from HIV-negatives. In contrast, in FHLN from HIV+ patients a high number of IFN-γ, RANTES, MIP-1α, and MIP-1β mRNA-containing cells were detectable. Remarkably, only single individual IL-12p35 mRNA-producing cells were present in the T-dependent area from both HIV+ and HIV− lymph nodes. Furthermore, the low number of IL-12p40 mRNA-expressing cells did not differ between HIV+ and HIV− lymph nodes. This indicates that IFN-γ is expressed independently of IL-12, possibly by a direct T cell-mediated reaction. IL-4 mRNA-producing cells were hardly detectable in infected and control lymph nodes. The same findings were made in a limited number of samples from patients with advanced disease. Thus, these results demonstrate that a high IFN-γ production is accompanied by a strong expression of MIP-1α, MIP-1β, and RANTES in the lymph node after HIV infection. This favours the idea that a Th1-type immune response correlates with a preferential production of C-C chemokines in FHLN of HIV+ patients