The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.     

Pemphiguserkrankungen bei Kindern und Jugendlichen

The pemphigus diseases, which include some of the most severe bullous autoimmune skin reactions, are seen predominantly in middle-aged and elderly individuals. Only endemic pemphigus foliaceus in South America most frequently affects juveniles and children. All non-endemic pemphigus diseases, including paraneoplastic pemphigus, have been reported to occur in adolescents and even very rarely in children younger than 10 years. Pemphigus vulgaris in pregnancy represents a frequently overseen medical problem and may result in fetal growth retardation, intrauterine death, premature delivery and – in about 30% – in neonatal pemphigus vulgaris of the newborn. Contrary to pemphigus vulgaris, the transplacental crossing of autoantibodies against desmoglein1 in pregnant women with pemphigus foliaceus hardly ever leads to neonatal skin lesions in the offspring. This phenomenon can be explained by differences in the distribution and cross-compensation of the pemphigus antigens desmoglein3 and 1 in neonatal and adult skin or mucosa, respectively.     

Autoantibodies against desmoglein 2 are not pathogenic in pemphigus

BackgroundAnti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical.ObjectiveTo compare the participation of desmogleins 1, 2 and 3 through the production of serum autoantibodies, and protein and gene expression in the skin/mucosa of patients with pemphigus foliaceus and pemphigus vulgaris.MethodsThe autoantibodies were titrated by ELISA in 202 samples of pemphigus foliaceus, 131 pemphigus vulgaris, 50 and 57 relatives of patients with pemphigus foliaceus and pemphigus vulgaris, respectively, and 114 controls. Protein and gene expressions were determined by immunohistochemistry and qPCR in the skin/mucosa of 3 patients with pemphigus foliaceus and 3 patients with pemphigus vulgaris.ResultsHigher titers of anti-desmoglein 2 (optical density) resulted in pemphigus foliaceus and pemphigus vulgaris, when compared to controls (0.166; 0.180; 0.102; respectively; p < 0.0001). There was a correlation between anti-desmoglein 2 and anti-desmoglein 1 titers in pemphigus foliaceus (r = 0.1680; p = 0.0206). There was no cross-reaction of anti-desmoglein 2 with desmoglein 1 and 3. Protein overexpression of desmoglein 2 was observed in intact and lesional skin of patients with pemphigus compared to the skin of controls. Internalization granules of desmoglein 1 and 3, but not of desmoglein 2, were observed in lesions of pemphigus foliaceus and pemphigus vulgaris, respectively. Gene overexpression of desmoglein 2 was observed in the mucosa.Study limitationsSmall sample size for the statistical analysis of protein and gene expression.ConclusionAutoantibodies against desmoglein 2 are not pathogenic in pemphigus; protein and gene overexpression of desmoglein 2 in the skin and mucosa may be involved in acantholysis repair.     

Intercellular IgA dermatosis (IgA pemphigus)--two cases illustrating the clinical heterogeneity of this disorder

IgA pemphigus is rare but may be underdiagnosed. We describe two cases, a 50-year-old female with a pustular eruption resembling subcorneal pustular dermatosis and a 55-year-old male with a pruritic vesiculopustular eruption simulating dermatitis herpetiformis. They illustrate the clinical heterogeneity of IgA pemphigus which is likely to reflect differences in autoantigens, analogous to pemphigus vulgaris and pemphigus foliaceus. There is now evidence that IgA pemphigus encompasses at least two subgroups: a subcorneal pustular dermatosis (SPD)-type, (see case 1) characterized by subcorneal pustules and autoantibodies to desmocollin 1; and intra-epidermal neutrophilic dermatosis (IEN)-type cases (see case 2) which show intra-epidermal pustules and in whom the autoantigen may be desmoglein 3, the pemphigus vulgaris antigen.     

