Neutrophil-specific autoantibodies in chronic inflammatory bowel diseases
Introduction
Many chronic immunoinflammatory diseases give rise to the production of autoantibodies, and the particular type of antibody revealed in a given patient is likely to reflect immunopathological mechanisms orchestrating the disease. Strong associations have been found between certain autoantibodies and disease manifestations or subsets of disease syndromes in patients suffering from inflammatory rheumatic diseases, however, many autoantibodies are not specific for a given nosographic entity of disease. This certainly is also true in patients where an autoantibody to neutrophils is found. The more precise the characterization the autoantibody profile is done, the better it can be used in differential diagnosis of disease.
Autoantibodies to leucocytes in UC patients have already been described by Yale University in 1961 [1]. These antibodies were not investigated in detail, but judging from the IF photo presented in this paper, the antibodies might be specific for neutrophils. We described similar antibodies, at that time termed ‘granulocyte-specific anti-nuclear antibodies’, in 25% of UC patients [2] using the IF technique, which was later adopted as a standard method while testing for IgG ANCA [3].
The early IF studies cannot easily be compared with regard to the prevalence of NSA in CIBD since different investigators used different dilutions of patient sera (undiluted to 1:20 dilution) and conjugates recognizing all Ig classes [1], [4], [5] or conjugates directed only to IgG [2], [6], [7]. In addition, one study did not separate UC from CD patients, but looked at CIBD as one group [4]. As could be expected, NSA was found to be more prevalent in studies where a polyspecific conjugate was used (71–83%) than when an IgG-specific conjugate was used (25–79%).
Section snippets
Nomenclature
The nomenclature used to describe the various autoantibodies to neutrophils has been far from uniform. The name ‘leucocyte-specific anti-nuclear factors’ was used in the beginning to describe NSA in patients with Felty's syndrome and rheumatoid arthritis [8], and later changed to the more precise term ‘granulocyte-specific anti-nuclear antibodies’ [2], [9]. The term ‘anti-cytoplasmic antibodies’ was used in the first publication on ANCA in Wegener's granulomatosis [10], but this name was soon
Methods to detect NSA
The IF technique has been the method of choice for screening purposes. When the standard method is strictly adhered, the categorization of SSVV-associated ANCA into cytoplasmic and perinuclear staining patterns is reproducible in most laboratories [22]. In SSVV patients, the ANCA either target PR3 or MPO, and the detection of cytoplasmic ANCA with PR3 specificity as well as the combination of perinuclear ANCA having MPO specificity is highly specific for a diagnosis of SSVV [22]. Both of these
Autoantigens recognized by NSA
Until recently it has been difficult to demonstrate any major autoantigen(s) targeted by NSA, most likely due to the assumption that the main targets should be searched for in the cytoplasmic compartment of neutrophils [17], [18], [19], [20], [21], [29], [30]. The cytoplasmic components published as antigens seen by NSA are mainly derived from the specific granules and the cytosol, while the azurophil granule constituents PR3 and MPO are not reactive (Table 1). Only relatively weak reactions
Clinical value of NSA in CIBD
Practically all studies done up to now agree that NSA occur more frequently in UC than in CD, and in CD they predominate in cases exhibiting colonic involvement. The prevalence does not increase with disease activity or disease extent, and does not change with drug treatment or surgical removal of the affected colon. Some investigators, however, have found higher IF titers of NSA in patients with active than in quiescent disease [5], [7], [17], [31]. These findings may reflect a pre-disposition
NSA in other chronic inflammatory diseases
NSA detected by IF are prevalently found in patients with primary sclerosing cholangitis as an extraintestinal manifestation of CIBD (88%), but are less frequent in cholangitis patients without CIBD (40%) [5]. Up to 92% of patients with autoimmune hepatitis type I were found to express NSA [26], mostly at high IF titers [34]. In patients with Felty's syndrome, approximately 90% of them produce high levels of NSA [35] which commonly engage in a circulating immune complex formation [36], but NSA
Differences between NSA and ANCA
A very important feature of NSA is the striking multi-target reactivity, which is best illustrated by immunoblotting [15], [17], [18]. These targets are mainly derived from the nucleus, the cytosol and the specific granules, and more rarely, from the azurophilic granules. The antibody response to neutrophils may thus be assumed to represent an immune response attempt to rid the body of cellular debris when numerous neutrophils are dying in an active inflammatory site. Until now, no data have
Summary
To avoid clinical misinterpretation, NSA should be clearly distinguished from ANCA. The separation of UC-associated NSA from SSVV-associated ANCA and drug-induced ANCA is fairly easy once the differences are recognized. The studies done until now on NSA in UC patient sera have not been able to clearly separate them from those seen in primary sclerosing cholangitis, chronic active hepatitis and rheumatoid arthritis. The presence of NSA in a UC patient subgroup and in CD has little value in
References (39)
- et al.
A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease
J Allergy Clin Immunol
(1990) - et al.
A new type of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in active ulcerative colitis but not in Crohn's disease
Immunobiol
(1990) - et al.
An antinuclear factor specific for leucocytes
Lancet
(1964) - et al.
Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis
Lancet
(1985) - et al.
‘Atypical p-ANCA’ in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines
Gastroenterology
(2000) - et al.
Identification of histone H1 as a cognate antigen of the ulcerative colitis-associated marker antibody pANCA
J Autoimmun
(2000) - et al.
The diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies (ANCA) in idiopathic systemic vasculitis. Results of an international collaborative study
Kidney Int
(1998) - et al.
Serologic testing for inflammatory bowel disease
J Pediatr
(1999) - et al.
Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease
Gastroenterology
(1998) - et al.
Neutrophil autoantibodies in ulcerative colitis: familial aggregation and genetic heterogeneity
Gastroenterology
(1992)