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Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosi-Schumacher, Baker, Waris, Seiffert-Sinha and Sinha.)

Pemphigus vulgaris (PV) is a potentially life-threatening blistering disorder characterized by autoantibodies directed against cell-cell adhesion molecules that serves as an excellent model to study human autoimmune development. Numerous studies have identified specific Human Leukocyte Antigen (HLA) genes, in particular DRB1*0402 and DQB1*0503, that confer disease risk. Although HLA is required, it is not sufficient for the initiation of disease. As with all autoimmune diseases, the etio-pathogenesis of PV is complex, meaning it is multifactorial. Susceptibility is polygenic, and the search for non-HLA disease-linked genes continues. Moreover, twin studies across autoimmune conditions indicate that non-genetic environmental and lifestyle factors, which can be collectively grouped under the term "exposome", are also major contributors to disease development. The literature presents evidence for the potential role of multiple triggers such as medications, infections, stress, diet, immunizations, and sleep to influence the etiology, pathophysiology, and prognosis of PV. However, a clear understanding of the degree to which specific factors impact PV is lacking. In this investigation, we comprehensively review the environmental elements listed above and consider the strength of evidence for these factors. The overall goals of this work are to provide greater insights into the factors that influence disease susceptibility, disease development and disease course and ultimately help to better guide clinicians and inform patients in the management of PV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Adebiyi, Galloway, Augustin and Sinha.)

Background and Aim: Pemphigus vulgaris (PV) is known to have one of the strongest HLA associations among autoimmune diseases. DRB1*0402 and DQB1*0503 in particular are significantly overrepresented in PV patients in certain worldwide populations. Yet, there remain significant gaps in our understanding regarding the precise link between PV-associated HLA molecules, the specificity of the autoimmune response, and clinical expression. In this study we assessed correlations between factors including HLA genotype, ethnicity, autoantibody levels, and lesion distribution in a cohort of 293 patients., Methods and Population: Participants were recruited from multiple outpatient dermatology clinic settings and patient support meetings in the USA. On intake, patients provided venous blood samples and answered questionnaires regarding their current disease activity., Results: Eighty-one percent of patients typed as either DRB1*0402 or DQB1*0503 with a high prevalence of DRB1*0402 in patients of Ashkenazi Jewish or Caucasian (non-Jewish) descent (86% and 42%, respectively) and DQB1*0503 in patients of Southeast Asian descent (78%). Patients typing as HLA DRB1*0402 had higher levels of anti-desmoglein (Dsg)3 antibodies (204.6 +/- 340.5 IU/ml) than patients without DRB1*0402 (138.5 +/- 236.4 IU/ml) (p=0.03) and had mucosal only lesions more often than cutaneous only or mucocutaneous lesions. Patients typing as DQB1*0503 had higher levels of anti-Dsg1 antibodies (47.3 +/- 59.8 IU/ml) compared to other groups (27.8 +/- 43.7 IU/ml) (p=0.06) and higher rates of mucocutaneous disease than other lesion types. We also report an unexpected HLA association of DRB1*0804 in PV patients of African descent. Sixty-four percent of this population carried the DRB1*0804 allele, and presented with highly elevated levels of anti-Dsg3 (p=0.02). However, neither African heritage nor the presence of DRB1*0804 correlated with a predilection to any specific lesion morphology. Patients that carried neither DRB1*0402, nor DQB1*0503 or DRB1*0804 had the lowest levels of anti-Dsg3 antibodies (60.0 +/- 80.0 IU/ml) and the highest rate of solely cutaneous disease compared to carriers of these alleles., Conclusion: Our data illuminate the broader impact of genetic factors on disease development by showing that differences in HLA expression among patients and ethnicities play a large role in driving distinct patterns of antibody selection and disease phenotype in PV. These findings provide insights regarding clinical heterogeneity, and are relevant to developing improved, patient tailored management strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baker, Seiffert-Sinha and Sinha.)

Selective destruction of epidermal melanocytes is central to vitiligo (VL), a common acquired, autoimmune depigmentory disorder of the skin. Like other autoimmune diseases, the pathogenesis of VL is obscure and both multifactorial and polygenic. The prevailing theory is that VL may be part of an autoimmune diathesis. To evaluate mechanisms underlying disease development and progression, we studied genome-wide gene expression from lesional and non-lesional skin of patients with non-segmental VL. Unbiased clustering and principal components analyses reveals a 'lesional pathology'-based signature. Pathway-based analyses of the differentially expressed genes underscore processes such as melanocyte development and cell cycle as central drivers of the disease state. Interactome analysis identifies several key transcriptional regulators potentially affecting disease pathogenesis both within and 'hidden' from the data set. Finally, two genes within six identified transcriptional 'hot spots' coincide with previous VL-associated genetic elements. The remaining genes in the 'hot spots' offer an additional set of potential disease-linked loci that may help to guide future studies aimed at identifying disease risk genes.

There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3. We demonstrate that pathogenic (blister-forming) anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming) anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps--an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a "2-Hit" model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.

Alopecia areata (AA) is a common, non-scarring, autoimmune hair-loss disorder with a complex genetic and environmental etiology. A higher incidence rate of AA in the female population is well described. It is unclear why females are more likely to be diagnosed with AA and what, if any, differences in disease phenotype exist between males and females. The identification of gender specific characteristics of disease may help clinical management and patient education in cases of AA. Accordingly, we recruited 481 North-American Caucasian AA patients (336 female, 145 male) to assess age of onset, autoimmune and atopic co-morbidity, nail involvement, family history of AA and autoimmune disease, and disease subtype. There was a female predominance (female to male ratio 2.3:1) in this AA study population. We found that male AA patients are more likely to be diagnosed in childhood (age <10 years, P= 0.067) and have a family history of AA (P= 0.004). On the other hand, female AA patients are more likely to be diagnosed in adolescence (age 10-20 years, P= 0.083), have co-morbid nail involvement (P= 0.0257), and have concomitant autoimmune disease (P= 0.014), particularly thyroid disease (P= 0.058). The clinical implications of disease heterogeneity between males and females remains to be determined.

