Binding Of IgG Autoantibodies Research Articles

Chronic exposure to the anti-M3 muscarinic acetylcholine receptor autoantibody in pemphigus vulgaris contributes to disease pathophysiology

Pemphigus vulgaris (PV) is a potentially lethal autoimmune mucocutaneous blistering disease characterized by binding of IgG autoantibodies (AuAbs) to keratinocytes (KCs). In addition to AuAbs against adhesion molecules desmogleins 1 and 3, PV patients also produce an AuAb against the M3 muscarinic acetylcholine (ACh) receptor (M3AR) that plays an important role in regulation of vital functions of KCs upon binding endogenous ACh. This anti-M3AR AuAb is pathogenic because its adsorption eliminates the acantholytic activity of PV IgG; however, the molecular mechanism of its action is unclear. In the present study, we sought to elucidate the mode of immunopharmacologic action of the anti-M3AR AuAb in PV. Short-term exposures of cultured KCs to PV IgG or the muscarinic agonist muscarine both induced changes in the expression of keratins 5 and 10, consistent with the inhibition of proliferation and upregulated differentiation and in keeping with the biological function of M3AR. In contrast, long-term incubations induced a keratin expression pattern consistent with upregulated proliferation and decreased differentiation, in keeping with the hyperproliferative state of KCs in PV. This change could result from desensitization of the M3AR, representing the net antagonist-like effect of the AuAb. Therefore, chronic exposure of KCs to the anti-M3AR AuAb interrupts the physiological regulation of KCs by endogenous ACh, contributing to the onset of acantholysis. Since cholinergic agents have already demonstrated antiacantholytic activity in a mouse model of PV and in PV patients, our results have translational significance and can guide future development of therapies for PV patients employing cholinergic drugs.

Oral Pemphigus Vulgaris: A case report

Pemphigus vulgaris is an autoimmune blistering disease clinically presenting as vesicles, bullae and erosion on the skin and mucous membrane. Histopathologically, it is characterized by acantholy­sis and supra basilar split. The underlying mechanism causing intra epithelial split in pemphigus vulgaris is binding of IgG autoantibodies to desmoglin 3 which belongs to a transmembrane gly­coprotein adhesion molecule. Here we present a case of 27 years old male patient suffering from pemphigus vulgaris. This Case report highlights the importance of detailed case history, thorough clinical examination and appropriate investigation to reach a diagnosis of vesiculobullous lesion.

ORAL PEMPHIGUS VULGARIS: A CASE REPORT

Pemphigus vulgaris is an autoimmune blistering disease clinically presenting as vesicles, bullae and erosion on the skin and mucous membrane. Histopathologically, it is characterized by acantholy­sis and supra basilar split. The underlying mechanism causing intra epithelial split in pemphigus vulgaris is binding of IgG autoantibodies to desmoglin 3 which belongs to a transmembrane gly­coprotein adhesion molecule. Here we present a case of 27 years old male patient suffering from pemphigus vulgaris. This Case report highlights the importance of detailed case history, thorough clinical examination and appropriate investigation to reach a diagnosis of vesiculobullous lesion.

Pemphigus: Current and Future Therapeutic Strategies.

Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.

Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune astrocytopathies characterized by predominant involvement of the optic nerves and spinal cord. In most patients, an IgG autoantibody binding to astrocytic aquaporin 4, the principal water channel of the central nervous system, is detected. Rituximab, a chimeric monoclonal antibody specific for the CD20 B-lymphocyte surface antigen, has been increasingly adopted as a first-line off-label treatment for patients with NMOSDs. To perform a systematic review and a meta-analysis of the efficacy and safety of rituximab use in NMOSDs, considering the potential predictive factors related to patient response to rituximab in this disease. English-language studies published between January 1, 2000, and July 31, 2015, were searched in the MEDLINE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases. Patient characteristics, outcome measures, treatment regimens, and recorded adverse effects were extracted. Forty-six studies were included in the systematic review. Twenty-five studies that included 2 or more patients with NMOSDs treated with rituximab were included in the meta-analysis. Differences in the annualized relapse rate ratio and Expanded Disability Status Scale score before and after rituximab therapy were the main efficacy measures. Safety outcomes included the proportion of deaths, withdrawals because of toxic effects, and adverse effects. Among 46 studies involving 438 patients (381 female and 56 male [sex was not specified in 1 patient]; mean age at the outset of treatment, 32 years [age range, 2-77 years]), rituximab therapy resulted in a mean (SE) 0.79 (0.15) (95% CI, -1.08 to -0.49) reduction in the mean annualized relapse rate ratio and a mean (SE) 0.64 (0.27) (95% CI, -1.18 to -0.10) reduction in the mean Expanded Disability Status Scale score. A significant correlation was observed between disease duration and the Expanded Disability Status Scale score. Adverse effects were recorded in 114 of 438 (26%) patients treated with rituximab. Specifically, 45 patients (10.3%) experienced infusion-related adverse effects, 40 patients (9.1%) had an infection, 20 patients (4.6%) developed persistent leukopenia, 2 patients (0.5%) were diagnosed as having posterior reversible encephalopathy, and 7 patients (1.6%) died. This systematic review and meta-analysis provides evidence that rituximab therapy reduces the frequency of NMOSD relapses and neurological disability in patients with NMOSDs. However, the safety profile suggests caution in prescribing rituximab as a first-line therapy.

Physiopathologie de l’urticaire

Urticaria is a dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major mediator responsible for urticaria is histamine. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig) E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgEbound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50 % of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

Management of Suspected Pemphigus Vulgaris in Elderly Patient with Chronic Diseases

72 1024x768 Pemphigus vulgaris (PV) is a group of vesicobullous disease affecting skin and mucous membranes. PV is associated with autoimmune diseases, characterized by binding of IgG autoantibodies to desmoglein 3. PV lesion is a thin-walled bulla arising on the skin or mucosa. Oral mucous bulla are fragile and easily breakdown, forming irreguler ulcers. There are several factors that trigger PV, including genetic factors, age, drugs and food. This paper aimed to report treatment of suspected pemphigus vulgaris in elderly patient with history of chronic diseases. A 75-year-old woman with 2 months history of bulla formation on skin and history of persistent oral ulceration. Ulcers were covered with fibrin and erosive erythematous on labial, buccal and gingival mucosa. History of hypertension, diabetes mellitus and hepatitis was revealed. Routine complete blood count showed thrombocytopenia. Diagnosis was confirmed by anamnesis, clinical examination and complete blood investigation. PV should be distinguished from other vesicobullous disease. Systemic corticosteroid was given concurrently with hepato-protector, mouthwash, supportive therapy and topical lip cream. Bulla on skin and persistent erosive ulcers of the oral mucosa are the manifestations of PV. Elderly patient with history of chronic diseases showed a complex care of PV requiring more intensive and comprehensive treatment. DOI: 10.14693/jdi.v20i1.129

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice

Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

Intravenous neuromyelitis optica autoantibody in mice targets aquaporin-4 in peripheral organs and area postrema.

The pathogenesis of neuromyelitis optica (NMO) involves binding of IgG autoantibodies (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system (CNS). We studied the in vivo processing in mice of a recombinant monoclonal human NMO-IgG that binds strongly to mouse AQP4. Following intravenous administration, serum [NMO-IgG] decreased with t1/2 ∼18 hours in wildtype mice and ∼41 hours in AQP4 knockout mice. NMO-IgG was localized to AQP4-expressing cell membranes in kidney (collecting duct), skeletal muscle, trachea (epithelial cells) and stomach (parietal cells). NMO-IgG was seen on astrocytes in the area postrema in brain, but not elsewhere in brain, spinal cord, optic nerve or retina. Intravenously administered NMO-IgG was also seen in brain following mechanical disruption of the blood-brain barrier. Selective cellular localization was not found for control (non-NMO) IgG, or for NMO-IgG in AQP4 knockout mice. NMO-IgG injected directly into brain parenchyma diffused over an area of ∼5 mm2 over 24 hours and targeted astrocyte foot-processes. Our data establish NMO-IgG pharmacokinetics and tissue distribution in mice. The rapid access of serum NMO-IgG to AQP4 in peripheral organs but not the CNS indicates that restricted antibody access cannot account for the absence of NMO pathology in peripheral organs.

