In a previous report, we found an association between HLA-DR4 and secondary Sjogrens syndrome with abnormal pulmonary function in patients with rheumatoid arthritis. This same association had been supported by other investigators. Radoux et al found that 80 percent of rheumatoid patients with airway dysfunction were HLA-DR4 positive and that a generalized abnormality of exocrine glands was present. Clinically defined pulmonary manifestations have also been reported to be more common in HLA-DR4-positive patients with rheumatoid arthritis. The present study suggests that this DR4 association may be of only secondary importance, since the variability of pulmonary function in this group can be adequately accounted for by the associated subtypes at the DQ locus. At the genomic level, studies have found one a and three P chain genes at the HLA-DR loci and two a and two P genes encoding for HLA-DQ molecules.
Polymorphism of the DR subregion is primarily restricted to the P genes, while both a and P genes contribute to the polymorphism of the DQ subregion. It has been suggested and demonstrated that two types of hybrid molecules can be produced by gene complementation resulting from trans association of p chain from one chromosome and a chain from the other. Thus, DQ locus heterozygotes could potentially manifest hybrid HLA antigen molecules which are different from either parent. This might lead to increased expression of autoimmune disease, as has been shown in patients with Sjogrens syndrome. natural breast enhancement
We found that the heterozygotic phenotype, DQwl/ DQw3, is associated with keratoconjunctivitis sicca (secondary Sjogrens syndrome), as well as obstructive pulmonary disease. Sjogrens syndrome has been associated with chronic inflammatory cell infiltration of both small airways and interstitium, a process which has been implicated in the development of both restrictive and obstructive pulmonary disease. Three general explanations for this finding are apparent. First, the DQwl/DQw3 patients may be predisposed to keratoconjunctivitis sicca, which then leads to pulmonary involvement by direct involvement of the pulmonary parenchyma, as well as other organs by lymphocytic infiltration. These heterozygotes could be at risk for autoimmune phenomenon because of the development of hybrid antigens which are not recognized as native tissue. Secondly, the DQwl/DQw3 heterozygotic state may be a marker of other yet unknown traits which make subjects susceptible to cigarette smoke, environmental toxins, or infectious agents which lead to obstructive pulmonary disease. Thirdly, the DQw2 alloantigen may confer some protective attribute, and the DQwl/DQw3 heterozygotes are, by definition, lacking the DQw2 alloantigen.
In summary, we found that patients with rheumatoid arthritis who are HLA-DQwl positive have pulmonary dysfunction consistent with interstitial pulmonary disease. The heterozygotic DQwl/DQw3 phenotype is associated with obstructive disease of the airways, especially in smokers. The DQ phenotype accounts for much of the variance in pulmonary function in our population with rheumatoid arthritis in comparison to other clinical, demographic, serologic, and immuno-genetic tests. We conclude that analysis of DQ phenotype can account for differences in the expression of pulmonary disease among patients with rheumatoid arthritis, although the precise biochemical, cellular, and physiologic mechanisms linking histocompatibility antigens to pulmonary dysfunction are still in need of explanation.