Autoimmune Subepidermal Blistering Disorder Research Articles

Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature

BackgroundBullous pemphigoid is the most common autoimmune subepidermal blistering disorder with a low incidence in childhood. Combined immunodeficiencies (CIDs) are a group of monogenic inborn errors of immunity (IEIs) characterized by T- and B-cell dysfunction leading to recurrent infections, lymphoproliferation, predisposition to malignancy, and autoimmunity. Here, we report two Afghan siblings with a diagnosis of CID and extremely rare manifestation of diffuse bullous pemphigoid skin lesions.Case presentationThe older sibling (patient 1) was a 32-month-old male with facial dysmorphism, protracted diarrhea, failure to thrive, recurrent oral candidiasis, recurrent otitis media with tympanic membrane perforation, who had been previously diagnosed with CID. While he was under treatment with intravenous immunoglobulin (IVIg), he developed extensive blistering lesions, which were diagnosed as childhood bullous pemphigoid. Methylprednisolone and azathioprine were added to the regimen, which resulted in a remarkable improvement of the skin lesions and also the feeding condition. However,2 weeks later, he was re-admitted to the intensive care unit (ICU) and eventually died due to fulminant sepsis. Later, his 12-month-old sister (patient 2) with similar facial dysmorphism and a history of developmental delay, food allergy, recurrent oral candidiasis, and respiratory tract infections also developed blistering skin lesions. She was under treatment for occasional eczematous lesions, and had been receiving IVIg for 3 months due to low levels of immunoglobulins. Further immunologic workup showed an underlying CID and thus treatment with IVIg continued, gradually improving her clinical condition. The genetic study of both siblings revealed a novel homozygous mutation in exon 7 of the PGM3 gene, c.845 T > C (p.Val282Ala).ConclusionsDermatologic disorders may be the presenting sign in patients with CID and mutated PGM3. This case report further extends the spectrum of skin manifestations that could be observed in PGM3 deficiency and emphasizes the importance of considering CIDs during the assessment of skin disorders, particularly if they are extensive, recurrent, refractory to treatment, and/or associated with other signs of IEIs.

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients.

Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs.

Emerging Biomarkers and Therapeutic Strategies for Refractory Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in the elderly. Systemic and topical use of glucocorticoids and immunosuppressants has been shown to be effective in most patients. However, refractory BP patients are challenged to clinicians with severe clinical symptoms, resistance to treatment, and high relapse rate. How to predict and assess the refractory and severity of bullous pemphigoid is the key issue in clinical practice, and the urgent need for precision medicine in refractory patients is driving the search for biomarkers and biologics. Recently, some biomarkers, such as the level of specific autoantibodies and released cytokines, have been proposed as the potential parameters to reflect the disease severity and predict the treatment response and relapse of refractory BP. Moreover, new biologics targeting pathogenic antibodies, complement, Th2 axis, eosinophils, and Th17 axis have shown potent efficacy on refractory BP. Here, we review the literature and give an overview of emerging biomarkers and therapeutic strategies for refractory bullous pemphigoid to improve the prognosis of the patient.

27154 Lichen planus pemphigoides in a patient recently started on lisinopril

Background: Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal blistering disorder with autoantibodies to BP180. Lesions of lichen planus (LP) are seen in combination with tense blisters most often involving sites not affected by LP. In contrast to bullous pemphigoid patients are generally younger and the clinical course is usually shorter and less severe.

Omalizumab: an underutilized treatment option in bullous pemphigoid patients with co‐morbidities

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disorder commonly affecting the elderly in the age group of 60-80 years.1 IgG autoantibodies against the hemidesmosomal proteins BP180 and BP 230 have been deemed central in pathogenesis. However, IgE also appears to be important in pathogenesis and targeting IgE autoantibodies may be an interesting and effective treatment option.

Diagnosis of autoimmune subepidermal bullous diseases with mucous membrane involvement based on laser-scanning confocal microscopy.