Antioxidants play the important role in our body of neutralizing free radicals and peroxides that are formed during normal physiologic events. While these reactive oxygen species are necessary for numerous biological processes, when created in excess they can have deleterious effects. The skin as an organ is constantly under attack by reactive oxygen species from both endogenous and exogenous sources. The pathophysiology of many autoimmune diseases is unknown and recently oxidative stress has come to light as a possible triggering mechanism. Recent investigations attempting to link autoimmune skin diseases and oxidative stress have had varying degrees of success. In this article, we review the current literature regarding antioxidants in alopecia areata, pemphigus vulgaris and other blistering diseases, vitiligo, and psoriasis, and suggest possible future studies and treatment options.

Background: Several lines of evidence support a genetic component to alopecia areata (AA), including differences in patients based on severity of AA, associated diseases and family history., Objective: We aimed to examine clinical and genetic features of patients with AA with a focus on associated diseases, especially atopy, and family history of AA in the USA., Methods: From 1998 to 2001, 513 patients with AA completed interviews consisting of demographic information, patient's medical history, and family history of AA., Results: Forty per cent of respondents had alopecia totalis and/or universalis (AT/AU). These patients were younger at the age of onset than those with patchy AA (P < 0.001), were more likely to have associated autoimmune or atopic disease (P = 0.047), most notably atopic dermatitis (P = 0.021) and thyroid disease (P = 0.012). They also had a greater number of relatives affected by AA (P < 0.05)., Conclusions: Our findings show marked associations between severity of AA, atopic dermatitis, thyroid disease and other autoimmune diseases, and extensive family history of AA, suggesting two clinically distinct subtypes of AA with the severe subtype possibly associated with greater familial autoimmunity. Further research exploring the possibility of a genetic basis to explain these clinical findings will be helpful in clarifying our understanding of AA, leading to improvements in diagnosis and treatment.

Much emphasis has been placed on the so-called "biologics" in the treatment of immune disorders within the last few years. Here we discuss the expanding horizon of potential strategies for immunotherapies targeting T lymphocytes as key effectors and regulators of autoimmunity. We review emerging reagents in a variety of animal models and human disorders that may offer new therapeutic options in current or modified iterations.

T cells assume a fundamental function in immunosurveillance and maintenance of the cutaneous immune barrier, yet derangement of their requisite role effects a range of cutaneous autoimmune diseases with significant associated morbidity. While blistering skin diseases, such as pemphigus vulgaris (PV), pemphigus foliaceus (PF) and bullous pemphigoid (BP) are mediated by antibodies directed against autoantigens found in the skin, recent evidence has shown that T cell activation is crucial for the initiation and coordination of this humoral response. Non-blistering skin diseases, such as alopecia areata (AA), vitiligo (VL) and psoriasis (PS) are increasingly believed to be directly mediated by the activities of autoreactive T cells. Here, we examine T lymphocyte control of antibody-mediated and cell-mediated processes involved in the pathoimmunology of the above mentioned skin diseases.

Alopecia areata (AA) is a heterogeneous disease characterized by nonscarring hair loss on the scalp or any hair-bearing surface. A wide range of clinical presentations can occur -- from a single patch of hair loss to complete loss of hair on the scalp (alopecia totalis) or the entire body (alopecia universalis). Particularly in severe or chronic cases, AA may cause considerable psychological and emotional distress for affected individuals. The estimated lifetime risk of developing AA is 1.7%. While the precise etiology of this common disorder has not been elucidated, a substantial body of evidence suggests that AA is an organ-specific, autoimmune disease, targeted to hair follicles. However, the antigenic target(s), mechanisms, and consequences of autoimmune attack in AA have yet to be determined. Here, we critically explore the evidence supporting the hypothesis that AA is an autoimmune disease and propose specific pathways by which self-directed immune responses are generated.

The ability to discriminate between self and nonself antigens is vital to the functioning of the immune system as a specific defense against invading microorganisms. Failure of the immune system to "tolerate" self tissues can result in pathological autoimmune states leading to debilitating illness and sometimes death. The induction of autoimmunity involves genetic and environmental factors that have focused the attention of researchers on the trimolecular complex formed by major histocompatibility complex molecules, antigen, and T cell receptors. Detailed molecular characterization of these components points to potential strategies for disease intervention.

The inheritance of particular alleles of major histocompatibility complex class II genes increases the risk for various human autoimmune diseases; however, only a small percentage of individuals having an allele associated with susceptibility develop disease. The identification of allelic variants more precisely correlated with disease susceptibility would greatly facilitate clinical screening and diagnosis. Oligonucleotide-primed gene amplification in vitro was used to determine the nucleotide sequence of a class II variant found almost exclusively in patients with the autoimmune skin disease pemphigus vulgaris. In addition to clinical implications, the disease-restricted distribution of this variant should provide insight into the molecular mechanisms underlying associations between diseases and HLA-class II genes.

Class II major histocompatibility (MHC) molecules have an immunoregulatory role. These cell-surface glycoproteins present fragments of protein antigens (or peptides) to thymus-derived lymphocytes (T cells). Nucleotide sequence polymorphism in the genes that encode the class II MHC products determines the specificity of the immune response and is correlated with the development of autoimmune diseases. This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris. These findings implicate particular class II MHC isotypes in susceptibility to each disease and suggest new prophylactic and therapeutic strategies.