Pemphigus vulgaris—a case report and detailed review of literature

Pemphigus vulgaris is a common oral mucosal disease characterized by the occurrence of chronic multiple ulcerative lesions. Although exact etiology is not known, the underlying mechanism responsible for causing intra-epithelial lesion of pemphigus vulgaris is binding of IgG autoantibodies to desmoglein 3, a transmembrane glycoprotein adhesion molecule. The characteristic oral lesions of pemphigus vulgaris are thin-walled flaccid bullae arising on otherwise normal skin or mucosa. The bullae rupture and extend peripherally, giving a large area of denuded skin or mucosa. Here, we report a case of a 56-year-old female patient suffering from exacerbations and remissions of pemphigus vulgaris since last 2 years, with a detailed review of literature. The present case report emphasizes a need of detailed case history, thorough oral and systemic examination, investigative measures, and a proper treatment regimen.

Pemphigus Vulgaris: Application of Occlusal Soft Splint with Topical Steroid in the Treatment

Pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis with a high mortality rate if untreated. It is characterized by the binding of IgG autoantibodies to desmogleins 3 (DSG 3), a transmembrane glycoprotein adhesion molecule present on desmosomes. This glycoprotein strengthens the intercellular connection, and loss of this connection due to the antigen-antibody reaction weakens and finally breaks the connection between epithelial cells resulting in blisters and desquamation. Patients with PV mainly involving the mucosa have antibodies directed against DSG 3, but patients with PV involving both the skin and mucosa will have antibodies against both DSG 3 and DSG 1. Most patients are initially misdiagnosed and improperly treated for many months or even years. Dental professionals must be sufficiently familiar with the clinical manifestations of PV to ensure early diagnosis and treatment, since this in turn determines the prognosis and course of the disease.

IgE autoantibodies against the intracellular domain of BP180

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. BP not only involves IgG-mediated neutrophil activation, leading to blistering, but also IgE-dependent activation of mast cells and basophils. While IgG and IgE autoantibodies target the extracellular noncollagenous (NC) 16A domain of BP180, little is known whether other BP180 regions are targeted by these antibody classes. To characterize IgE and IgG autoantibody binding to antigenic sites on the intracellular domain (ICD) of BP180 compared with BP180 NC16A. IgE/IgG autoreactivity against recombinant BP180 ICD and NC16A was determined by immunoblotting of sera from 18 patients with BP and 10 controls. Total serum IgE was elevated in 16 of 18 BP sera. Most BP sera tested positive (15 of 18) to NC16A with both immunoglobulin classes. Additionally, 14 of 18 sera showed IgE reactivity with an epitope mapped to the ICD of BP180 (amino acid residues 103-266). Mapping of ICD antigenic sites revealed similar IgE and IgG reactivities for most regions except for greater IgE reactivity to amino acid residues 234-398 (11 of 18 BP sera) than IgG (five of 18). Control sera failed to display IgE reactivity to these antigens. The results indicate that BP180 NC16A is not the only antigenic determinant of IgE autoantibodies in BP and that additional, novel epitopes exist on different regions of the ICD of BP180. The heterogeneous autoimmune response against BP180 suggests intramolecular epitope spreading during disease progression.