Mucosal involvement in autoimmune subepidermal blistering disorders (ASBD) may represent the only or predominant localization. Circulating autoantibodies are detected in 50% cases. The aim of this study was to evaluate the usefulness of fluorescence overlay antigen mapping by laser-scanning confocal microscopy (FOAM-LSCM) to identify ASBD with mucosal involvement in oral mucosa specimens. Thirty-two ASBD patients, diagnosed based on direct immunofluorescence between 2006 and 2016, were enrolled. Localization of IgG deposits bound at the basement membrane zone, relative to laminin-332 and collagen IV localization, was assessed in vivo. FOAM-LSCM disclosed four different immunofluorescence patterns. IgG deposits were located above laminin-332, as in bullous pemphigoid (BP-type), in 19% cases and co-localized with laminin-332 (anti-laminin-332-type) in 6% cases. IgG deposits were found below laminin-332 and above collagen IV (mucous membrane pemphigoid-type) in 59% cases, and below collagen IV (epidermolysis bullosa acquisita-type) in 16%. Circulating antibodies were found in 56% cases. The FOAM-LSCM method should be used in order to obtain a definitive diagnosis of ASBD with mucosal involvement, particularly in the presence of negative circulating antibodies.

Fc‐binding proteins enhance autoantibody‐induced BP180 depletion in pemphigoid

Immunoglobulins (Igs) consist of two antigen-binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for the Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc-binding proteins on the pathogenicity of antibody-induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune subepidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non-collagenous NC16A domain of the 180-kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, mAb against NC16A in combination with Fc-binding proteins was found to enhance BP180 depletion. Although mAb against the C-terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc-binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti-BP180 mAbs and Fc-binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti-BP180 mAb in combination with high-titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc-binding proteins than controls. Our results suggest that Fc-binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Malignancies in bullous pemphigoid: A controversial association.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disorder that has been reported to be associated with malignancies. Some authors described several cases of pemphigoid associated with malignancies (PAM); however, the evidence of this correlation still remains controversial. Several theories have been postulated to explain the relationship between malignant neoplasms and BP; the main theory suggests that antibodies directed against tumor-specific antigens of malignant cells may cross-react with antigens (like BP antigens) in the basement membrane zone leading to the formation of blisters. We performed an extensive review of the English published work focusing on the epidemiology, the pathogenetic theories and the clinical and histological aspects of the disease. We identified 40 cases of PAM: of these, seven cases were associated with hematological malignancies and 33 with solid tumors. Physicians should be aware of the existence of PAM and we suggest an oncological screening in early-onset pemphigoid, in patients with a former oncological history, in those with signs and symptoms that could be related to a neoplasm and in BP refractory to common immunosuppressive therapy.

Association of bullous pemphigoid with malignancy: a myth or reality?

Bullous pemphigoid (BP) is an autoimmune sub-epidermal blistering disorder of the skin. The association of BP with internal malignancy has always been a matter of debate with no consensus reached despite many published case reports and clinical trials. However, we report a hitherto unreported association of BP with squamous cell carcinoma of the tongue, wherein the patient had a recalcitrant downhill course despite adequate treatment measures with control of skin lesions being achieved only following excision of the tumor, and relapse coinciding with detection of metastasis. Hence, given the clinical behavior, it is reasonable to speculate that the association of malignancy was more than co-incidental.

Linear IgA bullous dermatosis

Linear IgA disease is a rare chronic autoimmune subepidermal blistering disorder characterized by the linear deposition of IgA along the dermoepidermal junction. A 40-year-old housewife presented with symmetrically distributed generalized intensely pruritic vesiculobullous lesions of 1 year duration. Previous treatment with oral and topical steroids had induced only a temporary remission of the skin lesions. There was no history of drug intake in the recent past and her medical history was insignificant and there was no similar illness in her family members. Examination findings included vesicles arranged at the periphery of healed lesions along with post-inflammatory hyperpigmented macules on the trunk and extremities. There was no genital, mucosal or ocular involvement. Skin biopsy from the leg showed dense neutrophilic infiltration along with eosinophils at the tip of the dermal papillae and focal areas showed dermoepidermal clefting with bulla formation. Direct immunofluorescence of perilesional skin revealed linear deposits of IgA at the basement membrane zone. Therapeutically the patient responded well to dapsone. Though the presentation was classical, the case is reported for its rarity.

