Association of IL-4RA single nucleotide polymorphisms, HLA-DR and HLA-DQ in children with Alternaria-sensitive moderate-severe asthma

<p>Abstract</p> <p>Background</p> <p>Asthma afflicts 6% to 8% of the United States population, and severe asthma represents approximately 10% of asthmatic patients. Several epidemiologic studies in the United States and Europe have linked <it>Alternaria </it>sensitivity to both persistence and severity of asthma. In order to begin to understand genetic risk factors underlying <it>Alternaria </it>sensitivity and asthma, in these studies we examined T cell responses to <it>Alternaria </it>antigens, HLA Class II restriction and HLA-DQ protection in children with severe asthma.</p> <p>Methods</p> <p>Sixty children with <it>Alternaria</it>-sensitive moderate-severe asthma were compared to 49 children with <it>Alternaria</it>-sensitive mild asthma. We examined HLA-DR and HLA-DQ frequencies in <it>Alternaria</it>-sensitive asthmatic by HLA typing. To determine ratios of Th1/Th2 <it>Alternaria</it>-specific T-cells, cultures were stimulated in media alone, <it>Alternaria alternata </it>extract and Alt a1. Sensitivity to IL-4 stimulation was measured by up-regulation of CD23 on B cells.</p> <p>Results</p> <p>Children with <it>Alternaria</it>-sensitive moderate-severe asthma trended to have increased sensitivities to <it>Cladosporium </it>(46% versus 35%), to <it>Aspergillus </it>(43% versus 28%), and significantly increased sensitivities to trees (78% versus 57%) and to weeds (68% versus 48%). The IL-4RA ile75val polymorphism was significantly increased in <it>Alternaria</it>-sensitive moderate-severe asthmatics, 83% (0.627 allele frequency) compared to <it>Alternaria</it>-sensitive mild asthmatics, 57% (0.388 allele frequency). This was associated with increased sensitivity to IL-4 stimulation measured by significantly increased IL-4 stimulated CD23 expression on CD19+ and CD86+CD19+ B cells of <it>Alternaria</it>-sensitive moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in <it>Alternaria</it>-sensitive moderate-severe asthmatics compared to mild asthmatics to <it>Alternaria </it>extract and Alt a1 stimulation. The frequency of HLA-DQB1*03 allele was significantly decreased in <it>Alternaria</it>-sensitive moderate-severe asthmatics compared to mild asthmatics, 39% versus 63%, with significantly decreased allele frequency, 0.220 versus 0.398.</p> <p>Summary</p> <p>In children with <it>Alternaria</it>-sensitive moderate severe asthma, there was an increased Th2 response to <it>Alternaria </it>stimulation and increased sensitivity to IL-4 stimulation. This skewing towards a Th2 response was associated with an increased frequency of the IL-4RA ile75val polymorphism. In evaluating the HLA association, there was a decreased frequency of HLA-DQB1*03 in <it>Alternaria</it>-sensitive moderate severe asthmatic children consistent with previous studies suggest that HLA-DQB1*03 may be protective against the development of mold-sensitive severe asthma.</p