IgG4 as the predominant IgG subclass in pemphigoides gestationis.

BACKGROUND: Pemphigoides gestationis (PG) is a blistering disorder of pregnancy caused by antibodies against basement membrane proteins. They are directed against the 180 kD bullous pemphigoid antigen (BPAg2), towards the epitopes within the NC 16A domain. There are many similarities between pemphigoid gestationis and bullous pemphigoid (BP), but the literature so far indicated different immunofluorescence results in regards with C3 and IgG, and IgG subclasses (IgG4 vs. IgG1). METHODS: We evaluated staining patterns and IgG subclasses, as well as C5b-9 membrane attack complex (MAC) in 10 pregnant patients with PG, using sandwich double antibody immunofluorescence (SDAI) and direct immunofluorescence (DIF). RESULTS: All ten specimens stained with C3 by DIF, but only five had trace amount of IgG reactants by this method. By SDAI, 100% were positive for the IgG4 and C5b-9 MAC, 70% for IgG2, 50% for IgG1, and 40% for IgG3. CONCLUSION: IgG4 was the predominant IgG subtype identified. This finding has not been reported for PG, but it mimics results reported for BP. One explanation is prolonged disease course, as well as blocking of antigenic domains by IgG4. Understanding this completely will help develop therapies and prevention strategies for immunobullous and other autoimmune diseases, and perhaps aid in an exact classification.

Complement-fixing properties of antinuclear antibodies distinguish drug-induced lupus from systemic lupus erythematosus.

The immunofluorescence antinuclear antibody (ANA) test has been widely used to monitor autoimmune disease, but its value for diagnostic purposes is compromised by low specificity and high prevalence in disease-free individuals. The capacity of autoantibodies to fix serum complement proteins when bound to antigen is an important effector function because this property is associated with acute and chronic inflammatory processes. The current study evaluates the complement-fixing properties of antinuclear antibodies (CANA) in three well-defined and clinically-related patient groups: systemic lupus erythematosus (SLE), drug-induced lupus (DIL) and drug-induced autoimmunity (DIA). Of 20 patients diagnosed with SLE, 90% displayed complement-fixing ANA while this feature was present in only two of 18 patients with DIL and no patients with DIA without associated disease even though the mean ANA titres were similar among these patient groups. CANA was significantly correlated with anti-Sm activity. Because SLE but not DIL or DIA can be a life-threatening disease associated with complement consumption in vivo, these results demonstrate that measurement of CANA is a diagnostically useful tool and may have immunopathologic implications.

Linear IgA bullous dermatosis in one of two piroxicam-induced eruptions: a distinct direct immunofluorescence trend revealed by the literature.

BACKGROUND: The report focuses first on two patients with piroxicam-induced bullous eruption, one whose disease was diagnosed as linear IgA bullous dermatosis (LABD) and the other with no disease-specific immunologic findings using immunofluorescence methods. A review of the literature points to a distinctive direct immunofluorescence feature of drug-induced LABD cases. OBJECTIVE: Our purposes were to focus on divergent piroxicam reactions and to compare immunofluorescence findings in our and other reported drug-induced LABD cases to randomly occurring LABD cases. METHODS: Direct and indirect immunofluorescence methods were used to study biopsy and serum samples from both cases and biopsy specimens of 40 other LABD cases. RESULTS: Tense blisters developed in two patients medicated with piroxicam. Immunofluorescence studies demonstrated deposits of IgA at the basement membrane zone (BMZ) in case 1 and only non-disease-specific fibrin deposits at the BMZ in case 2. Within 1 month of discontinuation of piroxicam, all lesions were gone in both patients. CONCLUSION: In LABD cases proven by direct immunofluorescence, (1) the index of suspicion of drug induction should be higher in cases with only IgA and no IgG in the BMZ; (2) possibly up to two thirds of all LABD cases may be drug induced; and (3) the negative immunofluorescence findings in case 2 and other cases reported in the literature suggest that LABD is one of several host responses in drug-induced blistering diseases.

Simultaneous presence of mucous membrane pemphigoid and pemphigus vulgaris: molecular characterization of both autoantibodies.

There are several reports in the literature describing the coexistence of features of pemphigus vulgaris and pemphigoid in the same patient. We describe 15 patients with clinical, histological, and immunopathological features of mucous membrane (cicatricial) pemphigoid at the time of initial diagnosis. All 15 patients failed to respond clinically to conventional systemic agents over a mean period of 7.2 years. Hence, IVIg therapy was used. Prior to initiating IVIg therapy, features of mucous membrane pemphigoid and pemphigus vulgaris were demonstrated by various serological tests. Different assays were performed to identify molecular characteristics of these two autoantibodies. Twenty-five healthy normal individuals, 22 patients with mucous membrane pemphigoid, 17 patients with pemphigus vulgaris, and 12 patients with pemphigus foliaceus served as controls for comparison of serological studies. On indirect immunofluorescence, using monkey esophagous as substrate, sera of all 15 patients had demonstrable levels of anti-intercellular cement substance (ICS) or anti-keratinocyte cell surface antibody. Sera of 14 patients on salt split skin bound to the epidermal side of the split, which was consistent with mucous membrane pemphigoid. Sera of all 15 patients demonstrated binding to a 205-kDa protein (human B4 integrin) and a 130-kDa protein (desmoglein 3) on immunoblot. In a sample of sera from each of the 6 patients with mucous membrane pemphigoid and pemphigus vulgaris, the anti-ICS antibody was of the IgG4 subclass. The IgG4 subclass is a characteristic feature associated with pathogenic autoantibodies in pemphigus vulgaris. Hence, in such patients, a dual diagnosis should be considered and confirmed by various serological assays. It is possible that the presence of two pathogenic autoantibodies in these patients could have contributed to the lack of response to conventional immunosuppressive therapy.