Postpartum pemphigoid gestationis

Pemphigoid gestationis (PG) or herpes gestationis is a rare autoimmune subepidermal blistering disorder associated with pregnancy. The condition typically develops during the second or third trimester of pregnancy, but has been rarely reported in the first trimester and postpartum period. Here, we report a case of PG that presented for the first time in the postpartum period, associated with a low birth weight baby.

IgA Anti-p200 Pemphigoid

Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disorder. Clinically, it may resemble bullous pemphigoid, linear IgA bullous dermatosis, or dermatitis herpetiformis. Immunologically, anti-p200 pemphigoid is characterized by the development of IgG antibodies directed against a basement membrane zone protein with a molecular weight of 200 kDa. We report the first case, to our knowledge, of anti-p200 pemphigoid associated with IgA antibodies and having clinical features resembling pemphigus herpetiformis or dermatitis herpetiformis localized on traumatized areas. Histopathological examination of lesional skin showed dermal-epidermal separation and microabscesses composed of neutrophils in the dermal papillae. Direct immunofluorescence disclosed the presence exclusively of linear in vivo-bound IgA along the basement membrane zone. With the use of laser scanning confocal microscopy, in vivo-bound IgA was localized above collagen type IV and colocalized with laminin 332. Indirect immunofluorescence showed circulating IgA antibodies against basement membrane zone at a titer of 1:160 that reacted with the floor of an artificial blister of salt-split skin. Western immunoblot analysis using dermal extract confirmed the reactivity of circulating IgA antibodies with the 200-kDa antigen corresponding to laminin γ1; however, immunoblotting using recombinant protein of 107 amino acid C-terminus of laminin γ1 was negative for circulating IgA antibodies. Immunoelectron microscopy disclosed the reactivity of circulating IgA autoantibodies within the lower lamina lucida. To the best of our knowledge, this is the first case fulfilling the immunopathological criteria for anti-p200 pemphigoid associated with IgA antibodies and having unusual clinical features.

Bullous Pemphigoid and Percutaneous Endoscopic Gastrostomy

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disorder. It is rare in the general population but the prevalence was reported to be relatively high among the elderly in nursing homes. The aim of the study was to analyze the clinical characteristics and risk factor for BP in elderly patients with a long hospital stay. This was a retrospective survey with 36 hospitalized patients, aged 64 to 101 years, staying more than 2 years from July 2005 to April 2009. We encountered 5 newly occurring BP cases during this survey period and the remaining 31 patients were non-BP cases. All of these subjects were disabled elderly patients because of cerebral stroke, etc. We assessed the clinical variables as follows: age, sex, underling disease of hospitalization, length of hospital stay, feeding method, medication, tracheal tube indwelling and frequency of death and compared these 2 groups. All of the patients underwent enteral feeding by percutaneous endoscopic gastrostomy (PEG) or nasogastric (NG) tube. In the univariate analysis, PEG and tube feeding (PEG and NG) were associated with BP (p<0.05). The multivariate logistic and Cox proportional hazard regression analysis were performed with age, sex (elderly female is well known feature of BP) and PEG or tube feeding, demonstrating only PEG was significantly and independently associated with BP (p<0.05). We found that PEG was significant risk factor for BP. Since the sample size was small in this survey, further study is required. Greater awareness of BP is needed for physicians managing institutionalized elderly patients with PEG.

Linear IgA bullous dermatosis induced by interferon-α 2a

Linear Ig A bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering disorder with linear deposits of IgA along the basement membrane zone. Its cause is unclear, although it appears to have an immune-mediated basis. Idiopathic, systemic disorder-related, and rarely drug-induced forms of LABD have been described. We describe a case of LABD associated with interferon-alpha 2A used for the treatment of Kaposi's sarcoma.