Childhood Pemphigus Foliaceus with Exclusive Immunoglobulin G Autoantibodies to Desmocollins

Pemphigus refers to a group of potentially fatal blistering skin diseases that are often due to the deleterious effects of autoantibodies directed against desmosomal antigens. Although desmogleins have been mainly implicated as autoantigens in pemphigus, a steadily growing body of evidence suggests that other desmosomal proteins may be causally involved as well. Antibodies directed against desmocollin‐3 have been shown to play a direct role in the pathogenesis of several types of pemphigus. Here we describe the case of a child with localized pemphigus foliaceus and immunoglobulin G (IgG) reactivity exclusively directed to desmocollins. The present report suggests that autoantibodies against nondesmoglein antigens may play a role in the pathogenesis of superficial pemphigus, in addition to pemphigus vulgaris, paraneoplastic pemphigus, and IgA pemphigus.     

Autoantibodies against desmocollins in European patients with pemphigus

Background. Autoimmune bullous disorders of the pemphigus group are characterized by autoantibodies targeting desmoglein (Dsg)1, Dsg3 and Dsg4 and occasionally, desmocollin (Dsc)1, Dsc2 and Dsc3. Both Dsg and Dsc are components of desmosomal adhesion complexes. Aim. To investigate the presence of IgG and IgA autoantibodies against Dsc1, Dsc2 and Dsc3 in a cohort of patients with bullous disorders. Methods. IgG and IgA autoantibodies against Dsc1, Dsc2 and Dsc3 were investigated by ELISA and immunoblotting analysis in a cohort of European patients with pemphigus vulgaris (PV; n = 74), IgA pemphigus (n = 3), paraneoplastic pemphigus (PNP; n = 3) and two cases of atypical pemphigus (n = 2). Results. Of the two cases with atypical pemphigus, one showed IgA reactivity against Dsc1 and Dsc3 and weak reactivity against Dsc2, and the other showed both IgG and IgA reactivity against Dsc1. One patient with IgA pemphigus had IgA autoantibodies against Dsc1, Dsc2 and Dsg1, and one patient with PNP had IgG reactivity against with Dsc3. In contrast, all the PV sera showed IgG reactivity against Dsg3 but not against Dsc1–3. Thus, IgG and IgA reactivity against Dsc was restricted to cases of PNP, IgA pemphigus and atypical pemphigus. Conclusions. These findings support the concept that desmocollins are not important autoantigens in PV.     

Pemphigus vegetans Neumann type with anti-desmoglein and anti-periplakin autoantibodies

Pemphigus vegetans is a rare variant of pemphigus vulgaris characterized by vegetating lesions in the folds and mouth and by the presence of autoantibodies against desmoglein 3. We describe two Caucasian patients with pemphigus vegetans, one of them presented antibodies to desmoglein 3 and 1 and the other one to desmoglein 3. Both patients also had circulating antibodies against a 190 kDa protein co-migrating with periplakin. Anti-periplakin reactivity is usually detected in paraneoplastic pemphigus, while it has never been reported in pemphigus vegetans. Our observation enlarges the spectrum of autoantibodies which may be associated with pemphigus vegetans. However, the pathophysiological significance of anti-periplakin reactivity in this pemphigus variant remains to be determined.     

Non-pathogenic anti-desmoglein 3 IgG autoantibodies in Fogo Selvagem

The endemic form of pemphigus foliaceus, fogo selvagem, is caused by IgG autoantibodies directed against desmoglein 1 (Dsg1). Hilario-Vargas and his colleagues describe a high prevalence of IgG autoantibodies against Dsg3, the target antigen of pemphigus vulgaris, in a Brazilian population where fogo selvagem is endemic, although those patients do not develop any apparent clinical phenotype of pemphigus vulgaris.     

