Human leukocyte antigen (HLA) types play a crucial role in the development of pemphigus by facilitating the presentation of self-antigens to Th cells, activating humoral immunity, and generating self-antibodies. These antibodies disrupt intercellular adhesion, leading to the formation of erosions and blisters ^[1][2]. The two major categories of pemphigus are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), accounting for 70% and 15–20% of all pemphigus cases, respectively. Less common variations of pemphigus are pemphigus herpetiformis (PH), paraneoplastic pemphigus (PNP), and IgA pemphigus (AP) ^[2][3]. The frequency of pemphigus diseases fluctuates across demographics, and this geographical distribution often aligns with specific HLA types within populations (Table 1).

PV involves autoantibodies targeting desmoglein 3 (Dsg3) and, occasionally, desmoglein 1 (Dsg1) ^[3][4]. The distribution of Dsg3 in the lower epidermal layers and epithelium makes mucous membranes the primary site of impact, while the presence of Dsg1 autoantibodies determines skin involvement ^[3][4]. There is an interesting variation in the types of HLA that are associated with PV. While some HLA types display population specificity, others link to PV across different ethnicities ^[4][5]. PV is commonly linked to alleles found on the HLA-A10, B38, DR4, DQw3.2 haplotype, prevalent among Jewish individuals ^[5][6][7][6,7,8]. HLA-DR4 polymorphism is governed by nucleotide sequence variability in the third hypervariable region of the DRB1 gene, specifically the Dw10 subtype on the A10, B38, DR4 haplotype that predisposes to pemphigus ^[8][9]. On the contrary, individuals lacking this DR4 haplotype generally carry HLA-DRw6 ^[1][2]. The two most common PV-associated alleles are HLA-DQB1*0503 and HAL-DRB1*0402, both of which were found to be associated with the disease in different populations ^[9][10]. In the Italian population, two PV susceptibility haplotypes were found: HLA-DRB1*0402, DQAl*0301, DQB1*0302 and HLA-DRB1*1401, DQA1*0104, DQB1*0503 ^[10][11]. The former was particularly widespread among Sardinian patients, integrated into an extended haplotype HLA-A2, Cw4, B35, S31, DR4, DQ8. Genetic resilience to PV seemed to be linked to the HLA-DR3, DQ2 haplotype within the Sardinian population ^[10][11]. Associations between PV and HLA class I alleles are observed in diverse populations: HLA-A3, HLA-A26, and HLA-B60 in Han Chinese; HLA-B38, HLA-C12, HLA-B57, and HLA-C15 in Brazilians; HLA-A10 and HLA-B15 in Japanese; HLA-B35 and HLA-B44 in Turks; HLA-B38 in Jewish and Spanish individuals; and HLA-B*4402, HLA-C*0401, and HLA-C*1502 in Iranians ^{[11][12][13][14]}[12,13,14,15].

Population studies uncovered further links between specific class II alleles and PV within distinct ethnic groups. HLA-DRB1*0402 is associated with PV in over 90% of Ashkenazi Jews, while HLA-DQB1*0503 is associated with non-Jewish populations. HLA-DRB1*1404 emerges as an important risk factor within Indo-Asian populations. Furthermore, investigations highlight an association between PV and non-classic HLA class Ib alleles (HLA-E, HLA-F, and HLA-G). HLA g polymorphisms significantly associate with Jewish PV patients, while those of HLA-E—already implicated in multiple autoimmune conditions—are shared between Caucasian and Ashkenazi Jewish, potentially disrupting immune tolerance in these patients ^{[11][12][13][14][15][16]}[12,13,14,15,16,17]. Apart from demographic variations, it is notable that PV affects females with a slight predominance, showing a female-to-male ratio of 1.5:1 ^[17][18]. This differential prevalence highlights potential sex-related genetic factors that may contribute to the development of PV. A recent analysis suggested a link between severe PV outcomes and specific HLA alleles-DRB1*0402 and DQB1*0302, which are predominant among female patients ^[4][5]. Familial occurrences of PV have also been documented, albeit infrequently ^[18][19]. These cases are rare and typically involve first-degree relatives in parent–child and/or sibling–sibling scenarios ^{[19][20][21][22]}[20,21,22,23].

