Apheresis of Immune Diseases and Apheresis Using Immunological Specificity

Abstract: It has been clearly shown that autoimmune diseases can be treated by apheresis by eliminating immune complexes, however, the effects of therapeutic apheresis are not limited to immune disorders. Almost all diseases are associated with immune systems. Immune systems can be regulated by advanced techniques of apheresis, including immunoadsorption and immunocytapheresis, removing immune effector molecules and various immune‐associated cells selectively. Therefore, apheresis can be used as a nondrug treatment for many diseases. In addition, disease‐associated proteins that cause disease or are produced in the course of diseases and accumulate in the body could be eliminated selectively by apheresis using the extremely powerful ability of the immune system to recognize polypeptide structures specifically and distinguish miniscale differences among molecules. In this article, we discuss the current status of treatment of immune diseases by apheresis and possible treatment approach of a variety of diseases by apheresis based on immune reactions.     

Apheresis Therapy for Living‐Donor Liver Transplantation

Abstract: Liver transplantation is a fundamental treatment for patients with end‐stage hepatic failure. In order to perform living‐donor liver transplantations under safer conditions, apheresis plays a major role in Japan due to the prevalence of living‐donor liver transplantation wherein later retransplantation is difficult. In our department, the roles of apheresis in liver transplantation are as follows: as bridge therapy to liver transplantation (n = 45); as a supplement to the graft liver until the recovery of hepatic function (n = 77); as treatment for multiple organ failure including posttransplantation renal failure (n = 15); and as a means with which to reduce antibody titers for antibodies such as anti‐A or anti‐B in persons with ABO blood type = incompatible liver transplantation (n = 23). In our department, we have performed 822 liver transplantations at present. Of those cases, 183 were selected wherein apheresis was performed around the time of the operation. In all cases, transplantation with sufficient apheresis was performed before the surgical operation, however, 22 patients (48.9%) died after undergoing surgery. Among the patients who underwent the postoperative apheresis, those in the nonsurvivor group had lower grafted liver weights compared to those of the survivor group. The kidney was the organ that most frequently failed due to postoperative complications. In cases of ABO blood type‐incompatible liver transplantations, patients with high preoperative anti‐A/B IgM antibody titers sustained bile duct complications, patients with high preoperative anti‐IgG antibody titers sustained hepatic necrosis, and patients with high postoperative anti‐A/B IgM and anti‐IgG antibody titers sustained hepatic necrosis most frequently.     

Reducing the incidence of TRALI in the UK: the results of screening for donor leucocyte antibodies and the development of national guidelines

Background and Objectives Transfusion‐related acute lung injury (TRALI) is associated with the passive transfusion of leucocyte antibodies in blood products. Blood Transfusion Services have adopted a number of different strategies for reducing the incidence of TRALI, but, while these have been successful, TRALI has not been completely eliminated. Many Transfusion Services have introduced leucocyte antibody screening of donors to further reduce TRALI. This report describes the results of donor leucocyte antibody screening within NHS Blood and Transplant and the guidelines that have been developed for Transfusion Services within the United Kingdom (UK) to reduce the incidence of TRALI. Materials and Methods Blood samples from newly recruited female apheresis donors were tested for human leucocyte antigens (HLA) class I and class II antibodies and granulocyte‐specific antibodies. Results A total of 1157 female donors were evaluated. Three hundred and fifteen (27·23%) donors had HLA class I or II antibodies and were returned to red cell component donation. Fifty‐seven (6·77%) of the remaining 842 donors were found to have granulocyte‐specific antibodies of which 11 (1·31%) had HNA‐specific antibodies. A total of 818 donors (70·70%) were accepted for platelet apheresis, 336 donors (29·04%) were returned to red cell component donation, and three donors with HNA‐3a antibodies (0·26%) were deferred from therapeutic donation. Conclusions Female donors with leucocyte antibodies were identified in a stratified screening programme. Donors with antibodies were either directed to red cell donation or deferred. This process, combined with other measures that have already been introduced, is anticipated to further reduce the incidence of TRALI.     