Spectrum of autoantibodies other than anti‐desmoglein in pemphigus patients

Background Pemphigus is a life‐threatening autoimmune blistering disease mediated by autoantibodies against adhesion molecule of the skin. Its concurrence with systemic and organ‐specific autoimmune disease was described in case reports. Objectives To evaluate the presence of a broad spectrum of organ‐specific and non‐organ‐specific autoantibodies other than anti‐desmoglein antibodies in pemphigus patients. Patients and methods Serum samples were obtained from 105 pemphigus foliaceus (PF) patients, 51 pemphigus vulgaris (PV) patients and 50 controls. Both indirect immunofluorescence assay and ELISA were used to assess the presence of autoantibodies related to connective tissue diseases, autoimmune hepatitis, vasculitis, rheumatoid arthritis, coeliac disease, diabetes and thyroiditis. Results Significant difference was observed between the three groups for anti‐thyroglobulin antibodies in the pemphigus foliaceus group (18% vs. 4%, P = 0.03). A significantly higher occurrence of IgM anti‐cardiolipin (P = 0.03), IgG anti‐reticulin (P = 0.01) and IgG anti‐gliadin antibodies (P = 0.008) were observed in the PV group. Cases with more than four autoantibodies were frequently positives for both anti‐desmoglein 1 and anti‐desmoglein 3. Conclusion Autoantibodies other than anti‐desmoglein antibodies are not rare in pemphigus patients. Clinical and serological follow‐up of pemphigus patients with positive autoantibodies are needed to clarify their impact in disease evolution.     

Comparative study of pemphigus vulgaris and pemphigus foliaceus in Singapore

This is a retrospective study of all patients diagnosed to have pemphigus in our centre over a 3 year period. The case records of all patients with pemphigus from January 1995 to December 1997 were analysed. Fifty patients were diagnosed to have pemphigus during the study period. The diagnoses were pemphigus vulgaris in 31 patients, pemphigus foliaceus in 16, paraneoplastic pemphigus in two and IgA pemphigus in one. The average titre of anti-intercellular antibodies in patients with pemphigus vulgaris (1:96) was higher than the titre in patients with pemphigus foliaceus (1:69). The average initial dose of prednisolone required for disease control in patients with pemphigus vulgaris (62 mg/day) was significantly higher than that required for patients with pemphigus foliaceus (44 mg/day). In our study population, pemphigus vulgaris is a more severe and chronic disease than pemphigus foliaceus, as reflected in the higher titre of anti-intercellular antibodies, higher dose of systemic corticosteroids required for control of the disease, the longer duration to achieve complete remission and longer follow-up period.     

IgA pemphigus

Pemphigus is a life-threatening autoimmune blistering disease. Pemphigus is divided into 4 major types; pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and IgA pemphigus. Among them, IgA pemphigus is characterized by tissue-bound and circulating IgA antibodies targeting desmosomal or nondesmosomal cell surface components in the epidermis. Histopathologically, slight epidermal acantholysis and extensive neutrophilic infiltration in either the upper part or all layers of the epidermis were observed. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still unknown (probably nondesmosomal cell surface protein), and subcorneal pustular dermatosis-type (SPD-type), whose target antigen is desmocollin 1 (Dsc1). We summarize reported cases of IgA pemphigus and describe current knowledge including epidemiology, clinical manifestations, pathology, laboratory tests, pathophysiology, associated diseases, prognosis and treatment, and future perspectives of IgA pemphigus.     

Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients.

Pemphigus refers to a group of autoimmune blistering skin diseases, mainly identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by the presence of autoantibodies against keratinocyte adhesion molecules, leading to loss of cell-cell adhesion with consequent blister formation. Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4. We here report human leukocyte antigen molecular typing on a total of 87 patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128 healthy matched controls. Generic typing showed an increase of DRB1*04 and DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a highly significant association between the DRB1*1401 and both pemphigus vulgaris (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001; pemphigus foliaceus p < 0.0001). Moreover, whereas the association between DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant association between a specific allele of the DR4 group and pemphigus foliaceus, has been found. Therefore, at least in Italian patients, pemphigus vulgaris and pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte antigen alleles, whereas DRB1*0402 is only found associated with pemphigus vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus foliaceus, carry the same susceptible human leukocyte antigen alleles has been interpreted as a common genetic background predisposing to pemphigus as, like in other autoimmune disorders, it is not sufficient to explain the onset of the disease on the basis of the sole aforementioned alleles. Other linked genes and/or environmental factors should play a facilitating role in the outbreak of pemphigus, either pemphigus vulgaris or pemphigus foliaceus.     