In PF, autoantibodies target Dsg1, while those targeting Dsg3 remain undetected. Consequently, PF primarily affects the skin, with mucosal surfaces having no involvement ^[23][24]. Endemic forms of PF have been identified in regions like Tunisia, Brazil, Peru, and Colombia, showcasing variations in incidence rates and sexual predisposition: Colombian PF displays a notable male prevalence ^[4][24][5,25]. Although PF is rare globally, it occurs with a high frequency in specific parts of South America: this confined variant, known as endemic pemphigus foliaceus or “fogo selvagem” in Brazil, shares clinical, immunological, and histological similarities with the sporadic form ^[25][26]. The existence of endemic subtypes underscores the influence of environmental factors in shaping their pathogenesis, as well as the significance of specific HLA imbalances within particular geographic regions. The significance of MHC class II alleles in determining susceptibility to PF was first recognized in 1989 following the demonstration of associations with HLA-DR and -DQ antigens. Haplotypes DR1–DQ1 and DR4–DQ3 were significantly increased in patients, while DR7–DQ2 and DR3–DQ2 were significantly decreased ^[26][27]. Subsequent analysis of HLA-DRB1 alleles and genotypes confirmed these associations and unveiled several risk alleles (e.g., DRB1*0101, *0102, *0103, *0404, *0406, *0410, *1406, and *1601) as well as protective alleles (e.g., *0301, *0701, *0801, *1101, *1104, and *1402) ^[27][28]. Notably, HLA-DQ allele DQw2 appears to be associated with factors preventing the development of disease in individuals living in endemic areas ^[28][29]. An analysis of 31 PF patients and 84 healthy controls confirmed the common DRB1*04 and DRB1*14 genetic background in French Caucasian PF patients. This research atudy also identified susceptibility MHC class II alleles, including DRB1*0102, DRB1*0402, DRB1*0406, and DRB1*1404 ^[29][30]. In Italian patients, a shared susceptibility between PV and PF has been identified and is thought to reside in DRB1*1401 and DQB1*0503 susceptibility HLA alleles ^[30][31].

PNP is a type of pemphigus disease often associated with both malignant and benign neoplasms, frequently of hematologic, and lymphoid origin ^[4][5]. In PNP, autoantibodies typically target Dsg3 as well as various proteins within the plakin family, such as periplakin, envoplakin, plectin, desmoplakin 1 and 2, BP230, and the protease inhibitor alpha-2-macroglobulin-like-1 ^[31][32]. The genetic predisposition to PNP may exhibit variations among patients of different ethnicities and geographical regions. In Chinese patients, the HLA-Cw*14 allele has been proposed as a predisposing factor to PNP ^[32][33].

PH is categorized as a clinical variant of pemphigus, merging the clinical attributes of DH with the immunopathological characteristics of pemphigus ^[33][34][34,35]. A case study detailing the development of PH subsequent to D-penicillamine treatment in a 57-year-old patient has been described ^[35][36]: HLA antigen typing identified HLA B8, A1, A2, and Bw39 ^[35][36].

AP is marked by the presence of IgA autoantibodies targeting both desmosomal and non-desmosomal keratinocyte cell surface components. The predominant types within IgA pemphigus are subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN). In SPD, the autoantigen Dsc1 has been identified, whereas the antigen in the case of IEN is variable ^[36][37]. Associations between HLA classes and this specific type of pemphigus have not yet been described.