A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescent findings.

A patient with clinical findings of dermatitis herpetiformis (DH), negative direct immunofluorescent (DIF) findings for junctional IgA deposits in 2 biopsy specimens, and positive for IgA endomysial (AEmA) and tissue transglutaminase (tTG) antibodies responded initially to dapsone. After dapsone had to be discontinued because of side effects, a gluten-free diet and supportive therapy controlled the disease; the AEmA and tTG antibodies became negative. Our data on 10 consecutive DH cases examined by DIF and by serum studies for AEmA and antibodies to tTG, point to frequencies of 90% DIF positive and 70% AEmA and tTG positive cases. The use of both DIF and serum tests for AEmA and tTG reveals DH cases not detected by DIF alone that respond to gluten-free diet. Findings on autoantibodies to tTG, an enzyme that metabolizes gliadin, points to a role of tTG in the immunopathology of gluten-sensitive enteropathy and helps to explain the need for a gluten-free diet in the management of DH cases.

Pemphigus erythematosus associated with thymoma: a case report.

A 52-year-old Chinese man was found to have a benign thymoma and pemphigus erythematosus (PE). Initially, most of his skin lesions appeared on the scars of the surgical incisions and suture sites three months after he underwent thymectomy. To our knowledge, this is the first report documenting the skin lesions of PE on the scars after thymectomy. Most of the previous cases had myasthenia gravis and skeletal muscle antibodies. However, in this patient, neither condition was present.

Relevance of complement fixing antinuclear antibodies.

BACKGROUND: Connective tissue diseases (CTDs) are a heterogeneous group of disorders defined by the association of a variety of clinical manifestations with immunologic and other laboratory findings. Overlap of syndromes and aberrant findings appear rather frequently. METHODS: Sera of eight antinuclear antibody (ANA) negative, cases of subacute cutaneous lupus erythematosus (SCLE) with antibodies to Ro (SS-A) and a ninth case with clinical and laboratory signs of Sjögren's syndrome and systemic lupus erythematosus (SLE) were tested for complement (C') fixing antinuclear antibodies (C-ANAs). The ninth case was examined in depth by direct immunofluorescence (DIF) and a two-step "C + DIF" test of biopsies for C' fixation to in vivo bound ANAs, as well as serum tests for C-ANA, ANA, and SCLE markers. RESULTS: Sera of five of the eight ANA negative, Ro(SS-A) positive SCLE cases had C-ANAs. The ninth case, a 50-year-old woman with clinical and laboratory signs of Sjögren's syndrome and SLE, gave a strong positive C + DIF reaction in the skin biopsy for in vivo bound ANAs that fix C', but negative ANAs and C-ANAs in routine serum tests; they revealed antimitochondrial antibodies. Serum tests on normal skin, however, revealed weak ANA and strong C-ANA reactions with in vitro fixed C'. CONCLUSIONS: ANA negative cases of SCLE or Sjögren's syndrome may have C-ANAs. A case with Sjögren's syndrome and signs of SLE had both in vivo and in vitro C' fixing ANAs. C-ANA tests can aid in the identification of such cases.

Antinuclear antibodies (ANA) and complement fixing ANA in systemic connective tissue diseases.

Screening for antinuclear antibodies (ANA) with parallel tests for complement fixing ANA (C-ANA) reveal that C-ANA react either as strongly as or more strongly than ANA in most cases of systemic lupus erythematosus (SLE) and related disorders including CREST syndrome. But sera of drug induced LE and other ANA positive subjects have weak or no C-ANA. (P < 0.0005). Titrations with parallel C-ANA/ANA tests of two cases reveal primarily ANA and less C-ANA reactions in a case of drug induced LE but in CREST syndrome both ANA and C-ANA tests yield elevated titers with stronger C-ANA reactions. These findings point to distinct immunochemical mechanisms in C-ANA and ANA reactions.

Chronic ulcerative stomatitis with stratified epithelium-specific antinuclear antibodies.