Pathophysiology of Urticaria

Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig)E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgE-bound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

Anti‐laminin 5 mucous membrane pemphigoid

A 70-year-old patient presented erosions on the oral mucosa and skin, predominantly in perianal and inguinal areas. Histopathologically, subepidermal blistering was observed. By direct immunofluorescence microscopy, linear deposits of IgG and C(3) were seen at the dermal-epidermal junction. By indirect immunofluorescence microscopy, binding of IgG autoantibodies to the dermal side of NaCl-split skin was detected. These autoantibodies were shown to target both the non-processed and processed alpha(3)- as well as the beta(3)-subunit of laminin 5 by immunoblot analysis using extracellular matrix of cultured human keratinocytes. Based on these results, the diagnosis of an anti-laminin 5 mucous membrane pemphigoid was established. Oral treatment with dapsone, combined with intravenous dexamethasone pulse therapy, led to rapid improvement.

Schleimhautpemphigoid mit Autoantikörpern gegen Laminin 5

A 70-year-old patient presented erosions on the oral mucosa and skin, predominantly in perianal and inguinal areas. Histopathologically, subepidermal blistering was observed. By direct immunofluorescence microscopy, linear deposits of IgG and C 3 were seen at the dermal-epidermal junction. By indirect immunofluorescence microscopy, binding of IgG autoantibodies to the dermal side of NaCl-split skin was detected. These autoantibodies were shown to target both the non-processed and processed α 3 - as well as the β 3 -subunit of laminin 5 by immunoblot analysis using extracellular matrix of cultured human keratinocytes. Based on these results, the diagnosis of an anti-laminin 5 mucous membrane pemphigoid was established. Oral treatment with dapsone, combined with intravenous dexamethasone pulses, led to a rapid improvement.

Serum IgM, IgG and IgA block by F(ab′)2‐dependent mechanism the binding of natural IgG autoantibodies from therapeutic immunoglobulin preparations to self‐antigens

Natural polyreactive IgG autoantibodies are present in the plasma of healthy individuals and as a result in pooled therapeutic intravenous immunoglobulin (i.v.Ig) preparations. The spectrum of self-antigens to which these autoantibodies bind, their fate after intravenous infusion and their biological activity are not well understood. The identity of serum proteins that mask binding of natural autoantibodies to self-proteins is a matter of controversy. The spectrum of native serum proteins bound by i.v.Ig was analyzed by two-dimensional electrophoresis. The reactivity of i.v.Ig was directed mainly to circulating immunoglobulins. The binding of the IgG autoantibodies from i.v.Ig to native human liver antigens was blocked not only by a F(ab')2-dependent mechanism by circulating IgM and IgG (as has been previously suggested), but also by serum IgA. This control of anti-self reactivity may be inefficient in some autoimmune diseases.

Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes

Pemphigus vulgaris (PV) is an autoimmune disease characterized by binding of IgG autoantibodies to epidermal keratinocyte desmosomes. IgG autoantibodies obtained from a patient with mucocutaneous PV reacted with plakoglobin (Plkg) in addition to desmoglein-3 (Dsg3) and Dsg1. Immunofluorescence analysis confirmed that IgG autoantibodies, unlike antibodies from a healthy volunteer, caused disruption of cell–cell contacts in HaCaT keratinocytes. Moreover, apoptosis was enhanced in cells treated with autoantibodies compared to those treated with normal antibodies. The apoptotic process induced by IgG autoantibodies was characterized by caspase-3 activation, Bcl-2 depletion and Bax expression. The present report demonstrates that PV IgG autoantibodies promote apoptosis in HaCaT keratinocytes.

Characterization of autoantibodies from patients with Goodpasture's disease using a resonant mirror biosensor.