Epidermolysis bullosa acquisita: concise review and practical considerations

Introduction Epidermolysis bullosa acquisita (EBA) is a cutaneous subepi-dermal autoimmune blistering disorder (CSEAIBD) that resultsfrom the effects of IgG autoantibodies directed against the145-kDa noncollagenous amino-terminal (NC-1) domain ofcollagen VII, a major component of anchoring fibrils (Fig. 1).

The role of collagen IV immunomapping in the evaluation of cutaneous autoimmune subepidermal blistering disorders

The role of collagen IV immunomapping in the evaluation of cutaneous autoimmune subepidermal blistering disorders

Rituximab in Treatment-Resistant Autoimmune Blistering Skin Disorders

Autoimmune blistering diseases are associated with autoantibodies to desmosomal (pemphigus group) or hemidesmosomal proteins (autoimmune subepidermal blistering disorders) that are essential for the structural integrity of the epidermis and dermoepidermal junction. Treatment is usually based on systemic glucocorticosteroids, which are often combined with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators including dapsone, antibiotics, and intravenous immunoglobulins. These interventions are sometimes not sufficient to induce remission and/or may be associated with intolerable adverse events. In such situations, the anti-CD20 antibody rituximab has been successfully applied in recent years. Rituximab transitorily depletes CD20-positive B lymphocytes from the circulation. It has been employed in more than 1 million patients with CD20-positive non-Hodgkin's lymphoma and severe side effects were only rarely observed. Subsequently, the B cell-modulating effect of rituximab has encouraged its use in a variety of autoimmune diseases, including more than 40 patients with pemphigus. In addition, a few patients with bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa acquisita have received rituximab. In the majority of these patients, clinical remission was induced; however, serious adverse events were considerable higher compared to both patients with non-Hodgkin's lymphoma or nonbullous autoimmune disorders like lupus erythematosus, dermatomyositis, and rheumatoid arthritis.

Childhood bullous pemphigoid treated by i.v. immunoglobulin

Bullous pemphigoid is an acquired autoimmune subepidermal blistering disorder mostly seen in the elderly. Childhood bullous pemphigoid is very rare. For the first time we report a case of childhood bullous pemphigoid associated with infantile eczema. Two weeks after a routine vaccination, a 3.5-month-old boy with infantile eczema developed a generalized blistering disorder. Histopathology revealed a subepidermal blister. Direct immunofluorescence showed linear depositions of C3 along the basement membrane zone. Indirect immunofluorescence studies demonstrated the presence of circulating immunoglobulin G antibodies directed against the epidermal side of salt-split skin. Enzyme-linked immunosorbent assay demonstrated serum level of anti-BP180 antibody elevated. The patient was successfully treated by high-dose i.v. immunoglobulin.

Role of T cells in the pathogenesis of mucous membrane pemphigoid

There are a number of autoimmune subepidermal blistering disorders in which the presence of autoantibodies has been well documented. These include pemphigoid gestationis, linear immunoglobulin A disease, bullous pemphigoid, lichen planus pemphigoides and mucous membrane pemphigoid. The antibodies involved in these diseases are commonly directed against protein components of the basement membrane zone. The requirement for T cells in the production of autoantibodies, the infiltration of T cells into lesions and HLA-associations have led to a number of investigations into the role of T cells in these diseases. This review will concentrate on the evidence for the role of T cells in the pathogenesis of mucous membrane pemphigoid.

Naproxen-Associated Linear IgA Bullous Dermatosis: Case Report and Review

Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering disorder in which linear deposits of IgA are found along the basement membrane. Idiopathic, systemic disorder-related, and drug-induced forms of LABD have been described. Drug-induced LABD occurs in association with drug administration and resolves when the offending agent is discontinued. Other forms of LABD assume a more chronic course. The nonsteroidal anti-inflammatory drugs piroxicam and diclofenac have been previously reported to induce LABD. To our knowledge, this article describes the first documented case of LABD associated with naproxen administration, which resolved after discontinuation of the drug.