Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris

Abstract

Background and aimPemphigus 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 populationParticipants 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.ResultsEighty-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.ConclusionOur 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.

The genetic basis of pemphigus vulgaris

“…The two most prevalent PV‐associated alleles, DQB1*0503 and DRB1*0402 , have been linked to the condition in populations from Spain, France, Italy, Slovak Republic, North America and Brazil 52–58 . HLA‐DRB1*0402 and DQB1*0302 were shown to be associated with PV in the Jewish population, 8,71 while HLA‐DQB1*0503 is associated with PV in non‐Jewish populations 71,72 . Interestingly, compared with other HLA alleles, patients carrying HLA‐DRB1*0402 or DQB1*0503 were found to have higher levels of anti‐Dsg3 or anti‐Dsg1 antibodies, respectively, and exhibited higher rates of mucosal only or mucocutaneous lesions, respectively 71 .…”

“…HLA‐DRB1*0402 and DQB1*0302 were shown to be associated with PV in the Jewish population, 8,71 while HLA‐DQB1*0503 is associated with PV in non‐Jewish populations 71,72 . Interestingly, compared with other HLA alleles, patients carrying HLA‐DRB1*0402 or DQB1*0503 were found to have higher levels of anti‐Dsg3 or anti‐Dsg1 antibodies, respectively, and exhibited higher rates of mucosal only or mucocutaneous lesions, respectively 71 . HLA‐DRB1*04 , HLA‐DRB1*14 and HLA‐ DRB1*08 , were also found to be significant PV susceptibility factors 73 .…”

“…71,72 Interestingly, compared with other HLA alleles, patients carrying HLA-DRB1*0402 or DQB1*0503 were found to have higher levels of anti-Dsg3 or anti-Dsg1 antibodies, respectively, and exhibited higher rates of mucosal only or mucocutaneous lesions, respectively. 71 HLA-DRB1*04, HLA-DRB1*14 and HLA-DRB1*08, were also found to be significant PV susceptibility factors. 73 According to a meta-analysis of the association between PV and HLA-DQB1 polymorphisms, HLA-DQB1*0503, which is often found in Asian patients, and HLA-DQB1*0302, which is decreased in Caucasian population, were both found to be susceptibility factors for PV, while HLA−DQB1*0501, -DQB1*02, −DQB1*0601 and −DQB1*0303 were negatively associated with PV.…”

“…74 Two recent GWAS performed in Han Chinese patients identified HLA−DQB1*0503, HLA−DRB1*0406 and HLA−DRB1*14 to be associated with PV, with HLA−DRB1*1404 showing the strongest association in one study and HLA−DRB1*1401 in the second GWAS. 37,75 In a recent study of almost 300 patients from the United States, HLA−DRB1*0804 was found in association with 11 patients of African descent, as compared to other patients ethnic groups, 71 though it is known to be associated with African descent in general. 76 In addition to HLA class II alleles, several studies have shown evidence for association between PV and HLA class I alleles, including HLA−B38, −B57, −C12 and −C15 in the Brazilian population, 57,77 HLA-A03, −B35 and −B44 in Turks, 70,78 HLA−A3, −A26 and −B60 in Han Chinese, 66 HLA−A10 and −B15 in Japanese patients, 79,80 HLA−A26 and −B38 in the Jewish population, 60,81 HLA-A26 in the Spanish population 55 and HLA-B4402, −C0401 and −C1502 in Iranians.…”

“…HLA traits have been known for decades to pass on a genetic propensity to develop autoimmune disorders 50 and thus, it not surprising that most studies of the genetic predisposition to PV have revealed associations to HLA genes. The strongest and most widely reported association is between PV and HLA genes belonging to the class II region 8,51–71 . While some of these HLA associations are population‐specific (Figure 1), others are linked to PV across a wide range of ethnic groups.…”