BACKGROUND: In 1990 a new disease-associated antinuclear antibody was first recognized as a specific immunologic marker for a chronic form of ulcerative stomatitis (CUS). METHODS: Another case is reported herein and the subject of chronic ulcerative stomatitis with stratified epithelium-specific antinuclear antibodies (SES-ANA) is reviewed. Intraoral biopsies from this patient were submitted for microscopic examination and direct immunofluorescence. Indirect immunofluorescence studies were also performed. Serial SES-ANA titers were obtained with the patient on maintenance treatment with hydroxychloroquine. A skin biopsy of a recent lichenoid eruption was obtained and skin explants grown in the serum of this patient were studied in tissue culture with reference to SES-ANA binding and complement fixation. RESULTS: Biopsy and serum studies confirmed a diagnosis of CUS with SES-ANA in the patient reported. Skin biopsy showed lichen planus. The patient was treated with hydroxychloroquine with a favorable response. Serial SES-ANA titers did not parallel the disease activity. Among the substantive observations made from skin explants cultured in the serum of this patient was widespread fixation of C3 to the nuclei of basal cells. CONCLUSIONS: The case described herein extends the findings in CUS to include lichenoid skin lesions. Records show that at least four of 11 cases of CUS had skin lesions, whereas all had oral lesions. Stratified epithelium-specific antinuclear antibodies serve as the key marker of CUS. Skin explants grown in the serum of this CUS patient bind SES-ANA in tissue culture. Sections of explants fix complement. Titers of SES-ANA have been reported to parallel disease activity in one case, but not in the present case. Thus, there appears to be case-to-case variation. The treatment of choice for CUS is hydroxychloroquine.

Cicatrizing conjunctivitis as a predominant manifestation of linear IgA bullous dermatosis.

Linear IgA bullous dermatosis is an uncommon mucocutaneous autoimmune disorder that is distinct from dermatitis herpetiformis and bullous pemphigoid. Two patients who had significant conjunctival involvement but minimal skin disease are described. Irreversible conjunctival scarring indistinguishable from ocular pemphigoid developed in both patients.

Erythema annulare-like acantholytic dermatosis (EAAD): nonbullous pemphigus or a new entity?

This article describes a case of unusual annular erythema-like dermatosis, with histological features of pemphigus foliaceus (subcorneal acantholysis) and IgG antibodies in circulation and bound in vivo to the keratinocyte surface. The reactivity of the antibodies, restricted to human squamous epithelium, was unique, differing from that of all known forms of pemphigus. This also was confirmed by immunoprecipitation. The problem is that these circulating antibodies could be missed if not determined on human substrate. It is to be established whether such cases present a new type of pemphigus or a unknown dermatosis with an autoimmune response of a pemphigus type.

Preliminary, dermatologic first step criteria for lupus erythematosus and second step criteria for systemic lupus erythematosus.

BACKGROUND: Comparisons of cases of systemic lupus erythematosus (SLE) with cases of rheumatoid arthritis and other rheumatologic disorders affords the basis of the 1982 revised criteria of the American Rheumatism Association (ARA) for classifying SLE cases. We address three questions: Do comparisons of LE cases with non-LE cases that have suggestive skin lesions yield criteria for use in dermatology clinics for primary classification of cases with photo distributions of skin lesions? Do comparisons of SLE with cutaneous LE cases yield the same or similar criteria to the revised ARA criteria for SLE? How should subacute cutaneous LE cases be evaluated for signs of significant systemic involvement? METHODS: Discriminant analyses on 168 cases with skin lesions suggestive of LE were performed using data based on the ARA criteria for SLE and study factors for cutaneous LE suggested by the European Academy of Dermatology and Venereology. RESULTS: These yielded two sets of criteria: (1) The 11 preliminary, dermatologic first step criteria (10 plus 1 for discoid lesions and histology) serve to classify cases as LE or non-LE. (2) The 11 preliminary, dermatologic second step criteria classify LE cases as cutaneous LE or systemic LE. Interestingly, 5 of 11 of these second step criteria differ from the 11 ARA criteria for systemic LE. These second step criteria afford a useful means of distinguishing between subacute cutaneous LE cases with or without significant systemic involvement. CONCLUSIONS: The study factors included in both the first and the second step criteria fall into three groups, notably clinical criteria, laboratory criteria, and "added study factors." The latter factors distinguish between the groups compared (LE vs. non-LE and cutaneous vs. systemic LE) but not as well as the study factors included as "criteria."

Linkage of pemphigus vulgaris antibody to the major histocompatibility complex in healthy relatives of patients.

Pemphigus vulgaris (PV) is an autoimmune disease caused by high concentrations of antibody to an epidermal cadherin. The disease is associated with two kinds of HLA-DR4, DQ8 haplotypes dominantly distributed among Jewish patients, and these plus DR6, DQ5 haplotypes in non-Jewish patients. Low levels of the PV antibody were found in 48% of a total of 120 asymptomatic parents, children, and siblings of 31 patients, thus exhibiting dominant inheritance. The inheritance of these low levels of antibody in asymptomatic relatives was linked to the major histocompatibility complex with a highly significant logarithm of the odds score of 9.07, almost always to a DR4 or DR6 haplotype of the patient. Disease appears to occur in susceptible individuals with low levels of antibody when a second factor, either environmental or genetic, induces high levels, sufficient to produce blisters.