Immunomodulation effects and clinical evidence of apheresis in renal diseases

This article overviews the immunomodulation effects and clinical evidence of apheresis in renal diseases, in particular primary and secondary glomerulonephritis. A considerable permeability factor(s) derived from circulating T cells is speculated to have a crucial role in the proteinuria of nephrotic syndrome (NS). Plasma exchange (PE), immunoadsorption using Protein A sepharose cartridges, low-density lipoprotein apheresis and lymphocyte apheresis (LCAP) were tried to remove such factors or pathogenic T cells. Other glomerular diseases induced by specific antibodies such as antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies and immune-complexes such as lupus nephritis were also treated with PE, double filtration plasma apheresis. IAPP and LCAP. Many reports suggested that apheresis might have beneficial immunomodulation effects for the treatment of glomerular diseases: however, the recommendations based on evidence from small cohorts remain at low-level in most.     

Clinical Outcome of Patients With Coexistent Antineutrophil Cytoplasmic Antibodies and Antibodies Against Glomerular Basement Membrane

Antineutrophil cytoplasmic antibodies (ANCA) and antibodies against glomerular basement membrane (anti‐GBM) rarely coexist. Both antibodies may be associated with rapidly progressive glomerulonephritis and pulmonary hemorrhage. We describe the clinical, serological and histological features of our patients with dual antibodies. From 1977 to 2008, 48 patients with anti‐GBM antibody‐associated renal disease were observed. Eight out of the 30 tested patients (26.7%), all females, had positive myeloperoxidase (MPO)‐ANCA coexistent with anti‐GBM antibodies. The patients' mean age was 63.4 ± 7.8 years. Five presented with pulmonary‐renal syndrome, all but one were dialysis‐dependent on admission. They had constitutional symptoms and different organ involvement. The kidney biopsies revealed intense linear staining for immunoglobulin G and C3 along the glomerular and distal tubular basement membrane associated with irregular diffuse or focal extracapillary crescentic glomerulonephritis with necrosis of varying extent. Lesions of varying ages were characteristically expressed. Seven patients were treated with methylprednisolone and plasma exchange, four with cyclophosphamide, and one with intravenous immunoglobulin. After 28–74 months, there were three dialysis‐dependent survivors and one patient with stable chronic renal disease. Two clinical relapses with pulmonary involvement and MPO‐ANCA positivity without anti‐GBM antibodies occurred in two dialysis‐dependent patients. In summary, screening for ANCA and anti‐GBM antibodies should be undertaken in patients with clinical signs of systemic vasculitis. In dialysis‐dependent patients, the goal of treatment is to limit the damage of other involved organs and not to preserve renal function. Careful follow‐up is necessary due to the relapsing nature of the ANCA component of the disease.     

Leptospirosis severity may be associated with the intensity of humoral immune response

Leptospirosis severity may be increasing, with pulmonary involvement becoming more frequent. Does this increase result from an intense immune response to leptospire? Notice that renal failure, thrombocytopenia and pulmonary complications are found during the immune phase. Thirty-five hospitalized patients with Weil's disease had 5 blood samples drawn, from the 15th day to the 12th month of symptoms, for ELISA-IgM, -IgG and -IgA specific antibody detection. According their 1st IgG titer, the patients were divided into: group 1 (n = 13) titer > 1:400 (positive) and group 2 (n = 22) titer < or =1:400 (negative). Early IgG antibodies in group 1 showed high avidity which may indicate reinfection. Group 1 was older, had worse pulmonary and renal function, and fever for a longer period than group 2. Throughout the study, IgG and IgA titers remained higher in group 1. In conclusion, the severity of Weil's disease may be associated with the intensity of the humoral immune response to leptospire.     

Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors

K. Ishibashi T. Tokumoto, H. Shirakawa, K. Hashimoto, K. Ikuta, N. Kushida, T. Yanagida, K. Shishido, K. Aikawa, H. Toma, N. Inoue, O. Yamaguchi, K. Tanabe, T. Suzutani. Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors.
Transpl Infect Dis 2011: 13: 318–323. All rights reserved Abstract: Cytomegalovirus (CMV) reinfection of seropositive individuals has been associated with adverse outcomes in organ transplantation and is a frequent cause of congenital infection. Previously we demonstrated that mismatching of CMV glycoprotein H (gH) serotypes was associated with CMV disease after renal transplantation. Because the antigen domain 2 (AD2) epitope of glycoprotein B (gB) is conserved among CMV isolates and is one of the known targets of neutralizing antibodies, in this study we investigated whether antibodies against the epitope contribute to protection from CMV reinfection in renal transplantation, irrespective of gH serological matching. For this purpose, the gB and gH serology and clinical outcomes were analyzed retrospectively for 77 transplant recipients in the donor positive/recipient positive setting, who were managed by preemptive strategy. We found that there was a good negative correlation between the numbers of antigenemia‐positive cells and the levels of antibodies against gB AD2 in the CMV‐gH antibody matched group, but not in the CMV‐gH antibody mismatched group. None of the recipients with antibodies against both gB AD2 and strain‐specific epitopes of gH have experienced CMV disease during 6 month after transplantation, while 28% of those who lacked either/both antibody response needed preemptive therapy. Because the outcome was statistically significant, antibodies against gB AD2 can be a useful indicator to predict emergence of CMV disease for preemptive therapy, in addition to antibodies against the mismatched gH types.     

Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodies – Perspectives for immunoadsorption

Immediate antibody elimination, pulsed induction of antibody redistribution, and immunomodulation are major forces of efficacy of therapeutic apheresis (i.e. plasma exchange [PE] or immunoadsorption [IA]) for autoimmune neurologic disorders. Therapeutic apheresis can offer rapid response for severe acute neurologic symptoms, and stable rehabilitation in long-term clinical courses being refractory to drug based strategies or complicated by drug side effects. PE or IA in these situations must be considered as part of multimodal or escalating immune treatment strategies in combination or in competition with intravenously administered immunoglobulins (ivIg), corticosteroids, the full spectrum of immunosuppressive drugs, and bioengineered antibodies. Selective IA is increasingly replacing PE due to its superior safety profile and increasing knowledge on pathogenic relevance of autoantibodies. Recent experiences in autoimmune diseases of the central nervous system, e.g. multiple sclerosis, neuromyelitis optica, and autoimmune encephalitis confirmed this concept.     

Anti-nucleosome antibody: significance in lupus patients lacking anti-double-stranded DNA antibody

OBJECTIVE: To investigate the clinical significance of anti-nucleosome antibodies in SLE patients lacking anti-double stranded DNA (dsDNA) antibodies. METHODS: IgG anti-nucleosome antibodies were detected by enzyme-linked immunosorbent assays (ELISA) in the sera of SLE patients. Anti-dsDNA antibodies were measured by Farr assays and ELISA, not only in the samples taken for anti-nucleosome testing, but also in sera obtained regularly during the follow-up. RESULTS: Ninety-eight (76.0%) out of 129 patients with SLE had anti-nucleosome antibodies. Twenty-five patients (19.4%) consistently showed little or no anti-dsDNA reactivity during the course of their disease, and among these anti-nucleosome antibodies were present in the sera of 15 (60.0%). Of the patients with anti-dsDNA-negative SLE, renal disorders were present in 8 patients (32.0%), all of whom had anti-nucleosome antibodies. Renal disorders were not found in patients (n = 10) who had neither anti-dsDNA nor anti-nucleosome antibodies. Other autoantibodies such as anti-Ro, anti-Sm and anti-cardiolipin were not associated with renal disorders in this group. The levels of anti-nucleosome antibody strongly correlated with the SLEDAI scores, but inversely correlated with serum complement levels in anti-dsDNA negative SLE patients. CONCLUSION: Our data suggest that the anti-nucleosome antibody may be a useful marker for diagnosis and activity assessment of anti-dsDNA negative SLE. Anti-nucleosome antibody may be an important factor for renal involvement in this subgroup of patients.     