Goodpasture's disease is characterized by the binding of IgG autoantibodies to the glomerular basement membrane, leading to glomerular inflammation. The autoantigen has been identified as the noncollagenous domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). We have used the IAsys resonant mirror biosensor to analyse the extent and affinity of binding of anti-GBM antibodies from sera of patients to purified alpha3(IV) NC1. alpha3(IV) NC1 monomers were immobilized to a carboxylate cuvette, with the simultaneous use of a control well. The binding of serum from patients with Goodpasture's disease (n = 12), normal controls (n = 14) and disease controls with vasculitis (n = 14) was analysed. Antibody binding was detected in sera from all patients with Goodpasture's disease but not from controls. IAsys measurements of binding correlated with antibody levels assessed by the standardized ELISA used for clinical assays. Both ELISA and biosensor measurements showed declining antibody levels in serial serum samples from treated patients; however, the biosensor detected antibody recrudescence when ELISA remained negative. Autoantibodies from patients' serum had average affinity constants (Kd) of 6.5 x 10-11M to 52.07 x 10-10M, as determined by an inhibition assay, indicating high affinity. Sips analysis showed that the antibody response was relatively homogeneous (values of 0.46-1). Biosensor techniques can therefore be used to detect and characterize anti-GBM antibodies in serum from patients, with high sensitivity and without need for antibody purification. This technique may be useful in diagnosis and monitoring of patients with Goodpasture's disease, and may be applicable to other autoantibody mediated diseases.

Reduction in glomerular heparan sulfate correlates with complement deposition and albuminuria in active Heymann nephritis.

In a time-study of active Heymann nephritis, the expression of agrin, the main heparan sulfate proteoglycan in the glomerular basement membrane, was analyzed in relation to deposition of IgG and complement in the glomerular capillary wall and the development of albuminuria. Binding of IgG autoantibodies to the glomerular capillary wall could be detected from 2 wk onward, followed by activation of complement after 6 wk. Progressive albuminuria developed from 6 wk onward to a level of 274+/-68 mg/18 h at week 12. The staining intensity for the agrin core protein decreased slightly, and the staining intensity for the heparan sulfate stubs that were still attached to the core protein after heparitinase digestion remained normal. From week 6 onward, however, a progressive decrease was seen in the staining of two monoclonal antibodies (mAb) directed against different epitopes on the heparan sulfate polysaccharide side chain of agrin (to 35 and 30% of the control level, respectively, at week 12, both mAb P = 0.016). Moreover, albuminuria was inversely correlated with heparan sulfate staining as revealed by these antibodies (r(s) = -0.82 and r(s) = -0.75, respectively, both mAb P < 0.0001). This decrease in heparan sulfate staining was due to a progressive reduction of glomerular heparan sulfate content to 46 and 32% of control level at week 10 and week 12 of the disease, respectively, as measured biochemically. It is speculated that the observed decrease in glomerular heparan sulfate in active Heymann nephritis is due to complement-mediated cleavage of heparan sulfate, resulting in an increased permeability of the glomerular basement membrane to macromolecules.

Coexistence of psoriasis and an unusual IgG-mediated subepidermal bullous dermatosis: identification of a novel 200-kDa lower lamina lucida target antigen

Bullous pemphigoid (BP) is characterized by autoantibodies against 230- and 180-kDa hemidesmosomal antigens located in the most superficial layers of the basement membrane zone (BMZ). Histologically, there is a predominance of eosinophils in the infiltrate. In a psoriatic patient, we identified an unusual autoimmune subepidermal bullous eruption which clinically resembled BP, but which was characterized by IgG autoantibodies against a novel 200-kDa lower lamina lucida component. Histologically there was a predominance of neutrophils in the infiltrate. Direct immunofluorescence showed linear immunoglobulin (Ig)G and C3 deposition at the BMZ. The patient's IgG autoantibodies bound exclusively to the dermal side of salt-split normal human skin. Indirect immunogold electron microscopy showed a marked deposition of IgG at the lower lamina lucida and minimal deposition at the hemidesmosomes. Immunoblot analysis identified a unique 200-kDa autoantigen in dermal extracts and a faint band of the 230-kDa BP antigen in epidermal extracts. The patient responded dramatically well to cyclosporin A. Although the patient's serum also reacted slightly with the 230-kDa BP antigen, there were significant findings different from the usual immunopathological changes of BP. These included finding a novel 200-kDa lower lamina lucida target antigen, the binding of IgG autoantibodies exclusively to the dermal side of the split skin and a predominance of neutrophils in blister infiltrate. The IgG autoantibodies against the 200-kDa lamina lucida target antigen seemed to play a major role in the pathogenesis of this unique autoimmune subepidermal dermatosis.