Autoimmune blistering disorders belonging to the pemphigoid group are defined by the presence of pathogenic autoantibodies targeting agents of the epithelial basement membrane zone (BMZ)—dermal epidermal junction or epidermal stromal junction—of the skin and mucosae. When there is a clinical suspicion, a specific diagnosis is confirmed by histology and direct immunofluorescence studies and supported by the serum detection of pathogenic autoantibodies. Histology is significant for subepidermal blister formation associated with a dermal infiltrate of neutrophils and eosinophils. In current clinical practice, serologic studies based on indirect immunofluorescence and ELISA may be sufficient for diagnosis, especially when the clinical presentation is clearly suggestive. The HLA-DQβ1*0301 allele (HLA-DQ7) has been reported as a shared susceptibility gene for all subsets in the pemphigoid group (Table 2). To support the notion that a single HLA allele is responsible for binding different antigens across pemphigoid disease subsets, predictive computational models have been employed to identify potential binding sites for DQβ1*0301 on BP180, BP230 and on integrins alpha 6 and beta 4 ^[37][38].

Bullous pemphigoid (BP) usually affects elderly subjects and is the most commonly observed autoimmune blistering disorder (AIBD), partly owing to the constant aging of the general population. Its management may be challenging owing to the fragility and frequent comorbidities of patients, which may limit therapeutic options and increase overall morbidity. The onset of disease is the result of an interaction between genetic predisposition and potential triggering factors, including certain drugs. The role of HLA in mediating predisposition to autoantibody-mediated skin blistering conditions is established in the literature, with HLA class II genes such as DR and DQ reporting high prevalence in subjects with BP ^[4][5]. HLA-DQB1*0301 constitutes the most strongly established disease association in Caucasians and other ethnicities—including in Brazilian and Iranian studies ^{[38][39][40][41]}[39,40,41,42]—but not in studies on Japanese and Northern Chinese populations ^[42][43][43,44]. However, according to one study, this association was restricted to men ^[44][45]. Moreover, DQA1*0505 was associated with Brazilian, Japanese, and Han Chinese groups, as well as in a German study, together with DRB1*0701 ^[45][46]. A recent metanalysis highlighted that HLA-DQA1*0505 is associated with an increased odds of PB, while DQA1*0201 carries protection from this disease ^[46][47]. Drug-induced BP may be triggered following exposure to certain drug classes, principally inhibitors of dipeptidyl peptidase 4 (DPP-4i) for the treatment of diabetes mellitus and oncologic immunotherapy with inhibitors of the PD-1 immune checkpoint ^[47][48][48,49]. Japanese patients who presented BP during treatment with DPP-4i had the following risk alleles: DQB1*0301, DQA1*0505, DRB1*1101, and DRB1*1201. In the same study, two additional alleles were associated with protection: DQA1*0103 and DQB1*0601 ^[49][50].

The definition of mucous membrane pemphigoid (MMP) encompasses a heterogeneous disease phenotype with two key features: a predilection for mucosal involvement and a scarring tendency, which explains its progressive course, leading occasionally to serious sequelae. This is particularly relevant for ocular cicatricial pemphigoid, where scarring affects the conjunctival surfaces, leading to severe vision impairment. Autoantibodies targeting different antigens of the BMZ are detected in MMP: BP180, laminin 332, and integrin beta4 subunit in ocular MMP. The HLA class II allele most studied in MMP is DQB1*0301, the association of which has been highlighted in Caucasian populations and in subsets of patients with ocular cicatricial pemphigoid ^[50][51][52][51,52,53]. Additional specific HLA class II alleles in MMP are DRB1*04 and DRB1*11 ^[53][54].

Pemphigoid gestationis (PG) is a rare though well-characterized dermatosis of pregnancy that usually develops in the later periods of gestation or postpartum. A cutaneous vescicobullous eruption is the result of IgG1 autoantibodies produced against BP180. The development of disease is related to HLA class II mismatch in the placenta, and specifically to maternal exposure to paternal tissue, being the placental genome of paternal origin ^[54][55]. PG has been related to maternal HLA-DR3 and DR4 haplotypes and with DRB1*0301 and DRB1*0401/040X polymorphisms ^[55][56].