Apheresis for Renal Disease

Abstract: Many primary renal diseases are associated with either antibody deposition within the glomerulus or an antibody associated autoimmunity, as may be seen with certain vasculitidies. Examples of these diseases include Goodpasture's syndrome, cryoglobulinemia, antineutrophil cytoplasmic antibody positive syndromes, and other forms of rapidly progressive glomerulonephritis. Immunoglobulins also may be nephrotoxic to the tubules such as is the case with myeloma related light chains. Given the rapid removal of immunoglobulins by therapeutic plasma exchange, this modality has been considered an appealing management option in the treatment of these renal diseases. Although not classically considered as autoimmune diseases, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes which often involve the kidneys. Although previously unexplained, it has been long appreciated that therapeutic plasma exchange (PE) can be a useful treatment for these microangiopathic hemolytic anemias, but the most recent insights into their pathogenesis suggest that PE may be beneficial by replacing a missing enzyme or removing pathogenic autoantibodies.     

Therapeutic Apheresis in Immunologic Renal and Neurological Diseases

Since the mid 1970s, when membrane modules became available, plasma separation techniques have gained in importance especially in the past few years. The advantages of this method are a complete separation of the corpuscular components from the plasma and due to increased blood flow rate and higher efficacy. Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a poor prognosis without treatment. Therapeutic apheresis (TA) in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 40 years. The updated information on immunology and molecular biology of different immunologic diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different diseases can be treated by various apheresis methods such as therapeutic plasma exchange (TPE) with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non‐biological agents. Here, the authors provide an overview of the most important pathogenic aspects indicating that TA can be a supportive therapy in systemic autoimmune diseases such as renal and neurological disorders. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Committee of the American Society for Apheresis are cited.     

Autoantibodies specific for alpha-enolase in systemic autoimmune disorders

OBJECTIVE: To analyze the presence and specificity of anti-alpha-enolase antibodies in various systemic autoimmune diseases. METHODS: Sera from patients with systemic lupus erythematosus (SLE), mixed cryoglobulinemia (MC), systemic sclerosis (SSc), and rheumatoid arthritis (RA) were tested by immunoblot on partially purified a-enolase from human kidney and on beta- and gamma-enolase. The isotype of anti-enolase antibodies was determined by means of isotype-specific monoclonal antibodies. RESULTS: IgG anti-alpha-enolase antibodies were detected in 9/33 (27%) SLE sera (6/9 patients had active renal disease), in 6/19 sera from patients with MC and nephritis, in 0/15 sera from MC patients without renal involvement, in 6/20 (30%) SSc sera, in 2/35 (6%) disease controls with RA, and in 2/32 (6%) healthy controls. The antibodies were not species-specific, but in most cases were specific for the alpha isoform of enolase. The anti-enolase immune response was not isotypically restricted. In half of the patients with SLE the anti-alpha-enolase and anti-DNA antibodies constituted distinct antibody populations, while in the other half a partial overlap of the 2 antibody specificities was observed. CONCLUSION: Anti-alpha-enolase antibodies can frequently be detected in systemic autoimmune disorders. In SLE and MC they are associated with nephritis and in SSc they are associated with severe endothelial damage. Alpha-enolase is ubiquitous, but is highly expressed in the kidney and also on the membrane of several cell types including endothelial cells. Thus, anti-alpha-enolase antibodies could contribute to renal injury not only by the local formation of immune complexes, but also by direct damage to endothelial cells.     

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自身免疫性脑炎是一组可能由某些自身抗体、活性细胞或者相关因子与中枢神经系统神经元表面的蛋白等相互作用而导致的疾病。该组疾病中各个疾病典型的临床表现分别与目前已知的某个特异性抗体相对应,病情通常与抗体水平相关,少数病例可能与某些潜在的肿瘤有关。目前已知的自身免疫性脑炎常见的有边缘叶脑炎(lim-bic encephalitis,LE)、莫万综合征(movan’s syndrome,MOS)、桥本脑病(Hashimoto’s encephalitis)以及抗NMDA受体脑炎等,广义的讲还包括免疫相关疾病的脑炎表现。疾病分类复杂,诊断主要依靠临床表现和有关特异性检查(免疫标记物、影像)等做出,本文将对目前这一组疾病的诊断和鉴别做一总结。     

