1. Introduction
Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology that is characterized by vascular dysfunction and cutaneous and visceral fibrosis. Women are more frequently affected than men at a ratio of 4 : 11, and the peak incidence occurs in the fourth and fifth decades of life. The incidence varies from 2.3 to 22.8/1 million/year [1]. The prevalence appears to be increasing due to improved survival in recent decades [2]. The symptoms with greater prognostic impact that are the main causes of death in SSc patients are pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH) [3].
Although the pathogenesis of SSc remains unclear, genetic factors are thought to contribute to the disease. The HLA (human  leukocyte  antigen) genes have been implicated in the susceptibility to SSc and in its clinical and serological manifestations [4–10]. 
HLA widely participates in immunological processes. Class I (HLA A, B, and C) and class II (HLA DR, DQ, and DP) molecules are expressed on the cell surface and participate in antigen presentation and T lymphocyte activation. Class I molecules also activate natural killer (NK) cell receptors [11], and class II molecules appear to stimulate the secretion of IL-6 and monocyte chemotactic protein (MCP-1) by fibroblasts, especially in antibody antitopoisomerase (ATA) associated clinical forms [12].
Susceptibility to the disease was found to be associated with the HLA-DQA1*0501 and DQB1*0301 alleles in all ethnic groups. The DRB1*1104 allele was associated with SSc in Caucasian and Hispanic patients, whereas DRB1*0804 was correlated with the disease in African Americans [13] and DRB1*1502 with Japanese and Koreans [14]. HLA-DRB1*01 and DRB1*11 (mainly DRB1*1101 and DRB1*1104) were also associated with SSc [15]. A multicenter study (GWAS, Genome Wide Association Study) established HLA-DQB1 as the main allele related to susceptibility [16]. Zhou et al. found an association of HLA-DPB1 and DPB2 with increased susceptibility to the disease, primarily associated with ATA [17]. HLA-A*30, A*32, B*57, Cw14, DRB1*0701, DQA1*0201, DQB1*0202, and DRB1*1501 were identified as protectors [4, 13].
However, much stronger correlations have been demonstrated between certain HLA alleles and each of the SSc-specific autoantibodies, which may be clinically relevant because each autoantibody subset of scleroderma is associated with certain disease features and has different prognostic implications [14, 18–22]. ATA antibodies have a higher frequency of the HLA-DRB1*1104, DQA1*0501, DQB1*0301, and DPB1*1301 alleles [13]. Caucasian patients were associated with HLA-DR5 [23–25], corresponding to DRB1*05, and Japanese patients were associated with HLA-DR2 [5], DRB1*15, or DRB1*16 in the current nomenclature. The anticentromere antibody (ACA) was related to the HLA-DRB1*01, DRB1*04, DQA1*0101, and DQB1*0501 alleles [7, 12, 13, 23].
Considering the clinical features, the HLA-DRB1 allele has been associated with the limited cutaneous form (lcSSc) [4] and B*62, DRB1*11 (DRB1*1104), and DRB1*07 with the diffuse cutaneous form (dcSSc) [4, 9]. An association between HLA alleles and visceral involvement in SSc is not well established. Some previous studies reported a correlation of the internal organ involvement of SSc and autoimmune patterns with different specific serological HLA statuses, and these associations appeared to differ according to ethnicity [7, 13].
A high frequency of the DRw6 and DRB3 alleles related to PAH has been described by Langevitz et al., with DRw6 associated with a higher mortality [26]. Some class I alleles were also related, such as A*30, B*13, B*65 [4], and B*35, which appear to play a role in the production of endothelin-1 (ET-1) in SSc [27, 28]. HLA-DRB1*01, DRB1*03, and DQB1*0501 were also related to PAH and ACA [29, 30].
Similarly, the DR52a and Cw*0602 alleles were found more frequently in SSc with PF [4, 26]. Other alleles described for PF in the presence of ATA are DRB1*11 (DRB1*1104) [10, 31], DPB1*1301 [29], and DQB1*0301 [29, 30].
In Brazil, a South American country with a multiethnic population, there has been no study concerning HLA and SSc. The aims of this study were to evaluate HLA involvement in the disease expression and to correlate the HLA alleles with the poor prognostic clinical features in patients diagnosed with SSc at a university referral hospital in the city of Campinas, state of Sao Paulo, Brazil.