few years, a growing body of evidence indicates that a subgroup of patients with hypersensitivity pneumonitis develop serum or even clinical features of autoimmunity, although the underlying mechanisms are still unknown. Moreover, except for higher mortality, this “phenotype” has not been characterised.

Similarly, in recent years a subset of patients has been described, who have idiopathic interstitial pneumonia (IIP) and autoimmune features (IPAF), who do not meet the criteria for a connective tissue disease (CTD) but have at least one sign or symptom suggestive of a CTD and at least one serological test reflective of an autoimmune process [21]. These patients have been better characterised, and some studies also suggest that patients who met the IPAF criteria had a significantly worse survival than those with IIP without autoimmune features [22], although substantial variability in outcome has been reported [23]. As in hypersensitivity pneumonitis, the mechanisms and genetic susceptibility triggering the autoimmune process is unknown.

In this study, we found that approximately a third of the patients with hypersensitivity pneumonitis may present autoantibodies. This proportion is higher than reported by Adegunsoyeet al. [11], to our knowledge the only study to have shown this association, although the reasons are currently unknown.

In this study, we aimed to identify putative genetic factors associated with the HLA class II system that may increase the risk of developing autoimmune features in patients with hypersensitivity pneumonitis. Our results revealed, for the first time, some of the genetic alleles conferring risk of developing autoantibodies in these patients. Thus, a significant increase in the frequency of the HLA-DRB1*03:01 allele as well as the haplotype DRB1*03:01-DQB1*02:01 was observed in the group of patients with autoantibodies compared with patients without them.

Interestingly, these alleles have been described in the formation of autoantibodies in classic and rare autoimmune disorders. For example, alleles HLA-DRB1*03:01 and DQB1*06:01 are associated with the development of autoantibodies in systemic lupus erythematosus [24, 25]. Likewise, the presence of anti-Jo-1 or anti-PM-Scl antibodies was found to be strongly associated with HLA-DRB1*03:01 and DQA1*05:01 alleles in a cohort of patients with adult and juvenile myositis [26–28]. The DQB1*02:01 allele is linked genetically to DQA1*05:01 and is classically described in coeliac disease, type 1 diabetes and other autoimmune disorders [29].

Haplotype analysis revealed a significant increase in the frequency of HLA-DRB1*03:01-DQB1*02:01, commonly observed in the European population [30] and associated with several autoimmune disorders, such as primary Sjögren's syndrome with autoantibody production [31]. This haplotype contains two main alleles that are part of 8.1 ancestral haplotype. The ancestral haplotype is an exceptionally long (more than four megabases) conserved combination of alleles: HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*03:01, DRB3*01:01, DQA1*05:01 and DQB1*02:01. It is accepted as the most critical immunological determinant conferring risk to several autoimmune diseases [10]. Moreover, even healthy carriers of this haplotype show high values of autoantibodies, blood-activated T-cells and blood immune complexes. Therefore, the 8.1 ancestral haplotype enhances immune dysfunctions and autoimmune disorders, and our results suggest that it may also contribute to the development of autoimmunity in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis is a complex disease, where the interaction of environmental and genetic factors influences the development of the disease and the phenotype, e.g. fibrotic or nonfibrotic disease [4]. For example, it has been demonstrated that the minor allele frequency of MUC5B rs35705950 is higher in patients with chronic hypersensitivity pneumonitis than in healthy controls, and more importantly, that the extent of radiographic fibrosis is associated with this common variant [32].

Our findings suggest that the presence of specific alleles and haplotypes of the HLA system may lead to the development of autoimmune features, modifying the course and outcome of hypersensitivity pneumonitis. Moreover, to carry the risk allele, HLA-DRB1*03:01 was associated with reduced survival. Interestingly, immune dysfunctions associated with the 8.1 ancestral haplotype appear to be a factor to early morbidity and mortality in older females [33]; females were markedly more frequent in our hypersensitivity pneumonitis cohort.

In addition, we found that mortality in the group of HPAbs⁺ was higher than in the group without autoantibodies, coinciding with a previous study in which the presence of autoimmunity was found to be associated with poor prognosis [11]. However, after adjusting by the allele HLA-DRB1*03:01, the presence of autoantibodies lost significance. Surprisingly, mortality did not show differences between chronic fibrotic and nonfibrotic hypersensitivity pneumonitis patients, probably because of the short time of follow-up and the small sample size.

Our research has some limitations, including the relatively small sample size. Besides, we excluded patients with hypersensitivity pneumonitis and confirmed connective tissue disease or a history of inflammatory disorders.

Further studies are needed to validate these findings and to determine the molecular mechanisms of the underlying autoimmune process in patients with hypersensitivity pneumonitis.