Therapeutic Apheresis for Renal Disorders

Many primary renal diseases are associated with either antibody deposition within the glomerulus or an antibody associated autoimmunity, as may be seen with certain vasculitidies. Other immunoglobulins may be nephrotoxic or glomerulopathic; such may be the case with myeloma related light chains or cryoglobulins. Given the rapid removal of immunoglobulins by therapeutic plasma exchange, this modality has been considered an appealing management option in the treatment of these autoimmune related renal diseases. Although not classically considered as autoimmune diseases, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes which often involve the kidneys. In many cases therapeutic plasma exchange has been found to be a useful treatment modality for these microangiopathic hemolytic anemias. This paper will provide a concise review of the renal indications for therapeutic plasma exchange.     

Safety and efficacy of single‐needle leukocyte apheresis for treatment of ulcerative colitis

Leukocyte apheresis (LCAP) is a safe and effective treatment for active ulcerative colitis (UC) in Japan. Nevertheless, a limitation of LCAP is its requirement for two puncture sites (double‐needle [DN] apheresis), sometimes leading to problems with needle puncture. Single‐needle (SN) apheresis is useful in hemodialysis and reduces needle puncture pain. If SN apheresis were found to be useful in LCAP for UC, it may reduce patient burden. The aim of this study was to compare the safety and efficacy of SN apheresis with that of DN apheresis. Twenty‐four patients with active UC were retrospectively enrolled. They underwent either SN apheresis (n = 12) or conventional double‐needle (DN) apheresis (n = 12) at the Kurume University Hospital from February 2014 to March 2018. At each session, we recorded access problems defined by the time required to initiate apheresis and the frequency of puncture‐related problems, as well as blood circuit clotting, defined as clotting necessitating interruption of apheresis and changing of the circuit. Efficacy was assessed using partial Mayo scores. The number of apheresis sessions was comparable between SN and DN apheresis (9.0 ± 2.0 times vs 9.6 ± 1.4 times, mean ± SEM). SN significantly reduced the time required to start apheresis (10.0 ± 5.4 minutes vs 19.4 ± 11.9 minutes, P < .05) as well as needle puncture troubles (0.9% vs 11.5%, P < .05). SN had comparable frequency of blood clotting episodes (5.6% vs 8.7%). SN apheresis had similar clinical efficacy (P < .001 in SN and P < .01 in DN). The improvement and remission rates were comparable between groups. SN apheresis may be safe and effective and may reduce patient burden during UC treatment. Nevertheless, further comparative studies are needed.     

Granulocyte and monocyte adsorption apheresis (GCAP) for refractory skin diseases caused by activated neutrophils and psoriatic arthritis: evidence that GCAP removes Mac-1-expressing neutrophils

In the present study, we have shown that granulocyte and monocyte adsorption apheresis (GCAP), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is useful for skin diseases attributable to activated granulocytes and psoriatic arthritis (PsA). We assessed the clinical effectiveness of GCAP and investigated the mechanisms underlying the adsorption of pathogenic granulocytes. The effect of GCAP was assessed in 14 patients with neutrophilic dermatoses and 16 with PsA. The mechanisms by which the instrument adsorbs activated granulocytes were investigated using an in vitro mini-column system that mimics the GCAP. Skin lesions and arthropathy improved in 22 of 29 patients (75.9%) and 14 of 18 (77.8%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, increased compared with normal subjects, was reduced by GCAP. In the mini-column system, CA beads adsorbed 50% neutrophils; and adsorption was inhibited significantly by treating plasma with EDTA and blood cells with antihuman CD11b monoclonal antibody. GCAP was useful for treating neutrophilic dermatoses and PsA. GCAP adsorbs Mac-1-expressing neutrophils to the CA beads by the binding of complement component (iC3b) on CA beads and CD11b expressed on activated neutrophils.     