Pemphigus,a pathomechanism of acantholysis

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti‐desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti‐desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling‐dependent and signalling‐independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.     

Management of the immunobullous disorders. II. Pemphigus

In the second of our reviews on the management of the immunobullous disorders, we review the therapy of pemphigus disorders, including pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, pemphigus herpetiformis, drug-induced pemphigus, IgA pemphigus and paraneoplastic pemphigus.     

Blistering diseases in the mature patient

Autoimmune blistering diseases (AIBD) are a group of chronic diseases affecting the skin and mucous membranes, with different presentation, clinical course, histologic and immunopathologic findings, and different therapeutic approach. Blisters develop as a result of autoantibodies directed against distinct adhesion structures within desmosomes or within the basement membrane zone. The most common AIBD that develops in the elderly is bullous pemphigoid (previously also named “pemphigoid senilis”), but mature patients can also present with other AIBD as mucous membrane pemphigoid, epidermolysis bullosa acquisita, paraneoplastic pemphigus, pemphigus vulgaris, pemphigus foliaceus, linear IgA dermatosis, and dermatitis herpetiformis. There are no differences in treatment approach to mature patients with AIBD, but due to more common comorbidities, systemic therapy should be given with more caution and control, and due to distorted skin integrity in the aged skin, the safety concerns are increased with the long-term use of any topical medication.     

Five Japanese cases of antidesmoglein 1 antibody-positive and antidesmoglein 3 antibody-negative pemphigus with oral lesions

Background Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the ‘desmoglein (Dsg) compensation theory’. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti‐Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti‐Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus. Objectives We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme‐linked immunosorbent assay. Methods To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation‐immunoblotting analysis using five Dsg1/Dsg2 domain‐swapped molecules. Results The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus. Conclusions These results indicate that antigenic diversity of anti‐Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms.     

Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus

Pemphigus is an autoimmune blistering disease characterized by circulating autoantibodies directed against the keratinocyte cell surface. The two variants, pemphigus foliaceus and pemphigus vulgaris, can be distinguished at the molecular level by immunochemical studies. The large majority of patients with pemphigus develop the disease spontaneously; however, there is a small group of patients who develop pemphigus after treatment with certain medications, of which penicillamine and captopril are the best documented. Most patients with drug-induced pemphigus have circulating and/or tissue bound epidermal cell surface autoantibodies; however, the molecular specificity of these autoantibodies has not been studied. We performed immunoprecipitation studies utilizing extracts of 125I-labeled suction blister epidermis and the sera of three patients with drug-induced pemphigus foliaceus (two due to penicillamine and one due to captopril) and one patient with captopril-induced pemphigus vulgaris. We found that the three patients with drug-induced pemphigus foliaceus had circulating autoantibodies that are directed against the pemphigus foliaceus antigen complex and that the one patient with drug-induced pemphigus vulgaris had circulating autoantibodies that are directed against the pemphigus vulgaris antigen complex. This study demonstrates that autoantibodies from drug-induced pemphigus patients have the same antigenic specificity, on a molecular level, as do autoantibodies from other pemphigus patients.     

Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins

Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are life‐threatening autoimmune blistering skin diseases. They are characterized by circulating autoantibodies which bind to the ectodomains of desmoglein (Dsg) 1 and Dsg3. These antibodies induce acantholysis in skin and mucous membranes. In severe cases of pemphigus, immunoadsorption is applied to remove total IgG from patient plasma using protein A or other ligands. To develop a specific adsorber for anti‐Dsg antibodies, epitope mapping studies of Dsg1 and Dsg3 ectodomains were conducted. Dsg variants were expressed on the surface of HEK‐293 cells and analysed for reactivity with pemphigus and control sera by indirect immunofluorescence technique. For Dsg1, a construct consisting of domain 1 directly fused to domain 5, seemed to be suitable for specific immunoadsorption of anti‐Dsg1 antibodies. The recognized epitopes were mainly conformation‐dependent. However, adsorption of pemphigus foliaceus IgG using this protein coupled to a Sepharose matrix did not completely remove pathogenicity from the sera, as proven by a keratinocyte dissociation assay. In contrast, full‐length Dsg1 and Dsg3 ectodomains were able to specifically adsorb anti‐Dsg antibodies and to efficiently eliminate pathogenicity. Therefore, the complete and correctly folded ectodomains of both desmogleins are required for therapeutic immunoadsorption.     