Inhibition of Inflammatory Cytokines and Induction of Myeloid‐Derived Suppressor Cells by the Effects of Granulocyte and Monocyte Adsorption Apheresis

Pro‐inflammatory cytokines are involved in the pathogenesis of inflammatory skin diseases attributable to activated neutrophils and macrophages. Myeloid‐derived suppressor cells (MDSCs) play an important role in the regulation of the immune response and possess strong immunosuppressive and anti‐inflammatory properties. Granulocyte and monocyte adsorption apheresis (GMA), an extracorporeal apheresis instrument featuring columns containing cellulose acetate (CA) beads, is designed to remove pathogenic myeloid lineage cells. The purpose of this study was to investigate the effects of GMA on cytokine production and MDSC induction. The serum level of various inflammatory cytokines and the incidence of MDSCs in peripheral blood before and after GMA treatment were recorded. Cytokines were assayed with the suspension‐array method in 38 patients. The incidence of MDSCs was analyzed by FACS in eight patients and the effect of GMA on in vitro MDSC induction was examined using a mini‐column system that mimics GMA. The serum level of IL‐2Rα (P = 0.030), IL‐8 (P = 0.018), and MIF (P = 0.0002) was significantly decreased by GMA and the incidence of MDSCs was increased (P = 0.030). With the mini‐column system, MDSCs were induced in the peripheral blood of five healthy volunteers; the in vitro induction was significantly inhibited by inactivation of the complement component iC3b. The clinical effectiveness of GMA may be attributable to the inhibition of pro‐inflammatory cytokines and the induction of anti‐inflammatory MDSCs by iC3b activation via the CA beads in the GMA column.     

Low‐Density Lipoprotein Apheresis and Changes in Plasma Components

Abstract: Several different techniques of low‐density lipoprotein (LDL) apheresis are available for management of severe hypercholesterolemia. Among them, the adsorption system with a dextran‐sulfate cellulose (DSC) column is most widely used. In addition to adsorption of LDL, DSC adsorbs plasma constituents that have the following characteristics: proteins containing apolipoprotein B (Lp[a]); proteins involved in the initial contact phase of the intrinsic coagulation pathway (coagulation factor XII, high‐molecular‐weight kininogen and prekallikrein); factors with lipophilic characteristics (coagulation factor VII, coagulation factor VIII, and vitamin E); and proteins with adhesive or other characteristics (von Willebrand factor, fibronectin, serum amyloid P component, hepatocyte growth factor). The adsorption of these proteins seems to ameliorate prevention or regression of atherosclerosis. Moreover, plasma treatment by the DSC column may be useful for treatment of inexorable diseases, such as amyloidosis. On the other hand, the DSC column generates bradykinin by activation of the initial contact phase of the intrinsic coagulation pathway. Bradykinin generation may explain the functional improvement in the circulatory system, as well as hypotension during LDL apheresis, which is observed in patients taking ACE inhibitors.     

Significance of antibodies to soluble liver antigen/liver pancreas: a large French study

Background: Antibodies to soluble liver antigen (SLA)/liver pancreas (LP) are generally considered as highly specific diagnostic markers of type 1 auto‐immune hepatitis (AIH‐1), and are particularly useful in patients without conventional antibodies. However, the presence of anti‐SLA/LP in type 2 auto‐immune hepatitis (AIH‐2), primary sclerosing cholangitis (PSC) and hepatitis C has recently been reported. The aim was thus to describe the characteristics of anti‐SLA/LP‐positive patients in the largest series reported to date. Methods: Sera were selected from the period between 1998 and 2005, based on the presence of antibodies to SLA/LP detected by two methods. The clinical status of patients was determined from their medical records. Results: Eighty‐one anti‐SLA/LP‐positive patients with available clinical data were included: 89% (72/81) had a diagnosis of AIH‐1, including 10 (12%) associated with cholestatic diseases (primary biliary cirrhosis in seven cases and PSC in three cases). Six patients (7%) suffered from another liver disease: hepatitis C (n=3) and drug‐induced hepatitis (n=3). No specific diagnosis was made in three patients. Conclusions: Antibodies to SLA/LP are of a major diagnostic value for AIH‐1, including paediatric forms and overlap syndromes with cholestatic diseases, but are not found in association with anti‐liver/kidney/microsome type 1 or antibodies to liver cytosol type 1. They are rarely present in other liver diseases such as hepatitis C and drug‐induced hepatitis.