Immunologic and histopathologic characterization of an active disease mouse model for pemphigus vulgaris

Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by anti-desmoglein 3 IgG autoantibodies. Recently, we generated an active disease mouse model for pemphigus vulgaris by adoptive transfer of splenocytes from immunized desmoglein 3-/- mice to Rag2-/- mice. In this study, we performed immunologic and histopathologic studies using this pemphigus vulgaris model in mice and compared the gross and microscopic phenotypes of pemphigus vulgaris model mice and desmoglein 3-/- mice. Pemphigus vulgaris model mice showed strong in vivo IgG, and weak IgA deposition on keratinocyte cell surfaces in stratified squamous epithelia, and produced circulating anti-desmoglein 3 IgG antibodies without apparent cross-reactivity to desmoglein 1, in enzyme-linked immunosorbent assays. The predominant IgG subclass was IgG1. Pemphigus vulgaris model mice and desmoglein 3-/- mice were almost indistinguishable in terms of both gross and microscopic findings. Both types of mice showed suprabasilar acantholysis in the stratified squamous epithelia, including the oral mucous membranes and traumatized skin around the snout or paws; however, some pemphigus vulgaris model mice demonstrated a more severe phenotype than desmoglein 3-/- mice. The esophagus and forestomach were affected in some pemphigus vulgaris model mice, but not in desmoglein 3-/- mice. Furthermore, eosinophilic spongiosis, which is found in early pemphigus vulgaris lesions in patients, was observed in pemphigus vulgaris model mice but not in desmoglein 3-/- mice. Pemphigus vulgaris model mice reflect several of the histopathologic and immunologic features seen in pemphigus vulgaris patients, and provide a valuable tool to investigate the pathophysiologic mechanisms of pemphigus vulgaris.     

Recent advances in the study of the pathophysiology of pemphigus

Recent rapid advances in the basic research into pemphigus have provided many insights into its pathophysiology. In particular, a recently developed enzyme-linked immunosorbent assay (ELISA) for desmogleins 1 and 3 (Dsg1 and Dsg3), antigens for pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively, has led to great progress in the diagnosis and classification of pemphigus, as well as in understanding its pathomechanisms. Studies with the anti-Dsg1 and anti-Dsg3 antibodies have indicated that there are two types of PV, the mucosal dominant type and the mucocutaneous type. The same ELISA has identified the antigens in pemphigus herpetiformis. The autoantigens detected by this ELISA correlate well with the clinical features in pemphigus patients in showing the shift between PV and PF. In addition, the Dsg compensation theory proposed by Stanley and Amagai can reasonably explain the different depths of skin lesions and the different occurrences of skin and oral mucosal lesions between PV and PF. Furthermore, a complicated profile of autoantigens in paraneoplastic pemphigus (PNP) has been indicated in various biochemical studies, and IgG anti-Dsg1 and anti-Dsg3 antibodies have been detected in serum from all the PNP patients by the above ELISA. On the other hand, serum from subcorneal pustular dermatosis type IgA pemphigus patients have been shown to react with Dsc1, another type of desmosomal cadherin, by a novel cDNA transfection method. In addition, IgA anti-Dsg1 and anti-Dsg3 antibodies have been detected in a few patients with IgA pemphigus by an ELISA for IgA antibodies. Various autoimmune bullous diseases, including several types of pemphigus, are the only diseases in which the pathogenic role of circulating autoantibodies has been confirmed using the newborn mouse animal model. Therefore, studies of the pathophysiology of pemphigus are extremely important as a paradigm for research into various types of autoimmune diseases in other fields.